BACKGROUND Pancreatic cancer,a formidable gastrointestinal neoplasm,is characterized by its insidious onset,rapid progression,and resistance to treatment,which often lead to a grim prognosis.While the complex pathogen...BACKGROUND Pancreatic cancer,a formidable gastrointestinal neoplasm,is characterized by its insidious onset,rapid progression,and resistance to treatment,which often lead to a grim prognosis.While the complex pathogenesis of pancreatic cancer is well recognized,recent attention has focused on the oncogenic roles of senescent tumor-associated fibroblasts.However,their precise role in pancreatic cancer remains unknown.Resveratrol is a natural polyphenol known for its multifaceted biological actions,including antioxidative and neuroprotective properties,as well as its potential to inhibit tumor proliferation and migration.Our current investigation builds on prior research and reveals the remarkable ability of resveratrol to inhibit pancreatic cancer proliferation and metastasis.AIM To explore the potential of resveratrol in inhibiting pancreatic cancer by targeting senescent tumor-associated fibroblasts.METHODS Immunofluorescence staining of pancreatic cancer tissues revealed prominent coexpression ofα-SMA and p16.HP-1 expression was determined using immunohistochemistry.Cells were treated with the senescence-inducing factors known as 3CKs.Long-term growth assays confirmed that 3CKs significantly decreased the CAF growth rate.Western blotting was conducted to assess the expression levels of p16 and p21.Immunofluorescence was performed to assess LaminB1 expression.Quantitative real-time polymerase chain reaction was used to measure the levels of several senescence-associated secretory phenotype factors,including IL-4,IL-6,IL-8,IL-13,MMP-2,MMP-9,CXCL1,and CXCL12.A scratch assay was used to assess the migratory capacity of the cells,whereas Transwell assays were used to evaluate their invasive potential.RESULTS Specifically,we identified the presence of senescent tumor-associated fibroblasts within pancreatic cancer tissues,linking their abundance to cancer progression.Intriguingly,Resveratrol effectively eradicated these fibroblasts and hindered their senescence,which consequently impeded pancreatic cancer progression.CONCLUSION This groundbreaking discovery reinforces Resveratrol's stature as a potential antitumor agent and positions senescent tumor-associated fibroblasts as pivotal contenders in future therapeutic strategies against pancreatic cancer.展开更多
Regulatory changes in senescent cells could potentially affect the composition of extracellular vehicles(EVs),specifically altering their size and cargo.As a result,the released senescent EVs contain an unpredictable ...Regulatory changes in senescent cells could potentially affect the composition of extracellular vehicles(EVs),specifically altering their size and cargo.As a result,the released senescent EVs contain an unpredictable cocktail of growth factors and cytokines.These biomolecules have dual effects,potentially guiding the induction of senescence in affected cells and promoting an inflammation-related“domino effect”within the cellular environment,ultimately leading to tissue inflammaging.展开更多
Cellular senescence is the results of aging and age-related diseases,and the development of anti-aging methods may improve health and extend longevity.The natural flavonol fisetin has been shown to antagonize senescen...Cellular senescence is the results of aging and age-related diseases,and the development of anti-aging methods may improve health and extend longevity.The natural flavonol fisetin has been shown to antagonize senescence in vitro and increases longevity in vivo,but has poor water solubility and limited bioavailability.In this study,a food-grade and senescent cell-targeted delivery system for fisetin was developed based on whey protein isolate-galactooligosaccharides(WPI-GOS)Maillard conjugate,which could recognize senescence associatedβ-galactosidase in senescent cells.The fisetin nanoparticles possessed a high encapsulation efficiency,excellent dispersibility in water,good storage stability and well biocompatibility.Moreover,they could effectively accumulate and retain in senescent cells with excellent senescent cell-targeting efficacy,and inhibit the oxidative stress-induced cellular senescence in vitro.Thus,this novel nanoparticle system based on WPI-GOS Maillard conjugate showed promise to deliver hydrophobic bioactive ingredients like fisetin to senescent cells to improve their bioavailability and anti-senescence effect.展开更多
Aging is well known to be the main risk factor for the neurodegenerative pathologies,in particular,Parkinson’s disease（PD）and Alzheimer’s disease（AD）.In aging and in the diseases,similar changes in various hallm...Aging is well known to be the main risk factor for the neurodegenerative pathologies,in particular,Parkinson’s disease（PD）and Alzheimer’s disease（AD）.In aging and in the diseases,similar changes in various hallmarks of neurodegeneration（lipofuscin accumulation,autophagia weakening,and disturbances in functions of mitochondriaand lysosomes） were shown （Tan et al., 2014）. Furthermore, dopami- nergic system （DAS） involvement in mechanisms of aging, PD, and AD were revealed （Martorana and Koch, 2014）.展开更多
Mesenchymal stem/stromal cells(MSCs)have various properties that make them promising candidates for stem cell-based therapies in clinical settings.These include self-renewal,multilineage differentiation,and immunoregu...Mesenchymal stem/stromal cells(MSCs)have various properties that make them promising candidates for stem cell-based therapies in clinical settings.These include self-renewal,multilineage differentiation,and immunoregulation.However,recent studies have confirmed that aging is a vital factor that limits their function and therapeutic properties as standardized clinical products.Understanding the features of senescence and exploration of cell rejuvenation methods are necessary to develop effective strategies that can overcome the shortage and instability of MSCs.This review will summarize the current knowledge on characteristics and functional changes of aged MSCs.Additionally,it will highlight cell rejuvenation strategies such as molecular regulation,noncoding RNA modifications,and microenvironment controls that may enhance the therapeutic potential of MSCs in clinical settings.展开更多
Heat stress occurs frequently in energy-saving sunlight greenhouses(ESSG) at the late growth stage. Three-year delayed cultivation(DC) of the Red Globe cultivar of Vitis vinifera L. was used to clarify the physiologic...Heat stress occurs frequently in energy-saving sunlight greenhouses(ESSG) at the late growth stage. Three-year delayed cultivation(DC) of the Red Globe cultivar of Vitis vinifera L. was used to clarify the physiological mechanisms of short-term heat stress on PSII and subsequent recovery from heat stress. By November, the photosynthetic function had declined and the fall in transpiration rate(E) with heating time increased the possibility of heat damage. In July, the most obvious increase was in the relative variable fluorescence at J point at 40°C, and in November it changed to K point. The 5 min of heat treatment resulted in a significant increase of the relative variable fluorescence at 0.3 ms(W), and after 10 min of heat treatment, the number of reactive centres per excited cross section(RC/CS), probability that a trapped exciton moves an electron into the electron transport chain beyond Q–(at t=0)(Ψ) and quantum yield of electron transport at t=0(φ) decreased significantly(P<0.05), suggesting that the reaction centre, donor and acceptor side of photosystem II(PSII) were all significantly inhibited(P<0.05) and that the thermal stability of the photosynthetic mechanism was reduced. The inhibition of energy fluxes for senescent leaves in November was earlier and more pronounced than that for healthy leaves, which did not recover from heat stress of more than 15 min after 2 h recovery at room temperature.展开更多
