scholarly journals Rapamycin Treatment of Tendon Stem/Progenitor Cells Reduces Cellular Senescence by Upregulating Autophagy

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Daibang Nie ◽  
Jianying Zhang ◽  
Yiqin Zhou ◽  
Jiuyi Sun ◽  
Wang Wang ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Cellular Senescence ◽  
Elderly Population ◽  
Mtor Inhibitor ◽  
The Elderly ◽  
Rapamycin Treatment ◽  
Morphological Alterations ◽  
Tnf Α ◽  
Elevated Expression

The elderly population is prone to tendinopathy due to aging-related tendon changes such as cellular senescence and a decreased ability to modulate inflammation. Aging can render tendon stem/progenitor cells (TSCs) into premature senescence. We investigated the effects of rapamycin, a specific mTOR inhibitor, on the senescence of TSCs. We first showed that after treatment with bleomycin in vitro, rat patellar TSCs (PTSCs) underwent senescence, characterized by morphological alterations, induction of senescence-associated β-galactosidase (SA-β-gal) activity, and an increase in p53, p21, and p62 protein expression. Senescence of PTSCs was also characterized by the elevated expression of MMP-13 and TNF-α genes, both of which are molecular hallmarks of chronic tendinopathy. We then showed that rapamycin treatment was able to reverse the above senescent phenotypes and increase autophagy in the senescent PTSCs. The activation of autophagy and senescence rescue was, at least partly, due to the translocation of HMGB1 from the nucleus to the cytosol that functions as an autophagy promoter. By reducing TSC senescence, rapamycin may be used as a therapeutic to inhibit tendinopathy development in the aging population by promoting autophagy.

scholarly journals Resveratrol Mitigates Hippocampal Tau Acetylation and Cognitive Deficit by Activation SIRT1 in Aged Rats following Anesthesia and Surgery

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Jing Yan ◽  
Ailin Luo ◽  
Rao Sun ◽  
Xiaole Tang ◽  
Yilin Zhao ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Elderly Population ◽  
Cognitive Deficit ◽  
Neurological Complication ◽  
Postoperative Cognitive Dysfunction ◽  
The Elderly ◽  
Dependent Manner ◽  
Promising Avenue ◽  
Tau Acetylation

Postoperative cognitive dysfunction (POCD) is a sever postsurgical neurological complication in the elderly population. As the global acceleration of population ageing, POCD is proved to be a great challenge to the present labor market and healthcare system. In the present study, our findings showed that tau acetylation mediated by SIRT1 deficiency resulted in tau hyperphosphorylation in the hippocampus of the aged POCD model and consequently contributed to cognitive impairment. Interestingly, pretreatment with resveratrol almost restored the expression of SIRT1, reduced the levels of acetylated tau and hyperphosphorylated tau in the hippocampus, and improved the cognitive performance in the behavioral tests. What is more, we observed that microglia-derived neuroinflammation resulting from SIRT1 inhibition in microglia probably aggravated the tau acetylation in cultured neurons in vitro. Our findings supported the notion that activation SIRT1 provided dually beneficial effect in the aged POCD model. Taken together, our findings provided the initial evidence that tau acetylation was associated with cognitive impairment in the aged POCD model and paved a promising avenue to prevent POCD by inhibiting tau acetylation in a SIRT1-dependent manner.

Characterization of Hematopoietic Stem Cell Frequency and Function In Unexplained Anemia of the Elderly

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2047-2047
Author(s):  
Wendy Pang ◽  
Elizabeth Price ◽  
Irving L. Weissman ◽  
Stanley L. Schrier
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
In Vitro Culture ◽  
Progenitor Cells ◽  
The Elderly ◽  
Elderly Subjects ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells ◽  
And Function

