Редактирование: TLR4

Toll-like receptor 4 precursor (EC 3.2.2.6) (hToll) (CD284 antigen)

==Publications==

{{medline-entry
|title=Cigarette smoke induction of [[S100A9]] contributes to chronic obstructive pulmonary disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32964723
|abstract=S100 calcium-binding protein A9 ([[S100A9]]), is elevated in plasma and bronchoalveolar lavage fluid (BALF) of COPD patients and aging enhances [[S100A9]] expression in several tissues. Currently, the direct impact of [[S100A9]]-mediated signaling on lung function and within the aging lung is unknown. Here, we observed that elevated [[S100A9]] levels in human BALF correlated with age. Elevated lung levels of [[S100A9]] were higher in older mice compared to young animals and coincided with pulmonary function changes. Both acute and chronic exposure to cigarette smoke enhanced [[S100A9]] levels in age-matched mice. To examine the direct role of [[S100A9]] on the development of COPD, S100a9  mice or inhibited activity with paquinimod, and exposed the models to chronic cigarette smoke [[S100A9]] depletion and inhibition attenuated the loss of lung function, pressure-volume loops, airway inflammation, lung compliance, and [[FEV]] /FVC, compared to age-matched wild type or vehicle administered animals. Loss of S100a9 signaling reduced cigarette smoke-induced airspace enlargement, alveolar remodeling, lung destruction, ERK, and c-RAF phosphorylation, MMP-3, MMP-9, MCP-1, IL-6, and KC release into the airways. Paquinimod administered to non-smoked aged animals reduced age-associated loss of lung function. Since fibroblasts play a major role in the production and maintenance of extracellular matrix in emphysema, primary lung fibroblasts were treated with the ERK inhibitor, LY3214996, or the c-RAF inhibitor, GW5074, resulting in less [[S100A9]]-induced MMP-3, MMP-9, MCP-1, IL-6, and IL-8. Silencing [[TLR4]], RAGE or EMMPRIN prevented [[S100A9]]-induced phosphorylation of ERK and c-RAF. Our data suggest that [[S100A9]] signaling contributes to the progression of smoke and age-related COPD.

|keywords=* Cigarette smoke
* S100A9
* aging
* kinase
* pulmonary function
|full-text-url=https://sci-hub.do/10.1152/ajplung.00207.2020
}}
{{medline-entry
|title=Age-Dependent Changes of Adipokine and Cytokine Secretion From Rat Adipose Tissue by Endogenous and Exogenous Toll-Like Receptor Agonists.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32973755
|abstract=White adipose tissue but recently also brown adipose tissue have emerged as endocrine organs. Age-associated obesity is accompanied by prolonged and elevated lipopolysaccharide (LPS)-induced sickness symptoms and increased cytokine and adipokine levels in the circulation partially originating from adipose tissue. In the present study, [i]ex vivo[/i] fat explants were used to investigate how the exogenous pathogen-associated molecular pattern (PAMP) LPS or the endogenous danger-associated molecular patterns (DAMPs) high mobility group box-1 protein ([[HMGB1]]) and biglycan modulate the release of cytokines and adipokines/batokines and, thus, could influence systemic and/or local inflammation. The response of adipose tissue (epididymal, retroperitoneal, subcutaneous, and brown) was compared between young lean and old obese rats (2 vs. 24 months old). LPS induced a strong interleukin (IL)-6 and tumor necrosis factor (TNF) alpha release into the supernatant of all adipose tissue types investigated. [[HMGB1]] (subcutaneous) and biglycan (retroperitoneal) led to an increased release of IL-6 and TNFalpha ([[HMGB1]]) and decreased visfatin and adiponectin (biglycan) secretion from epididymal adipose tissue (young rats). Visfatin was also decreased by [[HMGB1]] in retroperitoneal adipose tissue of old rats. We found significantly higher leptin (all fat pads) and adiponectin (subcutaneous) levels in supernatants of adipose tissue from old compared to young rats, whereas visfatin secretion showed the opposite. The expression of the biglycan receptor Toll-like receptor (TLR) 2 as well as the LPS and [[HMGB1]] receptors [[TLR4]] and receptor for advanced glycation end products (RAGE) were reduced with age ([[TLR4]]/RAGE) and by stimulation with their ligands (subcutaneous). Overall, we revealed that adipokines/adipose-tissue released cytokines show some modulation of their release caused by mediators of septic (batokines) and sterile inflammation with potential implication for acute and chronic disease. Moreover, aging may increase or decrease the release of fat-derived mediators. These data show that DAMPS and LPS locally modulate cytokine secretion while only DAMPS but not LPS can locally alter adipokine secretion during inflammation.