Breast cancer is the predominant form of carcinoma among women worldwide,with 70%of advanced patients developing bone metastases,with a high mortality rate.In this sense,the bone marrow(BM)mesenchymal stem/stromal cel...Breast cancer is the predominant form of carcinoma among women worldwide,with 70%of advanced patients developing bone metastases,with a high mortality rate.In this sense,the bone marrow(BM)mesenchymal stem/stromal cells(MSCs)are critical for BM/bone homeostasis,and failures in their functionality,transform the BM into a premetastatic niche(PMN).We previously found that BM-MSCs from advanced breast cancer patients(BCPs,infiltrative ductal carcinoma,stage III-B)have an abnormal profile.This work aims to study some of the metabolic and molecular mechanisms underlying MSCs shift from a normal to an abnormal profile in this group of patients.A comparative analysis was undertaken,which included self-renewal capacity,morphology,proliferation capacity,cell cycle,reactive oxygen species(ROS)levels,and senescence-associatedβ‑galactosidase(SA‑β‑gal)staining of BMderived MSCs isolated from 14 BCPs and 9 healthy volunteers(HVs).Additionally,the expression and activity of the telomerase subunit TERT,as well as telomere length,were measured.Expression levels of pluripotency,osteogenic,and osteoclastogenic genes(OCT-4,SOX-2,M-CAM,RUNX-2,BMP-2,CCL-2,M-CSF,and IL-6)were also determined.The results showed that MSCs from BCPs had reduced,self-renewal and proliferation capacity.These cells also exhibited inhibited cell cycle progression and phenotypic changes,such as an enlarged and flattened appearance.Additionally,there was an increase in ROS and senescence levels and a decrease in the functional capacity of TERT to preserve telomere length.We also found an increase in pro-inflammatory/pro-osteoclastogenic gene expression and a decrease in pluripotency gene expression.We conclude that these changes could be responsible for the abnormal functional profile that MSCs show in this group of patients.展开更多
Objective： To determine whether balloon catheter denudation can induce vascular smooth muscle cells （VSMCs） to senescence, and whether this senescence can result in inflammation activity. Methods： Twelve male Chin...Objective： To determine whether balloon catheter denudation can induce vascular smooth muscle cells （VSMCs） to senescence, and whether this senescence can result in inflammation activity. Methods： Twelve male Chinese white rabbits were denuded of the carotid arteries or VSMCs. Acidic β-galactosidase activity of carotid arteries or VSMCs was detected. Transfection and chloramphenicol acetyltransferase （CAT） assay for iNOS gene and nitrite （NO2^-） assay were undertaken. Reverse transcription-polymerase chain reaction （RT-PCR） was used to evaluate inflammation cytokines mRNA expression. Measurement of NF-kB activity was detected by electrophoretic mobility shift assay （EMSA）. MMP-9, ICAM-1, P-p65, and IkBα expressions were analyzed by Western blotting. Results： After denudation VSMCs from denuded arteries showed an accumulation of significantly more senescence-associated β-galactosidase （SA-β-Gal） positive ceils and greater iNOS activity. Transcriptional activity of iNOS was highly expressed. The mRNA expressions of IL-1β, ICAM-1,MMP-9, TNF-α and the iNOS enzyme were significantly increased in injuring-induced senescence SMCs. However, the TNF-α or IL-1β-induced the protein production （ICAM-1 and MMP-9） was prevented by PDTC and MG132, which are inhibitors of NF-kB activation. Also, activation of NF-kB and cytokine-induced degradation of IKBα in the denuded VSMC were significantly affected. Conclusion： Intraluminal injury to the artery may lead to the emergence of senescent VSMC. Inflammation activity in SMCs is closely related to the senescence and the activation of NF-kB is involved.展开更多
The aim of the present study was to investigate the effect of one capsule of the micro-immunotherapy medicine (MIM) 2LMISEN®compared to vehicle, in a neuronal aging model. Senescence and apoptosis of hippocamp...The aim of the present study was to investigate the effect of one capsule of the micro-immunotherapy medicine (MIM) 2LMISEN®compared to vehicle, in a neuronal aging model. Senescence and apoptosis of hippocampal neurons were evaluated by measuring p16INK4a and caspase 3 levels, respectively. The data presented is a single observation. Mice hippocampal neuron cultures were treated with MIM (11 mM) or vehicle (11 mM) from 22 days in vitro (DIV) until 27 DIV. After incubation, hippocampal neuron cultures were fixed at 15 (control condition), 22, 25 and 27 DIV and then incubated with primary antibodies p16INK4a, MAP2 and Caspase 3. Quantification of p16INK4a and Caspase 3-positive neurons was done using Developer software. We found that vehicle had no effect on p16INK4a expression, whereas MIM was able to decrease p16INK4a levels at 22, 25 and 27 DIV in a statistically significant manner. The MIM had no significative effect on Caspase 3 expression. Our preliminary results showed that the MIM capsule significantly reduced neuronal senescence and not apoptosis.展开更多
Background: Mature red blood cells lack protein synthesis and are unable to restore inactivated enzymes, damaged cytoskeleton and membrane proteins. An oxidation breakdown of band 3 is probably part of the mechanism l...Background: Mature red blood cells lack protein synthesis and are unable to restore inactivated enzymes, damaged cytoskeleton and membrane proteins. An oxidation breakdown of band 3 is probably part of the mechanism leading to the generation of a senescent cell antigen. This specific signal serves for the clearance of RBCs by inducing the binding of autologous IgG and C3, leading to phagocytosis. In addition, phosphatidilserin molecules appear in the outer membrane and the CD47 expression diminishes. Methods: Erythrocytes of different ages from whole blood were studied by flow cytometry analysing light scatter proprieties, binding of autologous IgG, C3 complement deposits, externalization of phosphatidylserine and CD47 expression. Dot-plot analysis based on forward scatter versus side scatter parameters showed two RBCs populations of different sizes and density. RBCs were further incubated with Alexa 488 IgG, APC-anti-C3, PE-annexin-V and PE-CD47. The comparison of the values obtained for the different variables studied in SeRBC and YRBC populations was carried out by the Student t-test for matched samples or by the Wilcoxon test (after verification of the normality assumption). Results: The percentage of IgG and C3 positive cells was significantly higher in senescent red blood cells population. The fraction of annexin-V positive RBCs was also larger in SeRBCs while the CD47 expression was lower in this population. Conclusions: These results indicate that flow cytometry allow differenciation of erythrocytes populations of different ages, turning this tool into an useful alternative option to study erythrocyte aging process. These findings will contribute to a better understanding of the process and mechanisms involved in erythrocyte senescence process.展开更多
