Редактирование: STAT3

Signal transducer and activator of transcription 3 (Acute-phase response factor) [APRF]

==Publications==

{{medline-entry
|title=Dietary Restriction Suppresses Steatosis-Associated Hepatic Tumorigenesis in Hepatitis C Virus Core Gene Transgenic Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33083279
|abstract=Dietary restriction (DR) is a preventive strategy for obesity, metabolic syndrome, cardiovascular disease, and diabetes. Although an interconnection between obesity, metabolic syndrome, fatty liver, and hepatocellular carcinoma has been documented, the mechanism and impact of DR on steatosis-derived hepatocarcinogenesis are not fully understood. This study aimed to evaluate whether DR can prevent hepatic tumorigenesis. Male hepatitis C virus core gene transgenic (HCVcpTg) mice that develop spontaneous age-dependent insulin resistance, hepatic steatosis, and ensuing liver tumor development without apparent hepatic fibrosis, were fed with either a control diet ad libitum (control group) or 70% of the same control diet (DR group) for 15 months, and liver phenotypes were investigated. DR significantly reduced the number and volume of liver tumors. DR attenuated hepatic oxidative and endoplasmic reticulum stress and markedly suppressed nuclear factor-κB, signal transducer and activator of transcription 3 ([[STAT3]]) and STAT5, and phosphorylation of extracellular signal-regulated kinase, leading to downregulation of several pro-oncogenic mediators, such as cyclin D1. Serum insulin and insulin-like growth factor 1 levels, as well as hepatic expression of insulin receptor substrate 1/2, phosphatidylinositol-3 kinase, and serine/threonine-protein kinase AKT, were downregulated by DR. A transcriptome analysis revealed that [[STAT3]] signaling and lipogenesis were the most suppressed hepatocarcinogenic pathways affected by DR. Additionally, DR stimulated autophagy and p62/sequestosome 1 degradation, enhanced phosphorylation of AMP-activated protein kinase α, increased fibroblast growth factor 21 expression, and attenuated expression of senescence-associated secretory phenotypes. DR suppressed steatosis-associated hepatic tumorigenesis in HCVcpTg mice, mainly due to attenuation of pathways involved in inflammation, cellular stress, cell proliferation, insulin signaling, and senescence. These findings support the notion that persistent 30% reduction of daily food intake is beneficial for preventing steatosis-associated hepatocarcinogenesis caused by HCV core protein.

|keywords=* Cyclin D1
* NF-κB
* STAT3
* Senescence
* p62/SQSTM1
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548900
}}
{{medline-entry
|title=Skeletal glucocorticoid signalling determines leptin resistance and obesity in aging mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33045434
|abstract=Aging and chronic glucocorticoid excess share a number of critical features, including the development of central obesity, insulin resistance and osteoporosis. Previous studies have shown that skeletal glucocorticoid signalling increases with aging and that osteoblasts mediate the detrimental skeletal and metabolic effects of chronic glucocorticoid excess. Here, we investigated whether endogenous glucocorticoid action in the skeleton contributes to metabolic dysfunction during normal aging. Mice lacking glucocorticoid signalling in osteoblasts and osteocytes (HSD2 -tg mice) and their wild-type littermates were studied until 3, 6, 12 and 18 months of age. Body composition, adipose tissue morphology, skeletal gene expression and glucose/insulin tolerance were assessed at each timepoint. Leptin sensitivity was assessed by arcuate nucleus [[STAT3]] phosphorylation and inhibition of feeding following leptin administration. Tissue-specific glucose uptake and adipose tissue oxygen consumption rate were also measured. As they aged, wild-type mice became obese and insulin-resistant. In contrast, HSD2 -tg mice remained lean and insulin-sensitive during aging. Obesity in wild-type mice was due to leptin resistance, evidenced by an impaired ability of exogenous leptin to suppress food intake and phosphorylate hypothalamic [[STAT3]], from 6 months of age onwards. In contrast, HSD2 -tg mice remained leptin-sensitive throughout the study. Compared to HSD2 -tg mice, leptin-resistant wild-type mice displayed attenuated sympathetic outflow, with reduced tyrosine hydroxylase expression in both the hypothalamus and thermogenic adipose tissues. Adipose tissue oxygen consumption rate declined progressively in aging wild-type mice but was maintained in HSD2 -tg mice. At 18 months of age, adipose tissue glucose uptake was increased 3.7-fold in HSD2 -tg mice, compared to wild-type mice. Skeletal glucocorticoid signalling is critical for the development of leptin resistance, obesity and insulin resistance during aging. These findings underscore the skeleton's importance in the regulation of body weight and implicate osteoblastic/osteocytic glucocorticoid signalling in the aetiology of aging-related obesity and metabolic disease.

|keywords=* Aging
* Appetite
* Glucocorticoid
* Leptin
* Obesity
* Osteoblast
* Osteocyte
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596342
}}
{{medline-entry
|title=[[FGFR4]] Inhibitor BLU9931 Attenuates Pancreatic Cancer Cell Proliferation and Invasion While Inducing Senescence: Evidence for Senolytic Therapy Potential in Pancreatic Cancer.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33066597
|abstract=Fibroblast growth factor receptor 4 ([[FGFR4]]), one of four tyrosine kinase receptors for FGFs, is involved in diverse cellular processes. Activation of FGF19/[[FGFR4]] signaling is closely associated with cancer development and progression. In this study, we examined the expression and roles of FGF19/[[FGFR4]] signaling in human pancreatic ductal adenocarcinoma (PDAC). In human PDAC cases, [[FGFR4]] expression positively correlated with larger primary tumors and more advanced stages. Among eight PDAC cell lines, [[FGFR4]] was expressed at the highest levels in PK-1 cells, in which single-nucleotide polymorphism G388R in [i][[FGFR4]][/i] was detected. For inhibition of autocrine/paracrine FGF19/[[FGFR4]] signaling, we used BLU9931, a highly selective [[FGFR4]] inhibitor. Inhibition of signal transduction through ERK, AKT, and [[STAT3]] pathways by BLU9931 reduced proliferation in FGF19/[[FGFR4]] signaling-activated PDAC cells. By contrast, BLU9931 did not alter stemness features, including stemness marker expression, anticancer drug resistance, and sphere-forming ability. However, BLU9931 inhibited cell invasion, in part, by downregulating membrane-type matrix metalloproteinase-1 in FGF19/[[FGFR4]] signaling-activated PDAC cells. Furthermore, downregulation of [[SIRT1]] and [[SIRT6]] by BLU9931 contributed to senescence induction, priming these cells for quercetin-induced death, a process termed senolysis. Thus, we propose that BLU9931 is a promising therapeutic agent in [[FGFR4]]-positive PDAC, especially when combined with senolysis (195/200).

|keywords=* FGFR4
* FGFR4 inhibitor
* growth
* invasion
* pancreatic cancer
* senescence
* senolytic therapy
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602396
}}
{{medline-entry
|title=AMPK alleviates oxidative stress‑induced premature senescence via inhibition of NF-κB/[[STAT3]] axis-mediated positive feedback loop.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32882228
|abstract=Stress-induced premature senescence (SIPS) is characterized by the secretion of a variety of inflammatory cytokines, chemokines, and proteases, which are defined collectively as the senescence-associated secretory phenotype (SASP). AMP-activated protein kinase (AMPK) activation contributes to SIPS prevention, and the impact of AMPK on SASP may be included, but the mechanisms governing this phenomenon have not elucidated. In this study, we showed that SIPS is accompanied by a dynamic fluctuation of NF-κB activation, which induces SASP production, whilst reinforcing and amplifying local [[STAT3]] signalling and subsequently enhancing downstream senescence. NF-κB and [[STAT3]] inhibitors attenuate oxidative stress-induced senescence in a time-dependent manner. Conditioned medium (CM) from senescent cells rich in SASP factors can induce growth arrest and promote senescence in healthy cells; accordingly, a [[STAT3]] inhibitor blunts the SASP-induced senescence, indicating a positive feedback mechanism via the NF-κB/[[STAT3]] pathway that sustains SASP production and promotes senescence. In addition, we confirmed that AMPK negatively regulates SASP production and senescence development associated with NF-κB/[[STAT3]] inhibition. In summary, our results suggest that AMPK prevents oxidative stress-induced senescence development via inhibiting the NF-κB/SASP/[[STAT3]] signalling mediated positive feedback loop.

|keywords=* AMPK
* NF-κB/STAT3 signalling
* Oxidative stress
* SASP
* Senescence
|full-text-url=https://sci-hub.do/10.1016/j.mad.2020.111347
}}
{{medline-entry
|title=Senescence in Monocytes Facilitates Dengue Virus Infection by Increasing Infectivity.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32850477
|abstract=Aging and chronic condition increase the incidence of dengue virus (DENV) infection, generally through a mechanism involving immunosenescence; however, the alternative effects of cellular senescence, which alters cell susceptibility to viral infection, remain unknown. Human monocytic THP-1 cells (ATCC TIB-202) treated with D-galactose to induce cellular senescence were susceptible to DENV infection. These senescent cells showed increased viral entry/binding, gene/protein expression, and dsRNA replication. The use of a replicon system showed that pharmacologically induced senescence did not enhance the effects on viral protein translation. By examining viral receptor expression, we found increased expression of [[CD209]] (DC-SIGN) in the senescent cells. Interleukin (IL)-10 was aberrantly produced at high levels by the senescent cells, and the expression of the DENV receptor DC-SIGN was increased in these senescent cells, partially via IL-10-mediated regulation of the [[JAK2]]-[[STAT3]] signaling pathway. The results demonstrate that a senescent phenotype facilitates DENV infection, probably by increasing DC-SIGN expression.

|keywords=* DC-SIGN
* IL-10
* dengue virus
* monocytes
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399640
}}
{{medline-entry
|title=Age-related loss of neural stem cell O-GlcNAc promotes a glial fate switch through [[STAT3]] activation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32848054
|abstract=Increased neural stem cell (NSC) quiescence is a major determinant of age-related regenerative decline in the adult hippocampus. However, a coextensive model has been proposed in which division-coupled conversion of NSCs into differentiated astrocytes restrict the stem cell pool with age. Here we report that age-related loss of the posttranslational modification, O-linked β-[i]N[/i]-acetylglucosamine (O-GlcNAc), in NSCs promotes a glial fate switch. We detect an age-dependent decrease in NSC O-GlcNAc levels coincident with decreased neurogenesis and increased gliogenesis in the mature hippocampus. Mimicking an age-related loss of NSC O-GlcNAcylation in young mice reduces neurogenesis, increases astrocyte differentiation, and impairs associated cognitive function. Using RNA-sequencing of primary NSCs following decreased O-GlcNAcylation, we detected changes in the [[STAT3]] signaling pathway indicative of glial differentiation. Moreover, using O-GlcNAc-specific mass spectrometry analysis of the aging hippocampus, together with an in vitro site-directed mutagenesis approach, we identify loss of [[STAT3]] O-GlcNAc at Threonine 717 as a driver of astrocyte differentiation. Our data identify the posttranslational modification, O-GlcNAc, as a key molecular regulator of regenerative decline underlying an age-related NSC fate switch.
|mesh-terms=* Aging
* Animals
* Cell Differentiation
* Cell Proliferation
* Computational Biology
* Gene Expression Regulation
* Glucosamine
* Hippocampus
* Mice
* Neural Stem Cells
* Neurogenesis
* Neuroglia
* STAT3 Transcription Factor
* Sequence Analysis, RNA
|keywords=* O-GlcNAcylation
* aging
* gliogenesis
* neural stem cells
* neurogenesis
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486730
}}
{{medline-entry
|title=Cell Death by Gallotannin Is Associated with Inhibition of the JAK/STAT Pathway in Human Colon Cancer Cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32714471
|abstract=Gallotannin (GT) is a polyphenol that possesses interesting anticancer properties. However, the mechanisms underlying its antitumor effects have not been well defined. This study was designed to clarify the mechanisms underlying GT antitumor effects in colon cancer cell lines. Three isogenic HCT116 cell lines (p53 , p53 , and p21 ) were treated with GT for different time points then Western blot, flow cytometry, and senescence analysis were performed to examine the effect of GT on Mitogen-activated protein kinase (MAPK) and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) effectors, [[STAT3]] downstream apoptotic targets, Sub-G1 phase, and programmed cell death induction. Transfection using Invitrogen Lipofectamine 2000 Transfection Reagent (Thermo Fisher Scientific, Waltham, Massachusetts) were used to identify the role of p53 and p21 in the p53  and p21  cell lines. Both low and high GT concentrations caused MAPKs activation marked by upregulation of extracellular signal-regulated kinase (p-ERK). The preincubation with the antioxidant Tiron (Sigma-Aldrich, St Louis, Missouri) showed that GT's antitumor effects were not mediated by reactive oxygen species. We then examined the effect of GT on the JAK/STAT pathway, which is known to be activated in colorectal cancer. GT totally inhibited the JAK/STAT pathway effectors [[JAK2]], STAT1, and [[STAT3]] and their downstream apoptotic regulators B-cell lymphoma-extra large (Bcl-x ) and c-Myc in all 3 cell lines. HCT116 cancer cells exhibited differential sensitivity to GT with p21  cells being the most sensitive and p53  cells that express p21 protein being the least sensitive. In p53  cells, GT induced senescence, whereas in p53  and p21  cells, GT induced apoptosis in a caspase independent manner marked by Poly(ADP-Ribose) Polymerase (PARP) cleavage, Bcl-2 downregulation, and upregulation of the Bcl-2 associated X (Bax) to B-cell lymphoma 2 (Bcl-2) ratio. In addition, the sub-G1 phase exceeded 50% in p21  cells. Considered together, our results indicate that GT is potent inhibitor of the JAK/STAT pathway in colon cancer irrespective of the p53 and p21 status, which provides insights into its mechanism of anticancer activities and future potential for clinical translation. ([i]Curr Ther Res Clin Exp[/i]. 2020; 81:XXX-XXX).

|keywords=* Apoptosis
* JAK/STAT
* caspase
* colon cancer
* gallotannin
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378856
}}
{{medline-entry
|title=Hepatocyte growth factor ([[HGF]]) and stem cell factor (SCF) maintained the stemness of human bone marrow mesenchymal stem cells (hBMSCs) during long-term expansion by preserving mitochondrial function via the PI3K/AKT, ERK1/2, and [[STAT3]] signaling pathways.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32736659
|abstract=Mesenchymal stem cells (MSCs) have a limited self-renewal ability, impaired multi-differentiation potential, and undetermined cell senescence during in vitro series expansion. To address this concern, we investigated the effects of the microenvironment provided by stem cells from human exfoliated deciduous teeth (SHED) in maintaining the stemness of human bone marrow mesenchymal stem cells (hBMSCs) and identified the key factors and possible mechanisms responsible for maintaining the stemness of MSCs during long-term expansion in vitro. The passage 3 (P3) to passage 8 (P8) hBMSCs were cultured in the conditioned medium from SHED (SHED-CM). The percentage of senescent cells was evaluated by β-galactosidase staining. In addition, the osteogenic differentiation potential was analyzed by reverse transcription quantitative PCR (RT-qPCR), Western blot, alizarin red, and alkaline phosphatase (ALP) staining. Furthermore, RT-qPCR results identified hepatocyte growth factor ([[HGF]]) and stem cell factor (SCF) as key factors. Thus, the effects of [[HGF]] and SCF on mitochondrial function were assessed by measuring the ROS and mitochondrial membrane potential levels. Finally, selected mitochondrial-related proteins associated with the PI3K/AKT, ERK1/2, and [[STAT3]] signaling pathways were investigated to determine the effects of [[HGF]] and SCF in preserving the mitochondrial function of hBMSCs during long-term expansion. SHED-CM had significantly enhanced the cell proliferation, reduced the senescent cells, and maintained the osteogenesis and pro-angiogenic capacity in P8 hBMSCs during long-term expansion. In addition, hBMSCs treated with 100 ng/ml [[HGF]] and 10 ng/ml SCF had reduced ROS levels and preserved mitochondrial membrane potential compared with P8 hBMSCs during long-term expansion. Furthermore, [[HGF]] and SCF upregulated the expression of mitochondrial-related proteins associated with the PI3K/AKT, ERK1/2, and [[STAT3]] signaling pathways, possibly contributing to the maintenance of hBMSCs stemness by preserving mitochondrial function. Both [[HGF]] and SCF are key factors in maintaining the stemness of hBMSCs by preserving mitochondrial function through the expression of proteins associated with the PI3K/AKT, ERK1/2, and [[STAT3]] signaling pathways. This study provides new insights into the anti-senescence capability of [[HGF]] and SCF, as well as new evidence for their potential application in optimizing the long-term culture of MSCs.

|keywords=* Hepatocyte growth factor
* Mitochondrial function
* Osteogenic differentiation
* Senescence
* Stem cell factor
* Stem cells from human exfoliated deciduous teeth
* Stemness
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393921
}}
{{medline-entry
|title=The effect of interleukin 6 deficiency on myocardial signal transduction pathways activation induced by bacterial lipopolysaccharide in young and old mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32693349
|abstract=Exaggerated release of proinflammatory mediators during sepsis contributes to inadequate vasodilatation and depressed myocardial contractility, which lead to development of shock and circulatory collapse. The aim of the study was to evaluate the effect of IL-6 and aging on activation of intracellular signaling pathways in the myocardium induced by bacterial lipopolysaccharide (LPS) administration. LPS was injected intraperitoneally to male 3- and 24-month old mice with systemic IL-6 gene knock-out (IL-6KO) and the reference strain (WT). LPS was given intraperitoneally in single low (0.1 mg/kg) or high (10 mg/kg) dose, or in two doses (0.1   10 mg/kg) with 24-h delay. The expression and phosphorylation of [[STAT3]], ERK1/2, Akt1/2/3 proteins in the left ventricular myocardium was evaluated after 24 h using Western blotting. Low LPS dose induced higher [[STAT3]] phosphorylation only in old IL-6KO mice, not affecting ERK1/2 and Akt1/2/3 phosphorylation in any group. High LPS dose upregulated [[STAT3]] phosphorylation similarly in all groups, reduced ERK1/2 expression in young WT mice and upregulated Akt1/2/3 expression and phosphorylation in young IL-6KO mice. Pretreatment with low LPS dose attenuated phosphorylation of [[STAT3]] in both old groups and phosphorylation of Akt1/2/3 in young IL-6KO group. Two-dose approach also significantly potentiated ERK1/2 phosphorylation in both old groups. Obtained results show that IL-6 deficiency alters the activity of intracellular signaling pathways: JAK/STAT in old and Akt in young LPS-treated mice. This may indicate that lack of IL-6 attenuates Akt-related cytoprotective effect of pretreatment with low LPS dose in young but not in aged animals.