Abstract Abstract 2047 Anemia is both a highly prevalent and clinically important condition that causes significant morbidity and mortality in the elderly population. While anemia in the elderly can be attributed to a number of causes, approximately 30% of elderly subjects with anemia have no overt etiology and fall under the category of unexplained anemia of the elderly (UA). There is increasing evidence to suggest that changes in the frequency and/or function of hematopoietic stem and progenitor cells may contribute to the onset and pathophysiology of age-associated hematological conditions, such as UA. Hematopoietic stem cells (HSC) reside at the top of the hematopoietic hierarchy and can differentiate, via increasingly committed downstream progenitors, into all the mature cells of the hematopoietic system. Human myelo-erythroid development proceeds through a set of oligopotent progenitors: HSC give rise to multipotent progenitors (MPP), which give rise to common myeloid progenitors (CMP), which in turn give rise to granulocyte-macrophage progenitors (GMP) and megakaryocyte-erythrocyte progenitors (MEP). We use flow cytometry and in vitro culture of sorted human HSC (Lin-CD34+CD38-CD90+CD45RA-), MPP (Lin-CD34+CD38-CD90-CD45RA-), CMP (Lin-CD34+CD38+CD123+CD45RA-), GMP (Lin-CD34+CD38+CD123+CD45RA+), and MEP (Lin-CD34+CD38+CD123-CD45RA-) from hematologically normal young (23 samples; age 20–35) and elderly (11 samples; age 65+) and UA (5 samples; age 65+) bone marrow samples in order to characterize the changes in the distribution and function of hematopoietic stem and progenitor populations during the aging process and, in particular, in the development of UA. We found that UA patients contain higher frequencies of HSC compared to both elderly normal (1.5-fold; p<0.03) and young normal samples (2.8-fold; p<10-5). We also found increased frequencies of MPP from UA patients compared to MPP from elderly normal (2.6-fold; p<0.002) and young normal samples (5.8-fold; p<0.04). While we observed similar frequencies of CMP among the three groups, we found a notable trend suggesting decreased frequencies of GMP and corresponding increased frequencies of MEP in UA patients. Functionally, HSC from the three groups exhibit statistically insignificant differences in the efficiency of colony formation under the myeloid differentiation-promoting methylcellulose-based in vitro culture conditions; however, on average, HSC from elderly bone marrow samples, regardless of the presence or absence of anemia, tend to form fewer colonies in methylcellulose. Interestingly, HSC from UA patients produce more granulocyte-monocyte (CFU-GM) colonies and fewer erythroid (CFU-E and BFU-E) colonies, compared to HSC from normal samples (p<0.001). Similarly, CMP from UA patients, compared to normal CMP, yield skewed distributions of myeloid-erythroid colonies when plated in methylcellulose, significantly favoring production of CFU-GM colonies over CFU-E and BFU-E colonies (p<0.003). Additionally, MEP from UA patients form both CFU-E and BFU-E colonies in methylcellulose albeit at a significantly lower efficiency than MEP from normal bone marrow samples (p<0.01). This is the first study to examine the changes in hematopoietic stem and progenitor populations in UA patients. The changes in the distribution of hematopoietic stem and progenitor cells in UA patients indicate that the HSC and MPP populations, and possibly also the MEP population, expand in the context of anemia, potentially in response to homeostatic feedback mechanisms. Nevertheless, these expanded populations are functionally impaired in their ability to differentiate towards the erythroid lineage. Our data suggest that there are intrinsic defects in the HSC population of UA patients that lead to poor erythroid differentiation, which can be readily observed even in the earliest committed myelo-erythroid progenitors. We have generated gene expression profiling data from these purified hematopoietic stem and progenitor populations from UA patients to try to identify biological pathways and markers relevant to disease pathogenesis and potential therapeutic targets. Disclosures: Weissman: Amgen, Systemix, Stem cells Inc, Cellerant: Consultancy, Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Schrier:Celgene: Research Funding.

scholarly journals Neutrophil Elastase Induces Chondrocyte Apoptosis and Facilitates the Occurrence of Osteoarthritis via Caspase Signaling Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Ganyu Wang ◽  
Weiqiang Jing ◽  
Yuxuan Bi ◽  
Yue Li ◽  
Liang Ma ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Neutrophil Elastase ◽  
Elderly Population ◽  
The Elderly ◽  
Chondrocyte Apoptosis ◽  
Intracellular Ros ◽  
Induced Apoptosis

Osteoarthritis (OA) is the most common and prevalent chronic joint disorders in the elderly population across the globe, resulting in severe disability and impairment of quality of life. Existing treatment can only alleviate the symptoms and delay the progression of OA. Therefore, novel and effective therapeutics strategies for OA need to be developed. Our present study first found that neutrophil elastase (NE) was significantly increased in OA patients’ synovial fluid. Next, we examined the effect of neutrophil elastase (NE) on chondrocytes in vitro and in vivo. The results showed that NE suppressed cell proliferation, induced apoptosis and prevented cell migration in chondrocytes in vitro, accompanied by the elevation of intracellular ROS and calcium level. Moreover, NE enhanced the cleaved caspase-3 levels and disrupted the mitochondrial transmembrane potential balance. Meanwhile, chondrocytes apoptosis induced by NE can be alleviated by caspase inhibitor, zVAD-FMK and antioxidants, GSH. Besides, treatment of sivelestat, the inhibitor of NE, significantly reduced the pathological processes in OA model rats in vivo. The results of our study suggested that NE is an important factor in OA, which induces chondrocyte apoptosis and facilitates the occurrence of OA via caspase signaling pathway, and targeting the crucial signal centering around NE may be the potential therapies for OA.