Cellular senescence is characterized by a generally irreversible cell cycle arrest and the secretion of bioactive factors known as the senescence-associated secretory phenotype(SASP).In an oncogenic context,senescence...Cellular senescence is characterized by a generally irreversible cell cycle arrest and the secretion of bioactive factors known as the senescence-associated secretory phenotype(SASP).In an oncogenic context,senescence is considered a tumor suppressive mechanism as it prevents cell proliferation and inhibits the progression from pre-malignant to malignant disease.However,recent studies have demonstrated that senescent tumor cells,which could spontaneously exist within cancer tissues or arise in response to various cancer interventions(the so-called therapy-induced senescence,TIS),can acquire pro-tumorigenic properties and are capable of driving local and metastatic relapse.This highlights the complex and multifaceted nature of cellular senescence in cancer biology.Here,we summarize the current knowledge of the pathological function of therapy-induced senescent tumor cells and discuss possible mechanisms by which tumor cell senescence contributes to cancer relapse.We also discuss implications for future studies toward targeting these less appreciated cells.展开更多
Stem cell senescence is characterized by progressive functional dysfunction and secretory phenotypic changes including decreased proliferation,dysfunction of osteogenic and angiogenic differentiation,increased secreti...Stem cell senescence is characterized by progressive functional dysfunction and secretory phenotypic changes including decreased proliferation,dysfunction of osteogenic and angiogenic differentiation,increased secretion of the senescence-associated secretory phenotype(SASP),which bring difficulties for bone repair.Rescuing or delaying senescence of aged bone marrow mesenchymal stem cells(O-BMSCs)was considered as effective strategy for bone regeneration in aging microenvironment.Magnesium(Mg)ion released from bioceramics was reported to facilitate bone regeneration via enhancing osteogenesis and alleviating senescence.In this study,Akermanite biocreamics(Akt)containing Mg ion as a model was demonstrated to promote osteogenesis and angiogenesis effects of O-BMSCs by activating the MAPK signaling pathway in vitro.Moreover,the enhanced osteogenesis effects might be attributed to enhanced Mg-containing Akt-mediated exosomal miR-196a-5p cargo targeting Hoxa7 and activation of MAPK signaling pathway.Furthermore,the in vivo study confirmed that 3D-printed porous Mg-containing Akt scaffolds effectively increased bone regeneration in cranial defects of aged rats.The current results indicated that the exosomal-miR-196a-5p/Hoxa7/MAPK signaling axis might be the potential mechanism underlying Akt-mediated osteogenesis.The exosome-meditaed therapy stimulated by the released Mg ion contained in Akt biocreamics or other biomaterials might serve as a candidate strategy for bone repair in aged individuals.展开更多
Peroxisomes compartmentalize a dynamic suite of biochemical reactions and play a central role in plant metabolism, such as the degradation of hydrogen peroxide, metabolism of fatty acids, photorespiration, and the bio...Peroxisomes compartmentalize a dynamic suite of biochemical reactions and play a central role in plant metabolism, such as the degradation of hydrogen peroxide, metabolism of fatty acids, photorespiration, and the biosyn- thesis of plant hormones. Plant peroxisomes have been traditionally classified into three major subtypes, and in-depth mass spectrometry （MS）-based proteomics has been per- formed to explore the proteome of the two major subtypes present in green leaves and etiolated seedlings. Here, we carried out a comprehensive proteome analysis of perox- isomes from Arabidopsis leaves given a 48-h dark treatment. Our goal was to determine the proteome of the third major subtype of plant peroxisomes from senescent leaves, and further catalog the plant peroxisomal proteome. We identified a total of 111 peroxisomal proteins and verified the peroxisomal localization for six new proteins with potential roles in fatty acid metabolism and stress response by in vivo targeting analysis. Metabolic pathways compartmentalized in the three major subtypes of peroxisomes were also compared, which revealed a higher number of proteins involved in the detoxification of reactive oxygen species in peroxisomes from senescent leaves. Our study takes an important step towards mapping the full function of plant peroxisomes.展开更多
Clinical therapies developed for estrogen-deficiency-driven postmenopausal osteoporosis(PMO)and related diseases,such as bone degeneration,show multiple adverse effects nowadays.Targeting senescent cells(SnCs)and the ...Clinical therapies developed for estrogen-deficiency-driven postmenopausal osteoporosis(PMO)and related diseases,such as bone degeneration,show multiple adverse effects nowadays.Targeting senescent cells(SnCs)and the consequent senescence-associated secretory phenotype(SASP)with a combination of dasatinib and quercetin(DQ)is a recently developed novel therapy for multiple age-related diseases.Herein,we found that estrogen deficiency induced-bone loss was attributed to a pro-inflammatory microenvironment with SASP secretions and accelerated SnC accumulation,especially senescent mesenchymal stem cells(MSCs)characterized by exhaustion and dysfunction in middle aged rats.Systematically targeting SnCs with DQ strikingly ameliorated PMO and restored MSC function.Local administration of DQ and bone morphogenetic protein 2(BMP2)in combination promoted osteogenic differentiation of MSCs and rejuvenated osteoporotic bone regeneration.Our results repurposed DQ as an attractive therapy for treating PMO and related diseases.展开更多
Dear Editor,Over a half-century ago,Dr.Leonard Hayflick described the phenotype of a finite lifespan for human fibroblasts being passaged in in vitro cell culture(Hayflick et al.,1961),a phenomenon today known as repl...Dear Editor,Over a half-century ago,Dr.Leonard Hayflick described the phenotype of a finite lifespan for human fibroblasts being passaged in in vitro cell culture(Hayflick et al.,1961),a phenomenon today known as replicative cellular senescence.Cellular senescence has been defined as a state in which cells lose their potential to divide and are permanently arrested in either the G1,or arguably the G2 stage of the cell cycle(Mao et al.,2012).In addition to replicative cellular senescenee—which is induced by large amounts of DNA damage at telomeres due to loss of the specialized T-loop structure—xogenous sublethal stresses such as ionizing radiati on,genotoxic chemicals or hyper-activated on cogenes may also trigger a similar form of senescence,stress induced premature cellular senescenee(SIPS).展开更多