|keywords=* Aging
* For review: bacterial lipolisacharide (LPS)
* Heart
* Inflammation
* Interleukin-6
* Signal transduction
|full-text-url=https://sci-hub.do/10.1016/j.advms.2020.06.006
}}
{{medline-entry
|title=Wogonin induces cellular senescence in breast cancer via suppressing [[TXNRD2]] expression.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32671444
|abstract=Cellular senescence contributes to tumor regression through both cell autonomous and non-autonomous mechanisms. Drugs inducing cancer cell senescence and modulating senescence-associated secretory phenotype (SASP) render advantage to the cancer treatment. Breast cancer remains the second most cause of female cancer mortality, among which triple-negative breast cancer (TNBC) has a more aggressive clinical course. Our study showed that in TNBC cell lines including MDA-[[MB]]-231 and 4T1 cells, moderate concentrations of wogonin (5, 7-dihydroxy-8-methoxy-2-phenyl-4h-1-benzopyran-4-one) (50-100 μM) not only induced permanent proliferation inhibition, but also increased P16 expression, β-galactosidase activity, senescence-associated heterochromatin foci and SASP, which are the typical characteristics of cellular senescence. Moreover, results showed that wogonin-induced senescence was partially attributed to the reactive oxygen species (ROS) accumulation upon wogonin treatment in MDA-[[MB]]-231 cells, since elimination of ROS by N-acetylcysteine (NAC) was able to repress wogonin-induced β-galactosidase activity. Mechanistically, wogonin reduced the expression of [[TXNRD2]], an important antioxidant enzyme in controlling the levels of cellular ROS, by altering the histone acetylation at its regulatory region. In addition, senescent MDA-[[MB]]-231 cells induced by wogonin exhibited activated NF-κB and suppressed [[STAT3]], which were recognized as regulators of SASP. SASP from these senescent cells suppressed tumor cell growth, promoted macrophage M1 polarization in vitro and increased immune cell infiltration in xenografted tumors in vivo. These results reveal another mechanism for the anti-breast cancer activity of wogonin by inducing cellular senescence, which suppresses tumor progression both autonomously and non-autonomously.

|keywords=* Breast cancer
* Immune surveillance
* ROS
* Senescence
* TXNRD2
* Wogonin
|full-text-url=https://sci-hub.do/10.1007/s00204-020-02842-y
}}
{{medline-entry
|title=Silibinin and SARS-CoV-2: Dual Targeting of Host Cytokine Storm and Virus Replication Machinery for Clinical Management of COVID-19 Patients.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32517353
|abstract=COVID-19, the illness caused by infection with the novel coronavirus SARS-CoV-2, is a rapidly spreading global pandemic in urgent need of effective treatments. Here we present a comprehensive examination of the host- and virus-targeted functions of the flavonolignan silibinin, a potential drug candidate against COVID-19/SARS-CoV-2. As a direct inhibitor of [[STAT3]]-a master checkpoint regulator of inflammatory cytokine signaling and immune response-silibinin might be expected to phenotypically integrate the mechanisms of action of IL-6-targeted monoclonal antibodies and pan-JAK1/2 inhibitors to limit the cytokine storm and T-cell lymphopenia in the clinical setting of severe COVID-19. As a computationally predicted, remdesivir-like inhibitor of RNA-dependent RNA polymerase (RdRp)-the central component of the replication/transcription machinery of SARS-CoV-2-silibinin is expected to reduce viral load and impede delayed interferon responses. The dual ability of silibinin to target both the host cytokine storm and the virus replication machinery provides a strong rationale for the clinical testing of silibinin against the COVID-19 global public health emergency. A randomized, open-label, phase II multicentric clinical trial (SIL-COVID19) will evaluate the therapeutic efficacy of silibinin in the prevention of acute respiratory distress syndrome in moderate-to-severe COVID-19-positive onco-hematological patients at the Catalan Institute of Oncology in Catalonia, Spain.

|keywords=* IL-6
* JAK
* coronavirus
* cytokine storm
* remdesivir
* senescence
* stat3
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356916
}}
{{medline-entry
|title=Implication of [[JAK1]]/[[STAT3]]/[[SOCS3]] Pathway in Aging of Cerebellum of Male Rat: Histological and Molecular study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32483368
|abstract=Aging causes morphological and functional changes in the cerebellum. This work aimed to demonstrate the implication of [[JAK1]]/[[STAT3]]/[[SOCS3]] on aging-induced changes of rat cerebellum. Thirty male rats were divided into: adult (12 months), early senile (24 months) and late senile (32 months) groups. Immunohistochemical reaction of the cerebellum to [[GFAP]] and caspase-3 was assessed and the expression of [[JAK1]], [[STAT3]], [[SOCS3]] proteins was also evaluated. TNFα as well as the activities of malondialdehyde (MDA) and reduced glutathione (GSH) in cerebellar tissue were also measured. The cerebellum of late senile rats revealed more degenerative changes than early senile rats in the form of increase in [[GFAP]] and caspase-3 immunoreaction. Additionally, there was decrease in [[JAK1]]and [[STAT3]] expression in early and late senile rats and increase in [[SOCS3]] when compare early and late senile groups with adult one. Enhancement of TNFα was noticed with aging as well as significant decrease in GSH and increase in MDA in early senile group. Moreover, late senile group revealed significant decrease in GSH and increase in MDA. It could be concluded that aging resulting in variable changes of the cerebellum as detected by morphological changes, immunohistochemical reactions of caspase-3 and [[GFAP]] and expression of [[JAK1]]/[[STAT3]]/[[SOCS3]] proteins. Additionally, inflammatory marker TNFα and the activity of oxidative/antioxidative stress markers; malondialdehyde (MDA) and reduced glutathione (GSH) were also affected with aging.
|mesh-terms=* Aging
* Animals
* Caspase 3
* Cerebellum
* Glial Fibrillary Acidic Protein
* Glutathione
* Immunohistochemistry
* Janus Kinase 1
* Male
* Malondialdehyde
* Microscopy, Electron
* Rats
* Rats, Wistar
* STAT3 Transcription Factor
* Signal Transduction
* Suppressor of Cytokine Signaling 3 Protein
* Tumor Necrosis Factor-alpha

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264275
}}
{{medline-entry
|title=Atorvastatin-induced senescence of hepatocellular carcinoma is mediated by downregulation of hTERT through the suppression of the IL-6/[[STAT3]] pathway.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32257389
|abstract=Hepatocellular carcinoma (HCC), a hepatic malignancy, has a poor prognosis and contributes to cancer-related death worldwide. Cellular senescence is an anticancer therapeutic strategy that causes irreversible cell cycle arrest and enables immune-mediated clearance of cancer cells. Atorvastatin, an HMG-CoA reductase inhibitor, has been shown to inhibit tumor growth and induce apoptosis or autophagy in malignant tumors. However, whether atorvastatin can induce HCC cell senescence and the mechanisms involved are poorly understood. The effects of atorvastatin-induced senescence were examined in both HCC cells and mouse xenograft models. The phenomenon and mechanism of senescence were examined by cell cycle analysis, senescence-associated β-galactosidase (SA-β-gal) staining and western blotting in HCC cells, and HCC tissues from mice were analyzed by immunohistochemical (IHC) staining. We demonstrated that atorvastatin induced cell growth inhibition and G0/G1 phase cell cycle arrest, leading to senescence in HCC cells. Atorvastatin-induced senescence was independent of p53, p14, and p16, and atorvastatin not only decreased the secretion of IL-6, a major senescence-associated secretory phenotype (SASP) factor, and the phosphorylation of [[STAT3]] but also inhibited the expression of hTERT, a catalytic subunit of telomerase. Supplementation with exogenous IL-6 reversed both atorvastatin-induced suppression of [[STAT3]] phosphorylation and hTERT expression and atorvastatin-induced senescence. Overexpression of constitutively activated [[STAT3]] rescued HCC cells from atorvastatin-induced hTERT suppression and senescence. Moreover, atorvastatin decreased tumor growth in mouse xenograft models. Consistent with these results, atorvastatin decreased the IL-6, p-[[STAT3]], and hTERT levels and increased β-gal expression in tumor sections. Taken together, these data indicate that atorvastatin can induce atypical cellular senescence in HCC cells to inhibit tumor growth, an effect mediated by downregulation of hTERT through suppression of the IL-6/[[STAT3]] pathway.

|keywords=* Cancer therapy
* Senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105491
}}
{{medline-entry
|title=Deciphering the Molecular Mechanism of Spontaneous Senescence in Primary Epithelial Ovarian Cancer Cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32012719
|abstract=Spontaneous senescence of cancer cells remains a puzzling and poorly understood phenomenon. Here we comprehensively characterize this process in primary epithelial ovarian cancer cells (pEOCs). Analysis of tumors from ovarian cancer patients showed an abundance of senescent cells in vivo. Further, serially passaged pEOCs become senescent after a few divisions. These senescent cultures display trace proliferation, high expression of senescence biomarkers (SA--Gal, -H2A.X), growth-arrest in the G  phase, increased level of cyclins D1, D2, decreased cyclin B1, up-regulated p16, p21, and p53 proteins, eroded telomeres, reduced activity of telomerase, predominantly non-telomeric DNA damage, activated AKT, AP-1, and ERK1/2 signaling, diminished JNK, NF-B, and [[STAT3]] pathways, increased formation of reactive oxygen species, unchanged activity of antioxidants, increased oxidative damage to DNA and proteins, and dysfunctional mitochondria. Moreover, pEOC senescence is inducible by normal peritoneal mesothelium, fibroblasts, and malignant ascites via the paracrine activity of GRO-1, [[HGF]], and TGF-1. Collectively, pEOCs undergo spontaneous senescence in a mosaic, telomere-dependent and telomere-independent manner, plausibly in an oxidative stress-dependent mechanism. The process may also be activated by extracellular stimuli. The biological and clinical significance of pEOC senescence remains to be explored.

|keywords=* aging biomarkers
* cancer biology
* cellular senescence
* epithelial ovarian cancer
* oxidative stress
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072138
}}
{{medline-entry
|title=[[STAT3]] Relays a Differential Response to Melanoma-Associated [i][[NRAS]][/i] Mutations.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31906480
|abstract=Melanoma patients carrying an oncogenic [i][[NRAS]][/i] mutation represent 20% of all cases and present worse survival, relapse rate and therapy response than patients with wild type [i][[NRAS]][/i] or with [i][[BRAF]][/i] mutations. Nevertheless, no efficient targeted therapy has emerged so far for this group of patients in comparison with the classical combination of [[BRAF]] and MEK inhibitors for the patient group carrying a [i][[BRAF]][/i] mutation. [[NRAS]] key downstream actors should therefore be identified for drug targeting, possibly in combination with MEK inhibitors. Here, we investigated the influence of different melanoma-associated [i][[NRAS]][/i] mutations (codon 12, 13 or 61) on several parameters such as oncogene-induced senescence, cell proliferation, migration or colony formation in immortalized melanocytes and in melanoma cell lines. We identified AXL/[[STAT3]] axis as a main regulator of [i][[NRAS]]Q61[/i]-induced oncogene-induced senescence (OIS) and observed that [i][[NRAS]]Q61[/i] mutations are not only more tumorigenic than [i][[NRAS]]G12/13[/i] mutations but also associated to [[STAT3]] activation. In conclusion, these data bring new evidence of the potential tumorigenic role of [[STAT3]] in [i][[NRAS]][/i]-mutant melanomas and will help improving current therapy strategies for this particular patient group.

|keywords=* NRAS
* STAT3
* melanoma
* mutation
* oncogene-induced senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016650
}}
{{medline-entry
|title=Persistent Activation of [[STAT3]] Pathway in the Retina Induced Vision Impairment and Retinal Degenerative Changes in Ageing Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31884637
|abstract=Neurotrophic factors can promote the survival of degenerating retinal cells through the activation of [[STAT3]] pathway. Thus, augmenting [[STAT3]] activation in the retina has been proposed as potential therapy for retinal dystrophies. On the other hand, aberrant activation of [[STAT3]] pathway is oncogenic and implicated in diverse human diseases. Furthermore, the [[STAT3]]/[[SOCS3]] axis has been shown to induce the degradation of rhodopsin during retinal inflammation. In this study, we generated and used mice with constitutive activation of [[STAT3]] pathway in the retina to evaluate the safety and consequences of enhancing [[STAT3]] activities in the retina as a potential treatment for retinal degenerative diseases. We show that long-term activation of the [[STAT3]] pathway can induce retinal degenerative changes and also exacerbate uveitis and other intraocular inflammatory diseases. Mechanisms underlying the development of vision impairment in the [[STAT3]]c-Tg mice derived in part from [[STAT3]]-mediated inhibition of rhodopsin and overexpression of [[SOCS3]] in the retina. These results suggest that much caution should be exercised in the use of [[STAT3]] augmentation therapy for retinal dystrophies.
|mesh-terms=* Aging
* Animals
* Mice
* Mice, Inbred C57BL
* Retina
* Retinal Degeneration
* STAT3 Transcription Factor
* Suppressor of Cytokine Signaling 3 Protein
* Suppressor of Cytokine Signaling Proteins
* Uveitis
|keywords=* EAU
* Experimental autoimmune uveitis
* Retinal dystrophies
* SOCS3
* STAT3
* Transgenic mouse
* Uveitis
|full-text-url=https://sci-hub.do/10.1007/978-3-030-27378-1_58
}}
{{medline-entry
|title=The influence of fibroblast growth factor 2 on the senescence of human adipose-derived mesenchymal stem cells during long-term culture.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31840944
|abstract=Adipose-derived mesenchymal stem cells (ASCs) exhibit great potential in regenerative medicine, and in vitro expansion is frequently necessary to obtain a sufficient number of ASCs for clinical use. Fibroblast growth factor 2 ([[FGF2]]) is a common supplement in the ASC culture medium to enhance cell proliferation. To achieve clinical applicability of ASC-based products, prolonged culture of ASCs is sometimes required to obtain sufficient quantity of ASCs. However, the effect of [[FGF2]] on ASCs during prolonged culture has not been previously determined. In this study, ASCs were subjected to prolonged in vitro culture with or without [[FGF2]]. [[FGF2]] maintained the small cell morphology and expedited proliferation kinetics in early ASC passages. After prolonged in vitro expansion, [[FGF2]]-treated ASCs exhibited increased cell size, arrested cell proliferation, and increased cellular senescence relative to the control ASCs. We observed an upregulation of [[FGFR1]]c and enhanced expression of downstream [[STAT3]] in the initial passages of [[FGF2]]-treated ASCs. The application of an [[FGFR1]] or [[STAT3]] inhibitor effectively blocked the enhanced proliferation of ASCs induced by [[FGF2]] treatment. [[FGFR1]]c upregulation and enhanced [[STAT3]] expression were lost in the later passages of [[FGF2]]-treated ASCs, suggesting that the continuous stimulation of [[FGF2]] becomes ineffective because of the refractory downstream [[FGFR1]] and the [[STAT3]] signaling pathway. In addition, no evidence of tumorigenicity was noted in vitro and in vivo after prolonged expansion of [[FGF2]]-cultured ASCs. Our data indicate that ASCs have evolved a [[STAT3]]-dependent response to continuous [[FGF2]] stimulation which promotes the initial expansion but limits their long-term proliferation.

|keywords=* cell proliferation
* cellular senescence
* fibroblast growth factor 2
* long-term culture
* mesenchymal stem cell
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103622
}}
{{medline-entry
|title=Interleukin-10 induces senescence of activated hepatic stellate cells via [[STAT3]]-p53 pathway to attenuate liver fibrosis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31730896
|abstract=Hepatic fibrosis is a wound healing process which results in deposition of excessive abnormal extracellular matrix (ECM) in response to various liver injuries. Activated hepatic stellate cells (HSCs) are the major sources of ECM and induction of senescence of activated HSCs is an attractive therapeutic strategy for liver fibrosis. Our previous studies have shown that interleukin-10 (IL-10) attenuates the carbon tetrachloride (CCL ) - and porcine serum-induced liver fibrosis in rats. However, little is known about the mechanisms of IL-10 regulating the senescence of activated HSCs. The aim of this study is to uncover the underlying pathway by which IL-10 mediates activated HSCs senescence to attenuate liver fibrosis. In vivo, we found that IL-10 gene by hydrodynamics-based transfection attenuated CCL -induced liver fibrosis associated with senescence of activated HSCs in rats. In vitro experiment confirmed that IL-10 could induce senescence of activated HSCs via inhibiting cell proliferation, inducing cell cycle arrest, increasing the SA-β-Gal activity and enhancing expression of senescence marker protein p53 and p21. Treatment with Pifithrin-α, a specific inhibitor of p53, could abrogate IL-10-increased SA-β-Gal activity and expression of P53 and P21in activated HSCs. Lastly, IL-10 also increased the expression of total and phosphorylated signal transducers and activators of transcription 3([[STAT3]]) and promoted phosphorylated [[STAT3]] translocation from cytoplasm to nucleus. Treatment with cryptotanshinone, a specific inhibitor of [[STAT3]], could inhibit the phosphorylation of [[STAT3]] and its downstream proteins p53 and p21 expression and decrease the activity of SA-β-Gal in activated HSCs induced by IL-10. Taken together, IL-10 induced senescence of activated HSCs via [[STAT3]]-p53 pathway to attenuate liver fibrosis in rats and present study will provide a new mechanism of antifibrotic effects of IL-10.