scholarly journals Teneligliptin protects against ischemia/reperfusion-induced endothelial permeability in vivo and in vitro

RSC Advances ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 3765-3774 ◽  
Author(s):  
Lei Zhang ◽  
Weiqiong Yuan ◽  
Xiangli Kong ◽  
Bei Zhang
Keyword(s):  
Ischemic Stroke ◽  
Elderly Population ◽  
Ischemia Reperfusion ◽  
Endothelial Permeability ◽  
The Elderly

Ischemic stroke is a leading cause of disability and mortality worldwide, especially among the elderly population.

P6286Old age significantly worsens stroke outcome in old mice through a mechanism of inflamm-aging successfully countered by the tumour necrosis factor alpha antibody infliximab

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
N R Bonetti ◽  
L Liberale ◽  
L Pasterk ◽  
C Diaz-Canestro ◽  
A Akhmedov ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Elderly Population ◽  
The Elderly ◽  
Low Grade ◽  
Stroke Outcome ◽  
Detection Level ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Old Mice

Abstract Background Stroke is the second leading cause of death and the number one cause of adult disability worldwide. As a strongly age-dependant disease, its prevalence is expected to rise along with the average age in western populations. While the epidemiological evidence linking stroke to age is non-refutable, the specific and independent effects of age on stroke remain elusive. This presents an important missing link for developing targeted treatments tailored to the growing elderly population. A potential mechanism pertinent to stroke outcome in the elderly is a chronic low-grade inflammatory state, coined “inflamm-aging”. Such a phenomenon could not only increase the risk for stroke, but also negatively affect its outcome and thus offers both preventive and therapeutic value. Purpose To determine the specific effects of age on the outcome after stroke in mice and delineate culprit molecular pathways with a focus on inflammatory mediators and to assess the efficacy of specific anti-inflammatory treatment with the TNF-α antibody Infliximab in this setting. Methods Old (18–20 months) C57BL/6 wildtype mice were compared to young (12 weeks) controls. Baseline levels of inflammatory cytokines were assayed in plasma and brain homogenates by ELISA. Ischemic stroke was induced by transient middle cerebral artery occlusion (30 minutes/48 h). Neurological function was assessed by a Bederson based score and the RotaRod test. Anti-inflammatory treatment with Infliximab was administered to a subset of old mice via weekly intraperitoneal injections (10 mg/kg) for 4 weeks prior to stroke induction. Young and old control animals received vehicle. Results At baseline (prior to stroke), old animals showed significantly higher plasma levels of TNF-α compared to young (Fig. 1A), while IL-6 and IL-1β remained below detection level in both groups. In brain homogenates of healthy old and young animals, TNF-α and IL-1β did not differ, while IL-6 was below detection level. Old mice showed significantly larger stroke sizes (Fig.1B), performed worse neurologically (Fig. 1C) and suffered from higher post-stroke mortality compared to young (Fig. 1D). Pre-treatment with the TNF-α inhibitor Infliximab significantly decreased stroke size, neurological impairment and mortality in old animals (Fig1B-D). Figure 1 Conclusions In a model lacking additional confounding factors, we demonstrate a direct adverse effect of age per se on stroke outcome and mortality. Elevated TNF-α plasma levels in old mice outline the mechanism of “inflamm-aging” as a possible culprit. This concept is strongly supported by the beneficial effect of Infliximab on stroke outcome in old animals. Further investigation of the downstream mediators of the observed effect could help in tailoring treatments to the particularly vulnerable and growing elderly population.

scholarly journals Bmi-1 alleviates adventitial fibroblast senescence by eliminating ROS in pulmonary hypertension

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Kai Li ◽  
Yan Li ◽  
Youjia Yu ◽  
Jingjing Ding ◽  
Huijie Huang ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Cellular Senescence ◽  
Disease Process ◽  
The Elderly ◽  
Lung Fibroblasts ◽  
Adventitial Fibroblasts ◽  
Pulmonary Arteriole ◽  
Life Threatening