Objective To review the senescent remodeling of the immune system with aging and its relevance to the increased susceptibility of the elderly to infectious diseases, along with an outlook on emerging immunological bio...Objective To review the senescent remodeling of the immune system with aging and its relevance to the increased susceptibility of the elderly to infectious diseases, along with an outlook on emerging immunological biomarkers. Data sources The data selected were from PubMed with relevant published articles in English or French from 1995 to the present. Searches were made using the terms immunosenescence and aging paired with the following： innate immunity, T-celr, B-cell, adaptive immunity and biomarkers. Articles were reviewed for additional citations and some information was gathered from web searches. Study selection Articles on aging of both the innate and adaptive immunity were reviewed, with special attention to the remodeling effect on the ability of the immune system to fight infectious diseases. Articles related to biomarkers of immunosenescence were selected with the goal of identifying immunological biomarkers predisposing the elderly to infections. Results Innate immunity is generally thought to be relatively well preserved or enhanced during aging compared with adaptive immunity which manifests more profound alterations. However, evidence, particularly in the last decade, reveals that both limbs of the immune system undergo profound remodeling with aging. Reported data on adaptive immunity is consistent and changes are well established but conflicting results about innate immunity were reported between in vivo and in vitro studies, as well as between murine and human studies. Epidemiological data suggests increased predisposition of the elderly to infections, but no compelling scientific evidence has directly linked senescent immune remodeling to this increased susceptibility. Recently, growing interest in identifying immunological biomarkers and defining immune risk phenotypes/profiles （IRP） has been expressed. Identification of biomarkers is in its early days and few potential biomarkers have been identified, with the Swedish having defined one IRP based on the adaptive immune response. Conclusions Aging does not necessarily lead to an unavoidable decline in immune functions. Instead, a complex remodeling occurs. Despite the lack of compelling scientific evidence, senescent immune remodeling surely is a significant contributing factor to the increased risk and severity of infections in the elderly. Although, no immunological biomarker has been formally linked to the increased risk of infections in the elderly, biomarkers remain a promising tool to predict the likelihood of healthy aging, the level of immune competence, and mortality risk in the elderly. Hence, more research is required to define healthy aging and identify immunological biomarkers.展开更多
To determine the effects of preharvest arginine spraying on the nutritional level of broccoli and the mechanism of action of arginine in improving the storage quality of broccoli,arginine spraying(5 mmol/L)was conduct...To determine the effects of preharvest arginine spraying on the nutritional level of broccoli and the mechanism of action of arginine in improving the storage quality of broccoli,arginine spraying(5 mmol/L)was conducted at 0,1,3,and 5 days before harvest.The appearance,respiration rate,mass-loss rate,electrolyte leakage,glucosinolate,ascorbic acid,total phenol,total flavonoid,total sugar and sucrose contents,and sucrose phosphate synthase(SPS),invertase(INV),sucrose synthase synthesis(SSS)and cleavage(SSC)activities of broccoli samples were observed after 0,2,4,6,8,and 10 days of storage.The results showed that spraying arginine at 5 days preharvest(5-ARG)helped to inhibit broccoli respiration during storage,delay electrolyte leakage,and maintain broccoli color.Furthermore,during the growth stage,total sugar accumulation was higher in the 5-ARG group.In addition,during the storage period,sucrose synthesis was accelerated,while sucrose cleavage was inhibited,resulting in more sucrose retention in postharvest broccoli.In conclusion,5-ARG resulted in the accumulation of more nutrients during the growth process and effectively delayed the quality decline during storage,thereby prolonging the shelf life of broccoli.Therefore,this study provides a theoretical basis for improving postharvest storage characteristics of broccoli through preharvest treatments.展开更多
Aging-related diseases are gradually becoming a major problem with the rapid development of aged population in human society.Although many fluorescent probes have been employed to diagnosis senescence via imaging sene...Aging-related diseases are gradually becoming a major problem with the rapid development of aged population in human society.Although many fluorescent probes have been employed to diagnosis senescence via imaging senescence-associatedβ-galactosidase(SA-β-Gal),which is proved to be closely associated with senescent cells,the similar catalytic effectiveness of enzymatic reaction of ovarian cancer-associatedβ-Gal(OA-β-Gal)will interfere with imaging accuracy.Herein,a near-infrared(NIR)hemicyanine based fluorescent probe HCyXA-βGal was designed for light-up imaging of live cells containingβ-Gal.With the organelle-targeting morpholinyl and positive charge moieties,HCyxA-βGal was successfully applicated to image the difference of enzymatic location in senescent cells and ovarian cancer cells.Furthermore,inspired by the fast response performance,fast and precise imaging of the two cell lines was realized via covering another dimension of fluorescence signal:time-dependent intensity.展开更多
The limited potential for proliferation of human fibroblasts in culture represents cell level senescence. Aging is a programed process under generic control, and at certain stage of the life-span of animal cells, some...The limited potential for proliferation of human fibroblasts in culture represents cell level senescence. Aging is a programed process under generic control, and at certain stage of the life-span of animal cells, some genes start to express. Studying the biomarkers of senescent cells is important to understanding the basic mechanism of aging which may be relevant to the normal cell growth control and tumor biology. A protein with 72 000 Dalton molecular weight was detected by the hybridoma method in our laborotary. The protein shows specificity to senescent or presenescent cells of several cell lines, including WI-38, K.D., U2OS, etc.展开更多