|keywords=* Hepatic stellate cells
* Interleukin-10
* Liver fibrosis
* Senescence
* Signal pathway
|full-text-url=https://sci-hub.do/10.1016/j.cellsig.2019.109445
}}
{{medline-entry
|title=The proteasome activator REGγ counteracts immunoproteasome expression and autoimmunity.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31171475
|abstract=For quite a long time, the 11S proteasome activator REGɑ and REGβ, but not REGγ, are known to control immunoproteasome and promote antigen processing. Here, we demonstrate that REGγ functions as an inhibitor for immunoproteasome and autoimmune disease. Depletion of REGγ promotes MHC class I-restricted presentation to prime CD8  T cells in vitro and in vivo. Mice deficient for REGγ have elevation of CD8  T cells and DCs, and develop age-related spontaneous autoimmune symptoms. Mechanistically, REGγ specifically interacts with phosphorylated [[STAT3]] and promotes its degradation in vitro and in cells. Inhibition of [[STAT3]] dramatically attenuates levels of LMP2/LMP7 and antigen presentation in cells lacking REGγ. Importantly, treatment with [[STAT3]] or LMP2/7 inhibitor prevented accumulation of immune complex in REGγ  kidney. Moreover, REGγ  mice also expedites Pristane-induced lupus. Bioinformatics and immunohistological analyses of clinical samples have correlated lower expression of REGγ with enhanced expression of phosphorylated [[STAT3]], LMP2 and LMP7 in human Lupus Nephritis. Collectively, our results support the concept that REGγ is a new regulator of immunoproteasome to balance autoimmunity.
|mesh-terms=* Aging
* Animals
* Antigen Presentation
* Autoantigens
* Autoimmune Diseases
* CD8-Positive T-Lymphocytes
* Cells, Cultured
* Cysteine Endopeptidases
* Dendritic Cells
* Histocompatibility Antigens Class I
* Mice
* Mice, Knockout
* Proteasome Endopeptidase Complex
* Proteasome Inhibitors
* STAT3 Transcription Factor
|keywords=* Autoimmunity
* LMP2(7)
* Phosphorylated STAT3
* REGγ
|full-text-url=https://sci-hub.do/10.1016/j.jaut.2019.05.010
}}
{{medline-entry
|title=Sexual dimorphism in rat thymic involution: a correlation with thymic oxidative status and inflammation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31119497
|abstract=The study investigated mechanisms underlying sex differences in thymic involution in Dark Agouti rats. Adverse effects of aging on thymus were more pronounced in males than in females. Thymi from old males exhibited more prominent: (i) fibro-adipose degeneration which correlated with greater intensity of thymic oxidative stress and enhanced thymic TGF-β and IL-6 expression and (ii) decline in thymopoiesis, as suggested by the number of the most mature [[CD4]] CD8-/[[CD4]]-CD8  single positive (SP) TCRαβ  thymocytes. The greater accumulation of adipose tissue in old male thymus was linked with greater age-related increase in thymic expression of PPARγ and [[STAT3]], a transcription factor regulating the expression of PPARγ downstream genes, in male than in female rats. In aged thymi of both sexes the early [[CD4]]-CD8- double negative (DN) stage of thymocyte development was affected, so relative accumulation of the least mature [[CD4]]5RC CD2- cells followed by decreased frequency of their DN and [[CD4]] CD8  double positive (DP) TCRαβ  descendants was observed. Additionally, in old males, because of the increased thymic expression of Nur77, a nuclear receptor involved in negative selection, and decreased CD90 (a negative regulator of thymocyte selection threshold) [[MFI]] on DP TCRαβ  thymocytes, less efficient positive/more efficient negative selection was found. Moreover, in male rats, thymocyte post-selection differentiation/maturation was skewed towards [[CD4]]-CD8  SP TCRαβ  cells compared with age-matched females, reflecting, at least partly, greater IL-15 expression in their thymi. The study indicated mechanisms underlying sex-based differences in age-related thymic changes and consequently necessity of sex-specific approaches in designing strategies to rejuvenate thymus.
|mesh-terms=* Animals
* Antigens, CD
* Cellular Senescence
* Correlation of Data
* Fibrosis
* Inflammation
* Interleukin-6
* Oxidative Stress
* PPAR gamma
* Rats
* Sex Characteristics
* Thymocytes
* Thymus Gland
* Transforming Growth Factor beta
|keywords=* Aging
* Fibro-adipose thymic involution
* Sex differences
* Thymic inflammatory/redox state
* Thymopoiesis
|full-text-url=https://sci-hub.do/10.1007/s10522-019-09816-3
}}
{{medline-entry
|title=Inflammaging: Age and Systemic, Cellular, and Nuclear Inflammatory Biology in Older Adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31107949
|abstract=Systemic inflammation is associated with increasing age. Yet, there are limited data about the association between age and systemic inflammation within older adults, and whether older age is also associated with cellular and nuclear signaling markers of inflammation. In community-dwelling older adults (N = 262, 60-88 years), systemic levels of C-reactive protein, interleukin-6, and soluble tumor necrosis factor receptor II; levels of toll-like receptor-4-stimulated monocytic production of interleukin-6 and tumor necrosis factor α; and resting nuclear levels of activated nuclear factor kappa B and signal transducer and activator of transcription ([[STAT1]], [[STAT3]], STAT5) were evaluated. Adjusting for demographic and clinical factors, multivariate linear regression tested the association between age and each inflammatory marker. Age was positively associated with increased levels of interleukin-6 and soluble tumor necrosis factor receptor II (p's < .05) and with increases in [[STAT1]], [[STAT3]], and STAT5 activation (p's < .05). However, no relationship was found between age and C-reactive protein, toll-like receptor-4-stimulated interleukin-6/tumor necrosis factor alpha α production, or nuclear factor kappa B. Within a community-dwelling sample of older adults, older age is associated with increases in STAT activation, along with increases of systemic inflammatory cytokines. In older adults, heterogeneity in age-related increases in inflammatory disease risk may be related to individual variability in inflammation.
|mesh-terms=* Age Factors
* Aged
* Aged, 80 and over
* Aging
* C-Reactive Protein
* Cross-Sectional Studies
* Cytokines
* Female
* Gene Expression Regulation
* Humans
* Independent Living
* Inflammation
* Inflammation Mediators
* Linear Models
* Male
* Middle Aged
* Multivariate Analysis
* Risk Assessment
* STAT1 Transcription Factor
* STAT3 Transcription Factor
* STAT5 Transcription Factor
* Signal Transduction
* Tumor Necrosis Factor-alpha
* Tumor Suppressor Proteins
|keywords=* C-reactive protein
* Inflammation
* NF-κB
* Proinflammatory cytokines
* STAT signaling
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777092
}}
{{medline-entry
|title=A novel [[STAT3]] inhibitor, HJC0152, exerts potent antitumor activity in glioblastoma.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31105997
|abstract=Aberrant expression and activation of signal transducer and activator of transcription 3 ([[STAT3]]) is implicated in several malignancies, including glioblastoma, and is correlated with poor outcomes in patients with glioblastoma, rendering [[STAT3]] a potential therapeutic target. However, few [[STAT3]] inhibitors have been approved for clinical use. We recently developed an orally active small-molecule compound with anti-[[STAT3]] activity, HJC0152. This study aimed to test the effect of this novel drug on glioblastoma cell lines, and provide possibility to improve clinic prognosis of patients with glioblastoma in the future. In the present study, we aimed to determine the effects of HJC0152 on the growth, proliferation, and chemosensitivity of glioblastoma cell lines and xenograft tumors. We found that HJC0152 inactivated [[STAT3]] via inhibiting phosphorylation of the Tyr705 residue. [i]In vitro[/i], HJC0152 suppressed the proliferation and motility of glioblastoma cells, induced apoptosis, and enhanced the chemosensitivity of glioblastoma cells. Furthermore, HJC0152 inhibited the growth of glioblastoma xenograft tumors [i]in vivo[/i]. This study provides a rationale for developing HJC0152 as a [[STAT3]]-targeting therapy for treating human glioblastoma in the future.

|keywords=* HJC0152
* STAT3
* anti-tumor activity
* apoptosis
* epithelial-mesenchymal transition
* glioblastoma
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511646
}}
{{medline-entry
|title=Congenital Hypothyroidism is Associated With Impairment of the Leptin Signaling Pathway in the Hypothalamus in Male Wistar Animals in Adult Life.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30943548
|abstract=The goal of this study is to investigate whether congenital hypothyroidism induced by MMI during gestation (G) or gestation plus lactation (GL) would affect the leptin action upon body weight control on hypothalamus. Six to eight pups per group were killed at 90 days of age. For statistical analysis one-way ANOVA followed by the Holm-Sìdak post hoc test was used. Hypothyroidism resulted in a significant increase in leptin serum levels in G 20% and GL 25% (p<0.04). There was a significant expression decrease of OBR in G 45% and GL 63%; p[[STAT3]] in G 56% and GL 51%; pERK in G 50% and GL 48%; [[POMC]] in G 41% and GL 46% (p<0.04), while a significant increase was assigned to [[SOCS3]] in G 52% and GL 170% (p<0.04) protein expression. We can conclude that hypothyroxinemia condition in rats on adulthood results in impairment of the leptin signaling pathway via ObRb-[[STAT3]] in the hypothalamus, which is likely to be involved in the leptin resistance.
|mesh-terms=* Aging
* Animals
* Body Weight
* Congenital Hypothyroidism
* Feeding Behavior
* Female
* Hormones
* Hypothalamus
* Leptin
* Male
* Rats, Wistar
* Signal Transduction

|full-text-url=https://sci-hub.do/10.1055/a-0876-6007
}}
{{medline-entry
|title=mTORC1 underlies age-related muscle fiber damage and loss by inducing oxidative stress and catabolism.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30924297
|abstract=Aging leads to skeletal muscle atrophy (i.e., sarcopenia), and muscle fiber loss is a critical component of this process. The mechanisms underlying these age-related changes, however, remain unclear. We show here that mTORC1 signaling is activated in a subset of skeletal muscle fibers in aging mouse and human, colocalized with fiber damage. Activation of mTORC1 in [[TSC1]] knockout mouse muscle fibers increases the content of morphologically abnormal mitochondria and causes progressive oxidative stress, fiber damage, and fiber loss over the lifespan. Transcriptomic profiling reveals that mTORC1's activation increases the expression of growth differentiation factors (GDF3, 5, and 15), and of genes involved in mitochondrial oxidative stress and catabolism. We show that increased [[GDF15]] is sufficient to induce oxidative stress and catabolic changes, and that mTORC1 increases the expression of [[GDF15]] via phosphorylation of [[STAT3]]. Inhibition of mTORC1 in aging mouse decreases the expression of GDFs and [[STAT3]]'s phosphorylation in skeletal muscle, reducing oxidative stress and muscle fiber damage and loss. Thus, chronically increased mTORC1 activity contributes to age-related muscle atrophy, and GDF signaling is a proposed mechanism.
|mesh-terms=* Aging
* Animals
* Cells, Cultured
* Humans
* Mechanistic Target of Rapamycin Complex 1
* Mice
* Mice, Knockout
* Mice, Transgenic
* Muscle Fibers, Skeletal
* Oxidative Stress
* Tuberous Sclerosis Complex 1 Protein
|keywords=* aging
* mTORC1
* oxidative stress
* signal transduction
* skeletal muscle
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516169
}}
{{medline-entry
|title=[Tea polyphenols delays human glomerular mesangial cells senescence induced by high glucose via regulating [[STAT3]]/miR-126/telomere signaling pathway activation].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30717558
|abstract=The aim of this paper was to explore the effects and possible mechanisms in vitro of tea polyphenols (TP) delaying human glomerular mesangial cells (HGMCs) senescence induced by high glucose (HG). HGMCs were cultured in vitro and divided into the normal group (N, 5.5 mmol·L⁻¹ glucose), the mannitol group(MNT, 5.5 mmol·L⁻¹ glucose plus 24.5 mmol·L⁻¹ mannitol), the high dose of D-glucose group (HG, 30 mmol·L⁻¹ glucose), the low dose of TP group (L-TP, 30 mmol·L⁻¹ glucose plus 5 mg·L⁻¹ TP) and the high dose of TP group (H-TP, 30 mmol·L⁻¹ glucose plus 20 mg·L⁻¹ TP), which were cultured in 5% CO₂ at 37 °C, respectively. Firstly, the effects of TP on the cell morphology of HGMCs were observed after 72 h-intervention. Secondly, the cell cycle, the positive rate of senescence-associated-β-galactosidase (SA-β-gal) staining and the telomere length were detected, respectively. Finally, the protein expressions of p53, p21 and Rb in the p53-p21-Rb signaling pathway were investigated, respectively. And the expressions of p-[[STAT3]] and miR-126 were examined severally. The results indicated that HG not only arrested the cell cycle in G₁ phase but also increased the positive rate of SA-β-gal staining, and shortened the telomere length. HG led to the protein over-expressions of p53, p21 and Rb and HGMCs senescence by activating the p53-p21-Rb signaling pathway. In addition, L-TP delayed HGMCs senescence by improving the cell cycle G₁ arrest, reducing SA-β-gal staining positive rate and lengthening the telomere length. L-TP reduced the protein over-expressions of p53, P21 and Rb induced by HG and inhibited the telomere-p53-p21-Rb signaling pathway. Moreover, the expression of p-[[STAT3]] was increased and the expression of miR-126 was decreased in HGMCs induced by HG. L-TP reduced the expression of p-[[STAT3]] and increased the expression of miR-126 in HGMCs. In conclusion, HG could induce HGMCs senescence by activating the telomere-p53-p21-Rb signaling pathway in vitro. L-TP could delay HGMCs senescence through regulating [[STAT3]]/miR-126 expressions and inhibiting the telomere-p53-p21-Rb signaling pathway activation. These findings could provide the effective interventions in clinic for preventing and treating renal cell senescence in diabetic kidney disease.
|mesh-terms=* Cells, Cultured
* Cellular Senescence
* Cyclin-Dependent Kinase Inhibitor p21
* Glucose
* Humans
* Mesangial Cells
* MicroRNAs
* Polyphenols
* STAT3 Transcription Factor
* Tea
* Telomere
* Tumor Suppressor Protein p53
|keywords=*  STAT3 
*  diabetic kidney disease 
*  human glomerular mesangial cells senescence 
*  miR-126 
*  tea polyphenols 
*  telomere 
|full-text-url=https://sci-hub.do/10.19540/j.cnki.cjcmm.20181031.003
}}
{{medline-entry
|title=[[STAT3]] Regulates the Onset of Oxidant-induced Senescence in Lung Fibroblasts.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30608861
|abstract=Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease of unknown cause with a median survival of only 3 years. Other investigators and we have shown that fibroblasts derived from IPF lungs display characteristics of senescent cells, and that dysregulated activation of the transcription factor signal transducer and activator of transcription 3 ([[STAT3]]) correlates with IPF progression. The question of whether [[STAT3]] activation is involved in fibroblast senescence remains unanswered. We hypothesized that inhibiting [[STAT3]] activation after oxidant-induced senescence would attenuate characteristics of the senescent phenotype. We aimed to characterize a model of oxidant-induced senescence in human lung fibroblasts and to determine the effect of inhibiting [[STAT3]] activity on the development of senescence. Exposing human lung fibroblasts to 150 μM hydrogen peroxide (H O ) resulted in increased senescence-associated β-galactosidase content and expression of p21 and IL-6, all of which are features of senescence. The shift into senescence was accompanied by an increase of [[STAT3]] translocation to the nucleus and mitochondria. Additionally, Seahorse analysis provided evidence of increased mitochondrial respiration characterized by increased basal respiration, proton leak, and an associated increase in superoxide (O ) production in senescent fibroblasts. Targeting [[STAT3]] activity using the small-molecule inhibitor STA-21 attenuated IL-6 production, reduced p21 levels, decreased senescence-associated β-galactosidase accumulation, and restored normal mitochondrial function. The results of this study illustrate that stress-induced senescence in lung fibroblasts involves the activation of [[STAT3]], which can be pharmacologically modulated.
|mesh-terms=* Cell Nucleus
* Cell Respiration
* Cellular Senescence
* Fibroblasts
* Humans
* Lung
* Mitochondria
* Oxidants
* Phenotype
* Phosphorylation
* Polycyclic Compounds
* Protein Transport
* STAT3 Transcription Factor
|keywords=* fibroblast
* fibrosis
* mitochondrial dysfunction
* senescence
* signal transducer and activator of transcription 3
|full-text-url=https://sci-hub.do/10.1165/rcmb.2018-0328OC
}}
{{medline-entry
|title=Deciphering Molecular and Phenotypic Changes Associated with Early Autoimmune Disease in the Aire-Deficient Mouse Model of Sjögren's Syndrome.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30453645
|abstract=Sjögren's syndrome (SS) is characterized by extensive lymphocytic infiltration of the salivary and lacrimal gland (LG), resulting in acinar cell destruction and organ dysfunction. The underlying pathogenesis of SS remains largely unknown, and studies historically focus on defining late-stage disease. Here, we identify tissue programs associated with disease onset using transcriptomic and immunohistological analysis of LGs from 5- and 7-week-old mice deficient in autoimmune response element (Aire). At 5 weeks of age (wk), Aire-/- mice show minimal tissue dysfunction and destruction compared to 7 wk Aire-/-, which exhibit severe dry eye, poor tear secretion, extensive lymphocytic infiltration, reduced functional innervation, and increased vascularization. Despite this mild phenotype, 5 wk Aire-/- LGs were highly enriched for signaling pathways previously associated with SS, including interferon gamma (IFNγ), interleukin 1 beta (IL1β), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), toll-like receptor (TLR) signaling, and interleukin-6/signal transducer and activator of transcription 3 (IL6/[[STAT3]]) signaling. Novel signaling pathways such as the semaphorin⁻plexin pathway were also noted. Intriguingly, we found an expansion of the ductal network with increasing disease. Activated [[STAT3]], a blocker of apoptosis, was restricted to the ductal system and also increased with damage, highlighting its potential as a promoter of ductal cell survival. These data demonstrate the early activation of signaling pathways regulating inflammation, innervation, and cell survival before the onset of clinical disease indicators, suggesting their potential value as diagnostic biomarkers.
|mesh-terms=* Aging
* Animals
* Autoimmunity
* Cell Adhesion Molecules
* Denervation
* Disease Models, Animal
* Disease Progression
* Inflammation
* Lacrimal Apparatus
* Mice, Inbred BALB C
* Nerve Tissue Proteins
* Reproducibility of Results
* STAT Transcription Factors
* Semaphorins
* Signal Transduction
* Sjogren's Syndrome
* Transcription Factors
* Up-Regulation
|keywords=* Aire mouse
* Sjögren’s syndrome
* disease progression
* pathway activation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274681
}}
{{medline-entry
|title=Senescent Breast Luminal Cells Promote Carcinogenesis through Interleukin-8-Dependent Activation of Stromal Fibroblasts.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30397077
|abstract=Aging and stress promote senescence, which has intrinsic tumor suppressor functions and extrinsic tumor promoting properties. Therefore, it is of utmost importance to delineate the effects of senescence inducers on the various types of cells that compose the different organs. We show here that primary normal breast luminal (NBL) cells are more sensitive than their corresponding stromal fibroblasts to proliferative as well as oxidative damage-induced senescence. Like fibroblasts, senescent NBL cells secreted elevated amounts of various cytokines, including interleukin-6 (IL-6) and IL-8, and expressed high levels of p16, p21, and p53, while lamin B1 was downregulated. When senescent, luminal cells activated stromal fibroblasts in an IL-8-dependent manner, through the activation of the [[STAT3]] pathway. These myofibroblasts promoted the epithelial-to-mesenchymal transition and the stemness processes in breast cancer cells in a paracrine manner both [i]in vitro[/i] and in a breast cancer animal model. These results show the role of senescent breast luminal cells in promoting the inflammatory/carcinogenic microenvironment through the activation of fibroblasts in an IL-8-dependent manner.
|mesh-terms=* Breast Neoplasms
* Carcinogenesis
* Cell Line, Tumor
* Cell Movement
* Cell Transformation, Neoplastic
* Cellular Senescence
* Epithelial-Mesenchymal Transition
* Female
* Fibroblasts
* Humans
* Interleukin-6
* Interleukin-8
* Myofibroblasts
* Neovascularization, Pathologic
* Primary Cell Culture
* STAT3 Transcription Factor
* Signal Transduction
* Stromal Cells
* Tumor Microenvironment
* Tumor Suppressor Protein p53
|keywords=* IL-8
* breast cancer
* fibroblasts
* luminal cells
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321881
}}
{{medline-entry
|title=The role of [[STAT3]]/mTOR-regulated autophagy in angiotensin II-induced senescence of human glomerular mesangial cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30389500
|abstract=The kidney is one of the fastest-aging organs, and renal senescence has become a major disease affecting human health. Renal cellular senescence is regulated by the joint action of multiple signal transduction pathways. The previous study by our research group found that the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 ([[STAT3]]) pathway was involved in angiotensin II (Ang II)-induced senescence of human glomerular mesangial cells. However, the unique role of [[STAT3]] activation in Ang II-induced senescence of human glomerular mesangial cells and the underlying mechanisms remain unclear. The present study revealed that Ang II induced premature senescence, promoted autophagy and activated oxidative stress responses in human glomerular mesangial cells. Autophagy mediates the senescence-inducing effect of Ang II on human glomerular mesangial cells. Inhibition of oxidative stress with N-acetylcysteine (NAC) or interference with [[STAT3]]/mechanistic target of rapamycin (mTOR) activity with S3I-201 or [[STAT3]]-siRNA suppressed autophagy to a certain extent, which was conducive to delaying the senescence of glomerular mesangial cells. The antioxidant probucol reduced autophagy in human glomerular mesangial cells and alleviated the aging process of these cells by regulating [[STAT3]]/mTOR. These findings identify a role of [[STAT3]]/mTOR-regulated autophagy in Ang II-induced senescence of human glomerular mesangial cells and may provide a theoretical basis for anti-senescence treatment in clinical practice.
|mesh-terms=* Angiotensin II
* Autophagy
* Cell Line
* Cellular Senescence
* Humans
* Mesangial Cells
* STAT3 Transcription Factor
* TOR Serine-Threonine Kinases
|keywords=* Angiotensin II
* Autophagy
* Kidney
* STAT3
* Senescence
* mTOR
|full-text-url=https://sci-hub.do/10.1016/j.cellsig.2018.10.021
}}
{{medline-entry
|title=A Novel [i]Dnmt3a1[/i] Transcript Inhibits Adipogenesis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30333755
|abstract=[i]DNA (cytosine-5)-methyltransferase 3a[/i] ([i]Dnmt3a[/i]) is an enzyme that catalyzes the transfer of methyl groups to specific CpG forms in DNA. In mammals, two variant transcripts of [i]Dnmt3a[/i] have been successfully identified. To the best of our knowledge, no [i]Dnmt3a[/i] transcripts in an avian have been successfully identified. This study was performed to detect different transcripts of [i]Dnmt3a[/i] in chickens and to examine whether a novel [i]Dnmt3a[/i] transcript named [i]Dnmt3a1[/i] may regulate adipogenesis. In addition to cloning, sequencing, transcript detection, and expression studies, a novel [i]Dnmt3a1[/i] transcript overexpression and knockdown were conducted to explore the potential role of [i]Dnmt3a1[/i] in preadipocyte proliferation and the early stage of adipocyte differentiation. In chicken abdominal fat tissue, we detected a novel [i]Dnmt3a1[/i] transcript that differs from [i]Dnmt3a[/i] by lacking 23 amino acids at the exon-1/exon-2 border. [i]Dnmt3a1[/i] mRNA was ubiquitously expressed in a variety of tissues or cells and highly expressed in chicken adipose tissue/cells. The expression of [i]Dnmt3a1[/i] was regulated under different physiological conditions including aging, fasting, and high-fat diet. In addition, overexpression of [i]Dnmt3a1[/i] significantly decreased preadipocyte proliferation and induced cell-cycle arrest while its inhibition increased cell proliferation and S-phase cells. Furthermore, the overexpression of [i]Dnmt3a1[/i] significantly upregulated the mRNA level of cell-cycle-related genes, such as [i][[CDKN1A]][/i], [i][[CDKN1B]][/i], [i]CCNB3[/i], [i]CCND2[/i], [i][[CCNG2]][/i], [i]CDKN2B[/i], and [i]CDK9[/i], or the protein level of [[CDKN1A]], [[CDKN1B]], and [[CCNG2]]. Conversely, the knockdown of [i]Dnmt3a1[/i] by siRNA had the opposite effects. Moreover, during early adipocyte differentiation, the overexpression of [i]Dnmt3a1[/i] significantly decreased the mRNA and the protein levels of PPAR-γ, C/EBP-α, [[ADIPOR1]], and [[STAT3]], and the mRNA levels of [i]FAS[/i], [i]LEPR[/i], [i]LPL[/i], [i]PRKAB2[/i], and [i]ATGL.[/i] In contrast, their expression was significantly increased after the knockdown of [i]Dnmt3a1[/i]. Taken together, we identified a novel transcript of [i]Dnmt3a[/i], and it played a potential role in adipogenesis.