|keywords=* adipokines
* aging
* batokines
* biglycan
* cytokines
* fat explant cultures
* high mobility group box-1 protein
* lipopolysaccharide
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466552
}}
{{medline-entry
|title=Role of Toll Like Receptor 4 in Alzheimer's Disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32983082
|abstract=Long-term evidence has confirmed the involvement of an inflammatory component in neurodegenerative disorders including Alzheimer's disease (AD). This view is supported, in part, by data suggesting that selected non-steroidal anti-inflammatory drugs (NSAIDs) provide protection. Additionally, molecular players of the innate immune system have recently been proposed to contribute to these diseases. Toll-like receptors (TLRs) are transmembrane pattern-recognition receptors of the innate immune system that recognize different pathogen-derived and tissue damage-related ligands. [[TLR4]] mediated signaling has been reported to contribute to the pathogenesis of age-related neurodegenerative diseases, including AD. Although the pathophysiology of AD is not clear, soluble aggregates (oligomers) of the amyloid β peptide (Aβo) have been proven to be key players in the pathology of AD. Among others, Aβo promote Ca  entry and mitochondrial Ca  overload leading to cell death in neurons. [[TLR4]] has recently been found to be involved in AD but the mechanisms are unclear. Our group recently reported that lipopolysaccharide (LPS), a [[TLR4]] receptor agonist, increases cytosolic Ca  concentration leading to apoptosis. Strikingly, this effect was only observed in long-term cultured primary neurons considered a model of aging neurons, but not in short-term cultured neurons resembling young neurons. These effects were significantly prevented by pharmacological blockade of [[TLR4]] receptor signaling. Moreover, [[TLR4]] expression in rat hippocampal neurons increased significantly in aged neurons [i]in vitro[/i]. Therefore, molecular patterns associated with infection and/or brain cell damage may activate [[TLR4]] and Ca  signaling, an effect exacerbated during neuronal aging. Here, we briefly review the data regarding the involvement of [[TLR4]] in AD.

|keywords=* Alzheimer’s disease
* TLR4
* aging
* amyloid beta oligomers
* calcium
* hippocampal neurons
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479089
}}
{{medline-entry
|title=Effects of aging and lifelong aerobic exercise on expression of innate immune components in human skeletal muscle.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32969782
|abstract=The purpose of this investigation was to evaluate the effects of aging and lifelong exercise on skeletal muscle components of the innate immune system. Additionally, the effects of an acute resistance exercise (RE) challenge were explored. Three groups of men were studied: young exercisers (YE: [i]n[/i] = 10, 25 ± 1 yr; V̇o : 53 ± 3 mL/kg/min; quadriceps size: 78 ± 3 cm ), lifelong aerobic exercisers with a 53 ± 1 yr training history (LLE; [i]n[/i] = 21, 74 ± 1 yr; V̇o : 34 ± 1 mL/kg/min; quadriceps size: 67 ± 2 cm ), and old healthy nonexercisers (OH: [i]n[/i] = 10, 75 ± 1 yr; V̇o : 22 ± 1 mL/kg/min, quadriceps size: 56 ± 3 cm ). Vastus lateralis muscle biopsies were obtained in the basal state and 4 h after RE (3 × 10 reps, 70% of 1 repetition maximum) to assess Toll-like receptors (TLR)1-10, TLR adaptors (Myd88 and TRIF), and NF-κB pathway components (IκΒα and IKKβ) mRNA expression. Basal [[TLR3]], [[TLR6]], and [[TLR7]] tended to be higher ([i]P[/i] ≤ 0.10) with aging (LLE and OH combined). In general, RE increased expression of [[TLR1]] and [[TLR8]] ([i]P[/i] ≤ 0.10) and [[TLR3]] and [[TLR4]] ([i]P[/i] < 0.05), although [[TLR3]] did not respond in OH. Both TLR adaptors also responded to the exercise bout; these were primarily (Myd88, main effect [i]P[/i] ≤ 0.10) or exclusively (TRIF, [i]P[/i] < 0.05) driven by the OH group. In summary, aging appears to increase basal expression of some innate immune components in human skeletal muscle, and lifelong aerobic exercise does not affect this age-related increase. An exercise challenge stimulates the expression of several TLRs, while the TLR adaptor response appears to be dysregulated with aging and maintained with lifelong exercise. Partially preserved muscle mass, coupled with a notable immunity profile, suggests lifelong exercisers are likely better prepared for a stress that challenges the immune system.  Findings from this investigation provide novel insight into the effect of aging and lifelong aerobic exercise on structural components of the innate immune system in skeletal muscle of humans. Data presented here suggest aging increases basal expression of select Toll-like receptors (TLRs), and lifelong exercise does not impact this age-related increase. Additionally, acute exercise stimulates gene expression of several TLRs, while the adaptor response is likely dysregulated with aging and maintained with lifelong exercise.