Significant cellular senescence has been observed in cartilage harvested from patients with osteoarthritis(OA).In this study,we aim to develop a senescence-relevant OA-like cartilage model for developing disease-modif...Significant cellular senescence has been observed in cartilage harvested from patients with osteoarthritis(OA).In this study,we aim to develop a senescence-relevant OA-like cartilage model for developing disease-modifying OA drugs(DMOADs).Spe-cifically,human bone marrow-derived mesenchymal stromal cells(MSCs)were expanded in vitro up to passage 10(P10-MSCs).Following their senescent phenotype formation,P10-MSCs were subjected to pellet culture in chondrogenic medium.Results from qRT-PCR,histology,and immunostaining indicated that cartilage generated from P10-MSCs displayed both senescent and OA-like phenotypes without using other OA-inducing agents,when compared to that from normal passage 4(P4)-MSCs.Interestingly,the same gene expression differences observed between P4-MSCs and P10-MSC-derived cartilage tissues were also observed between the preserved and damaged OA cartilage regions taken from human samples,as demonstrated by RNA sequencing data and other analysis methods.Lastly,the utility of this senescence-initiated OA-like cartilage model in drug development was assessed by testing several potential DMOADs and senolytics.The results suggest that pre-existing cellular senescence can induce the generation of OA-like changes in cartilage.The P4-and P10-MSCs derived cartilage models also represent a novel platform for predicting the efficacy and toxicity of potential DMOADs on both preserved and damaged cartilage in humans.展开更多
文摘BACKGROUND Pancreatic cancer,a formidable gastrointestinal neoplasm,is characterized by its insidious onset,rapid progression,and resistance to treatment,which often lead to a grim prognosis.While the complex pathogenesis of pancreatic cancer is well recognized,recent attention has focused on the oncogenic roles of senescent tumor-associated fibroblasts.However,their precise role in pancreatic cancer remains unknown.Resveratrol is a natural polyphenol known for its multifaceted biological actions,including antioxidative and neuroprotective properties,as well as its potential to inhibit tumor proliferation and migration.Our current investigation builds on prior research and reveals the remarkable ability of resveratrol to inhibit pancreatic cancer proliferation and metastasis.AIM To explore the potential of resveratrol in inhibiting pancreatic cancer by targeting senescent tumor-associated fibroblasts.METHODS Immunofluorescence staining of pancreatic cancer tissues revealed prominent coexpression ofα-SMA and p16.HP-1 expression was determined using immunohistochemistry.Cells were treated with the senescence-inducing factors known as 3CKs.Long-term growth assays confirmed that 3CKs significantly decreased the CAF growth rate.Western blotting was conducted to assess the expression levels of p16 and p21.Immunofluorescence was performed to assess LaminB1 expression.Quantitative real-time polymerase chain reaction was used to measure the levels of several senescence-associated secretory phenotype factors,including IL-4,IL-6,IL-8,IL-13,MMP-2,MMP-9,CXCL1,and CXCL12.A scratch assay was used to assess the migratory capacity of the cells,whereas Transwell assays were used to evaluate their invasive potential.RESULTS Specifically,we identified the presence of senescent tumor-associated fibroblasts within pancreatic cancer tissues,linking their abundance to cancer progression.Intriguingly,Resveratrol effectively eradicated these fibroblasts and hindered their senescence,which consequently impeded pancreatic cancer progression.CONCLUSION This groundbreaking discovery reinforces Resveratrol's stature as a potential antitumor agent and positions senescent tumor-associated fibroblasts as pivotal contenders in future therapeutic strategies against pancreatic cancer.
文摘Regulatory changes in senescent cells could potentially affect the composition of extracellular vehicles(EVs),specifically altering their size and cargo.As a result,the released senescent EVs contain an unpredictable cocktail of growth factors and cytokines.These biomolecules have dual effects,potentially guiding the induction of senescence in affected cells and promoting an inflammation-related“domino effect”within the cellular environment,ultimately leading to tissue inflammaging.
基金supported by Dalian Youth Science and Technology Star Project(2020RQ121)the National Science Fund for Distinguished Young Scholars of China(31925031)+1 种基金Doctoral Scientific Research Foundation of Liaoning Province(2020-BS-211)Liaoning Province Education Administration(J2020101)。
文摘Cellular senescence is the results of aging and age-related diseases,and the development of anti-aging methods may improve health and extend longevity.The natural flavonol fisetin has been shown to antagonize senescence in vitro and increases longevity in vivo,but has poor water solubility and limited bioavailability.In this study,a food-grade and senescent cell-targeted delivery system for fisetin was developed based on whey protein isolate-galactooligosaccharides(WPI-GOS)Maillard conjugate,which could recognize senescence associatedβ-galactosidase in senescent cells.The fisetin nanoparticles possessed a high encapsulation efficiency,excellent dispersibility in water,good storage stability and well biocompatibility.Moreover,they could effectively accumulate and retain in senescent cells with excellent senescent cell-targeting efficacy,and inhibit the oxidative stress-induced cellular senescence in vitro.Thus,this novel nanoparticle system based on WPI-GOS Maillard conjugate showed promise to deliver hydrophobic bioactive ingredients like fisetin to senescent cells to improve their bioavailability and anti-senescence effect.
文摘Aging is well known to be the main risk factor for the neurodegenerative pathologies,in particular,Parkinson’s disease（PD）and Alzheimer’s disease（AD）.In aging and in the diseases,similar changes in various hallmarks of neurodegeneration（lipofuscin accumulation,autophagia weakening,and disturbances in functions of mitochondriaand lysosomes） were shown （Tan et al., 2014）. Furthermore, dopami- nergic system （DAS） involvement in mechanisms of aging, PD, and AD were revealed （Martorana and Koch, 2014）.
基金Supported by the National Natural Science Foundation of China,Nos.81500207,81670458,and 81470393Shanghai Municipal Health and Family Planning Commission,No.ZY(2018-2020)-FWTX-2007+4 种基金Shanghai Key Medical Discipline for Critical Care Medicine,No.2017zz02017the National Key Research and Development Program of China,No.2017YFA0105600Major Program of Development Fund for Shanghai Zhangjiang National Innovtaion Demonstration Zone,No.ZJ2018-ZD-004the Science and Technology Commission of Shanghai Municipality,No.17431906600and the Top-level Clinical Discipline Project of Shanghai Pudong,No.PWYgf2018-05.
文摘Mesenchymal stem/stromal cells(MSCs)have various properties that make them promising candidates for stem cell-based therapies in clinical settings.These include self-renewal,multilineage differentiation,and immunoregulation.However,recent studies have confirmed that aging is a vital factor that limits their function and therapeutic properties as standardized clinical products.Understanding the features of senescence and exploration of cell rejuvenation methods are necessary to develop effective strategies that can overcome the shortage and instability of MSCs.This review will summarize the current knowledge on characteristics and functional changes of aged MSCs.Additionally,it will highlight cell rejuvenation strategies such as molecular regulation,noncoding RNA modifications,and microenvironment controls that may enhance the therapeutic potential of MSCs in clinical settings.
