Редактирование: PTEN

Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN (EC 3.1.3.16) (EC 3.1.3.48) (EC 3.1.3.67) (Mutated in multiple advanced cancers 1) (Phosphatase and tensin homolog) [MMAC1] [TEP1]

==Publications==

{{medline-entry
|title=Aberrant mitochondrial morphology and function associated with impaired mitophagy and [[DNM1L]]-MAPK/ERK signaling are found in aged mutant Parkinsonian [[LRRK2]]  mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33300446
|abstract=Mitochondrial dysfunction causes energy deficiency and nigrostriatal neurodegeneration which is integral to the pathogenesis of Parkinson disease (PD). Clearance of defective mitochondria involves fission and ubiquitin-dependent degradation via mitophagy to maintain energy homeostasis. We hypothesize that [[LRRK2]] (leucine-rich repeat kinase 2) mutation disrupts mitochondrial turnover causing accumulation of defective mitochondria in aging brain. We found more ubiquitinated mitochondria with aberrant morphology associated with impaired function in aged (but not young) [[LRRK2]]  knockin mutant mouse striatum compared to wild-type (WT) controls. [[LRRK2]]  mutant mouse embryonic fibroblasts (MEFs) exhibited reduced MAP1LC3/LC3 activation indicating impaired macroautophagy/autophagy. Mutant MEFs under FCCP-induced (mitochondrial uncoupler) stress showed increased LC3-aggregates demonstrating impaired mitophagy. Using a novel flow cytometry assay to quantify mitophagic rates in MEFs expressing photoactivatable [i]mito[/i]-PAmCherry, we found significantly slower mitochondria clearance in mutant cells. Specific [[LRRK2]] kinase inhibition using [[GNE]]-7915 did not alleviate impaired mitochondrial clearance suggesting a lack of direct relationship to increased kinase activity alone. [[DNM1L]]/Drp1 knockdown in MEFs slowed mitochondrial clearance indicating that [[DNM1L]] is a prerequisite for mitophagy. [[DNM1L]] knockdown in slowing mitochondrial clearance was less pronounced in mutant MEFs, indicating preexisting impaired [[DNM1L]] activation. [[DNM1L]] knockdown disrupted mitochondrial network which was more evident in mutant MEFs. [[DNM1L]]-Ser616 and MAPK/ERK phosphorylation which mediate mitochondrial fission and downstream mitophagic processes was apparent in WT using FCCP-induced stress but not mutant MEFs, despite similar total MAPK/ERK and [[DNM1L]] levels. In conclusion, aberrant mitochondria morphology and dysfunction associated with impaired mitophagy and [[DNM1L]]-MAPK/ERK signaling are found in mutant [[LRRK2]] MEFs and mouse brain.   ATP: adenosine triphosphate; BAX: [[BCL2]]-associated X protein; CDK1: cyclin-dependent kinase 1; CDK5: cyclin-dependent kinase 5; CQ: chloroquine; CSF: cerebrospinal fluid; [[DNM1L]]/DRP1: dynamin 1-like; ELISA: enzyme-linked immunosorbent assay; FACS: fluorescence-activated cell sorting; FCCP: carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; LAMP2A: lysosomal-associated membrane protein 2A; [[LRRK2]]: leucine-rich repeat kinase 2; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAPK1/ERK2: mitogen-activated protein kinase 1; MEF: mouse embryonic fibroblast; MFN1: mitofusin 1; MMP: mitochondrial membrane potential; PAmCherry: photoactivatable-mCherry; PD: Parkinson disease; PINK1: [[PTEN]] induced putative kinase 1; PRKN/PARKIN: parkin RBR E3 ubiquitin protein ligase; [[RAB10]]: [[RAB10]], member RAS oncogene family; RAF: v-raf-leukemia oncogene; SNCA: synuclein, alpha; TEM: transmission electron microscopy; VDAC: voltage-dependent anion channel; WT: wild type; SQSTM1/p62: sequestosome 1.

|keywords=* Aging
* Dnm1l/DRP1
* SQSTM1/p62
* knockin mice
* macroautophagy
* mitochondria dysfunction
* mitochondrial fission
* mitophagy
* parkinson disease
* ubiquitination
|full-text-url=https://sci-hub.do/10.1080/15548627.2020.1850008
}}
{{medline-entry
|title=Senescence Reprogramming by [[TIMP1]] Deficiency Promotes Prostate Cancer Metastasis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33186519
|abstract=Metastases account for most cancer-related deaths, yet the mechanisms underlying metastatic spread remain poorly understood. Recent evidence demonstrates that senescent cells, while initially restricting tumorigenesis, can induce tumor progression. Here, we identify the metalloproteinase inhibitor [[TIMP1]] as a molecular switch that determines the effects of senescence in prostate cancer. Senescence driven either by [[PTEN]] deficiency or chemotherapy limits the progression of prostate cancer in mice. [[TIMP1]] deletion allows senescence to promote metastasis, and elimination of senescent cells with a senolytic BCL-2 inhibitor impairs metastasis. Mechanistically, [[TIMP1]] loss reprograms the senescence-associated secretory phenotype (SASP) of senescent tumor cells through activation of matrix metalloproteinases (MMPs). Loss of [[PTEN]] and [[TIMP1]] in prostate cancer is frequent and correlates with resistance to docetaxel and worst clinical outcomes in patients treated in an adjuvant setting. Altogether, these findings provide insights into the dual roles of tumor-associated senescence and can potentially impact the treatment of prostate cancer.