|keywords=* Dnmt3a
* Dnmt3a1 transcript
* aging
* early differentiation
* expression
* high-fat diet
* preadipocytes proliferation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6176318
}}
{{medline-entry
|title=Targeting a phospho-[[STAT3]]-miRNAs pathway improves vesicular hepatic steatosis in an in vitro and in vivo model.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30206377
|abstract=Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease. Although genetic predisposition and epigenetic factors contribute to the development of NAFLD, our understanding of the molecular mechanism involved in the pathogenesis of the disease is still emerging. Here we investigated a possible role of a microRNAs-[[STAT3]] pathway in the induction of hepatic steatosis. Differentiated HepaRG cells treated with the fatty acid sodium oleate (fatty dHepaRG) recapitulated features of liver vesicular steatosis and activated a cell-autonomous inflammatory response, inducing [[STAT3]]-Tyrosine-phosphorylation. With a genome-wide approach (Chromatin Immunoprecipitation Sequencing), many phospho-[[STAT3]] binding sites were identified in fatty dHepaRG cells and several [[STAT3]] and/or NAFLD-regulated microRNAs showed increased expression levels, including miR-21. Innovative CARS (Coherent Anti-Stokes Raman Scattering) microscopy revealed that chemical inhibition of [[STAT3]] activity decreased lipid accumulation and deregulated [[STAT3]]-responsive microRNAs, including miR-21, in lipid overloaded dHepaRG cells. We were able to show in vivo that reducing phospho-[[STAT3]]-miR-21 levels in C57/BL6 mice liver, by long-term treatment with metformin, protected mice from aging-dependent hepatic vesicular steatosis. Our results identified a microRNAs-phospho[[STAT3]] pathway involved in the development of hepatic steatosis, which may represent a molecular marker for both diagnosis and therapeutic targeting.
|mesh-terms=* Aging
* Animals
* Cell Line, Tumor
* Disease Models, Animal
* Fatty Liver
* Genome-Wide Association Study
* Lipid Metabolism
* Metformin
* Mice
* MicroRNAs
* Nonlinear Optical Microscopy
* Phosphorylation
* STAT3 Transcription Factor

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134080
}}
{{medline-entry
|title=Decreased NAD Activates [[STAT3]] and Integrin Pathways to Drive Epithelial-Mesenchymal Transition.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29980616
|abstract=Nicotinamide adenine dinucleotide (NAD) plays an essential role in all aspects of human life. NAD levels decrease as humans age, and supplementation with NAD precursors plays a protective role against aging and associated disease. Less is known about the effects of decreased NAD on cellular processes, which is the basis for understanding the relationship between cellular NAD levels and aging-associated disease. In the present study, cellular NAD levels were decreased by overexpression of [[CD38]], a NAD hydrolase, or by treating cells with FK866, an inhibitor of nicotinamide phosphoribosyltransferase (NAMPT). Quantitative proteomics revealed that declining NAD levels downregulated proteins associated with primary metabolism and suppressed cell growth in culture and nude mice. Decreased glutathione synthesis caused a 4-fold increase in cellular reactive oxygen species levels, and more importantly upregulated proteins related to movement and adhesion. In turn, this significantly changed cell morphology and caused cells to undergo epithelial to mesenchymal transition (EMT). Secretomic analysis also showed that decreased NAD triggered interleukin-6 and transforming growth factor beta (TGFβ) secretion, which activated integrin-β-catenin, TGFβ-MAPK, and inflammation signaling pathways to sustain the signaling required for EMT. We further revealed that decreased NAD inactivated sirtuin 1, resulting in increased signal transducer and activator of transcription 3 ([[STAT3]]) acetylation and phosphorylation, and [[STAT3]] activation. Repletion of nicotinamide or nicotinic acid inactivated [[STAT3]] and reversed EMT, as did [[STAT3]] inhibition. Taken together, these results indicate that decreased NAD activates multiple signaling pathways to promote EMT and suggests that age-dependent decreases in NAD may contribute to tumor progression. Consequently, repletion of NAD precursors has potential benefits for inhibiting cancer progression.
|mesh-terms=* ADP-ribosyl Cyclase 1
* Acrylamides
* Animals
* Cell Line
* Cell Proliferation
* Epithelial-Mesenchymal Transition
* Female
* Humans
* Integrins
* Mice, Nude
* NAD
* Oxidative Stress
* Piperidines
* Proteome
* Proteomics
* Reactive Oxygen Species
* STAT3 Transcription Factor
* Signal Transduction
|keywords=* Aging
* Cell adhesion
* Epithelial-Mesenchymal Transition
* Lung cancer
* Omics
* Phosphoproteome
* SILAC
* Secretome
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166677
}}
{{medline-entry
|title=Integrative Analysis of Hippocampus Gene Expression Profiles Identifies Network Alterations in Aging and Alzheimer's Disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29875655
|abstract=Alzheimer's disease (AD) is a neurodegenerative disorder contributing to rapid decline in cognitive function and ultimately dementia. Most cases of AD occur in elderly and later years. There is a growing need for understanding the relationship between aging and AD to identify shared and unique hallmarks associated with the disease in a region and cell-type specific manner. Although genomic studies on AD have been performed extensively, the molecular mechanism of disease progression is still not clear. The major objective of our study is to obtain a higher-order network-level understanding of aging and AD, and their relationship using the hippocampal gene expression profiles of young (20-50 years), aging (70-99 years), and AD (70-99 years). The hippocampus is vulnerable to damage at early stages of AD and altered neurogenesis in the hippocampus is linked to the onset of AD. We combined the weighted gene co-expression network and weighted protein-protein interaction network-level approaches to study the transition from young to aging to AD. The network analysis revealed the organization of co-expression network into functional modules that are cell-type specific in aging and AD. We found that modules associated with astrocytes, endothelial cells and microglial cells are upregulated and significantly correlate with both aging and AD. The modules associated with neurons, mitochondria and endoplasmic reticulum are downregulated and significantly correlate with AD than aging. The oligodendrocytes module does not show significant correlation with neither aging nor disease. Further, we identified aging- and AD-specific interactions/subnetworks by integrating the gene expression with a human protein-protein interaction network. We found dysregulation of genes encoding protein kinases (FYN, [[SYK]], [[SRC]], PKC, [[MAPK1]], ephrin receptors) and transcription factors (FOS, [[STAT3]], [[CEBPB]], [[MYC]], NFKβ, and EGR1) in AD. Further, we found genes that encode proteins with neuroprotective function (14-3-3 proteins, [[PIN1]], [[ATXN1]], [[BDNF]], VEGFA) to be part of the downregulated AD subnetwork. Our study highlights that simultaneously analyzing aging and AD will help to understand the pre-clinical and clinical phase of AD and aid in developing the treatment strategies.

|keywords=* PPI network
* aging
* co-expression network
* glial cells
* graph theory
* hippocampus
* neurodegenerative disease
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5974201
}}
{{medline-entry
|title=Overexpression of Klotho Inhibits HELF Fibroblasts SASP-related Protumoral Effects on Non-small Cell Lung Cancer Cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29675106
|abstract=Lung cancer (LC) is the most common cause of death from cancer worldwide, and it is also a closely aging-related disease. Klotho, a new anti-aging gene, has been proven to play a critical role in regulating aging and the development of age-related diseases including LC. However, whether Klotho is a key link between aging and LC is still unknown. Here we report that Klotho can indirectly inhibit LC growth and development through regulating senescence-associated secretory phenotype (SASP). We found that senescent lung fibroblasts (SLF) can promote production of IL-6 and IL-8, which can be effectively inhibited by overexpressing Klotho. Using conditioned medium (CM) derived from SLF to culture LC cells, the LC cells show obvious increase of viability and migration rates, significant increase expression of p-[[STAT3]] and α-SMA, and decrease expression of P53 and E-cadherin. However, using CM derived from SLF overexpressed Klotho to culture LC cells, all above results are nearly completely reversed. Thus, these results suggest that Klotho can regulate SLF extracellular release of IL-6 and IL-8, which can influence [[STAT3]] activation, P53 expression and epithelial-mesenchymal transition (EMT) of LC cells, finally inhibiting LC cells growth and migration indirectly.

|keywords=* IL-6
* Klotho
* cellular senescence
* lung cancer
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5907673
}}
{{medline-entry
|title=Fibroblast senescence in the pathology of idiopathic pulmonary fibrosis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29696986
|abstract=Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing interstitial pneumonia of unknown cause with a median survival of only three years. Little is known about the mechanisms that precede the excessive collagen deposition seen in IPF, but cellular senescence has been strongly implicated in disease pathology. Senescence is a state of irreversible cell-cycle arrest accompanied by an abnormal secretory profile and is thought to play a critical role in both development and wound repair. Normally, once a senescent cell has contributed to wound repair, it is promptly removed from the environment via infiltrating immune cells. However, if immune clearance fails, the persistence of senescent cells is thought to drive disease pathology through their altered secretory profile. One of the major cell types involved in wound healing is fibroblasts, and senescent fibroblasts have been identified in the lungs of patients with IPF and in fibroblast cultures from IPF lungs. The question of what is driving abnormally high numbers of fibroblasts into senescence remains unanswered. The transcription factor signal transducer and activator of transcription 3 ([[STAT3]]) plays a role in a myriad of processes, including cell-cycle progression, gene transcription, as well as mitochondrial respiration, all of which are dysregulated during senescence. Activation of [[STAT3]] has previously been shown to correlate with IPF progression and therefore is a potential molecular target to modify early-stage senescence and restore normal fibroblast function. This review summarizes what is presently known about fibroblast senescence in IPF and how [[STAT3]] may contribute to this phenotype.
|mesh-terms=* Animals
* Cellular Senescence
* Fibroblasts
* Gene Expression Regulation
* Humans
* Idiopathic Pulmonary Fibrosis
* Lung
* Signal Transduction
|keywords=* fibroblast senescence
* idiopathic pulmonary fibrosis
* signal transducer and activator of transcription 3
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6139657
}}
{{medline-entry
|title=Age-Associated Differences in Infection of Human Skin in the SCID Mouse Model of Varicella-Zoster Virus Pathogenesis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29563288
|abstract=Varicella-zoster virus (VZV) is the skin-tropic human alphaherpesvirus responsible for both varicella-zoster and herpes zoster. Varicella-zoster and herpes zoster skin lesions have similar morphologies, but herpes zoster occurs disproportionally in older individuals and is often associated with a more extensive local rash and severe zoster-related neuralgia. We hypothesized that skin aging could also influence the outcome of the anterograde axonal transport of VZV to skin. We utilized human skin xenografts maintained in immunodeficient (SCID) mice to study VZV-induced skin pathology [i]in vivo[/i] in fetal and adult skin xenografts. Here we found that VZV replication is enhanced in skin from older compared to younger adults, correlating with clinical observations. In addition to measures of VZV infection, we examined the expression of type I interferon (IFN) pathway components in adult skin and investigated elements of the cutaneous proliferative and inflammatory response to VZV infection [i]in vivo[/i] Our results demonstrated that VZV infection of adult skin triggers intrinsic IFN-mediated responses such as we have described in VZV-infected fetal skin xenografts, including MxA as well as promyelocytic leukemia protein (PML), in skin cells surrounding lesions. Further, we observed that VZV elicited altered cell signaling and proliferative and inflammatory responses that are involved in wound healing, driven by follicular stem cells. These cellular changes are consistent with VZV-induced activation of [[STAT3]] and suggest that VZV exploits the wound healing process to ensure efficient delivery of the virus to keratinocytes. Adult skin xenografts offer an approach to further investigate VZV-induced skin pathologies [i]in vivo[/i]  Varicella-zoster virus (VZV) is the agent responsible for both varicella-zoster and herpes zoster. Herpes zoster occurs disproportionally in older individuals and is often associated with a more extensive local rash and severe zoster-related neuralgia. To examine the effect of skin aging on VZV skin lesions, we utilized fetal and adult human skin xenografts maintained in immunodeficient (SCID) mice. We measured VZV-induced skin pathology, examined the expression of type I interferon (IFN) pathway components in adult skin, and investigated elements of the cutaneous proliferative and inflammatory response to VZV infection [i]in vivo[/i] Our results demonstrate that characteristics of aging skin are preserved in xenografts; that VZV replication is enhanced in skin from older compared to younger adults, correlating with clinical observations; and that VZV infection elicits altered cell signaling and inflammatory responses. Adult skin xenografts offer an approach to further investigate VZV-induced skin pathologies [i]in vivo[/i].
|mesh-terms=* Adult
* Age Factors
* Aged
* Aging
* Animals
* Disease Models, Animal
* Enzyme Activation
* Herpesvirus 3, Human
* Humans
* Mice
* Mice, Inbred C57BL
* Mice, Inbred NOD
* Mice, SCID
* Middle Aged
* Promyelocytic Leukemia Protein
* STAT3 Transcription Factor
* Skin
* Skin Diseases
* Skin Transplantation
* Transplantation, Heterologous
* Varicella Zoster Virus Infection
* Virus Replication
* Wound Healing
|keywords=* STAT3
* interferons
* skin
* transmission
* varicella-zoster virus
* viral pathogenesis
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5952162
}}
{{medline-entry
|title=[[MMP2]]-[[A2M]] interaction increases ECM accumulation in aged rat kidney and its modulation by calorie restriction.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29464020
|abstract=Age-associated renal fibrosis is related with renal function decline during aging. Imbalance between accumulation and degradation of extracellular matrix is key feature of fibrosis. In this study, RNA-sequencing (RNA-Seq) results based on next-generation sequencing (NGS) data were analyzed to identify key proteins that change during aging and calorie restriction (CR). Among the changed genes, [[A2M]] and [[MMP2]], which are known to interact, exhibited the highest between centrality (BC) and degree values when analyzed by protein-protein interaction (PPI). Both mRNA and protein levels of [[MMP2]] and [[A2M]] were increased during aging. Furthermore, the interaction between [[MMP2]] and [[A2M]] was verified by immunoprecipitation and immunohistochemistry. [[MMP2]] activity was further measured under the presence or absence of [[A2M]]-[[MMP2]] interaction. [[MMP2]] activity, which was increased under the absence of [[A2M]]-[[MMP2]] interaction, was significantly decreased under the presence of interactions in aged kidney. We further hypothesized that the interaction between [[A2M]]-[[MMP2]] played a role in the inactivation of [[MMP2]] leading to accumulation of ECM including collagen type I and IV. Aged kidney showed highly accumulated [[MMP2]] substrate proteins despite of increased [[MMP2]] protein expression and CR blunted these accumulation. Additional [i]in vivo[/i] analysis revealed that the signal transducer and activator of transcription (STAT) 3 transcriptional factor was significantly increased thus increasing [[A2M]] expression during aging. [[STAT3]] activating cytokines were also highly increased in aged kidney. In conclusion, the results of the present study indicate that [[A2M]]-[[MMP2]] interaction has a role in age-associated renal ECM accumulation and in the suppression such fibrosis by CR.

|keywords=* A2M
* Aging
* Gerotarget
* MMP2
* extracellular matrix
* renal fibrosis
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5814160
}}
{{medline-entry
|title=Deficiency in Protein Tyrosine Phosphatase PTP1B Shortens Lifespan and Leads to Development of Acute Leukemia.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29122767
|abstract=Protein tyrosine phosphatase PTP1B is a critical regulator of signaling pathways controlling metabolic homeostasis, cell proliferation, and immunity. In this study, we report that global or myeloid-specific deficiency of PTP1B in mice decreases lifespan. We demonstrate that myeloid-specific deficiency of PTP1B is sufficient to promote the development of acute myeloid leukemia. LysM-PTP1B  mice lacking PTP1B in the innate myeloid cell lineage displayed a dysregulation of bone marrow cells with a rapid decline in population at midlife and a concomitant increase in peripheral blood blast cells. This phenotype manifested further with extramedullary tumors, hepatic macrophage infiltration, and metabolic reprogramming, suggesting increased hepatic lipid metabolism prior to overt tumor development. Mechanistic investigations revealed an increase in anti-inflammatory M2 macrophage responses in liver and spleen, as associated with increased expression of arginase I and the cytokines [[IL10]] and [[IL4]]. We also documented [[STAT3]] hypersphosphorylation and signaling along with JAK-dependent upregulation of antiapoptotic proteins Bcl2 and BclXL. Our results establish a tumor suppressor role for PTP1B in the myeloid lineage cells, with evidence that its genetic inactivation in mice is sufficient to drive acute myeloid leukemia.  This study defines a tumor suppressor function for the protein tyrosine phosphatase PTP1B in myeloid lineage cells, with evidence that its genetic inactivation in mice is sufficient to drive acute myeloid leukemia. [i]Cancer Res; 78(1); 75-87. ©2017 AACR[/i].
|mesh-terms=* Animals
* Cytokines
* Female
* Leukemia, Myeloid, Acute
* Liver
* Longevity
* Macrophages
* Male
* Mice, Knockout
* Myeloid Cells
* Protein Tyrosine Phosphatase, Non-Receptor Type 1
* Proto-Oncogene Proteins c-bcl-2
* Pyrazoles
* STAT3 Transcription Factor
* STAT5 Transcription Factor
* Spleen
* bcl-X Protein