|keywords=* TLR
* aging
* innate immunity
* lifelong exercise
* skeletal muscle
|full-text-url=https://sci-hub.do/10.1152/japplphysiol.00615.2020
}}
{{medline-entry
|title=Active Peptide KF-8 from Rice Bran Attenuates Oxidative Stress in a Mouse Model of Aging Induced by d-Galactose.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32942847
|abstract=This study investigated the effects of a physiologically active peptide derived from rice bran (KF-8) on oxidative stress in d-galactose (d-gal)-induced aging mice and the underlying molecular mechanisms. The aging model was developed by subcutaneously injecting Institute of Cancer Research mice with 250 mg/kg d-gal daily for 12 weeks and simultaneously treating them with 30 mg/kg KF-8. The relative expression levels of Nrf2 and NF-κB in the liver were determined by the western blot. The regulation of Nrf2 and NF-κBp65 by KF-8 was further validated in NIH/3T3 cells. Compared with the control mice, the aging mice had significantly decreased body weights as well as superoxide dismutase and GSH-Px levels ([i]p[/i] < 0.05); however, they had increased serum reactive oxygen species and malondialdehyde and 8-hydroxydeoxyguanosine levels accompanied by aortic and brain injuries. They also had elevated RAGE, [[TLR4]], IκB, Bax, and caspase-8 expressions and NF-κB/p65 phosphorylation but reduced BcL-2 expression in the liver. Moreover, [i]in vitro[/i] experiments demonstrated that the pretreatment of H O -treated NIH/3T3 cells with KF-8 significantly mitigated the NF-κB signaling and attenuated the Nrf2 nuclear transport (both [i]p[/i] < 0.05). In conclusion, KF-8 treatment inhibited aging-induced oxidative stress-related organ injury in mice by attenuating NF-κB/p38 signaling and preserving Nrf2 activity.

|keywords=* KF-8
* NF-κB
* Nrf2
* aging
* oxidative stress
|full-text-url=https://sci-hub.do/10.1021/acs.jafc.0c04358
}}
{{medline-entry
|title=Contribution of Porphyromonas gingivalis lipopolysaccharide to experimental periodontitis in relation to aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32851571
|abstract=Aging is associated with increased prevalence and severity of pathogenic outcomes of periodontal disease, including soft tissue degeneration and bone loss around the teeth. Although lipopolysaccharide (LPS) derived from the key periodontal pathogen Porphyromonas gingivalis (Pg) plays an important role in the promotion of inflammation and osteoclastogenesis via toll-like receptor (TLR)4 signaling, its pathophysiological role in age-associated periodontitis remains unclear. This study investigated the possible effects of Pg-LPS on RANKL-primed osteoclastogenesis and ligature-induced periodontitis in relation to aging using young (2 months old) and aged (24 months old) mice. To the best of our knowledge, our results indicated that expression of [[TLR4]] was significantly diminished on the surface of osteoclast precursors isolated from aged mice compared with that of young mice. Furthermore, our data demonstrated that the [[TLR4]] antagonist (TAK242) dramatically decreased the numbers of tartrate-resistant acid phosphatase positive (TRAP ) osteoclasts differentiated from RANKL-primed young osteoclast precursors (OCPs) compared with those isolated from aged mice in response to Pg-LPS. In addition, using a ligature-induced periodontitis mouse model, we demonstrated that Pg-LPS elevated (1) secretion of senescence-associated secretory phenotype (SASP) markers, including the pro-inflammatory cytokines [[TNF]]-α, IL-6, and IL-1β, as well as osteoclastogenic RANKL, and (2) the number of OCPs and TRAP  osteoclasts in the periodontal lesion induced in young mice. In contrast, Pg-LPS had little, or no, effect on the promotion of periodontitis inflammation induced in aged mice. Altogether, these results indicated that periodontal disease in older mice occurs in a manner independent of canonical signaling elicited by the Pg-LPS/[[TLR4]] axis.

|keywords=* Aging
* Bone loss
* Osteoclastogenesis
* Periodontitis
* Porphyromonas gingivalis lipopolysaccharide
|full-text-url=https://sci-hub.do/10.1007/s11357-020-00258-1
}}
{{medline-entry
|title=Commentary on Some Recent Theses Relevant to Combating Aging: August 2020.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32718230
|abstract=Theses reviewed in this issue include "Characterization and Purification of Putative Stem Cells from the Adult Murine Pancreas," "Inhibition of [[TLR4]] Minimizes Islet Damage due to Sterile Inflammation and Improves Islet Transplant Outcomes," "Liquefaction of the Brain Following Stroke Shares Multiple Characteristics with Atherosclerosis and Mediates Secondary Neurodegeneration in an Osteopontin-Dependent Mechanism," "Manipulating the Segregation of Human Mitochondrial DNA," "Role of Mitochondria in Plasma Membrane Repair and Pathogenesis of Muscular Dystrophy," and "The Role of Cytosolic Accumulation of Nuclear DNA in Retinal-Pigment Epithelium Dysfunction and Age-Related Macular Degeneration."