|keywords=* FGF1
* GDF-15
* MMPs
* PTEN
* TIMP1
* docetaxel
* prostate cancer metastasis
* senescence
* senescence-associated secretory phenotype (SASP)
* senolytic therapy
|full-text-url=https://sci-hub.do/10.1016/j.ccell.2020.10.012
}}
{{medline-entry
|title=Alterations in Mitochondrial Dynamic-related Genes in the Peripheral Blood of Alzheimer's Disease Patients.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33023448
|abstract=Mitochondrial dysfunction is a pathological feature that manifests early in the brains of patients with Alzheimer's Disease (AD). The disruption of mitochondrial dynamics contributes to mitochondrial morphological and functional impairments. Our previous study demonstrated that the expression of genes involved in amyloid beta generation was altered in the peripheral blood of AD patients. The aim of this study was to further investigate the relative levels of mitochondrial genes involved in mitochondrial dynamics, including mitochondrial fission and fusion, and mitophagy in peripheral blood samples from patients with AD compared to healthy controls. The mRNA levels were analyzed by real-time polymerase chain reaction. Gene expression profiles were assessed in relation to cognitive performance. Significant changes were observed in the mRNA expression levels of fission-related genes; Fission1 ([[FIS1]]) levels in AD subjects were significantly higher than those in healthy controls, whereas Dynamin- related protein 1 (DRP1) expression was significantly lower in AD subjects. The levels of the mitophagy-related genes, [[PTEN]]-induced kinase 1 (PINK1) and microtubule-associated protein 1 light chain 3 (LC3), were significantly increased in AD subjects and elderly controls compared to healthy young controls. The mRNA levels of Parkin (PARK2) were significantly decreased in AD. Correlations were found between the expression levels of [[FIS1]], DRP1 and PARK2 and cognitive performance scores. Alterations in mitochondrial dynamics in the blood may reflect impairments in mitochondrial functions in the central and peripheral tissues of AD patients. Mitochondrial fission, together with mitophagy gene profiles, might be potential considerations for the future development of blood-based biomarkers for AD.

|keywords=* Alzheimer's disease
* DRP1
* FIS1
* aging
* mitochondrial dynamics
* mitophagy
|full-text-url=https://sci-hub.do/10.2174/1567205017666201006162538
}}
{{medline-entry
|title=Data mining of human plasma proteins generates a multitude of highly predictive aging clocks that reflect different aspects of aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33031577
|abstract=We previously identified 529 proteins that had been reported by multiple different studies to change their expression level with age in human plasma. In the present study, we measured the q-value and age coefficient of these proteins in a plasma proteomic dataset derived from 4263 individuals. A bioinformatics enrichment analysis of proteins that significantly trend toward increased expression with age strongly implicated diverse inflammatory processes. A literature search revealed that at least 64 of these 529 proteins are capable of regulating life span in an animal model. Nine of these proteins (AKT2, [[GDF11]], [[GDF15]], [[GHR]], [[NAMPT]], [[PAPPA]], [[PLAU]], [[PTEN]], and SHC1) significantly extend life span when manipulated in mice or fish. By performing machine-learning modeling in a plasma proteomic dataset derived from 3301 individuals, we discover an ultra-predictive aging clock comprised of 491 protein entries. The Pearson correlation for this clock was 0.98 in the learning set and 0.96 in the test set while the median absolute error was 1.84 years in the learning set and 2.44 years in the test set. Using this clock, we demonstrate that aerobic-exercised trained individuals have a younger predicted age than physically sedentary subjects. By testing clocks associated with 1565 different Reactome pathways, we also show that proteins associated with signal transduction or the immune system are especially capable of predicting human age. We additionally generate a multitude of age predictors that reflect different aspects of aging. For example, a clock comprised of proteins that regulate life span in animal models accurately predicts age.

|keywords=* age-related disease
* aging
* aging clock
* health span
* life span
* longevity
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681068
}}
{{medline-entry
|title=Human ESC-sEVs alleviate age-related bone loss by rejuvenating senescent bone marrow-derived mesenchymal stem cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32944188
|abstract=Tissue-resident stem cell senescence leads to stem cell exhaustion, which is a major cause of physiological and pathological ageing. Stem cell-derived extracellular vesicles (SC-EVs) have been reported in preclinical studies to possess therapeutic potential for diverse diseases. However, whether SC-EVs can rejuvenate senescent tissue stem cells to prevent age-related disorders still remains unknown. Here, we show that chronic application of human embryonic stem cell-derived small extracellular vesicles (hESC-sEVs) rescues the function of senescent bone marrow mesenchymal stem cells (BM-MSCs) and prevents age-related bone loss in ageing mice. Transcriptome analysis revealed that hESC-sEVs treatment upregulated the expression of genes involved in antiaging, stem cell proliferation and osteogenic differentiation in BM-MSCs. Furthermore, liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis identified 4122 proteins encapsulated in hESC-sEVs. Bioinformatics analysis predicted that the protein components in the hESCs-sEVs function in a synergistic way to induce the activation of several canonical signalling pathways, including Wnt, Sirtuin, AMPK, [[PTEN]] signalling, which results in the upregulation of antiaging genes in BM-MSCs and then the recovery of senescent BM-MSCs function. Collectively, our findings reveal the effect of hESC-sEVs in reversing BM-MSCs senescence and age-related osteogenic dysfunction, thereby preventing age-related bone loss. Because hESC-sEVs could alleviate senescence of tissue-resident stem cells, they might be promising therapeutic candidates for age-related diseases.