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5756472
}}
{{medline-entry
|title=Chronic disruptions of circadian sleep regulation induce specific proinflammatory responses in the rat colon.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29039977
|abstract=Exposure to environmental conditions that disturb the daily rhythms has been shown to enhance the proinflammatory responses of immunostimulant-challenged immune system. However, it is not known whether circadian disturbances may stimulate unchallenged immune responses and thus contribute per se to the development of inflammation-related diseases. Our aim was to ascertain an effect of various conditions threatening the behavioral activity/rest cycle regulation, namely aging with or without melatonin, 6 h advance/delay phase shifts in the light/dark cycle repeated with a 2-day frequency and constant light, on expression of immune markers in the rat colon. The impact of these conditions on parameters of behavioral activity and mRNA levels of selected immune markers in the colonic mucosa of Wistar rats, namely TNFα (Tnf), IL1a (Il1a), [[IL17RA]] (Il17ra), [[STAT3]] (Stat3) and Rgs16 (Rsg16), were detected. Our results demonstrate that aging with or without melatonin as well as repeated 6 h advance/delay phase shifts in the light/dark cycle, which increased inactivity as a correlate of sleep during the dark phase of the light/dark cycle (i.e. during the active phase for nocturnal animals), had a minor effect on immune state in the colonic mucosa; all these conditions caused downregulation of gene Rgs16 which is involved in attenuation of the inflammatory response in the colon but did not affect expression of the other immune markers. Interestingly, a long-term absence of melatonin facilitated the aging-induced effect on immune state in the colon. In contrast, exposure to constant light, which perturbed the interval of inactivity (sleep) and led to the complete abolishment of activity/inactivity cycles, activated robustly proinflammatory state in the colon selectively via Stat3-dependent pathway. In spite all these experimental conditions (aging with or without melatonin, shifts in light/dark cycles, constant light) perturbed the activity/rest cycles, none of them induced sleep deprivation. These results provided the first evidence that disruptions in the behavioral activity/inactivity cycles may spontaneously (without immuno-stimulant) induce selective proinflammatory responses in the colonic mucosa. Such effects may take part in the mechanisms of modern lifestyle-induced inflammatory diseases of the gut. B2M: β2-microglobulin; DSS: dextran sodium sulfate; Gapdh: glyceraldehyde-3-phosphate dehydrogenase; Ifng: interferon g; Il1a: interleukin 1a; Il1b: interleukin 1b; Il2: interleukin 2; Il6: interleukin 6; Il17ra: interleukin 17 receptor a; LD: light/dark cycle; LL: constant light; LPS: lipopolysaccharide; Mntr1a: melatonin receptor 1a; PINX: pinealectomy; Rgs16: regulator of G protein signaling 16; RT qPCR: quantitative reverse transcription polymerase chain reaction; Stat3: signal transducer and activator of transcription 3; Th17: type 17 T helper cells; Tnfα: tumor necrosis factor α; Tnfrsf1b: tumor necrosis factor receptor superfamily member 1b.
|mesh-terms=* Activity Cycles
* Animals
* Circadian Rhythm
* Colon
* Light
* Melatonin
* Motor Activity
* Photoperiod
* Rats, Wistar
* Sleep
* Sleep Deprivation
* Time Factors
|keywords=* Aging
* Rgs16
* colon
* constant light
* melatonin
* proinflammatory cytokine
* sleep disruption
|full-text-url=https://sci-hub.do/10.1080/07420528.2017.1361436
}}
{{medline-entry
|title=Genome-wide association study and annotating candidate gene networks affecting age at first calving in Nellore cattle.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28994157
|abstract=We performed a genome-wide mapping for the age at first calving (AFC) with the goal of annotating candidate genes that regulate fertility in Nellore cattle. Phenotypic data from 762 cows and 777k SNP genotypes from 2,992 bulls and cows were used. Single nucleotide polymorphism (SNP) effects based on the single-step GBLUP methodology were blocked into adjacent windows of 1 Megabase (Mb) to explain the genetic variance. SNP windows explaining more than 0.40% of the AFC genetic variance were identified on chromosomes 2, 8, 9, 14, 16 and 17. From these windows, we identified 123 coding protein genes that were used to build gene networks. From the association study and derived gene networks, putative candidate genes (e.g., [[PAPPA]], [[PREP]], [[FER1L6]], [[TPR]], [[NMNAT1]], [[ACAD10]], [[PCMTD1]], [[CRH]], OPKR1, [[NPBWR1]] and NCOA2) and transcription factors (TF) (STAT1, [[STAT3]], [[RELA]], [[E2F1]] and EGR1) were strongly associated with female fertility (e.g., negative regulation of luteinizing hormone secretion, folliculogenesis and establishment of uterine receptivity). Evidence suggests that AFC inheritance is complex and controlled by multiple loci across the genome. As several windows explaining higher proportion of the genetic variance were identified on chromosome 14, further studies investigating the interaction across haplotypes to better understand the molecular architecture behind AFC in Nellore cattle should be undertaken.
|mesh-terms=* Aging
* Animals
* Breeding
* Cattle
* Female
* Fertility
* Gene Regulatory Networks
* Genome-Wide Association Study
* Genotype
* Phenotype
* Polymorphism, Single Nucleotide
* Quantitative Trait Loci
|keywords=* beef cattle
* gene function
* single-step
|full-text-url=https://sci-hub.do/10.1111/jbg.12299
}}
{{medline-entry
|title=The pathological roles of [[NDRG2]] in Alzheimer's disease, a study using animal models and APPwt-overexpressed cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28670853
|abstract=To investigate the roles of N-myc downstream-regulated gene 2 ([[NDRG2]]) in the pathology of aging and neurodegenerative disease such as Alzheimer's disease (AD). In this study, we confirmed the upregulation of [[NDRG2]] in the brains of aging and AD animal models. To explore the role of [[NDRG2]] in the pathology of AD at molecular level, we conducted a cell-based assay of highly expressed wild-type human APP695 SK-N-SH cells (SK-N-SH APPwt). By silencing and overexpressing gene of [[NDRG2]], we demonstrated that [[NDRG2]]-mediated increase in Aβ  was through the pathways of [[BACE1]] and [[GGA3]]. NGRG2 improved tau phosphorylation via enhanced activity of [[CDK5]] and decreased Pin1, but it was not affected by GSK3β pathway. [[NDRG2]] might also induce cell apoptosis through the extrinsic (caspase 8) apoptotic pathway by interaction with [[STAT3]]. Our study confirmed the upregulation of [[NDRG2]] in AD animal models and demonstrated its important roles in AD pathology. [[NDRG2]] might be a potential target for studying and treatment of AD.
|mesh-terms=* Adaptor Proteins, Signal Transducing
* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Animals
* Apoptosis
* Brain
* Cell Line, Tumor
* Cell Survival
* Disease Models, Animal
* Humans
* Male
* Mice, Inbred ICR
* Mice, Transgenic
* Nerve Tissue Proteins
* Peptide Fragments
* Presenilin-1
* Proteins
* Rats, Sprague-Dawley
* Tumor Suppressor Proteins
|keywords=* Alzheimer's disease
* NDRG2
* apoptosis
* beta-amyloid
* tau phosphorylation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492714
}}
{{medline-entry
|title=Maintenance of membrane organization in the aging mouse brain as the determining factor for preventing receptor dysfunction and for improving response to anti-Alzheimer treatments.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28347928
|abstract=Although a major risk factor for Alzheimer's disease (AD), the "aging" parameter is not systematically considered in preclinical validation of anti-AD drugs. To explore how aging affects neuronal reactivity to anti-AD agents, the ciliary neurotrophic factor ([[CNTF]])-associated pathway was chosen as a model. Comparison of the neuroprotective properties of [[CNTF]] in 6- and 18-month old mice revealed that [[CNTF]] resistance in the older animals is associated with the exclusion of the [[CNTF]]-receptor subunits from rafts and their subsequent dispersion to non-raft cortical membrane domains. This age-dependent membrane remodeling prevented both the formation of active [[CNTF]]-receptor complexes and the activation of prosurvival [[STAT3]] and ERK1/2 pathways, demonstrating that age-altered membranes impaired the reactivity of potential therapeutic targets. [[CNTF]]-receptor distribution and [[CNTF]] signaling responses were improved in older mice receiving dietary docosahexaenoic acid, with [[CNTF]]-receptor functionality being similar to those of younger mice, pointing toward dietary intervention as a promising adjuvant strategy to maintain functional neuronal membranes, thus allowing the associated receptors to respond appropriately to anti-AD agents.
|mesh-terms=* Aging
* Animals
* Brain
* Cell Membrane
* Ciliary Neurotrophic Factor
* Dietary Fats, Unsaturated
* Docosahexaenoic Acids
* MAP Kinase Signaling System
* Male
* Membrane Microdomains
* Mice, Inbred C57BL
* Neurons
* Nootropic Agents
* Receptor, Ciliary Neurotrophic Factor
* STAT3 Transcription Factor
* Signal Transduction
|keywords=* Brain aging
* Ciliary neurotrophic factor
* Dietary lipids
* Docosahexaenoic acid
* Lipid rafts
* Neuronal membranes
|full-text-url=https://sci-hub.do/10.1016/j.neurobiolaging.2017.02.015
}}
{{medline-entry
|title=JAK-STAT signaling mediates the senescence of bone marrow-mesenchymal stem cells from systemic lupus erythematosus patients.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28177455
|abstract=Previous studies have revealed that bone marrow-mesenchymal stem cells (BM-MSCs) from systemic lupus erythematosus (SLE) patients exhibited early signs of senescence, which may participate in the development of SLE. However, the molecular mechanisms about this phenomenon have not been fully elucidated. In the current study, we aimed to investigate whether Janus kinase (JAK)-signaling transducers and activators of transcription (STAT) signaling mediated the senescence of BM-MSCs from SLE patients. Twelve female SLE patients and healthy subjects were enrolled in the study. All BM-MSCs were isolated by density gradient centrifugation. Western blot analysis was used to test the expression of JAK-STAT signaling molecules. We observed the activity of β-gal of cells, the changes of cytoskeletal structure by F-actin staining, and the distribution of cell cycle by flow cytometry. BM-MSCs from SLE patients showed prominent features of senescence, and abnormal activation of JAK-STAT signaling transduction, high level of phosphorylated [[JAK2]], and [[STAT3]]. After stimulation of IFN-γ in normal MSCs, JAK-STAT signaling was activated. The cell volume and the number of senescence-associated β-galactosidase (SA-β-gal) positive in SLE BM-MSCs were increased. The organization of cytoskeleton was nearly disordered. The rate of cell proliferation was decreased. AG490, the inhibitor of [[JAK2]], and knockdown of [[STAT3]] in BM-MSCs, could significantly reverse the senescence. In summary, our study indicated that JAK-STAT signaling pathway may play a critical role in the senescence of SLE BM-MSCs.
|mesh-terms=* Adolescent
* Adult
* Bone Marrow
* Case-Control Studies
* Cell Proliferation
* Cells, Cultured
* Cellular Senescence
* Female
* Humans
* Janus Kinase 2
* Lupus Erythematosus, Systemic
* Male
* Mesenchymal Stem Cells
* Phosphorylation
* STAT3 Transcription Factor
* Signal Transduction
* Young Adult
|keywords=* IFN-γ
* JAK-STAT signaling
* mesenchymal stem cells
* senescence
* systemic lupus erythematosus
|full-text-url=https://sci-hub.do/10.1093/abbs/gmw134
}}
{{medline-entry
|title=Hypothalamic S1P/[[S1PR1]] axis controls energy homeostasis in Middle-Aged Rodents: the reversal effects of physical exercise.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28039439
|abstract=Recently, we demonstrated that the hypothalamic [[S1PR1]]/[[STAT3]] axis plays a critical role in the control of food consumption and energy expenditure in rodents. Here, we found that reduction of hypothalamic [[S1PR1]] expression occurs in an age-dependent manner, and was associated with defective thermogenic signaling and weight gain. To address the physiological relevance of these findings, we investigated the effects of chronic and acute exercise on the hypothalamic [[S1PR1]]/[[STAT3]] axis. Chronic exercise increased [[S1PR1]] expression and [[STAT3]] phosphorylation in the hypothalamus, restoring the anorexigenic and thermogenic signals in middle-aged mice. Acutely, exercise increased sphingosine-1-phosphate (S1P) levels in the cerebrospinal fluid (CSF) of young rats, whereas the administration of CSF from exercised young rats into the hypothalamus of middle-aged rats at rest was sufficient to reduce the food intake. Finally, the intracerebroventricular (ICV) administration of [[S1PR1]] activators, including the bioactive lipid molecule S1P, and pharmacological [[S1PR1]] activator, SEW2871, induced a potent [[STAT3]] phosphorylation and anorexigenic response in middle-aged rats. Overall, these results suggest that hypothalamic [[S1PR1]] is important for the maintenance of energy balance and provide new insights into the mechanism by which exercise controls the anorexigenic and thermogenic signals in the central nervous system during the aging process.
|mesh-terms=* Absorptiometry, Photon
* Adipose Tissue, Brown
* Aging
* Animals
* Energy Metabolism
* Homeostasis
* Hypothalamus
* Interleukin-6
* Lysophospholipids
* Male
* Mice
* Oxygen Consumption
* Physical Conditioning, Animal
* Rats
* Rats, Wistar
* Receptors, Lysosphingolipid
* Signal Transduction
* Sphingosine
* Sphingosine-1-Phosphate Receptors
* Uncoupling Protein 1
|keywords=* S1PR1/STAT3
* aging
* exercise
* hypothalamus
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5310661
}}
{{medline-entry
|title=Intracerebroventricular tempol administration in older rats reduces oxidative stress in the hypothalamus but does not change [[STAT3]] signalling or [[SIRT1]]/AMPK pathway.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28006433
|abstract=Hypothalamic inflammation and increased oxidative stress are believed to be mechanisms that contribute to obesity. 4-Hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (tempol), a free radical scavenger, has been shown to reduce inflammation and oxidative stress. We hypothesized that brain infusion of tempol would reduce oxidative stress, and thus would reduce food intake and body weight and improve body composition in rats with age-related obesity and known elevated oxidative stress. Furthermore, we predicted an associated increase in markers of leptin signalling, including the silent mating type information regulator 2 homolog 1 ([[SIRT1]])/5'AMP-activated protein kinase (AMPK) pathway and the signal transducer and activator of transcription 3 ([[STAT3]]) pathway. For this purpose, osmotic minipumps were placed in the intracerebroventricular region of young (3 months) and aged (23 months) male Fischer 344 x Brown Norway rats for the continuous infusion of tempol or vehicle for 2 weeks. Tempol significantly decreased (p < 0.01) nicotinamide adenine dinucleotide phosphate oxidase activity in the hypothalamus but failed to reduce food intake or weight gain and did not alter body composition. [[SIRT1]] activity and Acetyl p53 were decreased and phosphorylation of AMPK was increased with age, but they were unchanged with tempol. Basal phosphorylation of [[STAT3]] was unchanged with age or tempol. These results indicate that tempol decreases oxidative stress but fails to alter feeding behaviour, body weight, or body composition. Moreover, tempol does not modulate the [[SIRT1]]/AMPK/p53 pathway and does not change leptin signalling. Thus, a reduction in hypothalamic oxidative stress is not sufficient to reverse age-related obesity.
|mesh-terms=* AMP-Activated Protein Kinases
* Aging
* Animals
* Cognitive Dysfunction
* Crosses, Genetic
* Cyclic N-Oxides
* Energy Intake
* Free Radical Scavengers
* Hypothalamus
* Infusion Pumps, Implantable
* Infusions, Intraventricular
* Male
* Nerve Tissue Proteins
* Neurons
* Nootropic Agents
* Obesity
* Oxidative Stress
* Rats, Inbred BN
* Rats, Inbred F344
* STAT3 Transcription Factor
* Signal Transduction
* Sirtuin 1
* Spin Labels
|keywords=* AMPK
* FOXO
* SIRT1
* STAT3
* aging
* brain
* cerveau
* hypothalamus
* intracerebroventricular (icv)
* intracerebroventricular (« icv »)
* leptin
* leptine
* obesity
* obésité
* oxidative stress
* p53
* stress oxydatif
* tempol
* vieillissement
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5522741
}}
{{medline-entry
|title=[[STAT3]]-mediated [[SMAD3]] activation underlies Oncostatin M-induced Senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27892764
|abstract=Cytokines in the developing tumor microenvironment (TME) can drive transformation and subsequent progression toward metastasis. Elevated levels of the Interleukin-6 (IL-6) family cytokine Oncostatin M ([[OSM]]) in the breast TME correlate with aggressive, metastatic cancers, increased tumor recurrence, and poor patient prognosis. Paradoxically, [[OSM]] engages a tumor-suppressive, Signal Transducer and Activator of Transcription 3 ([[STAT3]])-dependent senescence response in normal and non-transformed human mammary epithelial cells (HMEC). Here, we identify a novel link between [[OSM]]-activated [[STAT3]] signaling and the Transforming Growth Factor-β (TGF-β) signaling pathway that engages senescence in HMEC. Inhibition of functional TGF-β/SMAD signaling by expressing a dominant-negative TGF-β receptor, treating with a TGF-β receptor inhibitor, or suppressing [[SMAD3]] expression using a [[SMAD3]]-shRNA prevented [[OSM]]-induced senescence. [[OSM]] promoted a protein complex involving activated-[[STAT3]] and [[SMAD3]], induced the nuclear localization of [[SMAD3]], and enhanced [[SMAD3]]-mediated transcription responsible for senescence. In contrast, expression of [[MYC]] (c-[[MYC]]) from a constitutive promoter abrogated senescence and strikingly, cooperated with [[OSM]] to promote a transformed phenotype, epithelial-mesenchymal transition (EMT), and invasiveness. Our findings suggest that a novel [[STAT3]]/[[SMAD3]]-signaling axis is required for [[OSM]]-mediated senescence that is coopted during the transformation process to confer aggressive cancer cell properties. Understanding how developing cancer cells bypass [[OSM]]/[[STAT3]]/[[SMAD3]]-mediated senescence may help identify novel targets for future "pro-senescence" therapies aiming to reengage this hidden tumor-suppressive response.
|mesh-terms=* Cell Nucleus
* Cellular Senescence
* Epithelial Cells
* Epithelial-Mesenchymal Transition
* Humans
* Mammary Glands, Human
* Models, Biological
* Neoplasm Invasiveness
* Oncostatin M
* Phosphorylation
* Protein Transport
* Proto-Oncogene Proteins c-myc
* Receptors, Transforming Growth Factor beta
* STAT3 Transcription Factor
* Signal Transduction
* Smad3 Protein
* Smad4 Protein
* Transcription, Genetic
|keywords=* MYC
* Oncostatin M
* SMAD3
* STAT3
* cytokine
* epithelial-mesenchymal transition
* human mammary epithelial cells
* invasion
* senescence
* transforming growth factor-β
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5324753
}}
{{medline-entry
|title=Impaired Epidermal to Dendritic T Cell Signaling Slows Wound Repair in Aged Skin.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27863246
|abstract=Aged skin heals wounds poorly, increasing susceptibility to infections. Restoring homeostasis after wounding requires the coordinated actions of epidermal and immune cells. Here we find that both intrinsic defects and communication with immune cells are impaired in aged keratinocytes, diminishing their efficiency in restoring the skin barrier after wounding. At the wound-edge, aged keratinocytes display reduced proliferation and migration. They also exhibit a dampened ability to transcriptionally activate epithelial-immune crosstalk regulators, including a failure to properly activate/maintain dendritic epithelial T cells (DETCs), which promote re-epithelialization following injury. Probing mechanism, we find that aged keratinocytes near the wound edge don't efficiently upregulate Skints or activate [[STAT3]]. Notably, when epidermal Stat3, Skints, or DETCs are silenced in young skin, re-epithelialization following wounding is perturbed. These findings underscore epithelial-immune crosstalk perturbations in general, and Skints in particular, as critical mediators in the age-related decline in wound-repair.
|mesh-terms=* Aging
* Animals
* Interleukin-6
* Keratinocytes
* Lymphocyte Subsets
* Mice
* Signal Transduction
* Skin
* Skin Physiological Phenomena
* Wound Healing
|keywords=* Aging
* DETC
* STAT3
* Skint
* epidermal-immune cell cross-talk
* re-epithelialization
* wound healing
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5364946
}}
{{medline-entry
|title=Aging amplifies multiple phenotypic defects in mice with zinc transporter Zip14 (Slc39a14) deletion.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27647172
|abstract=Inflammation and zinc dyshomeostasis are two common hallmarks of aging. A major zinc transporter ZIP14 (slc39a14) is upregulated by proinflammatory stimuli, e.g. interleukin-6. We have evaluated the influence of age on the Zip14 KO phenotype using wild-type (WT) and Zip14 knockout (KO) mice. Aging produced a major increase in serum IL-6 concentrations that was dramatically augmented in the Zip14 KO mice. In keeping with enhanced serum IL-6 concentrations, aging produced tissue-specific increases in zinc concentration of skeletal muscle and white adipose tissue. Metabolic endotoxemia produced by Zip14 ablation is maintained in aged KO mice. Muscle non-heme iron (NHI) was increased in aged WT mice but not in aged Zip14 KO mice demonstrating NHI uptake by muscle is ZIP14-dependent and increases with age. NF-κB and [[STAT3]] activation was greater in aged mice, but was tissue specific and inversely related to tissue zinc. Micro-CT analysis revealed that Zip14 KO mice had markedly reduced trabecular bone that was greatly amplified with aging. These results demonstrate that the inflammation-responsive zinc transporter ZIP14 has phenotypic effects that are amplified with aging.
|mesh-terms=* Adipose Tissue, White
* Aging
* Animals
* Cancellous Bone
* Cation Transport Proteins
* Gene Deletion
* Inflammation
* Interleukin-6
* Liver
* Male
* Mice
* Mice, Inbred C57BL
* Mice, Knockout
* Muscle, Skeletal
* NF-kappa B
* STAT3 Transcription Factor
* Signal Transduction
* Up-Regulation
* Zinc
|keywords=* Bone
* Growth
* Inflammation
* Interleukin-6
* Sarcopenia
* Signaling pathways
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5101137
}}
{{medline-entry
|title=The role of STAT transcription factors in apoptosis regulation of hypothalamic neurons in aging in HER-2/neu transgenic mice and wild-type FVB/N mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27417725
|abstract=For the firsts time, the involvement of the STAT pathway in the regulation of neuronal apoptosis in physiological aging and in old mice overexpressing the HER-2/neu oncogene was studied. We showed that suppression of [[STAT3]], STAT5, and [[STAT6]] and overexpression of the proapoptotic factor [[STAT1]], which provides p53-mediated apoptosis, are the causes for increasing the number of apoptotic neurons in physiological aging. HER-2 tyrosine kinase receptor overexpression promotes neuronal survival through activation of STAT-signaling pathway with simultaneous suppression of the proapoptotic factor [[STAT1]]. 
|mesh-terms=* Aging
* Analysis of Variance
* Animals
* Apoptosis
* Blotting, Western
* Caspase 3
* Cell Survival
* Female
* Gene Expression
* Hypothalamus
* In Situ Nick-End Labeling
* Mice, Transgenic
* Neurons
* Receptor, ErbB-2
* STAT Transcription Factors
* Tumor Suppressor Protein p53