|keywords=* aging
* dissertations
* theses
|full-text-url=https://sci-hub.do/10.1089/rej.2020.2378
}}
{{medline-entry
|title=Sialylation and Galectin-3 in Microglia-Mediated Neuroinflammation and Neurodegeneration.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32581723
|abstract=Microglia are brain macrophages that mediate neuroinflammation and contribute to and protect against neurodegeneration. The terminal sugar residue of all glycoproteins and glycolipids on the surface of mammalian cells is normally sialic acid, and addition of this negatively charged residue is known as "sialylation," whereas removal by sialidases is known as "desialylation." High sialylation of the neuronal cell surface inhibits microglial phagocytosis of such neurons, via: (i) activating sialic acid receptors (Siglecs) on microglia that inhibit phagocytosis and (ii) inhibiting binding of opsonins C1q, [[C3]], and galectin-3. Microglial sialylation inhibits inflammatory activation of microglia via: (i) activating Siglec receptors [[CD22]] and [[CD33]] on microglia that inhibit phagocytosis and (ii) inhibiting Toll-like receptor 4 ([[TLR4]]), complement receptor 3 (CR3), and other microglial receptors. When activated, microglia release a sialidase activity that desialylates both microglia and neurons, activating the microglia and rendering the neurons susceptible to phagocytosis. Activated microglia also release galectin-3 (Gal-3), which: (i) further activates microglia via binding to [[TLR4]] and [[TREM2]], (ii) binds to desialylated neurons opsonizing them for phagocytosis via Mer tyrosine kinase, and (iii) promotes Aβ aggregation and toxicity [i]in vivo[/i]. Gal-3 and desialylation may increase in a variety of brain pathologies. Thus, Gal-3 and sialidases are potential treatment targets to prevent neuroinflammation and neurodegeneration.

|keywords=* aging
* desialylation
* galectin-3
* microglia
* neurodegeneration
* phagocytosis
* sialic acid
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296093
}}
{{medline-entry
|title=Chemerin facilitates intervertebral disc degeneration via [[TLR4]] and [[CMKLR1]] and activation of NF-kB signaling pathway.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32526705
|abstract=Now days, obesity is a major risk factor for intervertebral disc degeneration (IDD). However, adipokine, such as chemerin is a novel cytokine, which is secreted by adipose tissue, and are thought to be played major roles in various degenerative diseases. Obese individuals are known to have high concentration of serum chemerin. Our purpose was to study whether chemerin acts as a biochemical relationship between obesity, and IDD. In this study, we found that the expression level of chemerin was significantly increased in the human degenerated nucleus pulposus (NP) tissues, and had higher level in the obese people than the normal people. Chemerin significantly increased the inflammatory mediator level, contributing to ECM degradation in nucleus pulposus cells (NPCs). Furthermore, chemerin overexpression aggravates the puncture-induced IVDD progression in rats, while knockdown [[CMKLR1]] reverses IVDD progression. Chemerin activates the NF-kB signaling pathway via its receptors [[CMKLR1]], and [[TLR4]] to release inflammatory mediators, which cause matrix degradation, and cell aging. These findings generally provide novel evidence supporting the causative role of obesity in IDD, which is essentially important to literally develop novel preventative or generally therapeutic treatment in the disc degenerative disorders.