|keywords=* Extracellular vesicle
* bone loss
* bone marrow MSCs
* cellular senescence
* embryonic stem cells
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480439
}}
{{medline-entry
|title=The precursor of PI(3,4,5)P  alleviates aging by activating daf-18(Pten) and independent of daf-16.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32901024
|abstract=Aging is characterized by the loss of homeostasis and the general decline of physiological functions, accompanied by various degenerative diseases and increased rates of mortality. Aging targeting small molecule screens have been performed many times, however, few have focused on endogenous metabolic intermediates-metabolites. Here, using C. elegans lifespan assays, we conducted a worm metabolite screen and identified an eukaryotes conserved metabolite, myo-inositol (MI), to extend lifespan, increase mobility and reduce fat content. Genetic analysis of enzymes in MI metabolic pathway suggest that MI alleviates aging through its derivative PI(4,5)P . MI and PI(4,5)P  are precursors of PI(3,4,5)P , which is negatively related to longevity. The longevity effect of MI is dependent on the tumor suppressor gene, daf-18 (homologous to mouse Pten), independent of its classical pathway downstream genes, akt or daf-16. Furthermore, we found MI effects on aging and lifespan act through mitophagy regulator [[PTEN]] induced kinase-1 (pink-1) and mitophagy. MI's anti-aging effect is also conserved in mouse, indicating a conserved mechanism in mammals.
|mesh-terms=* Aging
* Animals
* Animals, Genetically Modified
* Caenorhabditis elegans
* Caenorhabditis elegans Proteins
* Cell Line, Tumor
* Female
* Forkhead Transcription Factors
* Inositol
* Locomotion
* Longevity
* Metabolic Networks and Pathways
* Metabolomics
* Mice
* Mitophagy
* Models, Animal
* PTEN Phosphohydrolase
* Phosphatidylinositol Phosphates
* Protein Kinases
* Protein-Serine-Threonine Kinases
* RNA Interference
* RNA-Seq

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479145
}}
{{medline-entry
|title=Mechanism of [[PRL]]2 phosphatase-mediated [[PTEN]] degradation and tumorigenesis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32788364
|abstract=Tumor suppressor [[PTEN]] (phosphatase and tensin homologue deleted on chromosome 10) levels are frequently found reduced in human cancers, but how [[PTEN]] is down-regulated is not fully understood. In addition, although a compelling connection exists between [[PRL]] (phosphatase of regenerating liver) 2 and cancer, how this phosphatase induces oncogenesis has been an enigma. Here, we discovered that [[PRL]]2 ablation inhibits [[PTEN]] heterozygosity-induced tumorigenesis. [[PRL]]2 deficiency elevates [[PTEN]] and attenuates AKT signaling, leading to decreased proliferation and increased apoptosis in tumors. We also found that high [[PRL]]2 expression is correlated with low [[PTEN]] level with reduced overall patient survival. Mechanistically, we identified [[PTEN]] as a putative [[PRL]]2 substrate and demonstrated that [[PRL]]2 down-regulates [[PTEN]] by dephosphorylating [[PTEN]] at Y336, thereby augmenting [[NEDD4]]-mediated [[PTEN]] ubiquitination and proteasomal degradation. Given the strong cancer susceptibility to subtle reductions in [[PTEN]], the ability of [[PRL]]2 to down-regulate [[PTEN]] provides a biochemical basis for its oncogenic propensity. The results also suggest that pharmacological targeting of [[PRL]]2 could provide a novel therapeutic strategy to restore [[PTEN]], thereby obliterating [[PTEN]] deficiency-induced malignancies.