Abstract Objectives Pulmonary hypertension (PH) is a life-threatening progressive disease with high mortality in the elderly. However, the pathogenesis of PH has not been fully understood and there is no effective therapy to reverse the disease process. This study aims to determine whether cellular senescence is involved in the development of PH. Methods The rat PH model was established by intraperitoneal injection of monocrotaline and evaluated by pulmonary arteriole wall thickness and right ventricular hypertrophy index. Human lung fibroblasts (HLFs) were treated with CoCl2 or hypoxia to induce cellular senescence in vitro. SA-β-gal staining and the changes of senescent markers were used to examine cellular senescence. The molecular mechanism of cellular senescence was further explored by detecting reactive oxygen species (ROS) levels and culturing cells with a conditioned medium. Results We revealed the cellular senescence of pulmonary adventitial fibroblasts in vivo in the rat PH model. The expression of Bmi-1, an important regulator of senescence, was decreased in the lungs of PH rats and localized in adventitial fibroblasts. The in vitro experiments showed that p16 expression was increased while Bmi-1 expression was decreased after CoCl2 treatment in HLFs. Mechanistically, Bmi-1 could alleviate CoCl2-induced HLFs senescence by eliminating ROS which further promoted the proliferation of pulmonary artery smooth muscle cells by paracrine mode of action of HLFs. Conclusion Bmi-1 alleviates the cellular senescence of pulmonary fibroblasts in PH, which expands the pathogenesis of PH and provides a theoretical basis for targeting senescent cells in the treatment of PH.

scholarly journals IL-2/IL-2R Antibody Complex Enhances Treg-Induced Neuroprotection by Dampening TNF-α Inflammation in an In Vitro Stroke Model

2021 ◽  
Author(s):  
Mia C. Borlongan ◽  
Chase Kingsbury ◽  
Felipe Esparza Salazar ◽  
Alma R. Lezama Toledo ◽  
German Rivera Monroy ◽  
...  
Keyword(s):  
Cell Death ◽  
White Matter ◽  
Inflammatory Response ◽  
Progenitor Cells ◽  
Gray Matter ◽  
Inflammatory Marker ◽  
White Matter Injury ◽  
Tnf Α ◽  
Antibody Complex

AbstractThe present in vitro study showed that IL-2/IL-2R antibody complex facilitates Treg-induced neuroprotection in the oxygen glucose deprivation/reoxygenation (OGD/R) model of stroke. First, we examined the role of IL-2/IL-2R-treated Tregs in OGD/R-exposed rat primary cortical cells (PCCs), which represent the cell type of the ischemic gray matter in the stroke brain. Here, OGD/R induced cell death, which was attenuated by Tregs and more robustly by IL-2/IL-2R-treated Tregs, but not by IL-2/IL-2R treatment alone. Second, we next assessed IL-2/IL-2R effects in OGD/R-exposed human oligodendrocyte progenitor cells (OPCs), which correspond to the white matter injury after stroke. Results revealed that a similar pattern neuroprotection as seen in the gray matter, in that OGD/R triggered cell death, which was ameliorated by Tregs and more effectively by IL-2/IL-2R-treated Tregs, but IL-2/IL-2R treatment alone was not therapeutic. Third, as we begin to understand the mechanism underlying IL-2/IL-2R engagement of Tregs, we investigated the inflammatory response in OGD/R-exposed human neural progenitor cells (NPCs), which recapitulate both ischemic gray and white matter damage in stroke. Similar to PCCs and OPCs, OGD/R produced cell death and was blocked by Tregs and more efficiently by IL-2/IL-2R-treated Tregs, whereas IL-2/IL-2R treatment alone did not alter the ischemic insult. Moreover, the inflammatory marker, TNF-α, was upregulated after OGD/R, dampened by both Tregs and more efficiently by IL-2/IL-2R-treated Tregs but more pronounced in the latter, and not affected by IL-2/IL-2R treatment alone, suggesting IL-2/IL-2R-Treg-mediated modulation of inflammatory response in stroke. Altogether, these observations support the use of IL-2/IL-2R treatment in enhancing the anti-inflammatory effects of Tregs in stroke.

scholarly journals Sepsis Inflammation Impairs the Generation of Functional Dendritic Cells by Targeting Their Progenitors

2021 ◽  
Vol 12 ◽  
Author(s):  
Jie Lu ◽  
Kun Sun ◽  
Huiping Yang ◽  
Dan Fan ◽  
He Huang ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Progenitor Cells ◽  
Peripheral Blood ◽  
Hematopoietic Stem ◽  
Tnf Α ◽  
Ifn Γ ◽  
And Function ◽  
Antigen Presenting ◽  
The Impact