|keywords=* chemerin
* inflammation
* intervertebral disc
* nucleus pulposus
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343479
}}
{{medline-entry
|title=Brazilian berry extract (Myrciaria jaboticaba): A promising therapy to minimize prostatic inflammation and oxidative stress.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32460430
|abstract=Brazilian berry is a fruit popularly known as "Jaboticaba," rich in bioactive compounds with antioxidant and anti-inflammatory properties. Senescence and overweight are increasing worldwide and are considered risk factors to prostatic pathogenesis mainly due to oxidative and inflammatory processes induction. Thus, this study aimed to evaluate the effect of two increasing doses of the patented jaboticaba peel extract (PJE) on oxidative-stress and inflammation in the prostate of aging or high-fat-fed aging mice. PJE and/or high-fat diet (HFD) treatments started with 11-month-old mice and lasted 60 days. The levels or the immunoexpression of different inflammatory (nuclear factor κB [NFκB], CD3 , cyclooxygenase 2 [COX-2], toll-like receptor 4 [[[TLR4]]], phosphorylated signal transducers and activators of transcription 3 [pSTAT-3], tumor necrosis factor α [[[TNF]]-α], interleukin 6 [IL-6], and IL-1β) and oxidative-stress (catalase, superoxide dismutase 2 [[[SOD2]]], glutathione reductase [[[GSR]]], reduced glutathione, and glutathione peroxidase 3 [GPx3]) related molecules were analyzed by western-blotting, immunohistochemistry, and enzyme-linked immunosorbent assays. Both PJE doses reduced the levels of oxidative-stress-related molecules (GPx3, [[GSR]], catalase), lipid peroxidation (4-hydroxynonenal), inflammatory mediators (COX-2, [[TNF]]-α, and pSTAT-3) and CD3  T cells number, which were associated with the maintenance of the glandular morphological integrity in aging and HFD-fed-aging mice. Nevertheless, only the high PJE dose reduced the NFκB and [[TLR4]] levels in aging mice; and [[SOD2]], IL-6, and IL-1β levels in HFD-aging mice. Aging itself promoted an oxidative inflammation in the prostate, interfering in the levels of the different oxidative-stress, lipid peroxidation, and inflammatory mediators evaluated, in association with high incidence of prostate epithelial and stromal damages. The HFD intake intensified aging alterations, showing an unfavorable prostatic microenvironment prone to oxidative and inflammatory damages. PJE exerted a dose-dependent effect controlling inflammation and oxidative-stress in aging and HFD-fed aging mice prostate. This fact contributed to prostate microenvironment balance recovery, preserving the tissue architecture of this gland. Thus, the PJE emerges as a potential therapy to prevent inflammation and oxidative stress in the prostate.
|mesh-terms=* Age Factors
* Animals
* Anti-Inflammatory Agents
* Antioxidants
* Cyclooxygenase 2
* Diet, High-Fat
* Dose-Response Relationship, Drug
* Fruit
* Interleukin-1beta
* Interleukin-6
* Lipid Peroxidation
* Male
* Mice
* Myrtaceae
* Oxidative Stress
* Plant Extracts
* Prostatitis
* T-Lymphocytes
|keywords=* aging
* bioactive compounds
* obesity
* overweight
* polyphenols
|full-text-url=https://sci-hub.do/10.1002/pros.24017
}}
{{medline-entry
|title=Toll-like receptor 4 differentially regulates adult hippocampal neurogenesis in an age- and sex-dependent manner.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32343455
|abstract=Toll-like receptor 4 ([[TLR4]]) is primarily responsible for initiating an immune response following pathogen recognition. However, [[TLR4]] is also expressed on neural progenitor cells and has been reported to regulate hippocampal neurogenesis as young male [[TLR4]] knockout mice show increases in cell proliferation and doublecortin positive cells. Whether these effects occur in both sexes and are sustained with normal aging is currently unknown. The present study evaluated whether [[TLR4]] deficiency alters adult hippocampal neurogenesis in young (3-4 months) and aged (18-20 months), male and female, [[TLR4]] deficient ([[TLR4]]-/-; B6.B10ScN-Tlr4lps-del/JthJ) and wild type (WT) mice. Additionally, neurogenesis within the dorsal and the ventral hippocampal subdivisions was evaluated to determine if [[TLR4]] has differential effects across the hippocampus. Bromodeoxyuridine (BrdU) was administered to quantify new cell survival as well as cell differentiation. Ki-67 was measured to evaluate cell proliferation. Results show that young [[TLR4]]-/- females had higher rates of proliferation and neuronal differentiation in both the dorsal and ventral hippocampus relative to WT females. Young [[TLR4]]-/- males show elevated proliferation and neuronal differentiation mainly in the ventral hippocampus. While young [[TLR4]]-/- mice show enhanced neurogenesis compared to young WT mice, the increase was not apparent in the aged [[TLR4]]-/- mice. Both aged WT and [[TLR4]]-/- mice showed a decrease in proliferation, new cell survival, and neuronal differentiation compared to young WT and [[TLR4]]-/- mice. The data collectively indicate that [[TLR4]] regulates hippocampal neurogenesis in young adults, but that these effects are region-specific in males and that females show broader changes in neurogenesis throughout the hippocampus.

|keywords=* TLR4
* adult hippocampal neurogenesis
* aging
* proliferation
* sex differences
|full-text-url=https://sci-hub.do/10.1002/hipo.23209
}}
{{medline-entry
|title=Aerobic Training Down-Regulates Pentraxin 3 and Pentraxin 3/Toll-Like Receptor 4 Ratio, Irrespective of Oxidative Stress Response, in Elderly Subjects.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32012711
|abstract=Reactive oxygen and nitrogen species-mediated cellular aging has been linked to diseases such as atherothrombosis and cancer. Although pentraxin 3 ([[PTX3]]) is associated with aging-related diseases via [[TLR4]]-dependent anti-inflammatory effects, its relationship with oxidative stress in aging remains to be elucidated. Exercise is proposed as the key intervention for health maintenance in the elderly. This study aimed to examine the association of [[PTX3]] levels with changes in oxidative stress in both plasma and peripheral blood mononuclear cells (PBMCs), following aerobic training in elderly adults. Nine trained and five controls participated in an eight-week aerobic training protocol. Enzyme-linked immunosorbent assay (ELISA) and Western blot analyses were used to determine [[PTX3]], toll-like receptor 4 ([[TLR4]]), and levels of oxidative stress biomarkers [3-nitrotyrosine (3NT), 4-hydroxynonenal (4-HNE), reduced glutathione (GSH), protein carbonyl (PC), reactive oxygen/ nitrogen species (ROS/RNS), trolox equivalent antioxidant capacity (TEAC)] in plasma and/or PBMCs. Results showed a down-regulation of [[PTX3]] expression in PBMCs following aerobic training, along with decreased [[PTX3]]/[[TLR4]] ratios. Oxidative stress responses in PBMCs remained unchanged with the exercise protocol. Comparable levels of plasma [[PTX3]] and oxidative stress biomarkers were observed in trained vs. control groups. No correlation was found between [[PTX3]] and any oxidative stress biomarkers following training. These findings demonstrated the down-regulation of [[PTX3]] and [[PTX3]]/[[TLR4]] ratio, irrespective of oxidative stress response, in elderly adults following eight weeks of aerobic training.