|mesh-terms=* Animals
* Carcinogenesis
* Female
* HEK293 Cells
* Humans
* Immediate-Early Proteins
* Longevity
* Male
* Mice, Inbred C57BL
* Mice, Knockout
* Nedd4 Ubiquitin Protein Ligases
* PTEN Phosphohydrolase
* Protein Tyrosine Phosphatases
* Proto-Oncogene Proteins c-akt
* Ubiquitination
|keywords=* NEDD4
* PRL2
* PTEN
* protein tyrosine phosphatases
* ubiquitination
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456095
}}
{{medline-entry
|title=Quercetin alleviates kidney fibrosis by reducing renal tubular epithelial cell senescence through the [[SIRT1]]/PINK1/mitophagy axis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32702447
|abstract=Emerging evidence implicates accelerated renal tubular epithelial cell (RTEC) senescence in renal fibrosis progression. Mitophagy protects against kidney injury. However, the mechanistic interplay between cell senescence and mitophagy in RTECs is not clearly defined. The purpose of this study was to evaluate the inhibition of RTEC senescence and renal fibrosis by quercetin and explore the underlying mechanisms. We found that quercetin attenuated RTEC senescence induced by angiotensin II (AngII) in vitro and unilateral ureteral obstruction in vivo. Moreover, we demonstrated that mitochondrial abnormalities such as elevated reactive oxygen species, decreased membrane potential, and fragmentation and accumulation of mitochondrial mass, occurred in AngII-treated RTECs. Quercetin treatment reversed these effects. Furthermore, quercetin enhanced mitophagy in AngII-treated RTECs, which was markedly reduced by treatment with mitophagy-specific inhibitors. Sirtuin-1 ([[SIRT1]]) was involved in quercetin-mediated [[PTEN]]-induced kinase 1 (PINK1)/Parkin-associated mitophagy activation. Pharmacological antagonism of [[SIRT1]] in AngII-treated RTECs blocked the effects of quercetin on mitophagy and cellular senescence. Finally, quercetin alleviated kidney fibrosis by reducing RTEC senescence via mitophagy. Collectively, the antifibrotic effect of quercetin involved inhibition of RTEC senescence, possibly through activation of [[SIRT1]]/PINK1/Parkin-mediated mitophagy. These findings suggest that pharmacological elimination of senescent cells and stimulation of mitophagy represent effective therapeutic strategies to prevent kidney fibrosis.
|mesh-terms=* Animals
* Antioxidants
* Cell Line
* Cellular Senescence
* Epithelium
* Fibrosis
* Flow Cytometry
* Kidney
* Kidney Tubules, Proximal
* Mitophagy
* Protein Kinases
* Quercetin
* Rats
* Sirtuin 1
|keywords=* Fibrosis
* Mitochondria
* Mitophagy
* Quercetin
* Senescence
|full-text-url=https://sci-hub.do/10.1016/j.lfs.2020.118116
}}
{{medline-entry
|title=Downregulation of [[PTEN]] mediates bleomycin-induced premature senescence in lung cancer cells by suppressing autophagy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32436415
|abstract=Bleomycin is an important chemotherapeutic drug that activates premature senescence to decrease the tumorigenic process. We aimed to investigate the role of phosphatase and tensin homolog deleted on chromosome ten ([[PTEN]]) in bleomycin-induced premature senescence in lung cancer cells. Human lung cancer A549 cells were incubated in the presence of different concentrations of bleomycin for 5 days. A lentivirus vector was used to silence the [i][[PTEN]][/i] gene, followed by stimulation with bleomycin (1 µg/mL). Changes were evaluated by senescence-associated β-galactosidase staining, reverse transcription-polymerase chain reaction, and western blot. Treatment with bleomycin induced premature senescence. [[PTEN]] expression was decreased and key downstream molecules in the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway were gradually activated following bleomycin treatment. Silencing [i][[PTEN]][/i] reduced autophagy and accelerated senescence of A549 cells. Autophagy levels were also increased and senescence markers were reduced after inhibiting mTOR. Downregulation of [[PTEN]] mediates bleomycin-induced premature senescence in lung cancer cells by suppressing autophagy via the PI3K/Akt/mTOR pathway. These findings provide new insights into the potential role of [[PTEN]] as a molecular target for cancer chemotherapy.

|keywords=* PI3K/Akt/mTOR pathway
* PTEN
* autophagy
* bleomycin
* cancer cell
* premature senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287201
}}
{{medline-entry
|title=Inflamma-miR-21 Negatively Regulates Myogenesis during Ageing.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32340146
|abstract=Ageing is associated with disrupted redox signalling and increased circulating inflammatory cytokines. Skeletal muscle homeostasis depends on the balance between muscle hypertrophy, atrophy and regeneration, however during ageing this balance is disrupted. The molecular pathways underlying the age-related decline in muscle regenerative potential remain elusive. microRNAs are conserved robust gene expression regulators in all tissues including skeletal muscle. Here, we studied satellite cells from adult and old mice to demonstrate that inhibition of miR-21 in satellite cells from old mice improves myogenesis. We determined that increased levels of proinflammatory cytokines, TNFα and [[IL6]], as well as H O , increased miR-21 expression in primary myoblasts, which in turn resulted in their decreased viability and myogenic potential. Inhibition of miR-21 function rescued the decreased size of myotubes following TNFα or [[IL6]] treatment. Moreover, we demonstrated that miR-21 could inhibit myogenesis in vitro via regulating [[[[IL6]]R]], [[PTEN]] and [[FOXO3]] signalling. In summary, upregulation of miR-21 in satellite cells and muscle during ageing may occur in response to elevated levels of TNFα and [[IL6]], within satellite cells or myofibrillar environment contributing to skeletal muscle ageing and potentially a disease-related decline in potential for muscle regeneration.