|full-text-url=https://sci-hub.do/10.1134/S1607672916030169
}}
{{medline-entry
|title=Exogenous H2S contributes to recovery of ischemic post-conditioning-induced cardioprotection by decrease of ROS level via down-regulation of NF-κB and [[JAK2]]-[[STAT3]] pathways in the aging cardiomyocytes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27096074
|abstract=Hydrogen sulfide (H2S), a third member of gasotransmitter family along with nitric oxide and carbon monoxide, generated from mainly catalyzed by cystathionine-lyase, possesses important functions in the cardiovascular system. Ischemic post-conditioning ([[PC]]) strongly protects against the hypoxia/reoxygenation (H/R)-induced injury and apoptosis of cardiomyocytes. However, [[PC]] protection is ineffective in the aging cardiomyocytes. Whether H2S restores [[PC]]-induced cardioprotection by decrease of reactive oxygen species (ROS) level in the aging cardiomyocytes is unknown. The aging cardiomyocytes were induced by treatment of primary cultures of neonatal cardiomyocytes using d-galactose and were exposed to H/R and [[PC]] protocols. Cell viability was observed by [[CCK]]-8 kit. Apoptosis was detected by Hoechst 33342 staining and flow cytometry. ROS level was analyzed using spectrofluorimeter. Related protein expressions were detected through Western blot. Treatment of NaHS (a H2S donor) protected against H/R-induced apoptosis, cell damage, the expression of cleaved caspase-3 and cleaved caspase-9, the release of cytochrome c (Cyt c). The supplementation of NaHS also decreased the activity of LDH and CK, MDA contents, ROS levels and the phosphorylation of IκBα, NF-κB, JNK2 and [[STAT3]], and increased cell viability, the expression of Bcl-2, the activity of SOD, [[CAT]] and GSH-PX. [[PC]] alone did not provide cardioprotection in H/R-treated aging cardiomyocytes, which was significantly restored by the addition of NaHS. The beneficial role of NaHS was similar to the supply of N-acetyl-cysteine (NAC, an inhibitor of ROS), Ammonium pyrrolidinedithiocarbamate (PDTC, an inhibitor of NF-κB) and AG 490 (an inhibitor of JNK2), respectively, during [[PC]]. Our results suggest that exogenous H2S contributes to recovery of [[PC]]-induced cardioprotection by decrease of ROS level via down-regulation of NF-κB and [[JAK2]]/[[STAT3]] pathways in the aging cardiomyocytes.

|keywords=* Aging cardiomyocytes
* Hydrogen sulfide
* Oxidative stress
* Post-conditioning
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4836181
}}
{{medline-entry
|title=Enhanced Transcriptional Activity and Mitochondrial Localization of [[STAT3]] Co-induce Axon Regrowth in the Adult Central Nervous System.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27050520
|abstract=Signal transducer and activator of transcription 3 ([[STAT3]]) is a transcription factor central to axon regrowth with an enigmatic ability to act in different subcellular regions independently of its transcriptional roles. However, its roles in mature CNS neurons remain unclear. Here, we show that along with nuclear translocation, [[STAT3]] translocates to mitochondria in mature CNS neurons upon cytokine stimulation. Loss- and gain-of-function studies using knockout mice and viral expression of various [[STAT3]] mutants demonstrate that [[STAT3]]'s transcriptional function is indispensable for CNS axon regrowth, whereas mitochondrial [[STAT3]] enhances bioenergetics and further potentiates regrowth. [[STAT3]]'s localization, functions, and growth-promoting effects are regulated by mitogen-activated protein kinase kinase (MEK), an effect further enhanced by Pten deletion, leading to extensive axon regrowth in the mouse optic pathway and spinal cord. These results highlight CNS neuronal dependence on [[STAT3]] transcriptional activity, with mitochondrial [[STAT3]] providing ancillary roles, and illustrate a critical contribution for MEK in enhancing diverse [[STAT3]] functions and axon regrowth. 
|mesh-terms=* Adenosine Triphosphate
* Aging
* Animals
* Axons
* Central Nervous System
* Ciliary Neurotrophic Factor
* Electron Transport
* Female
* Gene Deletion
* Male
* Mice, Inbred C57BL
* Mitochondria
* Mitogen-Activated Protein Kinase Kinases
* Nerve Regeneration
* PTEN Phosphohydrolase
* Phosphorylation
* Phosphoserine
* Protein Domains
* Protein Transport
* Pyramidal Tracts
* Retinal Ganglion Cells
* STAT3 Transcription Factor
* Structure-Activity Relationship
* Subcellular Fractions
* Transcription, Genetic

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833545
}}
{{medline-entry
|title=The Inflammatory Transcription Factors NFκB, [[STAT1]] and [[STAT3]] Drive Age-Associated Transcriptional Changes in the Human Kidney.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26678048
|abstract=Human kidney function declines with age, accompanied by stereotyped changes in gene expression and histopathology, but the mechanisms underlying these changes are largely unknown. To identify potential regulators of kidney aging, we compared age-associated transcriptional changes in the human kidney with genome-wide maps of transcription factor occupancy from ChIP-seq datasets in human cells. The strongest candidates were the inflammation-associated transcription factors NFκB, [[STAT1]] and [[STAT3]], the activities of which increase with age in epithelial compartments of the renal cortex. Stimulation of renal tubular epithelial cells with the inflammatory cytokines IL-6 (a [[STAT3]] activator), IFNγ (a [[STAT1]] activator), or TNFα (an NFκB activator) recapitulated age-associated gene expression changes. We show that common DNA variants in [[RELA]] and [[NFKB1]], the two genes encoding subunits of the NFκB transcription factor, associate with kidney function and chronic kidney disease in gene association studies, providing the first evidence that genetic variation in NFκB contributes to renal aging phenotypes. Our results suggest that NFκB, [[STAT1]] and [[STAT3]] underlie transcriptional changes and chronic inflammation in the aging human kidney. 
|mesh-terms=* Aging
* Genetic Association Studies
* Humans
* Inflammation
* Interferon-gamma
* Interleukin-6
* NF-kappa B
* NF-kappa B p50 Subunit
* Renal Insufficiency, Chronic
* STAT1 Transcription Factor
* STAT3 Transcription Factor
* Transcription Factor RelA
* Transcription, Genetic
* Tumor Necrosis Factor-alpha

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4682820
}}
{{medline-entry
|title=[Epidermal aging and anti-aging strategies].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26636143
|abstract=Epithelial senescence is a complex process depending on intrinsic as well as extrinsic factors (e.g., UV or IR light, tobacco smoke) and must be seen in the context of the aging process especially of the corium and the subcutis. Morphological alterations become apparent in the form of epithelial atrophy, structural changes within the basal membrane, and a decrease in cell count of melanocytes and Langerhans cells. Signs of cellular senescence are reduced proliferation of keratinocytes, cumulation of dysplastic keratinocytes, various mutations (e.g., c-Fos/c-Jun, [[STAT3]], FoxO1), as well as multiple lipid or amino acid metabolic aberrations (e.g., production of advanced glycation endproducts). This causes functional changes within the physical (lipid deficiency, water distribution dysfunction, lack of hygroscopic substances), chemical (pH conditions, oxygen radicals), and immunological barrier. Prophylactically, barrier-protective care products, antioxidant substances (e.g., vitamin C, B3, E, polyphenols, flavonoids), sunscreen products/measurements, and retinoids are used. For correcting alterations in aged epidermis, chemical peelings (fruit acids, β-hydroxy acid, trichloroacetic acid, phenolic compounds), non-ablative (IPL, PDL, Nd:YAG) as well as ablative (CO2, Erbium-YAG) light-assisted methods are used.
|mesh-terms=* Aging
* Dermatologic Agents
* Epidermis
* Evidence-Based Medicine
* Female
* Humans
* Male
* Skin Absorption
* Skin Aging
|keywords=* Epidermis
* Geriatrics
* Peeling
* Senescence
* Sunscreen
|full-text-url=https://sci-hub.do/10.1007/s00105-015-3734-6
}}
{{medline-entry
|title=Seipin knockout in mice impairs stem cell proliferation and progenitor cell differentiation in the adult hippocampal dentate gyrus via reduced levels of PPARγ.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26398946
|abstract=The seipin gene (BSCL2) was originally identified in humans as a loss-of-function gene associated with congenital generalized lipodystrophy type 2 (CGL2). Neuronal seipin-knockout (seipin-nKO) mice display a depression-like phenotype with a reduced level of hippocampal peroxisome proliferator-activated receptor gamma (PPARγ). The present study investigated the influence of seipin deficiency on adult neurogenesis in the hippocampal dentate gyrus (DG) and the underlying mechanisms of the effects. We show that the proliferative capability of stem cells in seipin-nKO mice was substantially reduced compared to in wild-type (WT) mice, and that this could be rescued by the PPARγ agonist rosiglitazone (rosi). In seipin-nKO mice, neuronal differentiation of progenitor cells was inhibited, with the enhancement of astrogliogenesis; both of these effects were recovered by rosi treatment during early stages of progenitor cell differentiation. In addition, rosi treatment could correct the decline in hippocampal ERK2 phosphorylation and cyclin A mRNA level in seipin-nKO mice. The MEK inhibitor U0126 abolished the rosi-rescued cell proliferation and cyclin A expression in seipin-nKO mice. In seipin-nKO mice, the hippocampal Wnt3 protein level was less than that in WT mice, and there was a reduction of neurogenin 1 (Neurog1) and neurogenic differentiation 1 (NeuroD1) mRNA, levels of which were corrected by rosi treatment. [[STAT3]] phosphorylation (Tyr705) was enhanced in seipin-nKO mice, and was further elevated by rosi treatment. Finally, rosi treatment for 10 days could alleviate the depression-like phenotype in seipin-nKO mice, and this alleviation was blocked by the MEK inhibitor U0126. The results indicate that, by reducing PPARγ, seipin deficiency impairs proliferation and differentiation of neural stem and progenitor cells, respectively, in the adult DG, which might be responsible for the production of the depression-like phenotype in seipin-nKO mice.
|mesh-terms=* Aging
* Animals
* Cell Differentiation
* Cell Proliferation
* Cyclin A
* Dentate Gyrus
* Enzyme Activation
* Extracellular Signal-Regulated MAP Kinases
* Female
* GTP-Binding Protein gamma Subunits
* Heterotrimeric GTP-Binding Proteins
* Male
* Mice, Knockout
* Models, Biological
* Neural Stem Cells
* Neurogenesis
* Neurons
* PPAR gamma
* Phenotype
* Phosphorylation
* Signal Transduction
* Wnt3 Protein
|keywords=* BSCL2
* Cell proliferation
* Differentiation of progenitor cells
* Neurogenesis
* Peroxisome proliferator-activated receptor gamma (PPARγ)
* Seipin
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728316
}}
{{medline-entry
|title=[[IL10]]-driven [[STAT3]] signalling in senescent macrophages promotes pathological eye angiogenesis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26260587
|abstract=Macrophage dysfunction plays a pivotal role during neovascular proliferation in diseases of ageing including cancers, atherosclerosis and blinding eye disease. In the eye, choroidal neovascularization (CNV) causes blindness in patients with age-related macular degeneration (AMD). Here we report that increased [[IL10]], not [[IL4]] or [[IL13]], in senescent eyes activates [[STAT3]] signalling that induces the alternative activation of macrophages and vascular proliferation. Targeted inhibition of both [[IL10]] receptor-mediated signalling and [[STAT3]] activation in macrophages reverses the ageing phenotype. In addition, adoptive transfer of [[STAT3]]-deficient macrophages into eyes of old mice significantly reduces the amount of CNV. Systemic and CD163( ) eye macrophages obtained from AMD patients also demonstrate [[STAT3]] activation. Our studies demonstrate that impaired [[SOCS3]] feedback leads to permissive [[IL10]]/[[STAT3]] signalling that promotes alternative macrophage activation and pathological neovascularization. These findings have significant implications for our understanding of the pathobiology of age-associated diseases and may guide targeted immunotherapy. 
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Animals
* Eye
* Female
* Humans
* Interleukin-10
* Macrophages
* Macular Degeneration
* Male
* Mice
* Mice, Inbred C57BL
* Middle Aged
* Neovascularization, Pathologic
* Porphyrins
* RAW 264.7 Cells
* Receptors, Interleukin-10
* STAT3 Transcription Factor
* Suppressor of Cytokine Signaling 3 Protein
* Suppressor of Cytokine Signaling Proteins