|keywords=* aging
* endurance training
* exercise
* inflammation
* oxidative stress
* pentraxin 3
* toll-like receptor 4
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070734
}}
{{medline-entry
|title=Aging-associated immunosenescence via alterations in splenic immune cell populations in rat.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31838133
|abstract=Immunosenescence is the decline of the host immune system due to aging, resulting in various complications. The splenic lymphoid nodule is the pivotal compartment involved in immunosenescence. In this study, we investigated the important changes in the splenic immune cell populations of aged rats (18-24 months) in comparison with young rats (3-5 months). We, also, studied the effects of aging on the activities of total superoxide dismutase (T-SOD) and malondialdehyde (MDA) levels in spleen of both groups, besides the changes of the splenic architecture. Furthermore, immunohistochemical staining was performed to detect the aging effects in T cells, B cells, macrophages, granulocytes, mast cells, proliferating cells, apoptotic cells, and cells positive for interleukin-1β (IL-1β), interleukin-6 (IL-6), and Toll-like receptor 4 ([[TLR4]]). The aged rats had significantly lower spleen/body weight ratios and smaller splenic nodules, indicating a decline in general immunity in them. With aging, T-SOD activities were decreased, while MDA levels were increased, exhibiting that oxidative stress increases in spleens. In addition, the aged group also had significantly fewer T and B cells, macrophages, granulocytes, IL-6 and [[TLR4]] immuno-positive cells, and proliferating cells in the periarterial lymphatic sheaths, marginal zone, and lymphoid follicles compared with the young group. On the other hand, the number of mast cells and apoptotic cells was significantly increased with age. Therefore, we can conclude that cellular immunity and humoral immunity were crumpled with age.
|mesh-terms=* Animals
* B-Lymphocytes
* Cells, Cultured
* Immunity, Cellular
* Immunosenescence
* Male
* Malondialdehyde
* Oxidative Stress
* Rats
* Rats, Wistar
* Spleen
* Superoxide Dismutase
* T-Lymphocytes
|keywords=* Aging
* Immunohistochemistry
* Immunosenescence
* Oxidative stress
* Spleen
|full-text-url=https://sci-hub.do/10.1016/j.lfs.2019.117168
}}
{{medline-entry
|title=Leptin induces immunosenescence in human B cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31831137
|abstract=Leptin is an adipokine secreted primarily by the adipocytes. Leptin has endocrine and immune functions and increases the secretion of pro-inflammatory cytokines by immune cells. Here we show that incubation of B cells from young lean individuals with leptin increases the frequencies of pro-inflammatory B cells and induces intrinsic B cell inflammation, characterized by mRNA expression of pro-inflammatory cytokines (TNF-α and IL-6), chemokines (IL-8), micro-RNAs (miR-155 and miR-16), [[TLR4]] and p16, a cell cycle regulator associated with immunosenescence. We have previously shown that the expression of these pro-inflammatory markers in unstimulated B cells is negatively associated with the response of the same B cells after in vivo or in vitro stimulation. B cells from young lean individuals, after in vitro incubation with leptin, show reduced class switch and influenza vaccine-specific IgG production. Our results altogether show that leptin makes B cells from youn lean individuals similar to those from young obese and elderly lean individuals, suggesting that leptin may be a mechanisms of immunosenescence in human B cells.
|mesh-terms=* Adult
* Aged
* B-Lymphocytes
* Humans
* Immunoglobulin Class Switching
* Immunosenescence
* Leptin
* Middle Aged
* Obesity
|keywords=* B cells
* Immunosenescence
* Leptin
* Obesity
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002206
}}
{{medline-entry
|title=Cellular senescence induced by [[S100A9]] in mesenchymal stromal cells through [[NLRP3]] inflammasome activation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31727865
|abstract=Bone marrow stromal cells from patients with myelodysplastic syndrome (MDS) display a senescence phenotype, but the underlying mechanism has not been elucidated. Pro-inflammatory signaling within the malignant clone and the bone marrow microenvironment has been identified as a key pathogenetic driver of MDS. Our study revealed that [[S100A9]] is highly-expressed in lower-risk MDS. Moreover, normal primary mesenchymal stromal cells (MSCs) and the human stromal cell line HS-27a co-cultured with lower-risk MDS bone marrow mononuclear cells acquired a senescence phenotype. Exogenous supplemented [[S100A9]] also induced cellular senescence in MSCs and HS-27a cells. Importantly, Toll-like receptor 4 ([[TLR4]]) inhibition or knockdown attenuated the cellular senescence induced by [[S100A9]]. Furthermore, we showed that [[S100A9]] induces [[NLRP3]] inflammasome formation, and IL-1β secretion; findings in samples from MDS patients further confirmed these thoughts. Moreover, ROS and IL-1β inhibition suppressed the cellular senescence induced by [[S100A9]], whereas [[NLRP3]] overexpression and exogenous IL-1β supplementation induces cellular senescence. Our study demonstrated that [[S100A9]] promotes cellular senescence of bone marrow stromal cells via [[TLR4]], [[NLRP3]] inflammasome formation, and IL-1β secretion for its effects. Our findings deepen the understanding of the molecular mechanisms involved in MDS reprogramming of MSCs and indicated the essential role of [[S100A9]] in tumor-environment interactions in bone marrow.