基金supported by the National Natural Science Foundation of China(31660585)the Experimental Station for Scientific Observation of Fruit Trees in the Northwest of China(10218020)the earmarked fund for China Agriculture Research System(CARS-30-21)
文摘Heat stress occurs frequently in energy-saving sunlight greenhouses(ESSG) at the late growth stage. Three-year delayed cultivation(DC) of the Red Globe cultivar of Vitis vinifera L. was used to clarify the physiological mechanisms of short-term heat stress on PSII and subsequent recovery from heat stress. By November, the photosynthetic function had declined and the fall in transpiration rate(E) with heating time increased the possibility of heat damage. In July, the most obvious increase was in the relative variable fluorescence at J point at 40°C, and in November it changed to K point. The 5 min of heat treatment resulted in a significant increase of the relative variable fluorescence at 0.3 ms(W), and after 10 min of heat treatment, the number of reactive centres per excited cross section(RC/CS), probability that a trapped exciton moves an electron into the electron transport chain beyond Q–(at t=0)(Ψ) and quantum yield of electron transport at t=0(φ) decreased significantly(P<0.05), suggesting that the reaction centre, donor and acceptor side of photosystem II(PSII) were all significantly inhibited(P<0.05) and that the thermal stability of the photosynthetic mechanism was reduced. The inhibition of energy fluxes for senescent leaves in November was earlier and more pronounced than that for healthy leaves, which did not recover from heat stress of more than 15 min after 2 h recovery at room temperature.
基金Supported by the FONCYT,Argentina(PICT 2016-#1093)CONICET,Argentina(PIP2014-2016,#300)Fundación Florencio Fiorini(Subsidio 2021-2022),Argentina.
文摘Breast cancer is the predominant form of carcinoma among women worldwide,with 70%of advanced patients developing bone metastases,with a high mortality rate.In this sense,the bone marrow(BM)mesenchymal stem/stromal cells(MSCs)are critical for BM/bone homeostasis,and failures in their functionality,transform the BM into a premetastatic niche(PMN).We previously found that BM-MSCs from advanced breast cancer patients(BCPs,infiltrative ductal carcinoma,stage III-B)have an abnormal profile.This work aims to study some of the metabolic and molecular mechanisms underlying MSCs shift from a normal to an abnormal profile in this group of patients.A comparative analysis was undertaken,which included self-renewal capacity,morphology,proliferation capacity,cell cycle,reactive oxygen species(ROS)levels,and senescence-associatedβ‑galactosidase(SA‑β‑gal)staining of BMderived MSCs isolated from 14 BCPs and 9 healthy volunteers(HVs).Additionally,the expression and activity of the telomerase subunit TERT,as well as telomere length,were measured.Expression levels of pluripotency,osteogenic,and osteoclastogenic genes(OCT-4,SOX-2,M-CAM,RUNX-2,BMP-2,CCL-2,M-CSF,and IL-6)were also determined.The results showed that MSCs from BCPs had reduced,self-renewal and proliferation capacity.These cells also exhibited inhibited cell cycle progression and phenotypic changes,such as an enlarged and flattened appearance.Additionally,there was an increase in ROS and senescence levels and a decrease in the functional capacity of TERT to preserve telomere length.We also found an increase in pro-inflammatory/pro-osteoclastogenic gene expression and a decrease in pluripotency gene expression.We conclude that these changes could be responsible for the abnormal functional profile that MSCs show in this group of patients.
文摘Objective： To determine whether balloon catheter denudation can induce vascular smooth muscle cells （VSMCs） to senescence, and whether this senescence can result in inflammation activity. Methods： Twelve male Chinese white rabbits were denuded of the carotid arteries or VSMCs. Acidic β-galactosidase activity of carotid arteries or VSMCs was detected. Transfection and chloramphenicol acetyltransferase （CAT） assay for iNOS gene and nitrite （NO2^-） assay were undertaken. Reverse transcription-polymerase chain reaction （RT-PCR） was used to evaluate inflammation cytokines mRNA expression. Measurement of NF-kB activity was detected by electrophoretic mobility shift assay （EMSA）. MMP-9, ICAM-1, P-p65, and IkBα expressions were analyzed by Western blotting. Results： After denudation VSMCs from denuded arteries showed an accumulation of significantly more senescence-associated β-galactosidase （SA-β-Gal） positive ceils and greater iNOS activity. Transcriptional activity of iNOS was highly expressed. The mRNA expressions of IL-1β, ICAM-1,MMP-9, TNF-α and the iNOS enzyme were significantly increased in injuring-induced senescence SMCs. However, the TNF-α or IL-1β-induced the protein production （ICAM-1 and MMP-9） was prevented by PDTC and MG132, which are inhibitors of NF-kB activation. Also, activation of NF-kB and cytokine-induced degradation of IKBα in the denuded VSMC were significantly affected. Conclusion： Intraluminal injury to the artery may lead to the emergence of senescent VSMC. Inflammation activity in SMCs is closely related to the senescence and the activation of NF-kB is involved.
文摘The aim of the present study was to investigate the effect of one capsule of the micro-immunotherapy medicine (MIM) 2LMISEN®compared to vehicle, in a neuronal aging model. Senescence and apoptosis of hippocampal neurons were evaluated by measuring p16INK4a and caspase 3 levels, respectively. The data presented is a single observation. Mice hippocampal neuron cultures were treated with MIM (11 mM) or vehicle (11 mM) from 22 days in vitro (DIV) until 27 DIV. After incubation, hippocampal neuron cultures were fixed at 15 (control condition), 22, 25 and 27 DIV and then incubated with primary antibodies p16INK4a, MAP2 and Caspase 3. Quantification of p16INK4a and Caspase 3-positive neurons was done using Developer software. We found that vehicle had no effect on p16INK4a expression, whereas MIM was able to decrease p16INK4a levels at 22, 25 and 27 DIV in a statistically significant manner. The MIM had no significative effect on Caspase 3 expression. Our preliminary results showed that the MIM capsule significantly reduced neuronal senescence and not apoptosis.
文摘Background: Mature red blood cells lack protein synthesis and are unable to restore inactivated enzymes, damaged cytoskeleton and membrane proteins. An oxidation breakdown of band 3 is probably part of the mechanism leading to the generation of a senescent cell antigen. This specific signal serves for the clearance of RBCs by inducing the binding of autologous IgG and C3, leading to phagocytosis. In addition, phosphatidilserin molecules appear in the outer membrane and the CD47 expression diminishes. Methods: Erythrocytes of different ages from whole blood were studied by flow cytometry analysing light scatter proprieties, binding of autologous IgG, C3 complement deposits, externalization of phosphatidylserine and CD47 expression. Dot-plot analysis based on forward scatter versus side scatter parameters showed two RBCs populations of different sizes and density. RBCs were further incubated with Alexa 488 IgG, APC-anti-C3, PE-annexin-V and PE-CD47. The comparison of the values obtained for the different variables studied in SeRBC and YRBC populations was carried out by the Student t-test for matched samples or by the Wilcoxon test (after verification of the normality assumption). Results: The percentage of IgG and C3 positive cells was significantly higher in senescent red blood cells population. The fraction of annexin-V positive RBCs was also larger in SeRBCs while the CD47 expression was lower in this population. Conclusions: These results indicate that flow cytometry allow differenciation of erythrocytes populations of different ages, turning this tool into an useful alternative option to study erythrocyte aging process. These findings will contribute to a better understanding of the process and mechanisms involved in erythrocyte senescence process.