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4918330
}}
{{medline-entry
|title=Down-regulation of mir-542-3p promotes neointimal formation in the aging rat.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26026397
|abstract=To explore mir-542-3p mediated inhibition of vascular smooth muscle cell (VSMC) proliferation through the inhibition of Syk activation. MicroRNA (mir)-542-3p was selected for analysis based on miRNA microarray and qRT-PCR results. In vitro mir-542-3p expression was significantly downregulated in old (o)VSMCs compared with young (y)VSMCs under serum stimulation conditions. Upregulation of mir-542-3p in oVSMCs significantly inhibited VSMC proliferation, whereas downregulation of mir-542-3p in yVSMCs increased VSMC proliferation. We identified spleen tyrosine kinase (Syk) as a direct target of mir-542-3p by database search, and showed that its expression and phosphorylation were higher in oVSMCs than in yVSMCs after serum stimulation. Luciferase assays confirmed that Syk is a direct target of miR-3542-3p. Knock-down of mir-542-3p in yVSMCs inhibited the activation of the Syk downstream effectors [[STAT3]] and STAT5, whereas mir-542-3p overexpression enhanced [[STAT3]] and STAT5 activities. In a rat balloon injury model, mir-542-3p inhibited neointima formation and proliferating cell nuclear antigen (PCNA) protein expression. Mir-542-3p modulates VSMC proliferation via the Syk/[[STAT3]]-STAT5 axis. Downregulation of mir-542-3p may explain age-related neointimal hyperplasia in rats.
|mesh-terms=* Aging
* Animals
* Cell Proliferation
* Down-Regulation
* Male
* MicroRNAs
* Muscle, Smooth, Vascular
* Myocytes, Smooth Muscle
* Neointima
* Phosphorylation
* Rats
* Rats, Sprague-Dawley
* Signal Transduction
* Up-Regulation
|keywords=* Aging
* MicroRNA
* Proliferation
* Syk
* Vascular smooth muscle cells
|full-text-url=https://sci-hub.do/10.1016/j.vph.2015.05.010
}}
{{medline-entry
|title=CD4⁺[[CD28]]null T lymphocytes resemble CD8⁺[[CD28]]null T lymphocytes in their responses to IL-15 and IL-21 in HIV-infected patients.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26034206
|abstract=HIV-infected individuals suffer from accelerated immunologic aging. One of the most prominent changes during T lymphocyte aging is the accumulation of [[CD28]](null) T lymphocytes, mainly CD8( ) but also CD4( ) T lymphocytes. Enhancing the functional properties of these cells may be important because they provide antigen-specific defense against chronic infections. The objective of this study was to compare the responses of CD4( )[[CD28]](null) and CD8( )[[CD28]](null) T lymphocytes from HIV-infected patients to the immunomodulatory effects of cytokines IL-15 and IL-21. We quantified the frequencies of CD4( )[[CD28]](null) and CD8( )[[CD28]](null) T lymphocytes in peripheral blood from 110 consecutive, HIV-infected patients and 25 healthy controls. Patients showed increased frequencies of CD4( )[[CD28]](null) and CD8( )[[CD28]](null). Both subsets were positively correlated to each other and showed an inverse correlation with the absolute counts of CD4( ) T lymphocytes. Higher frequencies of HIV-specific and CMV-specific cells were found in [[CD28]](null) than in [[CD28]]( ) T lymphocytes. Activation of STAT5 by IL-15 and [[STAT3]] by IL-21 was higher in [[CD28]](null) compared with [[CD28]]( ) T lymphocytes. Proliferation, expression of [[CD69]], and IFN-γ production in [[CD28]](null) T lymphocytes were increased after treatment with IL-15, and IL-21 potentiated most of those effects. Nevertheless, IL-21 alone reduced IFN-γ production in response to anti-CD3 stimulation but increased [[CD28]] expression, even counteracting the inhibitory effect of IL-15. Intracytoplasmic stores of granzyme B and perforin were increased by IL-15, whereas IL-21 and simultaneous treatment with the 2 cytokines also significantly enhanced degranulation in CD4( )[[CD28]](null) and CD8( )[[CD28]](null) T lymphocytes. IL-15 and IL-21 could have a role in enhancing the effector response of [[CD28]](null) T lymphocytes against their specific chronic antigens in HIV-infected patients. 
|mesh-terms=* Adult
* Antigens, CD
* Antigens, Differentiation, T-Lymphocyte
* CD28 Antigens
* CD4-Positive T-Lymphocytes
* CD8-Positive T-Lymphocytes
* Cell Degranulation
* Cell Proliferation
* Cohort Studies
* Demography
* Female
* Granzymes
* HIV Antigens
* HIV Infections
* Humans
* Interferon-gamma
* Interleukin-15
* Interleukins
* Lectins, C-Type
* Male
* Middle Aged
* Perforin
* STAT3 Transcription Factor
* STAT5 Transcription Factor
* Tumor Suppressor Proteins
* Up-Regulation
* Young Adult
|keywords=* T lymphocyte differentiation
* cytotoxicity
* immunosenescence
|full-text-url=https://sci-hub.do/10.1189/jlb.1A0514-276RR
}}
{{medline-entry
|title=Constitutive [[STAT3]] activation in epidermal keratinocytes enhances cell clonogenicity and favours spontaneous immortalization by opposing differentiation and senescence checkpoints.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25382846
|abstract=[[STAT3]], a pleiotropic transcription factor acting downstream of cytokines and growth factors, is known to enhance proliferation, migration, invasion and aerobic glycolysis in tumors upon aberrant activation. In the murine epidermis, [[STAT3]] is necessary for experimentally induced carcinogenesis. Skin tumorigenesis is conversely enhanced by overexpression in keratinocytes of the constitutively active [[STAT3]]C mutant, which also induces robust, psoriasis-like epidermal hyperplasia. We show here that [[STAT3]]C expression at physiological levels in knock-in mice leads to mild epidermal hyperplasia and attenuated expression of terminal differentiation markers. Altered differentiation is confirmed in isolated primary epidermal keratinocytes in vitro, correlating with enhanced proliferative and clonogenic potential, attenuated senescence and, strikingly, high-frequency spontaneous immortalization. These results suggest that moderate levels of continuous [[STAT3]] activation, which closely resemble those triggered by chronic inflammation or persistent growth factor stimulation, may establish a preneoplastic state in part by promoting the escape of epidermal progenitor cells from differentiation and senescence checkpoints. 
|mesh-terms=* Animals
* Animals, Newborn
* Cell Differentiation
* Cell Movement
* Cell Proliferation
* Cellular Senescence
* Epidermal Cells
* Glycolysis
* Hyperplasia
* Keratinocytes
* Mice
* Mice, Transgenic
* Real-Time Polymerase Chain Reaction
* STAT3 Transcription Factor
* Skin
* Skin Aging
* Stem Cells
* beta-Galactosidase
|keywords=* STAT3
* differentiation
* immortalization
* keratinocytes
* senescence
|full-text-url=https://sci-hub.do/10.1111/exd.12585
}}
{{medline-entry
|title=[[STAT3]] signaling controls satellite cell expansion and skeletal muscle repair.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25194572
|abstract=The progressive loss of muscle regenerative capacity with age or disease results in part from a decline in the number and function of satellite cells, the direct cellular contributors to muscle repair. However, little is known about the molecular effectors underlying satellite cell impairment and depletion. Elevated levels of inflammatory cytokines, including interleukin-6 (IL-6), are associated with both age-related and muscle-wasting conditions. The levels of [[STAT3]], a downstream effector of IL-6, are also elevated with muscle wasting, and [[STAT3]] has been implicated in the regulation of self-renewal and stem cell fate in several tissues. Here we show that IL-6-activated Stat3 signaling regulates satellite cell behavior, promoting myogenic lineage progression through myogenic differentiation 1 (Myod1) regulation. Conditional ablation of Stat3 in Pax7-expressing satellite cells resulted in their increased expansion during regeneration, but compromised myogenic differentiation prevented the contribution of these cells to regenerating myofibers. In contrast, transient Stat3 inhibition promoted satellite cell expansion and enhanced tissue repair in both aged and dystrophic muscle. The effects of [[STAT3]] inhibition on cell fate and proliferation were conserved in human myoblasts. The results of this study indicate that pharmacological manipulation of [[STAT3]] activity can be used to counteract the functional exhaustion of satellite cells in pathological conditions, thereby maintaining the endogenous regenerative response and ameliorating muscle-wasting diseases. 
|mesh-terms=* Aging
* Animals
* Cell Proliferation
* Cells, Cultured
* Humans
* Male
* Mice
* Mice, Inbred C57BL
* Mice, Inbred mdx
* Mice, Knockout
* Muscle Development
* MyoD Protein
* PAX7 Transcription Factor
* Regeneration
* STAT3 Transcription Factor
* Satellite Cells, Skeletal Muscle
* Signal Transduction

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4332844
}}
{{medline-entry
|title=Aging impairs transcriptional regulation of vascular endothelial growth factor in human microvascular endothelial cells: implications for angiogenesis and cell survival.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24781730
|abstract=In some tissues, aging impairs angiogenesis and reduces expression of vascular endothelial growth factor A (VEGF), a fundamental regulator of angiogenesis. We previously examined angiogenesis in aging and young gastric mucosa in vivo and in vitro and showed that an imbalance between expressions of VEGF (pro-angiogenic factor) and endostatin (anti-angiogenic protein) results in an aging-related impairment of angiogenesis in rats. However, the human relevance of these findings, and whether these mechanisms apply to endothelial cells derived from other tissues, is not clear. Since P-[[STAT3]] and P-CREB are transcription factors that, in association with HIF-1α, can activate VEGF gene expression in some cells (e.g., liver cancer cells, vascular smooth muscle cells), we examined the expression of these two proteins in human dermal microvascular endothelial cells (HMVECs) derived from aging and neonatal individuals. We examined and quantified in vitro angiogenesis, expression of VEGF, P-[[STAT3]], P-CREB and importin-α in HMVECs isolated from neonates (neonatal) and a 66 year old subject (aging). We also examined the effects of treatment with exogenous VEGF and endostatin on in vitro angiogenesis in these cells. Endothelial cells isolated from aging individuals had impaired angiogenesis (vs. neonatal endothelial cells) and reduced expression of VEGF mRNA and protein. Aged HMVECs also had reduced importin-α expression, and reduced expression and nuclear translocation of P-[[STAT3]] and P-CREB. Reduced VEGF gene expression in aged HMVECs strongly correlated with the decreased levels of P-[[STAT3]], P-CREB and importin-α in these cells. Our study clearly demonstrates that endothelial cells from aging individuals have impaired angiogenesis and reduced expression of VEGF likely due to impaired nuclear transport of P-[[STAT3]] and P-CREB transcription factors in these cells. 
|mesh-terms=* Aged
* Aging
* Cells, Cultured
* Cyclic AMP Response Element-Binding Protein
* Endothelial Cells
* Humans
* Infant, Newborn
* Microvessels
* Neovascularization, Physiologic
* STAT3 Transcription Factor
* Transcription, Genetic
* Vascular Endothelial Growth Factor A
* alpha Karyopherins


}}
{{medline-entry
|title=Gene expression profiling of Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly reveals alterations of characteristic oncogenetic pathways.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24581222
|abstract=Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) of the elderly (EBV[ ]DLBCL-E) is classified as a subtype of DLBCL. Until now, its molecular pathogenesis has remained unknown. To identify pathways characteristic of EBV( )DLBCL-E, gene expression profiling of five EBV( )DLBCL-E and seven EBV-negative DLBCL (EBV[-]DLBCL) cases was undertaken using human oligonucleotide microarray analysis. Gene set enrichment analysis and gene ontology analysis showed that gene sets of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) and nuclear factor kappa B (NF-κB) pathways were enriched in EBV( )DLBCL-E cases. To confirm the results of the expression profiles, in vitro analysis was performed. Expression profiling analysis showed that high activation of the JAK-STAT and NF-κB pathways was induced by EBV infection into DLBCL cell lines. Activation of the NF-κB pathway was confirmed in EBV-infected cell lines using an electrophoretic mobility shift assay. Western blot analysis revealed an increased protein expression level of phosphorylated signal transducer and activator of transcription 3 ([[STAT3]]) in an EBV-infected cell line. Protein expression of phosphorylated [[STAT3]] was frequently observed in lymphoma cells of EBV( )DLBCL-E clinical samples using immunohistochemistry (EBV[ ]DLBCL-E: 80.0% [n = 20/25] versus EBV[-]DLBCL: 38.9% [n = 14/36]; P = 0.001). The results of the present study suggest that activation of the JAK-STAT and NF-κB pathways was characteristic of EBV( )DLBCL-E, which may reflect the nature of EBV-positive tumor cells. Targeting these pathways as therapies might improve clinical outcomes of EBV( )DLBCL-E.
|mesh-terms=* Adult
* Aged
* Aging
* Biomarkers, Tumor
* Electrophoretic Mobility Shift Assay
* Enzyme Activation
* Epstein-Barr Virus Infections
* Female
* Gene Expression Profiling
* Herpesvirus 4, Human
* Humans
* Janus Kinases
* Lymphoma, Large B-Cell, Diffuse
* Male
* Middle Aged
* NF-kappa B
* Oligonucleotide Array Sequence Analysis
* STAT3 Transcription Factor
|keywords=* Epstein-Barr virus
* NF-κB
* STAT3
* gene expression profiling
* lymphoma
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4317839
}}
{{medline-entry
|title=[[STAT3]] and metabolism: how many ways to use a single molecule?
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24500994
|abstract=The transcription factor Signal Transducer and Activator of Transcription (STAT)3 has been considered as a potential anticancer target since its first description as an oncogene in 1999, recently leading to [[STAT3]] inhibitors been brought to clinical trial for the treatment of solid tumors. However, the past 14 years of intense basic research have uncovered novel [[STAT3]]-mediated pathways that could affect the outcome of the designed therapies while at the same time help designing function-specific inhibitors. Particularly intriguing are the recent findings that suggest profound implications of [[STAT3]] with the regulation of cellular metabolism in both canonical, that is transcriptional, and non-canonical ways. Here, after a short description of the main known features of [[STAT3]] signaling and function, we review the recent literature on the role of [[STAT3]] in regulating cellular metabolism and discuss the potential consequences on the therapeutic approaches currently under clinical experimentation. 
|mesh-terms=* Animals
* Antineoplastic Agents
* Gene Expression Regulation, Neoplastic
* Humans
* Neoplasms
* STAT3 Transcription Factor
|keywords=* STAT3
* aging
* cancer
* clinical trial
* inhibitor
* metabolism
|full-text-url=https://sci-hub.do/10.1002/ijc.28767
}}
{{medline-entry
|title=Differential loss of prolyl isomerase or chaperone activity of Ran-binding protein 2 (Ranbp2) unveils distinct physiological roles of its cyclophilin domain in proteostasis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24403063
|abstract=The immunophilins, cyclophilins, catalyze peptidyl cis-trans prolyl-isomerization (PPIase), a rate-limiting step in protein folding and a conformational switch in protein function. Cyclophilins are also chaperones. Noncatalytic mutations affecting the only cyclophilins with known but distinct physiological substrates, the Drosophila NinaA and its mammalian homolog, cyclophilin-B, impair opsin biogenesis and cause osteogenesis imperfecta, respectively. However, the physiological roles and substrates of most cyclophilins remain unknown. It is also unclear if PPIase and chaperone activities reflect distinct cyclophilin properties. To elucidate the physiological idiosyncrasy stemming from potential cyclophilin functions, we generated mice lacking endogenous Ran-binding protein-2 (Ranbp2) and expressing bacterial artificial chromosomes of Ranbp2 with impaired C-terminal chaperone and with (Tg-Ranbp2(WT-HA)) or without PPIase activities (Tg-Ranbp2(R2944A-HA)). The transgenic lines exhibit unique effects in proteostasis. Either line presents selective deficits in M-opsin biogenesis with its accumulation and aggregation in cone photoreceptors but without proteostatic impairment of two novel Ranbp2 cyclophilin partners, the cytokine-responsive effectors, [[STAT3]]/STAT5. Stress-induced [[STAT3]] activation is also unaffected in Tg-Ranbp2(R2944A-HA)::Ranbp2(-/-). Conversely, proteomic analyses found that the multisystem proteinopathy/amyotrophic lateral sclerosis proteins, heterogeneous nuclear ribonucleoproteins A2/B1, are down-regulated post-transcriptionally only in Tg-Ranbp2(R2944A-HA)::Ranbp2(-/-). This is accompanied by the age- and tissue-dependent reductions of diubiquitin and ubiquitylated proteins, increased deubiquitylation activity, and accumulation of the 26 S proteasome subunits S1 and S5b. These manifestations are absent in another line, Tg-Ranbp2(CLDm-HA)::Ranbp2(-/-), harboring SUMO-1 and S1-binding mutations in the Ranbp2 cyclophilin-like domain. These results unveil distinct mechanistic and biological links between PPIase and chaperone activities of Ranbp2 cyclophilin toward proteostasis of selective substrates and with novel therapeutic potential. 
|mesh-terms=* Aging
* Animals
* Biocatalysis
* Down-Regulation
* Evoked Potentials, Visual
* GTPase-Activating Proteins
* HeLa Cells
* Heterogeneous-Nuclear Ribonucleoprotein Group A-B
* Histone Deacetylases
* Humans
* Mice
* Molecular Chaperones
* Mutant Proteins
* Mutation
* Nuclear Pore Complex Proteins
* Opsins
* Organ Specificity
* Peptidylprolyl Isomerase
* Protein Folding
* Protein Structure, Quaternary
* Protein Structure, Tertiary
* Protein Transport
* Retinal Cone Photoreceptor Cells
* STAT Transcription Factors
* Small Ubiquitin-Related Modifier Proteins
* Structure-Activity Relationship
* Ubiquitin
|keywords=* Chaperone Chaperonin
* Enzymes
* Proteasome
* Protein Misfolding
* Ubiquitination
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3931022
}}
{{medline-entry
|title=IL-6-[[STAT3]] signaling and premature senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24416650
|abstract=Cytokines play several roles in developing and/or reinforcing premature cellular senescence of young cells. One such cytokine, interleukin-6 (IL-6), regulates senescence in some systems in addition to its known functions of immune regulation and promotion of tumorigenesis. In this review, we describe recent advances in studies on the roles of IL-6 and its downstream signal transducer and activator of transcription 3 ([[STAT3]]) in regulating premature cellular senescence. IL-6/sIL-6Rα stimulation forms a senescence-inducing circuit involving the [[STAT3]]-insulin-like growth factor-binding protein 5 (IGFBP5) as a key axis triggering and reinforcing component in human fibroblasts. We describe how cytokines regulate the process of senescence by activating [[STAT3]] in one system and anti-senescence or tumorigenesis in other systems. The roles of other STAT members in premature senescence also will be discussed to show the multiple mechanisms leading to cytokine-induced senescence. 

|keywords=* IGFBP5
* STAT3
* cellular senescence
* cytokine
* interleukin-6
* tumorigenesis
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3876432
}}
{{medline-entry
|title=From cirrhosis to hepatocellular carcinoma: new molecular insights on inflammation and cellular senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24400224
|abstract=Sequential progression from chronic liver disease to fibrosis and to cirrhosis culminates in neoplasia in hepatocellular carcinoma (HCC). The preneoplastic setting of the cirrhotic background provides a conducive environment for cellular transformation. The role of classical inflammation in cirrhosis is widely known, but the exact mechanism linking inflammation and cancer remains elusive. Recent studies have elucidated roles for NF-κB, [[STAT3]] and JNK as possible missing links. In addition, the "inflammasome" (a multiprotein complex and sensor of cellular damage) is a recently identified player in this field. The hallmarks of cirrhosis include necroinflammation, deposition of extracellular matrix and shortening of telomeres, leading to senescence and regeneration. Additionally, the accumulation of genetic/epigenetic changes propels atypical cells toward a malignant phenotype. This review provides recent information on the classical inflammatory pathway, together with a spotlight on inflammasomes and the immunomodulatory role of cellular senescence during the progression from cirrhosis to HCC. Moreover, lacunae in the current knowledge were identified and key questions raised on whether the observed adaptive responses are beneficial or detrimental to tissue homeostasis in a complex organ like liver. 

|keywords=* Cellular senescence
* Cirrhosis
* Genetic/Epigenetic landscape
* Hepatocellular carcinoma
* Inflammasomes
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3881319
}}
{{medline-entry
|title=Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24367114
|abstract=Females have generally more robust immune responses than males for reasons that are not well-understood. Here we used a systems analysis to investigate these differences by analyzing the neutralizing antibody response to a trivalent inactivated seasonal influenza vaccine (TIV) and a large number of immune system components, including serum cytokines and chemokines, blood cell subset frequencies, genome-wide gene expression, and cellular responses to diverse in vitro stimuli, in 53 females and 34 males of different ages. We found elevated antibody responses to TIV and expression of inflammatory cytokines in the serum of females compared with males regardless of age. This inflammatory profile correlated with the levels of phosphorylated [[STAT3]] proteins in monocytes but not with the serological response to the vaccine. In contrast, using a machine learning approach, we identified a cluster of genes involved in lipid biosynthesis and previously shown to be up-regulated by testosterone that correlated with poor virus-neutralizing activity in men. Moreover, men with elevated serum testosterone levels and associated gene signatures exhibited the lowest antibody responses to TIV. These results demonstrate a strong association between androgens and genes involved in lipid metabolism, suggesting that these could be important drivers of the differences in immune responses between males and females. 
|mesh-terms=* Age Factors
* Antibodies, Neutralizing
* Artificial Intelligence
* Cytokines
* Enzyme-Linked Immunosorbent Assay
* Female
* Gene Expression Regulation
* Humans
* Influenza Vaccines
* Leukocytes, Mononuclear
* Lipid Metabolism
* Male
* Microarray Analysis
* Neutralization Tests
* Phosphorylation
* STAT3 Transcription Factor
* Sex Characteristics
* Systems Biology
* Testosterone
|keywords=* aging
* gender
* immuno-endocrine
* immunosenescence
* sexual dimorphism
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3896147
}}
{{medline-entry
|title=Altered methylation and expression of ER-associated degradation factors in long-term alcohol and constitutive ER stress-induced murine hepatic tumors.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24198826
|abstract=Mortality from liver cancer in humans is increasingly attributable to heavy or long-term alcohol consumption. The mechanisms by which alcohol exerts its carcinogenic effect are not well understood. In this study, the role of alcohol-induced endoplasmic reticulum (ER) stress response in liver cancer development was investigated using an animal model with a liver knockout (KO) of the chaperone BiP and under constitutive hepatic ER stress. Long-term alcohol and high fat diet feeding resulted in higher levels of serum alanine aminotransferase, impaired ER stress response, and higher incidence of liver tumor in older (aged 16 months) KO females than in either middle-aged (6 months) KOs or older (aged 16 months) wild type females. In the older KO females, stronger effects of the alcohol on methylation of CpG islands at promoter regions of genes involved in the ER-associated degradation (ERAD) were also detected. Altered expression of ERAD factors including derlin 3, Creld2 (cysteine-rich with epidermal growth factor-like domains 2), Herpud1 (homocysteine-inducible, endoplasmic reticulum stress-inducible, ubiquitin-like domain member), Wfs1 (Wolfram syndrome gene), and Yod1 (deubiquitinating enzyme 1) was co-present with decreased proteasome activities, increased estrogen receptor α variant (ERα36), and enhanced phosphorylations of ERK1/2 (extracellular signal-regulated protein kinases 1 and 2) and [[STAT3]] (the signal transducers and activators of transcription) in the older KO female fed alcohol. Our results suggest that long-term alcohol consumption and aging may promote liver tumorigenesis in females through interfering with DNA methylation and expression of genes involved in the ERAD. 