|mesh-terms=* Adolescent
* Adult
* Aged
* Aged, 80 and over
* Calgranulin B
* Case-Control Studies
* Cell Line
* Cells, Cultured
* Cellular Reprogramming
* Cellular Senescence
* Female
* Humans
* Inflammasomes
* Interleukin-1beta
* Male
* Mesenchymal Stem Cells
* Middle Aged
* Myelodysplastic Syndromes
* NLR Family, Pyrin Domain-Containing 3 Protein
* Reactive Oxygen Species
* Signal Transduction
* Stem Cell Niche
* Toll-Like Receptor 4
* Up-Regulation
* Young Adult
|keywords=* NLRP3
* S100A9
* cellular senescence
* mesenchymal stromal cells
* myelodysplastic syndromes
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874461
}}
{{medline-entry
|title=Biomarkers for vascular ageing in aorta tissues and blood samples.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31648011
|abstract=Functional and quantitative alterations and senescence of circulating and expanded endothelial progenitor cells (EPC), as well as systemic and tissue modifications of angiogenetic and inflammatory molecules, were evaluated for predicting age-related vessel wall remodeling, correlating them to intima media thickness (IMT) in the common carotid artery (CCA), a biomarker of early cardiovascular disease and aortic root dilation. A homogenous Caucasian population was included in the study, constituted by 160 healthy subjects (80 old subjects, mean age 72 ± 6.4, range 66-83 years; and 80 younger blood donors, mean age 26.2 ± 3.4, range 21-33 years), and 60 old subjects (mean age 73 ± 1.4 (range 66-83) years) with aortic root dilatation and hypertension, and 60 old people (70 ± 2.8 (age range 66-83)) with sporadic ascending aorta aneurysm (AAA). In addition, 20 control individuals (10 men and 10 women, mean age: 65 ± 8), were also included in the study for evaluating the gene expression's levels, in aorta tissues. Appropriate techniques, practises, protocols, gating strategies and statistical analyses were performed in our evaluations. Interestingly, old people had a significantly reduced functionality and a high grade of senescence (high SA-β-Gal activity and high levels of [[TP53]], p21 and p16 genes) of EPC expanded than younger subjects. The values of related parameters progressively augmented from the old subjects, in good healthy shape, to subjects with hypertension and aorta dilation, and AAA. Moreover, they significantly impacted the endothelium than the alterations in EPC number. No changes, but rather increased systemic levels of VEGF and SDF-1 were also assessed in old people vs. younger donors. Old people also showed significantly increased systemic levels of inflammatory cytokines, and a reciprocal significant reduction of systemic s-Notch 1 than younger subjects. These parameters, also including the number EPC alterations, resulted to be significantly sustained in old people bearers of an inflammatory combined genotype. Consistent with these data, a reduced expression of Notch-1 gene, accompanied by a sustained expression of inflammatory genes (i.e. [[TLR4]], IL-1β, IL-6 and IL-17) were detected in aortic tissues from old control people and AAA cases. Finally, we detected the biological effects induced by all the detected alterations on vessel wall age-related remodeling, by evaluating the IMT in the population studied and correlating it to these alterations. The analysis demonstrated that the unique independent risk predictors for vascular ageing are age, the EPC reduced migratory activity and senescence, high grade of expression of genes inducing EPC senescence and chronic tissue and systemic inflammation. Thus, we propose these parameters, of easy determination in biological samples (i.e. blood and tissue samples) from alive human population, as optimal biomarkers for vascular ageing.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Aging
* Aorta
* Biomarkers
* Carotid Artery, Common
* Carotid Intima-Media Thickness
* Chemokine CXCL12
* Chemotaxis
* Endothelial Progenitor Cells
* Female
* Humans
* Male
* Receptor, Notch1
* Toll-Like Receptor 4
* Vascular Endothelial Growth Factor A
* Young Adult
|keywords=* EPC cell populations
* Endothelium age-related impairment
* Inflammatory cytokines
* Notch and TLR4
* SA-β-Gal activity
* TP53, p21 and p16 genes
|full-text-url=https://sci-hub.do/10.1016/j.exger.2019.110741
}}
{{medline-entry
|title=Accelerated decline in cognition in a mouse model of increased oxidative stress.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31641924