基金supported by the National Natural Science Foundation of China(grant number:82372820)。
文摘Cellular senescence is characterized by a generally irreversible cell cycle arrest and the secretion of bioactive factors known as the senescence-associated secretory phenotype(SASP).In an oncogenic context,senescence is considered a tumor suppressive mechanism as it prevents cell proliferation and inhibits the progression from pre-malignant to malignant disease.However,recent studies have demonstrated that senescent tumor cells,which could spontaneously exist within cancer tissues or arise in response to various cancer interventions(the so-called therapy-induced senescence,TIS),can acquire pro-tumorigenic properties and are capable of driving local and metastatic relapse.This highlights the complex and multifaceted nature of cellular senescence in cancer biology.Here,we summarize the current knowledge of the pathological function of therapy-induced senescent tumor cells and discuss possible mechanisms by which tumor cell senescence contributes to cancer relapse.We also discuss implications for future studies toward targeting these less appreciated cells.
基金support National Natural Science Foundation of China(No.81970973)Science and Technology Commission of Shanghai Municipality(No.20ZR1432200,21140900102,21490711700,22010502600)+3 种基金Disciplinary Characteristic Biobank Project of Ninth People’s Hospital affiliated to Shanghai Jiao Tong University School of Medicine(No.YBKB202110)Cross Disciplinary Research Fund of Shanghai Ninth People’s Hospital,Shanghai JiaoTong University School of Medicine(No.JYJC202219)Shanghai’s Top Priority Research Center(No.2022ZZ01017)CAMS Innovation Fund for Medical Sciences(No.CIFMS,2019-I2M-5-037).
文摘Stem cell senescence is characterized by progressive functional dysfunction and secretory phenotypic changes including decreased proliferation,dysfunction of osteogenic and angiogenic differentiation,increased secretion of the senescence-associated secretory phenotype(SASP),which bring difficulties for bone repair.Rescuing or delaying senescence of aged bone marrow mesenchymal stem cells(O-BMSCs)was considered as effective strategy for bone regeneration in aging microenvironment.Magnesium(Mg)ion released from bioceramics was reported to facilitate bone regeneration via enhancing osteogenesis and alleviating senescence.In this study,Akermanite biocreamics(Akt)containing Mg ion as a model was demonstrated to promote osteogenesis and angiogenesis effects of O-BMSCs by activating the MAPK signaling pathway in vitro.Moreover,the enhanced osteogenesis effects might be attributed to enhanced Mg-containing Akt-mediated exosomal miR-196a-5p cargo targeting Hoxa7 and activation of MAPK signaling pathway.Furthermore,the in vivo study confirmed that 3D-printed porous Mg-containing Akt scaffolds effectively increased bone regeneration in cranial defects of aged rats.The current results indicated that the exosomal-miR-196a-5p/Hoxa7/MAPK signaling axis might be the potential mechanism underlying Akt-mediated osteogenesis.The exosome-meditaed therapy stimulated by the released Mg ion contained in Akt biocreamics or other biomaterials might serve as a candidate strategy for bone repair in aged individuals.
基金supported by grants from the National Science Foundation to J.H.(MCB 0618335MCB 1330441)and L.J.O.(MCB 0618279)
文摘Peroxisomes compartmentalize a dynamic suite of biochemical reactions and play a central role in plant metabolism, such as the degradation of hydrogen peroxide, metabolism of fatty acids, photorespiration, and the biosyn- thesis of plant hormones. Plant peroxisomes have been traditionally classified into three major subtypes, and in-depth mass spectrometry （MS）-based proteomics has been per- formed to explore the proteome of the two major subtypes present in green leaves and etiolated seedlings. Here, we carried out a comprehensive proteome analysis of perox- isomes from Arabidopsis leaves given a 48-h dark treatment. Our goal was to determine the proteome of the third major subtype of plant peroxisomes from senescent leaves, and further catalog the plant peroxisomal proteome. We identified a total of 111 peroxisomal proteins and verified the peroxisomal localization for six new proteins with potential roles in fatty acid metabolism and stress response by in vivo targeting analysis. Metabolic pathways compartmentalized in the three major subtypes of peroxisomes were also compared, which revealed a higher number of proteins involved in the detoxification of reactive oxygen species in peroxisomes from senescent leaves. Our study takes an important step towards mapping the full function of plant peroxisomes.
基金Frontiers Science Center for Materiobiology and Dynamic Chemistry(No.JKVD1211002)Natural Science Foundation of China for Innovative Research Groups(No.51621002)+1 种基金National Natural Science Foundation of China(Nos.81571828,31971264,32101151)Basic Science Center Project of National Natural Science Foundation of China(T2288102)。
文摘Clinical therapies developed for estrogen-deficiency-driven postmenopausal osteoporosis(PMO)and related diseases,such as bone degeneration,show multiple adverse effects nowadays.Targeting senescent cells(SnCs)and the consequent senescence-associated secretory phenotype(SASP)with a combination of dasatinib and quercetin(DQ)is a recently developed novel therapy for multiple age-related diseases.Herein,we found that estrogen deficiency induced-bone loss was attributed to a pro-inflammatory microenvironment with SASP secretions and accelerated SnC accumulation,especially senescent mesenchymal stem cells(MSCs)characterized by exhaustion and dysfunction in middle aged rats.Systematically targeting SnCs with DQ strikingly ameliorated PMO and restored MSC function.Local administration of DQ and bone morphogenetic protein 2(BMP2)in combination promoted osteogenic differentiation of MSCs and rejuvenated osteoporotic bone regeneration.Our results repurposed DQ as an attractive therapy for treating PMO and related diseases.
基金Chinese National Program on Key Basic Research Project(Grant Nos.2017YFA0103300,2015CB964800)the National Science Foundation of China(Grant Nos.81622019,81502385,31570813 and 81601212)the Fundamental Research Funds for the Central Un iversities.