|keywords=* ERAD
* aging
* alcohol
* hepatocellular tumorigenesis
* unfolded protein response
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3813967
}}
{{medline-entry
|title=Diabetes impairs an interleukin-1β-dependent pathway that enhances neurite outgrowth through JAK/[[STAT3]] modulation of mitochondrial bioenergetics in adult sensory neurons.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24152426
|abstract=A luminex-based screen of cytokine expression in dorsal root ganglia (DRG) and nerve of type 1 diabetic rodents revealed interleukin-1 (IL-1α) and IL-1β to be significantly depressed. We, therefore, tested the hypothesis that impaired IL-1α and IL-1β expression in DRG may contribute to aberrant axon regeneration and plasticity seen in diabetic sensory neuropathy. In addition, we determined if these cytokines could optimize mitochondrial bioenergetics since mitochondrial dysfunction is a key etiological factor in diabetic neuropathy. Cytokines IL-1α and IL-1β were reduced 2-fold (p<0.05) in DRG and/or nerve of 2 and 5 month streptozotocin (STZ)-diabetic rats. IL-2 and IL-10 were unchanged. IL-1α and IL-1β induced similar 2 to 3-fold increases in neurite outgrowth in cultures derived from control or diabetic rats (p<0.05). [[STAT3]] phosphorylation on Tyr705 or Ser727 was depressed in DRG from STZ-diabetic mice and treatment of cultures derived from STZ-diabetic rats with IL-1β for 30 min raised phosphorylation of [[STAT3]] on Tyr705 and Ser727 by 1.5 to 2-fold (p<0.05). shRNA-based or AG490 inhibition of [[STAT3]] activity or shRNA blockade of endogenous IL-1β expression completely blocked neurite outgrowth. Cultured neurons derived from STZ-diabetic mice were treated for 24 hr with IL-1β and maximal oxygen consumption rate and spare respiratory capacity, both key measures of bioenergetic fidelity that were depressed in diabetic compared with control neurons, were enhanced 2-fold. This effect was blocked by AG490. Endogenous synthesis of IL-1β is diminished in nerve tissue in type 1 diabetes and we propose this defect triggers reduced [[STAT3]] signaling and mitochondrial function leading to sup-optimal axonal regeneration and plasticity.
|mesh-terms=* Aging
* Animals
* Diabetes Mellitus, Experimental
* Energy Metabolism
* Ganglia, Spinal
* Immunohistochemistry
* Interleukin-1alpha
* Interleukin-1beta
* Janus Kinases
* Male
* Mice
* Mitochondria
* Neurites
* Phosphorylation
* Phosphotyrosine
* Rats
* Rats, Sprague-Dawley
* STAT3 Transcription Factor
* Sciatic Nerve
* Sensory Receptor Cells
* Signal Transduction
* Streptozocin
* Tyrphostins

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4016027
}}
{{medline-entry
|title=[[STAT3]] as a new autophagy regulator.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24069557
|abstract=Signal transducers and activators of transcription 3 ([[STAT3]]) proteins are cytoplasmic transcription factors that translocate into the nucleus to induce transcription following growth factor or cytokine stimulation. Besides their normal functions, these proteins play an important role in cancer cells through the abnormal activation of cell cycle progression and the deregulation of survival and senescence pathways. New data obtained from the laboratory of Guido Kroemer identifies [[STAT3]] as a new autophagy regulator. In the cytoplasm, in the absence of conventional phosphorylation on the tyrosine 705 residue, [[STAT3]] interacts with the PKR kinase to inhibit eIF2A phosphorylation and so reduce autophagic pathways. This new and nonconventional function of [[STAT3]] has an important role in normal cells but we suggest that it might also affect cancer cells and the response to chemotherapy treatment. 

|keywords=* STAT3
* autophagy
* cell death
* oncogene
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772109
}}
{{medline-entry
|title=Activation of interleukin-6/signal transducer and activator of transcription 3 by human papillomavirus early proteins 6 induces fibroblast senescence to promote cervical tumourigenesis through autocrine and paracrine pathways in tumour microenvironment.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23953057
|abstract=Although it is reported that interleukin (IL)-6/signal transducer and activator of transcription 3 ([[STAT3]]) is activated by human papillomavirus (HPV) infection in cervical cancer cells, little is known about the role of IL-6/[[STAT3]] in tumour microenvironment during development of the disease. In this study, we found that cancer-associated fibroblasts (CAF) but not normal fibroblasts (NF) secrete high level of IL-6 with activated [[STAT3]] and appear senescent at early passages in culture or in cervical cancer tissues infected with high-risk HPV, and that treatment of NF with recombinant IL-6 or CAF conditioned medium (CM) induces activation of [[STAT3]] and cellular senescence. IL-6 and [[STAT3]] are either upregulated or activated in Siha and Hela cells infected with HPV 16 or 18, but not in C33A and ME180 cells without HPV 16 or 18 infection. Overexpression of HPV early proteins 6 (E6) activates [[STAT3]], increases IL-6 expression and tumour burden in C33A and ME180 cells, while silencing of HPV E6 by specific shRNA reduces [[STAT3]] activation, IL-6 expression, and tumour formation in Siha and HeLa cells, so does silencing of [[STAT3]] by specific shRNA in HeLa and C33A/E6 cells. The tumour growth of cervical cancer cells reconstituted with CAF or NF is largely affected by inhibition of fibroblast senescence with [[STAT3]] inhibitor or with IL-6 antibody treatment. Thus, we have uncovered a mechanism that fibroblast senescence promotes cervical cancer development through high-risk HPV E6-activated IL-6/[[STAT3]] signalling in tumour microenvironment. 
|mesh-terms=* Animals
* Autocrine Communication
* Cell Line, Tumor
* Cell Transformation, Neoplastic
* Cellular Senescence
* DNA-Binding Proteins
* Female
* Fibroblasts
* HeLa Cells
* Host-Pathogen Interactions
* Human papillomavirus 16
* Human papillomavirus 18
* Humans
* Interleukin-6
* Mice
* Mice, Inbred BALB C
* Mice, Nude
* Oncogene Proteins, Viral
* Paracrine Communication
* RNA Interference
* Repressor Proteins
* STAT3 Transcription Factor
* Signal Transduction
* Transplantation, Heterologous
* Tumor Microenvironment
* Uterine Cervical Neoplasms
|keywords=* Cervical cancer
* Fibroblast senescence
* HPV E6
* IL-6
* STAT3
|full-text-url=https://sci-hub.do/10.1016/j.ejca.2013.07.140
}}
{{medline-entry
|title=Hepatoprotective and anti-fibrotic functions of interleukin-22: therapeutic potential for the treatment of alcoholic liver disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23855297
|abstract=Interleukin-22 (IL-22) plays a key role in promoting antimicrobial immunity and tissue repair at barrier surfaces by binding to the receptors IL-22R1, which is generally thought to be expressed exclusively in epithelial cells, and IL-10R2. Our laboratory previously demonstrated that IL-22 plays an important role in ameliorating liver injury in many rodent models by targeting hepatocytes that express high levels of IL-22R1 and IL-10R2. Recently, we have identified high expression levels of IL-22R1 and IL-10R2 in liver progenitor cells and hepatic stellate cells (HSCs). Overexpression of IL-22 in vivo or treatment with IL-22 in vitro promotes proliferation of liver progenitor cells via a signal transducer and activator of transcription 3 ([[STAT3]])-dependent mechanism. IL-22 treatment also prevents HSC apoptosis in vitro and in vivo. Surprisingly, overexpression of IL-22, via either gene targeting or exogenous administration of adenovirus expressing IL-22, reduces liver fibrosis and accelerates the resolution of liver fibrosis during recovery. The anti-fibrotic effects of IL-22 are mediated via the activation of [[STAT3]] in HSCs and subsequent induction of suppressor of cytokine signaling 3, which induces HSC senescence. Taken together, the hepatoprotective, mitogenic, and anti-fibrotic effects of IL-22 are beneficial in ameliorating alcoholic liver injury. Importantly, due to the restricted expression of IL-22R1, IL-22 therapy is expected to have few side effects, thus making IL-22 a potential candidate for treatment of alcoholic liver disease. 
|mesh-terms=* Animals
* Apoptosis
* Cell Proliferation
* Gene Expression
* Hepatic Stellate Cells
* Hepatocytes
* Humans
* Interleukins
* Liver
* Liver Diseases, Alcoholic
* Molecular Targeted Therapy
* Receptors, Interleukin
* Receptors, Interleukin-10
* STAT3 Transcription Factor
* Stem Cells
|keywords=* hepatic stellate cells
* liver fibrosis
* liver progenitor cells
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3779467
}}
{{medline-entry
|title=An age-related numerical and functional deficit in CD19( ) CD24(hi) CD38(hi) B cells is associated with an increase in systemic autoimmunity.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23755918
|abstract=Autoimmunity increases with aging indicative of reduced immune tolerance, but the mechanisms involved are poorly defined. In recent years, subsets of B cells with immunoregulatory properties have been identified in murine models of autoimmune disorders, and these cells downregulate immune responses via secretion of [[IL10]]. In humans, immature transitional B cells with a CD19( ) CD24(hi) CD38(hi) phenotype have been reported to regulate immune responses via [[IL10]] production. We found the frequency and numbers of CD19( ) CD24(hi) CD38(hi) cells were reduced in the PBMC pool with age. [[IL10]] expression and secretion following activation via either [[CD4]]0, or Toll-like receptors was also impaired in CD19( ) CD24(hi) CD38(hi) B cells from healthy older donors. When investigating the mechanisms involved, we found that CD19( ) CD24(hi) CD38(hi) B-cell function was compromised by age-related effects on both T cells and B cells: specifically, [[CD4]]0 ligand expression was lower in [[CD4]] T cells from older donors following CD3 stimulation, and signalling through [[CD4]]0 was impaired in CD19( ) CD24(hi) CD38(hi) B cells from elders as evidenced by reduced phosphorylation (Y705) and activation of [[STAT3]]. However, there was no age-associated change in expression of costimulatory molecules [[CD80]] and [[CD86]] on CD19( ) CD24(hi) CD38(hi) cells, suggesting [[IL10]]-dependent immune suppression is impaired, but contact-dependent suppressive capacity is intact with age. Finally, we found a negative correlation between CD19( ) CD24(hi) CD38(hi) B-cell [[IL10]] production and autoantibody (Rheumatoid factor) levels in older adults. We therefore propose that an age-related decline in CD19( ) CD24(hi) CD38(hi) B cell number and function may contribute towards the increased autoimmunity and reduced immune tolerance seen with aging. 
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Aging
* Antigens, CD
* Autoimmunity
* B-Lymphocytes
* Cell Differentiation
* Female
* Humans
* Male
* Middle Aged
* Signal Transduction
* Young Adult
|keywords=* B cells
* autoimmunity
* cellular immunology
* inflammation
* rheumatoid factor
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3814412
}}
{{medline-entry
|title=Timing of mTOR activation affects tuberous sclerosis complex neuropathology in mouse models.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23744272
|abstract=Tuberous sclerosis complex (TSC) is a dominantly inherited disease with high penetrance and morbidity, and is caused by mutations in either of two genes, [[TSC1]] or [[TSC2]]. Most affected individuals display severe neurological manifestations - such as intractable epilepsy, mental retardation and autism - that are intimately associated with peculiar CNS lesions known as cortical tubers (CTs). The existence of a significant genotype-phenotype correlation in individuals bearing mutations in either [[TSC1]] or [[TSC2]] is highly controversial. Similar to observations in humans, mouse modeling has suggested that a more severe phenotype is associated with mutation in Tsc2 rather than in Tsc1. However, in these mutant mice, deletion of either gene was achieved in differentiated astrocytes. Here, we report that loss of Tsc1 expression in undifferentiated radial glia cells (RGCs) early during development yields the same phenotype detected upon deletion of Tsc2 in the same cells. Indeed, the same aberrations in cortical cytoarchitecture, hippocampal disturbances and spontaneous epilepsy that have been detected in RGC-targeted Tsc2 mutants were observed in RGC-targeted Tsc1 mutant mice. Remarkably, thorough characterization of RGC-targeted Tsc1 mutants also highlighted subventricular zone (SVZ) disturbances as well as [[STAT3]]-dependent and -independent developmental-stage-specific defects in the differentiation potential of ex-vivo-derived embryonic and postnatal neural stem cells (NSCs). As such, deletion of either Tsc1 or Tsc2 induces mostly overlapping phenotypic neuropathological features when performed early during neurogenesis, thus suggesting that the timing of mTOR activation is a key event in proper neural development. 
|mesh-terms=* Animals
* Animals, Newborn
* Cell Differentiation
* Cell Proliferation
* Cell Size
* Cerebral Cortex
* Disease Models, Animal
* Embryo, Mammalian
* Embryonic Development
* Enzyme Activation
* Epilepsy
* Gene Silencing
* Longevity
* Megalencephaly
* Mice
* Mutagenesis
* Myelin Sheath
* Neuroglia
* Neurons
* STAT3 Transcription Factor
* Sirolimus
* TOR Serine-Threonine Kinases
* Time Factors
* Tuberous Sclerosis
* Tuberous Sclerosis Complex 1 Protein
* Tumor Suppressor Proteins

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759338
}}
{{medline-entry
|title=Age-dependent germline mosaicism of the most common noonan syndrome mutation shows the signature of germline selection.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23726368
|abstract=Noonan syndrome (NS) is among the most common Mendelian genetic diseases (∼1/2,000 live births). Most cases (50%-84%) are sporadic, and new mutations are virtually always paternally derived. More than 47 different sites of NS de novo missense mutations are known in the [[PTPN11]] gene that codes for the protein tyrosine phosphatase SHP-2. Surprisingly, many of these mutations are recurrent with nucleotide substitution rates substantially greater than the genome average; the most common mutation, c.922A>G, is at least 2,400 times greater. We examined the spatial distribution of the c.922A>G mutation in testes from 15 unaffected men and found that the mutations were not uniformly distributed across each testis as would be expected for a mutation hot spot but were highly clustered and showed an age-dependent germline mosaicism. Computational modeling that used different stem cell division schemes confirmed that the data were inconsistent with hypermutation, but consistent with germline selection: mutated spermatogonial stem cells gained an advantage that allowed them to increase in frequency. SHP-2 interacts with the transcriptional activator [[STAT3]]. Given [[STAT3]]'s function in mouse spermatogonial stem cells, we suggest that this interaction might explain the mutant's selective advantage by means of repression of stem cell differentiation signals. Repression of [[STAT3]] activity by cyclin D1 might also play a previously unrecognized role in providing a germline-selective advantage to spermatogonia for the recurrent mutations in the receptor tyrosine kinases that cause Apert syndrome and MEN2B. Looking at recurrent mutations driven by germline selection in different gene families can help highlight common causal signaling pathways.
|mesh-terms=* Adult
* Age Factors
* Aged
* Aged, 80 and over
* Aging
* Gene Frequency
* Genetic Association Studies
* Germ-Line Mutation
* Humans
* Male
* Middle Aged
* Models, Genetic
* Mosaicism
* Noonan Syndrome
* Protein Tyrosine Phosphatase, Non-Receptor Type 11
* Selection, Genetic
* Spermatogonia
* Testis
* Young Adult

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682763
}}
{{medline-entry
|title=Inactivation of [[JAK2]]/[[STAT3]] signaling axis and downregulation of M1 mAChR cause cognitive impairment in klotho mutant mice, a genetic model of aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23389690
|abstract=We previously reported cognitive dysfunction in klotho mutant mice. In the present study, we further examined novel mechanisms involved in cognitive impairment in these mice. Significantly decreased janus kinase 2 ([[JAK2]]) and signal transducer and activator of transcription3 ([[STAT3]]) phosphorylation were observed in the hippocampus of klotho mutant mice. A selective decrease in protein expression and binding density of the M1 muscarinic cholinergic receptor (M1 mAChR) was observed in these mice. Cholinergic parameters (ie, acetylcholine (ACh), choline acetyltransferase (ChAT), and acetylcholinesterase (AChE)) and NMDAR-dependent long-term potentiation (LTP) were significantly impaired in klotho mutant mice. McN-A-343 (McN), an M1 mAChR agonist, significantly attenuated these impairments. AG490 (AG), a [[JAK2]] inhibitor, counteracted the attenuating effects of McN, although AG did not significantly alter the McN-induced effect on AChE. Furthermore, AG significantly inhibited the attenuating effects of McN on decreased NMDAR-dependent LTP, protein kinase C βII, p-ERK, p-CREB, [[BDNF]], and p-[[JAK2]]/p-[[STAT3]]-expression in klotho mutant mice. In addition, k252a, a [[BDNF]] receptor tyrosine kinase B (TrkB) inhibitor, significantly counteracted McN effects on decreased ChAT, ACh, and M1 mAChR and p-[[JAK2]]/p-[[STAT3]] expression. McN-induced effects on cognitive impairment in klotho mutant mice were consistently counteracted by either AG or k252a. Our results suggest that inactivation of the [[JAK2]]/[[STAT3]] signaling axis and M1 mAChR downregulation play a critical role in cognitive impairment observed in klotho mutant mice.
|mesh-terms=* Aging
* Animals
* Cognition Disorders
* Down-Regulation
* Glucuronidase
* Hippocampus
* Janus Kinase 2
* Mice
* Mice, Mutant Strains
* Models, Animal
* Organ Culture Techniques
* Receptor, Muscarinic M1
* STAT3 Transcription Factor
* Signal Transduction

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682136
}}
{{medline-entry
|title=Attenuated expression of gelsolin in association with induction of aquaporin-1 and nitric oxide synthase in dysfunctional hearts of aging mice exposed to endotoxin.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23298482
|abstract=Sepsis triggered by endotoxinemia may impair cardiac function. A decline in tolerance to septic shock occurs with aging. This study addressed the hypothesis that aging negatively impairs expression of gelsolin, and axerts the regulatory effects on the water channel protein aquaporin-1 (AQP-1) and endotoxin-inducible nitric oxide synthase (iNOS). We explored whether the age-related gene changes are associated with the cardiac dysfunction induced by endotoxic stress exposure. Male mice at young (3-month) and old (12-month) ages received intraperitoneal injections of saline or lipopolysaccharide (LPS, 30mg/Kg). Cardiac performance and morphology were analyzed by echocardiography at baseline and 2 and 24 h after injection. At the end of treatment, the animals were sacrificed, and cardiac tissues were collected for assessing expression of gelsolin, AQP-1, iNOS, and transcription-3 ([[STAT3]]). LPS administration led to a decreased contractility while increasing cardiac dimensions in both young and old mice. LPS also markedly induced expression of gelsolin in both animal groups. However, compared to young mice, old mice showed compromised induction of gelsolin and cardiac performance in response to endotoxin. Meanwhile, the LPS-exposed old animals exhibited higher levels of AQP-1, iNOS, and phosphorylated [[STAT3]]. Gelsolin-null mice had increased expression of glycosylated AQP-1 and [[STAT3]] phosphorylation as well as cardiac dysfunction. Thus, endotoxin administration induces expression of gelsolin, AQP-1 and pro-inflammatory genes, such as iNOS. Our data suggest that changed expression of gelsolin, AQP-1 and iNOS may contribute to dysfunction of hearts in aged subjects with septic endotoxinemia.
|mesh-terms=* Actins
* Aging
* Animals
* Aquaporin 1
* Cells, Cultured
* Gelsolin
* Heart Failure
* Humans
* Lipopolysaccharides
* Male
* Mice
* Mice, Inbred C57BL
* Myocardium
* Nitric Oxide Synthase
* Phosphorylation
* STAT3 Transcription Factor

|full-text-url=https://sci-hub.do/10.1177/039463201202500409
}}