|keywords=* IL6
* IL6R
* aging
* cachexia
* miR-21
* microRNA
* muscle
* regeneration
* sarcopenia
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222422
}}
{{medline-entry
|title=Peripheral Circulating Exosomal miRNAs Potentially Contribute to the Regulation of Molecular Signaling Networks in Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32168775
|abstract=People are living longer than ever. Consequently, they have a greater chance for developing a functional impairment or aging-related disease, such as a neurodegenerative disease, later in life. Thus, it is important to identify and understand mechanisms underlying aging as well as the potential for rejuvenation. Therefore, we used next-generation sequencing to identify differentially expressed microRNAs (miRNAs) in serum exosomes isolated from young (three-month-old) and old (22-month-old) rats and then used bioinformatics to explore candidate genes and aging-related pathways. We identified 2844 mRNAs and 68 miRNAs that were differentially expressed with age. TargetScan revealed that 19 of these miRNAs are predicated to target the 766 mRNAs. Pathways analysis revealed signaling components targeted by these miRNAs: mTOR, AMPK, eNOS, IGF, [[PTEN]], p53, integrins, and growth hormone. In addition, the most frequently predicted target genes regulated by these miRNAs were [[EIF4EBP1]], insulin receptor, [[PDK1]], [[PTEN]], paxillin, and IGF-1 receptor. These signaling pathways and target genes may play critical roles in regulating aging and lifespan, thereby validating our analysis. Understanding the causes of aging and the underlying mechanisms may lead to interventions that could reverse certain aging processes and slow development of aging-related diseases.

|keywords=* aging
* aging-related disease
* exosomes
* functional enrichment analysis
* ingenuity pathway analysis
* miRNA-mRNA networks
* serum
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139634
}}
{{medline-entry
|title=HDAC inhibition leads to age-dependent opposite regenerative effect upon [[PTEN]] deletion in rubrospinal axons after SCI.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32171589
|abstract=Epigenetic changes associated with aging have been linked to functional and cognitive deficits in the adult CNS. Histone acetylation is involved in the control of the transcription of plasticity and regeneration-associated genes. The intrinsic axon growth capacity in the CNS is negatively regulated by phosphatase and tensin homolog (Pten). Inhibition of Pten is an effective method to stimulate axon growth following an injury to the optic nerve, corticospinal tract (CST), and rubrospinal tract (RST). Our laboratory has previously demonstrated that the deletion of Pten in aged animals diminishes the regenerative capacity in rubrospinal neurons. We hypothesize that changes in the chromatin structure might contribute to this age-associated decline. Here, we assessed whether Trichostatin A (TSA), a histone deacetylases (HDACs) inhibitor, reverses the decline in regeneration in aged Pten  mice. We demonstrate that HDAC inhibition induces changes in the expression of [[GAP43]] in both young and aged Pten  mice. The regenerative capacity of the RST did not improve significantly in young mice, neither their motor function on the horizontal ladder or cylinder test after TSA treatment for 7 days. Interestingly, TSA treatment in the aged mice worsened their motor function deficits, suggesting that the systemic treatment with TSA might have an overall adverse effect on motor recovery after SCI in aged animals.
|mesh-terms=* Aging
* Animals
* Axons
* GAP-43 Protein
* Gene Deletion
* Gene Expression
* Histone Deacetylase Inhibitors
* Histone Deacetylases
* Hydroxamic Acids
* Mice, Transgenic
* Motor Activity
* Nerve Regeneration
* PTEN Phosphohydrolase
* Recovery of Function
* Spinal Cord
* Spinal Cord Injuries
|keywords=* Aging
* Epigenetics
* Histone deacetylase
* Pten
* Regeneration
* Spinal cord injury
|full-text-url=https://sci-hub.do/10.1016/j.neurobiolaging.2020.02.006
}}
{{medline-entry
|title=miR-155 inhibits mitophagy through suppression of [[BAG5]], a partner protein of [[PINK1]].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31948758
|abstract=Removal of dysfunctional mitochondria is essential step to maintain normal cell physiology, and selective autophagy in mitochondria, called mitophagy, plays a critical role in quality control of mitochondria. While in several diseases and aging, disturbed mitophagy has been observed. In stem cells, accumulation of damaged mitochondria can lead to deterioration of stem cell properties. Here, we focused on miR-155-5p (miR-155), one of the most prominent miRNAs in inflammatory and aged tissues, and found that miR-155 disturbed mitophagy in mesenchymal stem cells (MSCs). As a molecular mechanism of miR-155-mediated mitophagy suppression, we found that [[BCL2]] associated athanogene 5 ([[BAG5]]) is a direct target of miR-155. Reduction of [[BAG5]] resulted in destabilization of [[PTEN]]-induced kinase ([[PINK1]]) and consequently disrupted mitophagy. Our study suggests a novel mechanism connecting aging and aging-associated inflammation with mitochondrial dysfunction in stem cells through a miRNA-mediated mechanism.