文摘Dear Editor,Over a half-century ago,Dr.Leonard Hayflick described the phenotype of a finite lifespan for human fibroblasts being passaged in in vitro cell culture(Hayflick et al.,1961),a phenomenon today known as replicative cellular senescence.Cellular senescence has been defined as a state in which cells lose their potential to divide and are permanently arrested in either the G1,or arguably the G2 stage of the cell cycle(Mao et al.,2012).In addition to replicative cellular senescenee—which is induced by large amounts of DNA damage at telomeres due to loss of the specialized T-loop structure—xogenous sublethal stresses such as ionizing radiati on,genotoxic chemicals or hyper-activated on cogenes may also trigger a similar form of senescence,stress induced premature cellular senescenee(SIPS).
文摘Objective To review the senescent remodeling of the immune system with aging and its relevance to the increased susceptibility of the elderly to infectious diseases, along with an outlook on emerging immunological biomarkers. Data sources The data selected were from PubMed with relevant published articles in English or French from 1995 to the present. Searches were made using the terms immunosenescence and aging paired with the following： innate immunity, T-celr, B-cell, adaptive immunity and biomarkers. Articles were reviewed for additional citations and some information was gathered from web searches. Study selection Articles on aging of both the innate and adaptive immunity were reviewed, with special attention to the remodeling effect on the ability of the immune system to fight infectious diseases. Articles related to biomarkers of immunosenescence were selected with the goal of identifying immunological biomarkers predisposing the elderly to infections. Results Innate immunity is generally thought to be relatively well preserved or enhanced during aging compared with adaptive immunity which manifests more profound alterations. However, evidence, particularly in the last decade, reveals that both limbs of the immune system undergo profound remodeling with aging. Reported data on adaptive immunity is consistent and changes are well established but conflicting results about innate immunity were reported between in vivo and in vitro studies, as well as between murine and human studies. Epidemiological data suggests increased predisposition of the elderly to infections, but no compelling scientific evidence has directly linked senescent immune remodeling to this increased susceptibility. Recently, growing interest in identifying immunological biomarkers and defining immune risk phenotypes/profiles （IRP） has been expressed. Identification of biomarkers is in its early days and few potential biomarkers have been identified, with the Swedish having defined one IRP based on the adaptive immune response. Conclusions Aging does not necessarily lead to an unavoidable decline in immune functions. Instead, a complex remodeling occurs. Despite the lack of compelling scientific evidence, senescent immune remodeling surely is a significant contributing factor to the increased risk and severity of infections in the elderly. Although, no immunological biomarker has been formally linked to the increased risk of infections in the elderly, biomarkers remain a promising tool to predict the likelihood of healthy aging, the level of immune competence, and mortality risk in the elderly. Hence, more research is required to define healthy aging and identify immunological biomarkers.
文摘To determine the effects of preharvest arginine spraying on the nutritional level of broccoli and the mechanism of action of arginine in improving the storage quality of broccoli,arginine spraying(5 mmol/L)was conducted at 0,1,3,and 5 days before harvest.The appearance,respiration rate,mass-loss rate,electrolyte leakage,glucosinolate,ascorbic acid,total phenol,total flavonoid,total sugar and sucrose contents,and sucrose phosphate synthase(SPS),invertase(INV),sucrose synthase synthesis(SSS)and cleavage(SSC)activities of broccoli samples were observed after 0,2,4,6,8,and 10 days of storage.The results showed that spraying arginine at 5 days preharvest(5-ARG)helped to inhibit broccoli respiration during storage,delay electrolyte leakage,and maintain broccoli color.Furthermore,during the growth stage,total sugar accumulation was higher in the 5-ARG group.In addition,during the storage period,sucrose synthesis was accelerated,while sucrose cleavage was inhibited,resulting in more sucrose retention in postharvest broccoli.In conclusion,5-ARG resulted in the accumulation of more nutrients during the growth process and effectively delayed the quality decline during storage,thereby prolonging the shelf life of broccoli.Therefore,this study provides a theoretical basis for improving postharvest storage characteristics of broccoli through preharvest treatments.
基金supported by National Natural Science Foundation of China(Nos.22122803 and 21788102)the National Natural Science Foundation of Jiangsu Province(No.BK20220644).
文摘Aging-related diseases are gradually becoming a major problem with the rapid development of aged population in human society.Although many fluorescent probes have been employed to diagnosis senescence via imaging senescence-associatedβ-galactosidase(SA-β-Gal),which is proved to be closely associated with senescent cells,the similar catalytic effectiveness of enzymatic reaction of ovarian cancer-associatedβ-Gal(OA-β-Gal)will interfere with imaging accuracy.Herein,a near-infrared(NIR)hemicyanine based fluorescent probe HCyXA-βGal was designed for light-up imaging of live cells containingβ-Gal.With the organelle-targeting morpholinyl and positive charge moieties,HCyxA-βGal was successfully applicated to image the difference of enzymatic location in senescent cells and ovarian cancer cells.Furthermore,inspired by the fast response performance,fast and precise imaging of the two cell lines was realized via covering another dimension of fluorescence signal:time-dependent intensity.
文摘The limited potential for proliferation of human fibroblasts in culture represents cell level senescence. Aging is a programed process under generic control, and at certain stage of the life-span of animal cells, some genes start to express. Studying the biomarkers of senescent cells is important to understanding the basic mechanism of aging which may be relevant to the normal cell growth control and tumor biology. A protein with 72 000 Dalton molecular weight was detected by the hybridoma method in our laborotary. The protein shows specificity to senescent or presenescent cells of several cell lines, including WI-38, K.D., U2OS, etc.
文摘Significant cellular senescence has been observed in cartilage harvested from patients with osteoarthritis(OA).In this study,we aim to develop a senescence-relevant OA-like cartilage model for developing disease-modifying OA drugs(DMOADs).Spe-cifically,human bone marrow-derived mesenchymal stromal cells(MSCs)were expanded in vitro up to passage 10(P10-MSCs).Following their senescent phenotype formation,P10-MSCs were subjected to pellet culture in chondrogenic medium.Results from qRT-PCR,histology,and immunostaining indicated that cartilage generated from P10-MSCs displayed both senescent and OA-like phenotypes without using other OA-inducing agents,when compared to that from normal passage 4(P4)-MSCs.Interestingly,the same gene expression differences observed between P4-MSCs and P10-MSC-derived cartilage tissues were also observed between the preserved and damaged OA cartilage regions taken from human samples,as demonstrated by RNA sequencing data and other analysis methods.Lastly,the utility of this senescence-initiated OA-like cartilage model in drug development was assessed by testing several potential DMOADs and senolytics.The results suggest that pre-existing cellular senescence can induce the generation of OA-like changes in cartilage.The P4-and P10-MSCs derived cartilage models also represent a novel platform for predicting the efficacy and toxicity of potential DMOADs on both preserved and damaged cartilage in humans.