BackgroundSepsis is a complex systemic immune dysfunction syndrome induced by infection. Sepsis has a high mortality rate, with most patients dying due to systemic organ failure or secondary infection. Dendritic cells (DCs) are professional antigen-presenting cells. Upon infection with microbes, DCs are activated to induce adaptive immune responses for controlling infection. DC generation and function are impaired during sepsis; however, the underlying mechanisms remain largely unknown.MethodsPeripheral blood samples from sepsis patients were collected to examine DC subsets, DC progenitors, and apoptosis of DCs by flow cytometer. In vitro induction of DCs from hematopoietic stem/progenitor cells were established and a variety of sepsis-associated inflammatory mediators [e.g., interferon-gamma (IFN-γ), interleukin-1beta (IL-1β), tumor necrosis factor-alpha (TNF-α) and granulocyte-colony stimulating factor (G-CSF)] and Lipopolysaccharide (LPS) were determined for the impact on DC generation and function in vitro.ResultsOur results demonstrate that sepsis-induced systemic inflammation impairs the capacity of hematopoietic stem and progenitor cells (HSPCs) to produce DCs, including conventional DCs (cDCs) and plasmacytoid DCs (pDCs). We investigated peripheral blood (PB) samples from 34 pediatric patients on days 1 to 7 following diagnosis. Compared to healthy donors (n = 18), the sepsis patients exhibited a significantly fewer percentage and number of pDCs and cDCs, and a lower expression of antigen presenting molecule HLD-DR and co-stimulatory molecules (e.g., CD86) on the surface of DCs. This sepsis-induced DC impairment was associated with significantly increased apoptotic death of DCs and marked decreases of progenitor cells that give rise to DCs. Furthermore, we observed that among the tested sepsis-associated cytokines (e.g., IFN-γ, IL-1β, TNF-α, and G-CSF), G-CSF and IFN-γ impaired DC development from cultured HSPCs. G-CSF also markedly decreased the expression of HLA-DR on HSPC-derived DCs and their cytokine production, including IL-12 and IFN-β.ConclusionsCollectively, these findings indicate that sepsis impairs the survival of functional DCs and their development from HSPCs. Strategies for improving DC reconstitution following sepsis may restore DC progenitors and their associated function.

SELE Downregulation Suppresses Mast Cell Accumulation to Protect against Inflammatory Response in Chronic Idiopathic Urticaria

2020 ◽  
pp. 1-11
Author(s):  
Hong Wang ◽  
Yangchun Xu ◽  
Meishan Jin ◽  
Wen Yuan
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Activation ◽  
Chronic Idiopathic Urticaria ◽  
Mast Cell Activation ◽  
Clinical Samples ◽  
Inflammatory Factor ◽  
Tnf Α ◽  
Elevated Expression

<b><i>Background:</i></b><i></i>Chronic idiopathic urticaria (CIU) represents a common skin disorder often characterized by mast cell activation and secretion of histamine and other proinflammatory factors. E-selectin (SELE) has been implicated in the pathogenesis of common inflammatory cutaneous disorders, while the role of SELE in CIU is yet to be fully understood. Thus, we aimed to investigate the mechanism by which SELE influences CIU in connection with the involvement of mast cells. <b><i>Methods:</i></b> SELE expression was measured in blood samples obtained from CIU patients and normal individuals. A CIU mouse model was subsequently established by intradermally injecting a normal saline solution with ovalbumin IgE antiserum into the mice. Loss- and gain-of-function investigations were conducted on the mouse models. The number of degranulated mast cells and the amount of histamine release in vitro were determined. The levels of SELE, tumor necrosis factor (TNF)-α, homologous restriction factor (HRF), and interleukin (IL)-6 levels were determined. <b><i>Results:</i></b> The CIU clinical samples exhibited upregulated SELE, while the CIU mice showed increased mast cell degranulation and an increased rate of histamine directional release, as well as an elevated expression of SELE, TNF-α, HRF, and IL-6. SELE silencing was found to decrease the number of degranulated mast cells and reduce the rate of histamine directional release, along with suppressed TNF-α, HRF, and IL-6 expression, in the serum of CIU mice. Ketotifen was observed to rescue the increased expression of TNF-α, HRF, and IL-6 caused by SELE overexpression. <b><i>Conclusions:</i></b><i></i>This study highlights the potential of SELE downregulation to repress inflammatory factor secretion caused by the accumulation of mast cells, which ultimately inhibits the development of CIU.

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