|mesh-terms=* Adaptor Proteins, Signal Transducing
* Aging
* Animals
* Cell Line
* Cells, Cultured
* Down-Regulation
* Humans
* Male
* Mesenchymal Stem Cells
* Mice, Inbred C57BL
* MicroRNAs
* Mitophagy
* Protein Interaction Maps
* Protein Kinases
* Up-Regulation
|keywords=* Aging
* Bone marrow MSCs
* Mitophagy
* miR-155
|full-text-url=https://sci-hub.do/10.1016/j.bbrc.2020.01.022
}}
{{medline-entry
|title=Environmental Exposures and Asthma Development: Autophagy, Mitophagy, and Cellular Senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31849968
|abstract=Environmental pollutants and allergens induce oxidative stress and mitochondrial dysfunction, leading to key features of allergic asthma. Dysregulations in autophagy, mitophagy, and cellular senescence have been associated with environmental pollutant and allergen-induced oxidative stress, mitochondrial dysfunction, secretion of multiple inflammatory proteins, and subsequently development of asthma. Particularly, particulate matter 2.5 (PM ) has been reported to induce autophagy in the bronchial epithelial cells through activation of AMP-activated protein kinase (AMPK), drive mitophagy through activating [[PTEN]]-induced kinase 1(PINK1)/Parkin pathway, and induce cell cycle arrest and senescence. Intriguingly, allergens, including [i]ovalbumin[/i] (OVA), [i]Alternaria alternata[/i], and [i]cockroach allergen[/i], have also been shown to induce autophagy through activation of different signaling pathways. Additionally, mitochondrial dysfunction can induce cell senescence due to excessive ROS production, which affects airway diseases. Although autophagy and senescence share similar properties, recent studies suggest that autophagy can either accelerate the development of senescence or prevent senescence. Thus, in this review, we evaluated the literature regarding the basic cellular processes, including autophagy, mitophagy, and cellular senescence, explored their molecular mechanisms in the regulation of the initiation and downstream signaling. Especially, we highlighted their involvement in environmental pollutant/allergen-induced major phenotypic changes of asthma such as airway inflammation and remodeling and reviewed novel and critical research areas for future studies. Ultimately, understanding the regulatory mechanisms of autophagy, mitophagy, and cellular senescence may allow for the development of new therapeutic targets for asthma.
|mesh-terms=* Airway Remodeling
* Asthma
* Autophagy
* Cellular Senescence
* Disease Susceptibility
* Environmental Exposure
* Humans
* Mitophagy
* Oxidative Stress
* Respiratory Mucosa
|keywords=* asthma
* autophagy
* mitophagy
* oxidative stress
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896909
}}
{{medline-entry
|title=Alcohol drinking exacerbates neural and behavioral pathology in the 3xTg-AD mouse model of Alzheimer's disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31733664
|abstract=Alzheimer's disease (AD) is a progressive neurodegenerative disorder that represents the most common cause of dementia in the United States. Although the link between alcohol use and AD has been studied, preclinical research has potential to elucidate neurobiological mechanisms that underlie this interaction. This study was designed to test the hypothesis that nondependent alcohol drinking exacerbates the onset and magnitude of AD-like neural and behavioral pathology. We first evaluated the impact of voluntary 24-h, two-bottle choice home-cage alcohol drinking on the prefrontal cortex and amygdala neuroproteome in C57BL/6J mice and found a striking association between alcohol drinking and AD-like pathology. Bioinformatics identified the AD-associated proteins [[MAPT]] (Tau), amyloid beta precursor protein ([[APP]]), and presenilin-1 (PSEN-1) as the main modulators of alcohol-sensitive protein networks that included AD-related proteins that regulate energy metabolism (ATP5D, [[HK1]], [[AK1]], [[PGAM1]], CKB), cytoskeletal development (BASP1, [[CAP1]], [[DPYSL2]] [CRMP2], [[ALDOA]], [[TUBA1A]], [[CFL2]], ACTG1), cellular/oxidative stress (HSPA5, [[HSPA8]], [[ENO1]], ENO2), and DNA regulation (PURA, YWHAZ). To address the impact of alcohol drinking on AD, studies were conducted using 3xTg-AD mice that express human [[MAPT]], [[APP]], and PSEN-1 transgenes and develop AD-like brain and behavioral pathology. 3xTg-AD and wild-type mice consumed alcohol or saccharin for 4 months. Behavioral tests were administered during a 1-month alcohol-free period. Alcohol intake induced AD-like behavioral pathologies in 3xTg-AD mice including impaired spatial memory in the Morris Water Maze, diminished sensorimotor gating as measured by prepulse inhibition, and exacerbated conditioned fear. Multiplex immunoassay conducted on brain lysates showed that alcohol drinking upregulated primary markers of AD pathology in 3xTg-AD mice: Aβ 42/40 ratio in the lateral entorhinal and prefrontal cortex and total Tau expression in the lateral entorhinal cortex, medial prefrontal cortex, and amygdala at 1-month post alcohol exposure. Immunocytochemistry showed that alcohol use upregulated expression of pTau (Ser199/Ser202) in the hippocampus, which is consistent with late-stage AD. According to the NIA-AA Research Framework, these results suggest that alcohol use is associated with Alzheimer's pathology. Results also showed that alcohol use was associated with a general reduction in Akt/mTOR signaling via several phosphoproteins (IR, [[IRS1]], [[IGF1R]], [[PTEN]], ERK, mTOR, p70S6K, RPS6) in multiple brain regions including hippocampus and entorhinal cortex. Dysregulation of Akt/mTOR phosphoproteins suggests alcohol may target this pathway in AD progression. These results suggest that nondependent alcohol drinking increases the onset and magnitude of AD-like neural and behavioral pathology in 3xTg-AD mice.