|abstract=Mice deficient in the antioxidant enzyme Cu/Zn-superoxide dismutase (Sod1KO mice) have a significant reduction in lifespan, exhibit many phenotypes of accelerated aging, and have high levels of oxidative stress in various tissues. Age-associated cognitive decline is a hallmark of aging and the increase in oxidative stress/damage with age is one of the mechanisms proposed for cognitive decline with age. Therefore, the goal of this study was to determine if Sod1KO mice exhibit an accelerated loss in cognitive function similar to that observed in aged animals. Cognition was assessed in Sod1KO and wild type (WT) mice using an automated home-cage testing apparatus (Noldus PhenoTyper) that included an initial discrimination and reversal task. Comparison of the total distance moved by the mice during light and dark phases of the study demonstrated that the Sod1KO mice do not show a deficit in movement. Assessment of cognitive function showed no significant difference between Sod1KO and WT mice during the initial discrimination phase of learning. However, during the reversal task, Sod1KO mice showed a significantly greater number of incorrect entries compared to WT mice indicating a decline in cognition similar to that observed in aged animals. Markers of oxidative stress (4-Hydroxynonenal, 4-HNE) and neuroinflammation [proinflammatory cytokines (IL6 and IL-1β) and neuroinflammatory markers (CD68, [[TLR4]], and MCP1)] were significantly elevated in the hippocampus of male and female Sod1KO compared to WT mice. This study provides important evidence that increases in oxidative stress alone are sufficient to induce neuroinflammation and cognitive dysfunction that parallels the memory deficits seen in advanced aging and neurodegenerative diseases.
|mesh-terms=* Aging
* Aldehydes
* Animals
* Antigens, CD
* Antigens, Differentiation, Myelomonocytic
* Biomarkers
* Chemokine CCL2
* Cognitive Dysfunction
* Disease Models, Animal
* Hippocampus
* Interleukin-1beta
* Interleukin-6
* Mice, Knockout
* Oxidative Stress
* Superoxide Dismutase-1
* Toll-Like Receptor 4
|keywords=* Accelerating aging
* Cognition
* Cu/Zn-superoxide dismutase
* Neuroinflammation
* Oxidative stress
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885085
}}
{{medline-entry
|title=Genetic Variation in the Magnitude and Longevity of the IgG Subclass Response to a Diphtheria-Tetanus-Acellular Pertussis (DTaP) Vaccine in Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31547158
|abstract=The type of IgG subclasses induced by vaccination is an important determinant of vaccine efficacy because the IgG subclasses vary in their biological function. The goal of this study was to determine the influence of the genetic background on the production and duration of vaccine-induced IgG subclasses. IgG1, IgG2b, and IgG3 titers against diphtheria toxoid (DT), pertussis toxin (PT), filamentous hemagglutinin (FHA), and pertactin (Prn) were measured in mice from 28 different inbred and wild-derived strains vaccinated with an aluminum hydroxide-adjuvanted DTaP vaccine. The titers and duration of vaccine-specific IgG subclass responses were different among mouse strains, indicating that genetic factors contribute to this variation. Statistical associations were used to identify potential mechanisms that contribute to antibody production and longevity. This analysis showed that the mechanisms guiding the magnitude of antibody production were antigen-dependent for IgG1 but antigen-independent for IgG2b and IgG3. However, the mechanisms driving the longevity of antibody titers were antigen-independent for IgG1, IgG2b, and IgG3. The ratio of IgG1 and IgG3 titers identified Th1 and Th2-prone mouse strains. [[TLR4]]-deficient C3H/HeJ mice had an enhanced IgG1 response compared with C3H/HeOuJ mice with intact [[TLR4]]. This work demonstrates that the genetic background contributes significantly to the magnitude and longevity of vaccine-induced IgG1, IgG2b, and IgG3 titers in mice.

|keywords=* DTaP
* IgG subclass
* antibody longevity
* antibody magnitude
* genetics
* vaccine
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963843
}}
{{medline-entry
|title=Rapamycin improves sevoflurane‑induced cognitive dysfunction in aged rats by mediating autophagy through the [[TLR4]]/MyD88/NF‑κB signaling pathway.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31432123
|abstract=The present study was aimed to observe the protective effect of rapamycin on cognitive dysfunction induced by sevoflurane in aged rats and its effect on autophagy‑related proteins, and to investigate the regulatory mechanism of the Toll‑like receptor 4/myeloid differentiation primary response 88/nuclear factor‑κB ([[TLR4]]/MyD88/NF‑κB) signaling pathway. Fifty Sprague‑Dawley rats were randomly assigned to a control group, a sevoflurane group, a rapamycin pretreatment group, a [[TLR4]] inhibitor group and a 3MA autophagy inhibitor group. A water maze test was used to evaluate the cognition and memory of rats. Hematoxylin and eosin (H