|mesh-terms=* Alcohol Drinking
* Alzheimer Disease
* Amyloid beta-Protein Precursor
* Animals
* Behavior, Animal
* Brain
* Disease Models, Animal
* Mice, Transgenic
* tau Proteins
|keywords=* Aging
* Amyloid beta
* Ethanol
* GSK
* Immunohistochemistry
* Morris Water Maze
* Prepulse inhibition
* Self-administration
* Tau pathology
* Transgenic mouse model
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939615
}}
{{medline-entry
|title=[[PTEN]] loss regulates alveolar epithelial cell senescence in pulmonary fibrosis depending on Akt activation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31527305
|abstract=Idiopathic pulmonary fibrosis (IPF) is an aging-associated disease with poor prognosis. The mechanisms underlying the role of alveolar epithelial cell (AEC) senescence in IPF remain poorly understood. We aimed to investigate if [[PTEN]]/Akt activates AEC senescence to induce pulmonary fibrosis. We investigated the association between [[PTEN]]/Akt and cellular senescence in lung tissues from IPF patients. As a result, decreased [[PTEN]] and activated Akt pathway were found in AECs in fibrotic lung tissues detected by immunohistochemistry (IHC) and immunofluorescence (IF). Increased expression levels of aging-associated markers (P21  and SA-β-gal) in AECs treated with bleomycin were found. AEC senescence was accelerated by [[PTEN]] knockdown and attenuated by [[PTEN]] overexpression. Bleomycin induced AEC senescence was reversed by Akt2 knockdown and the pharmacological inhibitors (LY294002 and MK2206) of the Akt pathway. Reducing Akt activation dramatically improved lung fibrosis in a fibrotic mice model. In addition, a co-immunoprecipitation (co-IP) assay demonstrated that [[PTEN]] physically associated with Akt. These indicated that senescent AECs modulated by the [[PTEN]]/Akt pathway promote lung fibrosis. In conclusion, our study demonstrated that as a trigger indicator in IPF, the senescence process in AECs should be a potential therapeutic target and that the [[PTEN]]/Akt pathway may be a promising candidate for intervention.
|mesh-terms=* Aging
* Cellular Senescence
* Epithelial Cells
* Humans
* Idiopathic Pulmonary Fibrosis
* PTEN Phosphohydrolase
* Proto-Oncogene Proteins c-akt
* Pulmonary Alveoli
* Respiratory Mucosa
|keywords=* aging
* cellular senescence
* phosphatase and tension homolog deleted on chromosome ten
* protein kinase B
* pulmonary fibrosis
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781970
}}
{{medline-entry
|title=Adipose-Derived Stem/Stromal Cells Recapitulate Aging Biomarkers and Show Reduced Stem Cell Plasticity Affecting Their Adipogenic Differentiation Capacity.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31298565
|abstract=Stromal mesenchymal stem cells ([[MSC]]s) have the capability to self-renew and can differentiate into multiple cell types of the mesoderm germ layer, but their properties are affected by molecular aging mechanisms. [[MSC]]s can be obtained from adipose tissue termed as adipose-derived stem/stromal cells (ASCs) representing a promising tool for studying age-related diseases in detail. ASCs from young (16 weeks) and old (>108 weeks) rabbits were successfully isolated and propagated. ASCs showed the typical morphology and stained positive for CD105, Vimentin, Collagenase 1A, and negative for [[CD14]], CD90, and CD73, demonstrating their mesenchymal origin. ASCs expressed [[MSC]] markers, including [i]MYC[/i], [i]KLF4[/i], [i]CHD1[/i], [i]REST[/i], and [i]KAT6A[/i], whereas pluripotency-related genes, such as [i]NANOG[/i], [i]OCT4[/i], and [i]SOX2[/i], were not expressed. Aged ASCs showed altered protein and mRNA levels of [[APOE]], [[ATG7]], [[FGF2]], [[PTEN]], and [[SIRT1]]. Adipogenic differentiation of old visceral ASCs was significantly decreased compared with young visceral ASCs. We successfully established rabbit ASC cultures representing an [i]in vitro[/i] model for the analysis of stem cell aging mechanisms. ASCs, obtained from old female rabbits, showed age- and source-specific alteration due to aging of the donor. Stem cell plasticity was altered with age as shown by reduced adipogenic differentiation capacity.
|mesh-terms=* Adipogenesis
* Adipose Tissue
* Aging
* Animals
* Biomarkers
* Cell Differentiation
* Cell Plasticity
* Cell Proliferation
* Cells, Cultured
* Female
* Mesenchymal Stem Cells
* Rabbits
|keywords=* adipogenic differentiation
* adipose-derived stem/stromal cells
* aging biomarkers
* and stem cell plasticity
* healthy aging
|full-text-url=https://sci-hub.do/10.1089/cell.2019.0010
}}
{{medline-entry
|title=Role of IL-37 in Cardiovascular Disease Inflammation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31292092
|abstract=Inflammation is closely related to the pathogenesis and prognosis of cardiovascular disease (CVD). Interleukin-37 (IL-37), an anti-inflammatory IL-1 family cytokine, shifts cytokine expression from pro- to anti-inflammation via regulation of macrophage polarization and lipid metabolism. In macrophages, IL-37 functions through both intracellular and extracellular pathways to regulate the activity of NF-kB and [[PTEN]] as well as the expression of cytokines, including IL-1β, IL-6, and IL-10. Moreover, IL-37 levels are increased in the serum of patients with heart failure, atherosclerosis, and acute coronary syndrome with no evidence of anti-inflammatory effects. However, transgenic overexpression of IL-37 improves cardiac infarct and attenuates atherosclerosis plaque expansion. Hence, it is worthwhile to investigate the precise mechanism and role of IL-37 in the pathogenesis of CVD, which may provide deeper understanding of the inflammatory response in this context. This review summarizes the regulatory role of IL-37 in systematic inflammation induced by CVD and highlights recent advancements in the clinical application of IL-37 as a therapeutic agent or biomarker for diagnosis of CVD.
|mesh-terms=* AMP-Activated Protein Kinases
* Aging
* Biomarkers
* Cardiovascular Diseases
* Cytokines
* Down-Regulation
* Humans
* Inflammation
* Interleukin-1
* Macrophages
* NF-kappa B
* Plaque, Atherosclerotic
* rho-Associated Kinases

|full-text-url=https://sci-hub.do/10.1016/j.cjca.2019.04.007
}}
{{medline-entry
|title=Abrogation of B-Raf  induced senescence by FoxM1 expression.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31270027
|abstract=B-Raf  oncogene mutation occurs in various cancers and is associated with tumor initiation. However, genetic modification of B-Raf  in cells induces MAPK activation and results in oncogene-induced senescence. Overcoming the oncogene-induced senescence by B-Raf  requires activation of another oncogene pathway, such as AKT signaling. In the present study, we explored the factors involved in overcoming the senescence program in cells activated by B-Raf  and AKT signaling. B-Raf  activation caused a feedback inhibition of AKT phosphorylation and resulted in downregulation of FoxM1, one of the AKT downstream components. AKT activation by [[PTEN]] downregulation induced FoxM1 expression, and co-expression of B-Raf  and FoxM1 overcame the cellular senescence. These observations suggested that FoxM1 is critical downstream gene of AKT and functions to overcome B-Raf -induced senescence.
|mesh-terms=* Amino Acid Substitution
* Cell Proliferation
* Cell Transformation, Neoplastic
* Cellular Senescence
* Feedback, Physiological
* Fibroblasts
* Forkhead Box Protein M1
* Gene Expression Regulation
* Humans
* Mutation
* PTEN Phosphohydrolase
* Phosphorylation
* Primary Cell Culture
* Proto-Oncogene Proteins B-raf
* Proto-Oncogene Proteins c-akt
* Signal Transduction
|keywords=* B-RafV600E induced senescence
* FoxM1
|full-text-url=https://sci-hub.do/10.1016/j.bbrc.2019.06.144
}}
{{medline-entry
|title=Oncogenic mutations in histologically normal endometrium: the new normal?
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31187483
|abstract=The advent of next generation sequencing has vastly improved the resolution of mutation detection, thereby both increasing the resolution of the analysis of cancer tissues and shining light on the existence of somatic driver mutations in normal tissues, even in the absence of cancer. Studies have described somatic driver mutations in normal skin, blood, peritoneal washings, and esophageal epithelium. Such findings prompt speculation on whether such mutations exist in other tissues, such as the eutopic endometrium in particular, due to the highly regenerative nature of the endometrium and the recent observation of recurrent somatic driver mutations in deep infiltrating and iatrogenic endometriosis (tissues believed to be derived from the eutopic endometrium) by our group and others. In the current study we investigated the presence of somatic driver mutations in histologically normal endometrium from women lacking evidence of gynecologic malignancy or endometrial hyperplasia. Twenty-five women who underwent hysterectomies and 85 women who underwent endometrial biopsies were included in this study. Formalin-fixed, paraffin-embedded tissue specimens were analyzed by means of targeted sequencing followed by orthogonal validation with droplet digital PCR. [[PTEN]] and [[ARID1A]] immunohistochemistry (IHC) was also performed as surrogates for inactivating mutations in the respective genes. Overall, we observed somatic driver-like events in over 50% of normal endometrial samples analyzed, including hotspot mutations in [[KRAS]], [[PIK3CA]], and [[FGFR2]] as well as [[PTEN]]-loss by IHC. Analysis of anterior and posterior samplings collected from women who underwent hysterectomies was consistent with the presence of somatic driver mutations within clonal pockets spread throughout the uterus. The prevalence of such oncogenic mutations also increased with age (OR: 1.05 [95% CI: 1.00-1.10], p = 0.035). These findings have implications on our understanding of aging and so-called 'normal tissues', thereby necessitating caution in the utilization of mutation-based early detection tools for endometrial or other cancers. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley