Within the cell, several mechanisms exist to maintain homeostasis of the endoplasmic reticulum （ER）. One of the primary mechanisms is the unfolded protein response （UPR）. In this review, we primarily focus on the ...Within the cell, several mechanisms exist to maintain homeostasis of the endoplasmic reticulum （ER）. One of the primary mechanisms is the unfolded protein response （UPR）. In this review, we primarily focus on the latest signal webs and regulation mechanisms of the UPR. The relationships among ER stress, apoptosis, and cancer are also discussed. Under the normal state, binding immunoglobulin protein （BiP） interacts with the three sensors （protein kinase RNA-like ER kinase （PERK）, activating transcription factor 6 （ATF6）, and inositol-requiring enzyme la （IREla）） Under ER stress, misfolded proteins interact with BiP, resulting in the release of BiP from the sensors. Subsequently, the three sensors dimerize and autophosphorylate to promote the signal cascades of ER stress. ER stress includes a series of positive and negative feedback signals, such as those regulating the stabilization of the sensors/BiP complex, activating and inactivating the sensors by autophosphorylation and dephosphorylation, activating specific transcription factors to enable selective transcription, and augmenting the ability to refold and export. Apart from the three basic pathways, vascular endothelial growth factor （VEGF）-VEGF receptor （VEGFR）-phospholipase C-~ （PLCy）-mammalian target of rapamycin complex 1 （mTORC1） pathway, induced only in solid tumors, can also activate ATF6 and PERK signal cascades, and IREla also can be activated by activated RAC-alpha serine/threonine-protein kinase （AKT）. A moderate UPR functions as a pro-survival signal to return the cell to its state of homeostasis. However, persistent ER stress will induce cells to undergo apoptosis in response to increasing reactive oxygen species （ROS）, Ca2＋ in the cytoplasmic matrix, and other apoptosis signal cascades, such as c-Jun N-terminal kinase （JNK）, signal transducer and activator of transcription 3 （STAT3）, and P38, when cellular damage exceeds the capacity of this adaptive response.展开更多
The melanoma differentiation-associated gene-7（mda-7）,IL-24,has the specific functions that induce cancer cell apoptosis without doing harm to normal cells. We systematically review the apoptotic signal pathways and...The melanoma differentiation-associated gene-7（mda-7）,IL-24,has the specific functions that induce cancer cell apoptosis without doing harm to normal cells. We systematically review the apoptotic signal pathways and their regulatory mechanisms induced by Ad.IL-24 and IL-24 in diverse cancer cells. IL-24 can participate in varied signal transduction pathways,including JAK,p38 MAPK,Wnt/β-catenin,JNK,ER stress and mitochondria-associated signal pathways. And we review five proteins interacting with IL-24,including Bip/GRP78,S1 R,PKR,Beclin1 and soluble clusterin,which are relative to the tumor-specific effect of IL-24. It is speculated that ER stress,G-protein pathways and MAPK signal pathways may be the primary upstream effectors which activate the sequential downstream mediators resulting in apoptosis induced by IL-24 in tumor cells. Experimental results also show that IL-24 sensitizes cancer cells and indirectly promotes apoptosis rather than functions as a direct apoptosis inducer itself.展开更多
The mini-review stemmed from a recent meeting on national aging research strategies in China discusses the components and challenges of aging research in China. Highlighted are the major efforts of a number of researc...The mini-review stemmed from a recent meeting on national aging research strategies in China discusses the components and challenges of aging research in China. Highlighted are the major efforts of a number of research teams, funding situations and outstanding examples of recent major research achievements. Finally, authors discuss potential targets and strategies of aging research in China.展开更多
DNA double-strand break(DSB) is the most severe form of DNA damage,which is repaired mainly through high-fidelity homologous recombination(HR) or error-prone non-homologous end joining(NHEJ).Defects in the DNA damage ...DNA double-strand break(DSB) is the most severe form of DNA damage,which is repaired mainly through high-fidelity homologous recombination(HR) or error-prone non-homologous end joining(NHEJ).Defects in the DNA damage response lead to genomic instability and ultimately predispose organs to cancer.Nicotinamide phosphoribosyltransferase(Nampt),which is involved in nicotinamide adenine dinucleotide metabolism,is overexpressed in a variety of tumors.In this report,we found that Nampt physically associated with CtIP and DNA-PKcs/Ku80,which are key factors in HR and NHEJ,respectively.Depletion of Nampt by small interfering RNA(siRNA) led to defective NHEJ-mediated DSB repair and enhanced HR-mediated repair.Furthermore,the inhibition of Nampt expression promoted proliferation of cancer cells and normal human fibroblasts and decreased β-galactosidase staining,indicating a delay in the onset of cellular senescence in normal human fibroblasts.Taken together,our results suggest that Nampt is a suppressor of HR-mediated DSB repair and an enhancer of NHEJ-mediated DSB repair,contributing to the acceleration of cellular senescence.展开更多
The process of aging is mitigated by the maintenance and repair of chromosome ends(telomeres),resulting in extended lifespan.This review examines the molecular mechanisms underlying the actions and regulation of the e...The process of aging is mitigated by the maintenance and repair of chromosome ends(telomeres),resulting in extended lifespan.This review examines the molecular mechanisms underlying the actions and regulation of the enzyme telomerase reverse transcriptase(TERT),which functions as the primary mechanism of telomere maintenance and regulates cellular life expectancy.Underpinning increased cell proliferation,telomerase is also a key factor in facilitating cancer cell immortalization.The review focuses on aspects of hormonal regulations of telomerase,and the intracellular pathways that converge to regulate telomerase activity with an emphasis on molecular interactions at protein and gene levels.In addition,the basic structure and function of two key telomerase enzyme components—the catalytic subunit TERTand the template RNA(TERC)are discussed briefly.展开更多
Background People over the age of 85 are a rapidly growing age group with a high incidence of congestive heart failure(CHF),in particular heart failure with preserved ejection fraction(HFp EF).The diagnosis of CHF is ...Background People over the age of 85 are a rapidly growing age group with a high incidence of congestive heart failure(CHF),in particular heart failure with preserved ejection fraction(HFp EF).The diagnosis of CHF is challenging and longitudinal data assessing cardiac structure and function are necessary to distinguish physiologic from pathologic cardiac aging.The objective of the study was to determine longitudinal changes in cardiac struture and function from ages 85 to 94 years using home echocardiography.Methods Subjects were recruited from the Jerusalem Longitudinal Cohort Study.Sixty three members of the initial cohort(32 F,31 M)who underwent home echocardiography at age 85 were the subjects of the current study and underwent repeat home 2-D and Doppler echocardiographic assessment at age 94.Results There were no significant longitudinal changes in left ventricular mass index(LVMI),however LV end-diastolic volume significantly decreased from 113.4±30 to 103.6±35.5 m L(P<0.02).Ejection fraction(EF)remained stable,however longitudinal systolic function significantly decreased with age from 7.9±1.8 to 6.6±1.4 cm/s2(P<0.0001).Diastolic function as assessed by increased E:e’(11.2±3.4 to 16±7.5,P<0.0001)and increased left atrial volume index(34.1±11.3 to 42.4±13.7 m L/m^2,P<0.0001)was reduced with aging.Conclusions This study demonstrated preserved EF with decreased longitudinal systolic function and diastolic function without significant change in LV mass.Changes in LV function in the very elderly may be independent of changes in LV geometry.展开更多
AIM：To identify the pathological role of amyloid beta（Aβ） deposition in retinal degeneration,and explore Aβ deposition on the retinal pigment epithelium cells（RPE） layer and the associated structural and functi...AIM：To identify the pathological role of amyloid beta（Aβ） deposition in retinal degeneration,and explore Aβ deposition on the retinal pigment epithelium cells（RPE） layer and the associated structural and functional changes in Alzheimer＇s disease transgenic mice.METHODS：RPE changes in the eyes of APPswe/PS1 transgenic and none transgenic（NTG） mice over 20 months old were examined.Histological changes were investigated via hematoxylin and eosin（H＆E） staining and transmission electron microscopy（TEM） examination,whereas the expression of amyloid precursor protein（APP）,Aβ,Zonula occludens-1（ZO-1） and Ionized calcium binding adaptor molecule-1（IBA-1） were investigated using immunohistochemistry and immunofluorescence techniques.All of the obtained results were quantitatively and statistically analyzed.RESULTS：In aged transgenic mice,an APP-positive immunoreaction and Aβ deposition were detected on the RPE layer but were undetectable in NTG mice.The RPE demonstrated some vacuole changes,shortened basal infoldings and basal deposition in histopathological examination and TEM tests,wherein irregular shapes were indicated by ZO-1 disorganization through fluorescence.Furthermore,IBA-1 positive cells were observed to have accumulated and infiltrated into the RPE layer and localized beneath the RPE/Bruch＇s membrane（Br M） complex,which was accompanied by an increase in BrM thickness in aged transgenic mice in comparison to NTG mice.The IBA-1 positive cells were found to be co-stained with Aβ deposition on the RPE flat mounts.CONCLUSION：The observed Aβ deposition in the RPE layer may cause RPE dysfunction,which is associated with microglia cells infiltration into the retina of aged transgenic mice,suggesting that Aβ deposition probably plays a significant role in RPE-related degenerative disease.展开更多
Remarkable progress has taken place in the research of stem cells during the past 30 years.General perceptions,experimental and clinical evidences pinpoint the fact that functional decline of tissue often coincides wi...Remarkable progress has taken place in the research of stem cells during the past 30 years.General perceptions,experimental and clinical evidences pinpoint the fact that functional decline of tissue often coincides with aging-related diseases.Stem cell aging plays a fundamental role in the dysregulation of tissue function,maintenance,and repairing.This review specifically focuses on the current findings and emerging concepts of hematopoietic stem cell aging and its mechanisms.展开更多
Aging is one of the contributing risk factors for kidney diseases. Accumulating evidence prompts the view that telomere length in kidney tissue cells is an indicator for organismal aging. Previously identified aging m...Aging is one of the contributing risk factors for kidney diseases. Accumulating evidence prompts the view that telomere length in kidney tissue cells is an indicator for organismal aging. Previously identified aging markers （cathelin-related antimicrobial peptide （CRAMP）, stathmin, elongation factor-1α （EF-1α）, and chitinase） were associated not only with telomere driven aging in mice but also with human aging and chronic diseases. This study focuses on the relationship between these biomarkers and IgA nephropathy （IgAN） progression in the Chinese population. For 260 individuals, the four markers are determined in blind datasets using direct enzyme-linked immunosorbent assay （ELISA） and immunofluorescence staining. The expression levels of CRAMP and chitinase increased in blood plasma, urine, and kidney tissues during human IgAN progression. And for the other nephropathy, such as systemic lupus erythematosus （SLE）, diabetic nephropathy （DN）, and focal segmental glomerulosclerosis （FSGS）, there is no protein upregulaUon with telomere shortening. Moreover, a combination of CRAMP and chitinase can distinguish patients with IgAN from healthy individuals with 88.2%/92.5% （plasma） and 74.3%/84.2% （urine） sensitivity/specificity. These data provide the experimental evidence that telomere shortening and related inflammatory proteins are associated with human IgAN, and it could be a new direction for the disease progression study.展开更多
Dear Editor,Telomere attrition is one of the hallmark of aging.Lategeneration Terc knockout mice exhibit impaired hematopoiesis,1 while the underling mechanisms remain poorly understood.Retrotransposon long interspers...Dear Editor,Telomere attrition is one of the hallmark of aging.Lategeneration Terc knockout mice exhibit impaired hematopoiesis,1 while the underling mechanisms remain poorly understood.Retrotransposon long interspersed element-1(L1)is the only human retrotransposable elements capable of autonomous retrotransposition,and evolutionarily inactive.Recent studies reported that L1 is derepressed during the aging process with redistribution and reorganization of the heterochromatin.2 Considering that telomere shortening can cause chromosome instability and rearrangements,3 we speculate that L1 may play a role in impaired hematopoiesis in telomere dysfunctional mice.展开更多
The gut microbiota plays a pivotal role in systemic metabolic processes and in particular functions,such as developing and preserving the skeletal muscle system.However,the interplay between gut microbiota/metabolites...The gut microbiota plays a pivotal role in systemic metabolic processes and in particular functions,such as developing and preserving the skeletal muscle system.However,the interplay between gut microbiota/metabolites and the regulation of satellite cell(SC)homeostasis,particularly during aging,remains elusive.We propose that gut microbiota and its metabolites modulate SC physiology and homeostasis throughout skeletal muscle development,regeneration,and aging process.Our investigation reveals that microbial dysbiosis manipulated by either antibiotic treatment or fecal microbiota transplantation from aged to adult mice,leads to the activation of SCs or a significant reduction in the total number.Furthermore,employing multi-omics(e.g.,RNA-seq,16S r RNA gene sequencing,and metabolomics)and bioinformatic analysis,we demonstrate that the reduced butyrate levels,alongside the gut microbial dysbiosis,could be the primary factor contributing to the reduction in the number of SCs and subsequent impairments during skeletal muscle aging.Meanwhile,butyrate supplementation can mitigate the antibiotics-induced SC activation irrespective of gut microbiota,potentially by inhibiting the proliferation and differentiation of SCs/myoblasts.The butyrate effect is likely facilitated through the monocarboxylate transporter 1(Mct1),a lactate transporter enriched on membranes of SCs and myoblasts.As a result,butyrate could serve as an alternative strategy to enhance SC homeostasis and function during skeletal muscle aging.Our findings shed light on the potential application of microbial metabolites in maintaining SC homeostasis and preventing skeletal muscle aging.展开更多
Telomere assumes intra-molecular G-quadruplex that is a significant drug target for inhibiting telomerase main- tenance of telomeres in cancer. Metal cations have been recognized as playing important roles in stabiliz...Telomere assumes intra-molecular G-quadruplex that is a significant drug target for inhibiting telomerase main- tenance of telomeres in cancer. Metal cations have been recognized as playing important roles in stabilizing G-quadruplex, but their binding processes to human telomeric G-quadruplex remain uncharacterized. To in- vestigate the detailed binding procedures, molecular dynamics simulations were conducted on the hybrid [3 ＋ 1] form-one human telomeric intra-molecular G-quadruplex. We show here that the binding of a potas- sium ion to a G-tetrad core is mediated by two alternative pathways. Principal component analysis illustrated the dominant concerted motions of G-quadruplex occurred at the loop domains. MM-PBSA calculations revealed that binding was energetically favorable and driven by the electrostatic interactions. The lower binding site was found more constructive favorable for binding. Our data provide useful information on a potassium-mediated stable structure of human telomeric intra-molecular G-quadruplex, implicating in ion disorder associated conformationa｜ changes and targeted drug design.展开更多
Skeletal muscle plays a significant role in both local and systemic energy metabolism.The current investigation aims to explore the role of the Bambi gene in skeletal muscle,focusing on its implications for muscle hyp...Skeletal muscle plays a significant role in both local and systemic energy metabolism.The current investigation aims to explore the role of the Bambi gene in skeletal muscle,focusing on its implications for muscle hypertrophy and systemic metabolism.We hypothesize that skeletal muscle-specific deletion of Bambi induces muscle hypertrophy,improves metabolic performance,and activates thermogenic adipocytes via the reprogramming of progenitor of iWAT,offering potential therapeutic strategies for metabolic syndromes.Leveraging the Chromatin immunoprecipitation(ChIP)-seq and bioinformatics analysis,Bambi gene is shown to be a direct target of HIF2α,which is further confirmed by ChIP-qPCR and promoter luciferase assay.Skeletal muscle-specific Bambi deletion led to significant muscle hypertrophy and improved metabolic parameters,even under high-fat diet conditions.This deletion induced metabolic reprogramming of stromal vascular fractions(SVFs)into thermogenic adipocytes,contributing to systemic metabolic improvements,potentially through the secretory factor.Notably,mice with skeletal muscle-specific Bambi deletion demonstrate resistance to high-fat diet-induced metabolic disorders,highlighting a potential therapeutic pathway for metabolic syndrome management.Thus,skeletal muscle-specific deletion of Bambi triggers muscle growth,enhances metabolic performance,and activates thermogenic adipocytes.These findings suggest Bambi as a novel therapeutic target for metabolic syndromes,providing new insights into the interaction between muscle hypertrophy and systemic metabolic improvement.The study underscores the potential of manipulating muscle physiology to regulate whole-body metabolism,offering a novel perspective on treating metabolic disorders.展开更多
Telomerase is a large ribonucleoprotein complex that contains a catalytic telomerase reverse transcriptase(TERT)and an RNA template.Telomerase activity is tightly controlled by TERT expression,which is regulated at bo...Telomerase is a large ribonucleoprotein complex that contains a catalytic telomerase reverse transcriptase(TERT)and an RNA template.Telomerase activity is tightly controlled by TERT expression,which is regulated at both the transcriptional and post-translational levels.However,the detailed molecular mechanisms of telomerase regulation and function are not fully understood.To identify cofactors that contribute to telomerase regulation,we employed a yeast two-hybrid system to screen for hTERT-interacting proteins,using the hTERT T-motif as bait.We identify C53 as a novel hTERT interaction partner.We show that C53 interacts with hTERT both in vivo and in vitro.C53 depletion increases telomerase activity,and C53 overexpression inhibits telomerase activity in MCF7 cells.In addition,the C53 leucine zipper domain(amino acids 301–400)is required for interaction with hTERT.Deleting the leucine zipper domain eliminates C53 interaction with hTERT and abrogates its inhibitory effect on telomerase activity.Taken together,our results demonstrate that C53 is a novel hTERT-associated protein that negatively regulates telomerase activity.展开更多
Ataxia telangiectasia mutated （ATM） kinase plays an essential role in the maintenance of genomic stability. ATM-deficient （ATM-/-） mice exhibit hematopoietic stem cell （HSC） dysfunction and a high incidence of l...Ataxia telangiectasia mutated （ATM） kinase plays an essential role in the maintenance of genomic stability. ATM-deficient （ATM-/-） mice exhibit hematopoietic stem cell （HSC） dysfunction and a high incidence of lym- phoma. Gadd45a controls cell cycle arrest, apoptosis and DNA repair, and is involved in the ATM-p53 mediated DNA damage response. However, the role of Gadd45a in regulating the functionality of ATM-/- HSCs is unknown. Here we report that Gadd45a deletion did not rescue the defects of T-cells and B-cells development in ATM-/- mice. Instead, ATM and Gadd45a double knockout （ATM-/- Gadd45a-/-） HSCs exhibited an aggravated defect in long-term self-renewal capacity compared to ATM-/- HSCs in HSC transplantation experiments. Fur- ther experiments revealed that the aggravated defect of ATM-/- Gadd45a-/- HSCs was due to a reduction of cell proliferation, associated with an accumulation of DNA damage and subsequent activation of DNA damage response including an up-regulation of p53-p21 signal- ing pathway. Additionally, ATM-/- Gadd45a-/- mice showed an increased incidence of hematopoietic malignancies, as well as an increased rate of metastasis than ATM-/- mice. In conclusion, Gadd45a deletion aggravated the DNA damage accumulation, which sub- sequently resulted in a further impaired self-renewal capacity and an increased malignant transformation in ATM-/- HSCs.展开更多
Human telomerase reverse transcriptase （hTERT） plays a central role in telomere lengthening for continuous cell proliferation, but it remains unclear how extracellular cues regulate telomerase lengthening of telomer...Human telomerase reverse transcriptase （hTERT） plays a central role in telomere lengthening for continuous cell proliferation, but it remains unclear how extracellular cues regulate telomerase lengthening of telomeres. Here we report that the cytokine bone morphogenetic protein-7 （BMP7） induces the hTERT gene repression in a BMPRII receptor- and Smad3-dependent manner in human breast cancer cells. Chonic exposure of human breast cancer cells to BMP7 results in short telomeres, cell senescence and apoptosis. Mutation of the BMPRII receptor, but not TGFbRII, ACTRIIA or ACTRIIB receptor, inhibits BMP7-induced repression of the hTERT gene promoter activity, leading to increased telomerase activity, lengthened telomeres and continued cell proliferation. Expression of hTERT prevents BMP7-induced breast cancer cell senescence and apoptosis. Thus, our data suggest that BMP7 induces breast cancer cell aging by a mechanism involving BMPRII receptor- and Smad3-mediated repression of the hTERT gene.展开更多
Objective:To investigate the therapeutic effect of Sanhuang Xiexin Decoction(SXD)on triplenegative breast cancer(TNBC)in mice and its underlying mechanism.Methods:The high-performance liquid chromatography(HHLC)was us...Objective:To investigate the therapeutic effect of Sanhuang Xiexin Decoction(SXD)on triplenegative breast cancer(TNBC)in mice and its underlying mechanism.Methods:The high-performance liquid chromatography(HHLC)was used to quantitate and qualify SXD.A total of 15 female BALB/c mice were inoculated subcutaneously on the right hypogastrium with 3×10^(5) of 4T1-Luc cells to establish TNBC mouse model.All mice were divided randomly into 3 groups,including phosphate buffered solution(PBS),SXD and doxorubicin(DOX)groups(positive drug).Additionally,tumor growth,pathological changes,serum lipid profiles,expression of Janus kinase 2(JAK2)-signal transducer and activator of transcription 3(STAT3)signaling pathway and its key targets including inflammatory factors,cell cycle and epithelial-mesenchymal transition(EMT)markers were investigated.Besides,the biosafety of SXD was also evaluated in mice.Results:Rhein,coptisine,berberine hydrochloride and baicalin were all found in SXD,and the concentrations of these 4 components were 0.57,2.61,2.93,and 46.04 mg/g3respectively.The mouse experiment showed that SXD could notably suppress the development of tumors and reduce the density of tumor cells(P<0.01).The serum lipid analysis and Oil-Red-O staining both showed the differences,SXD group exhibited higher serum adiponectin and HDL-C levels with lower TC and LDL-C levels compared to the PBS and DOX groups(P<0.05 or P<0.01),respectively.SXD also decreased the levels of phospho-JAK2(p-JAK2),phospho-STAT3(p-STAT3)expressions and its downstream factors,including mostly inflammatory cytokine,EMT markers,S phase of tumor cells and vascular endothelial growth factor(VEGF)expression(P<.05 or P<0.01),respectively.The biosafety assessment of SXD revealed low levels of toxicity in mice.Conclusion:SXD could inhibit TNBC by suppressing JAK2-STAT3 phosphorylation which may be associated with modulation of lipid metabolism.展开更多
Maintenance of tissue-specific stem cells is vital for organ homeostasis and organismal longevity.Hematopoietic stem cells（HSCs） are the most primitive cell type in the hematopoietic system.They divide asymmetricall...Maintenance of tissue-specific stem cells is vital for organ homeostasis and organismal longevity.Hematopoietic stem cells（HSCs） are the most primitive cell type in the hematopoietic system.They divide asymmetrically and give rise to daughter cells with HSC identity（selfrenewal） and progenitor progenies（differentiation）,which further proliferate and differentiate into full hematopoietic lineages.Mammalian ageing process is accompanied with abnormalities in the HSC self-renewal and differentiation.Transcriptional changes and epigenetic modulations have been implicated as the key regulators in HSC ageing process.The DNA damage response（DDR）in the cells involves an orchestrated signaling pathway,consisting of cell cycle regulation,cell death and senescence,transcriptional regulation,as well as chromatin remodeling.Recent studies employing DNA repair-deficient mouse models indicate that DDR could intrinsically and extrinsically regulate HSC maintenance and play important roles in tissue homeostasis of the hematopoietic system.In this review,we summarize the current understanding of how the DDR determines the HSC fates and finally contributes to organismal ageing.展开更多
Dear Editor,Emerging evidences show close associations between miRNAs and liver regeneration.MiR-126 is known as a governor of vascular integrity and angiogenesis.MiR-126 is involved in the self-renewal of hematopoiet...Dear Editor,Emerging evidences show close associations between miRNAs and liver regeneration.MiR-126 is known as a governor of vascular integrity and angiogenesis.MiR-126 is involved in the self-renewal of hematopoietic stem cells(HSCS)and leukemia stem cells.1,2 MiR-126 also plays a vital role in hepatocellular carcinogenesis,however,the functions of miR-126 in liver regeneration were still unclear.展开更多
The expression of coinhibitory receptors,such as CTLA-4,on effector T cells is a key mechanism for the negative regulation of T-cell activation.However,the transcriptional regulation of CTLA-4 is not well understood.Z...The expression of coinhibitory receptors,such as CTLA-4,on effector T cells is a key mechanism for the negative regulation of T-cell activation.However,the transcriptional regulation of CTLA-4 is not well understood.Zfp281,a C2H2 zinc finger protein,is a negative regulator of pluripotency maintenance of embryonic stem cells.Nevertheless,the function of Zfp281 in differentiated cells has not been studied.We generated Zfp281 conditional knockout mice in which the function of the Zfp281 gene was conditionally disrupted by the Cd4^(Cre) transgene to study its impact on T cell function.Zfp281 had no effect on T-cell development,but CD4^(+)T cell activation and cytokine production were impaired due to diminished T-cell receptor signaling.Furthermore,Zfp281 deficiency inhibited in vivo T cell responses to Listeria monocytogenes infection.Using genome-wide expression profiling assays,we determined that Zfp281 repressed Ctla-4 expression by directly binding to GC-rich sites in its promoter,which inhibited the negative feedback of T cell activation.In line with this result,CTLA-4 blockade and shRNA knockdown partly rescued the reduced cytokine production caused by Zfp281 deficiency.These findings indicate that Zfp281 sustains CD4^(+)T lymphocyte activation by directly repressing Ctla-4 transcription.展开更多
基金Project supported by the National Basic Research Program(973)of China(No.2012CB518900)the National Natural Science Foundation of China(Nos.31160240 and 31260621)+2 种基金the National Major Scientific and Technological Special Project during the Twelfth Five-year Plan Period of China(No.2012ZX10002006)the Hangzhou Normal University Supporting Project(No.PE13002004042)the Natural Science Foundation of Jiangxi Province(No.20114BAB204016),China
文摘Within the cell, several mechanisms exist to maintain homeostasis of the endoplasmic reticulum （ER）. One of the primary mechanisms is the unfolded protein response （UPR）. In this review, we primarily focus on the latest signal webs and regulation mechanisms of the UPR. The relationships among ER stress, apoptosis, and cancer are also discussed. Under the normal state, binding immunoglobulin protein （BiP） interacts with the three sensors （protein kinase RNA-like ER kinase （PERK）, activating transcription factor 6 （ATF6）, and inositol-requiring enzyme la （IREla）） Under ER stress, misfolded proteins interact with BiP, resulting in the release of BiP from the sensors. Subsequently, the three sensors dimerize and autophosphorylate to promote the signal cascades of ER stress. ER stress includes a series of positive and negative feedback signals, such as those regulating the stabilization of the sensors/BiP complex, activating and inactivating the sensors by autophosphorylation and dephosphorylation, activating specific transcription factors to enable selective transcription, and augmenting the ability to refold and export. Apart from the three basic pathways, vascular endothelial growth factor （VEGF）-VEGF receptor （VEGFR）-phospholipase C-~ （PLCy）-mammalian target of rapamycin complex 1 （mTORC1） pathway, induced only in solid tumors, can also activate ATF6 and PERK signal cascades, and IREla also can be activated by activated RAC-alpha serine/threonine-protein kinase （AKT）. A moderate UPR functions as a pro-survival signal to return the cell to its state of homeostasis. However, persistent ER stress will induce cells to undergo apoptosis in response to increasing reactive oxygen species （ROS）, Ca2＋ in the cytoplasmic matrix, and other apoptosis signal cascades, such as c-Jun N-terminal kinase （JNK）, signal transducer and activator of transcription 3 （STAT3）, and P38, when cellular damage exceeds the capacity of this adaptive response.
基金Supported by the National Program on Key Basic Research Project(973 Program)(2012CB518900)the National Natural Science Foundation of China(31160240,31260621)+2 种基金the 12th Five Years Key Programs for Science and Technology Development of China(2012ZX10002006)the Hangzhou Normal University Supporting Project(PE13002004042)the Natural Science Foundation of China of Jiangxi(20114BAB204016)
文摘The melanoma differentiation-associated gene-7（mda-7）,IL-24,has the specific functions that induce cancer cell apoptosis without doing harm to normal cells. We systematically review the apoptotic signal pathways and their regulatory mechanisms induced by Ad.IL-24 and IL-24 in diverse cancer cells. IL-24 can participate in varied signal transduction pathways,including JAK,p38 MAPK,Wnt/β-catenin,JNK,ER stress and mitochondria-associated signal pathways. And we review five proteins interacting with IL-24,including Bip/GRP78,S1 R,PKR,Beclin1 and soluble clusterin,which are relative to the tumor-specific effect of IL-24. It is speculated that ER stress,G-protein pathways and MAPK signal pathways may be the primary upstream effectors which activate the sequential downstream mediators resulting in apoptosis induced by IL-24 in tumor cells. Experimental results also show that IL-24 sensitizes cancer cells and indirectly promotes apoptosis rather than functions as a direct apoptosis inducer itself.
文摘The mini-review stemmed from a recent meeting on national aging research strategies in China discusses the components and challenges of aging research in China. Highlighted are the major efforts of a number of research teams, funding situations and outstanding examples of recent major research achievements. Finally, authors discuss potential targets and strategies of aging research in China.
基金was supported by the National Natural Science Foundation of China (No.31130017, 31071190, and 30711120570)the 973 project 2010CB911904+1 种基金Funding Project for Academic Human Resources Development in Institutions of Higher Learning Under the Jurisdiction of Beijing Municipality (No. PHR20110508) to XXthe 973 project 2012CB911203 to YSC
文摘DNA double-strand break(DSB) is the most severe form of DNA damage,which is repaired mainly through high-fidelity homologous recombination(HR) or error-prone non-homologous end joining(NHEJ).Defects in the DNA damage response lead to genomic instability and ultimately predispose organs to cancer.Nicotinamide phosphoribosyltransferase(Nampt),which is involved in nicotinamide adenine dinucleotide metabolism,is overexpressed in a variety of tumors.In this report,we found that Nampt physically associated with CtIP and DNA-PKcs/Ku80,which are key factors in HR and NHEJ,respectively.Depletion of Nampt by small interfering RNA(siRNA) led to defective NHEJ-mediated DSB repair and enhanced HR-mediated repair.Furthermore,the inhibition of Nampt expression promoted proliferation of cancer cells and normal human fibroblasts and decreased β-galactosidase staining,indicating a delay in the onset of cellular senescence in normal human fibroblasts.Taken together,our results suggest that Nampt is a suppressor of HR-mediated DSB repair and an enhancer of NHEJ-mediated DSB repair,contributing to the acceleration of cellular senescence.
基金supported by grants from the National Health and Medical Research Council of Australia,Cancer Council of Victoria,Australiathe National Basic Research Program of China(Grant No.2012CB911200)a recipient of Monash Postgraduate Scholarship.
文摘The process of aging is mitigated by the maintenance and repair of chromosome ends(telomeres),resulting in extended lifespan.This review examines the molecular mechanisms underlying the actions and regulation of the enzyme telomerase reverse transcriptase(TERT),which functions as the primary mechanism of telomere maintenance and regulates cellular life expectancy.Underpinning increased cell proliferation,telomerase is also a key factor in facilitating cancer cell immortalization.The review focuses on aspects of hormonal regulations of telomerase,and the intracellular pathways that converge to regulate telomerase activity with an emphasis on molecular interactions at protein and gene levels.In addition,the basic structure and function of two key telomerase enzyme components—the catalytic subunit TERTand the template RNA(TERC)are discussed briefly.
文摘Background People over the age of 85 are a rapidly growing age group with a high incidence of congestive heart failure(CHF),in particular heart failure with preserved ejection fraction(HFp EF).The diagnosis of CHF is challenging and longitudinal data assessing cardiac structure and function are necessary to distinguish physiologic from pathologic cardiac aging.The objective of the study was to determine longitudinal changes in cardiac struture and function from ages 85 to 94 years using home echocardiography.Methods Subjects were recruited from the Jerusalem Longitudinal Cohort Study.Sixty three members of the initial cohort(32 F,31 M)who underwent home echocardiography at age 85 were the subjects of the current study and underwent repeat home 2-D and Doppler echocardiographic assessment at age 94.Results There were no significant longitudinal changes in left ventricular mass index(LVMI),however LV end-diastolic volume significantly decreased from 113.4±30 to 103.6±35.5 m L(P<0.02).Ejection fraction(EF)remained stable,however longitudinal systolic function significantly decreased with age from 7.9±1.8 to 6.6±1.4 cm/s2(P<0.0001).Diastolic function as assessed by increased E:e’(11.2±3.4 to 16±7.5,P<0.0001)and increased left atrial volume index(34.1±11.3 to 42.4±13.7 m L/m^2,P<0.0001)was reduced with aging.Conclusions This study demonstrated preserved EF with decreased longitudinal systolic function and diastolic function without significant change in LV mass.Changes in LV function in the very elderly may be independent of changes in LV geometry.
基金Supported by the National Natural Science Foundation of China(No.81430009No.81400424)the Science and Technology Research and Development Project of Shaanxi Province(No.2014K11-03-07-04)
文摘AIM：To identify the pathological role of amyloid beta（Aβ） deposition in retinal degeneration,and explore Aβ deposition on the retinal pigment epithelium cells（RPE） layer and the associated structural and functional changes in Alzheimer＇s disease transgenic mice.METHODS：RPE changes in the eyes of APPswe/PS1 transgenic and none transgenic（NTG） mice over 20 months old were examined.Histological changes were investigated via hematoxylin and eosin（H＆E） staining and transmission electron microscopy（TEM） examination,whereas the expression of amyloid precursor protein（APP）,Aβ,Zonula occludens-1（ZO-1） and Ionized calcium binding adaptor molecule-1（IBA-1） were investigated using immunohistochemistry and immunofluorescence techniques.All of the obtained results were quantitatively and statistically analyzed.RESULTS：In aged transgenic mice,an APP-positive immunoreaction and Aβ deposition were detected on the RPE layer but were undetectable in NTG mice.The RPE demonstrated some vacuole changes,shortened basal infoldings and basal deposition in histopathological examination and TEM tests,wherein irregular shapes were indicated by ZO-1 disorganization through fluorescence.Furthermore,IBA-1 positive cells were observed to have accumulated and infiltrated into the RPE layer and localized beneath the RPE/Bruch＇s membrane（Br M） complex,which was accompanied by an increase in BrM thickness in aged transgenic mice in comparison to NTG mice.The IBA-1 positive cells were found to be co-stained with Aβ deposition on the RPE flat mounts.CONCLUSION：The observed Aβ deposition in the RPE layer may cause RPE dysfunction,which is associated with microglia cells infiltration into the retina of aged transgenic mice,suggesting that Aβ deposition probably plays a significant role in RPE-related degenerative disease.
基金funded by the National Natural Science Foundation of China(Grant Nos.81130074,81222003,81420108017,81400221and 81525010)
文摘Remarkable progress has taken place in the research of stem cells during the past 30 years.General perceptions,experimental and clinical evidences pinpoint the fact that functional decline of tissue often coincides with aging-related diseases.Stem cell aging plays a fundamental role in the dysregulation of tissue function,maintenance,and repairing.This review specifically focuses on the current findings and emerging concepts of hematopoietic stem cell aging and its mechanisms.
基金Project supported by the National Basic Research Program(973)of China(Nos.2011CB944002 and 2012CB517603)the National Natural Science Foundation of China(No.2011BAI10B07)the Major Special Project of Technology Office in Zhejiang Province(No.2012C13G2010133),China
文摘Aging is one of the contributing risk factors for kidney diseases. Accumulating evidence prompts the view that telomere length in kidney tissue cells is an indicator for organismal aging. Previously identified aging markers （cathelin-related antimicrobial peptide （CRAMP）, stathmin, elongation factor-1α （EF-1α）, and chitinase） were associated not only with telomere driven aging in mice but also with human aging and chronic diseases. This study focuses on the relationship between these biomarkers and IgA nephropathy （IgAN） progression in the Chinese population. For 260 individuals, the four markers are determined in blind datasets using direct enzyme-linked immunosorbent assay （ELISA） and immunofluorescence staining. The expression levels of CRAMP and chitinase increased in blood plasma, urine, and kidney tissues during human IgAN progression. And for the other nephropathy, such as systemic lupus erythematosus （SLE）, diabetic nephropathy （DN）, and focal segmental glomerulosclerosis （FSGS）, there is no protein upregulaUon with telomere shortening. Moreover, a combination of CRAMP and chitinase can distinguish patients with IgAN from healthy individuals with 88.2%/92.5% （plasma） and 74.3%/84.2% （urine） sensitivity/specificity. These data provide the experimental evidence that telomere shortening and related inflammatory proteins are associated with human IgAN, and it could be a new direction for the disease progression study.
基金supported by Grants 2016YFA0100602,2017YFA0103302,2018YFA0109300 from the National Key Research and Development Program of ChinaGrants 81525010,91749203,81871116,81501214,91749117,81770155,and 81771502 from the National Natural Science Foundation of China+2 种基金Grants LQ14C070002 from the Natural Science Foundation of Zhejiang Province of ChinaGrant 2018GZR110103002 from Innovative Team Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory and Grant 2017ZT07S347 from the Program for Guangdong Introducing Innovative and Enterpreneurial Teamssupported by the Science Foundation for Distinguished Young Scholars of Guangdong Province(2019B151502008)to Hu Wang.
文摘Dear Editor,Telomere attrition is one of the hallmark of aging.Lategeneration Terc knockout mice exhibit impaired hematopoiesis,1 while the underling mechanisms remain poorly understood.Retrotransposon long interspersed element-1(L1)is the only human retrotransposable elements capable of autonomous retrotransposition,and evolutionarily inactive.Recent studies reported that L1 is derepressed during the aging process with redistribution and reorganization of the heterochromatin.2 Considering that telomere shortening can cause chromosome instability and rearrangements,3 we speculate that L1 may play a role in impaired hematopoiesis in telomere dysfunctional mice.
基金supported by the Guangdong Basic and Applied Basic Research Foundation(2020B1515020046)“GDAS”Project of Science and Technology Development(2021GDASYL20210102003,2018GDASCX-0102)+4 种基金the National Natural Science Foundation of China(82072436,32130099)Open Program of Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics(GPKLMMD-OP202102)Outstanding Youth Fund of Hunan Natural Science Foundation(2021JJ20045)the Outstanding Youth Fund of Hunan Natural Science Foundation(2021JJ20045)Youth Innovation Promotion Association of Chinese Academy of Sciences(2022370)。
文摘The gut microbiota plays a pivotal role in systemic metabolic processes and in particular functions,such as developing and preserving the skeletal muscle system.However,the interplay between gut microbiota/metabolites and the regulation of satellite cell(SC)homeostasis,particularly during aging,remains elusive.We propose that gut microbiota and its metabolites modulate SC physiology and homeostasis throughout skeletal muscle development,regeneration,and aging process.Our investigation reveals that microbial dysbiosis manipulated by either antibiotic treatment or fecal microbiota transplantation from aged to adult mice,leads to the activation of SCs or a significant reduction in the total number.Furthermore,employing multi-omics(e.g.,RNA-seq,16S r RNA gene sequencing,and metabolomics)and bioinformatic analysis,we demonstrate that the reduced butyrate levels,alongside the gut microbial dysbiosis,could be the primary factor contributing to the reduction in the number of SCs and subsequent impairments during skeletal muscle aging.Meanwhile,butyrate supplementation can mitigate the antibiotics-induced SC activation irrespective of gut microbiota,potentially by inhibiting the proliferation and differentiation of SCs/myoblasts.The butyrate effect is likely facilitated through the monocarboxylate transporter 1(Mct1),a lactate transporter enriched on membranes of SCs and myoblasts.As a result,butyrate could serve as an alternative strategy to enhance SC homeostasis and function during skeletal muscle aging.Our findings shed light on the potential application of microbial metabolites in maintaining SC homeostasis and preventing skeletal muscle aging.
基金This work was supported by grants from the the National Basic Re- search Program （973 Program） （Nos. 2012CB911200 and 2012CB910104） and National Natural Science Foundation of China （Grant No. 31100584）.
文摘Telomere assumes intra-molecular G-quadruplex that is a significant drug target for inhibiting telomerase main- tenance of telomeres in cancer. Metal cations have been recognized as playing important roles in stabilizing G-quadruplex, but their binding processes to human telomeric G-quadruplex remain uncharacterized. To in- vestigate the detailed binding procedures, molecular dynamics simulations were conducted on the hybrid [3 ＋ 1] form-one human telomeric intra-molecular G-quadruplex. We show here that the binding of a potas- sium ion to a G-tetrad core is mediated by two alternative pathways. Principal component analysis illustrated the dominant concerted motions of G-quadruplex occurred at the loop domains. MM-PBSA calculations revealed that binding was energetically favorable and driven by the electrostatic interactions. The lower binding site was found more constructive favorable for binding. Our data provide useful information on a potassium-mediated stable structure of human telomeric intra-molecular G-quadruplex, implicating in ion disorder associated conformationa｜ changes and targeted drug design.
基金supported by National Natural Science Foundation of China(82072436)Guangdong Basic and Applied Basic Research Foundation(2020B1515020046)‘GDAS’Project of Science and Technology Development(2021GDASYL-20210102003,2018GDASCX-0102)。
文摘Skeletal muscle plays a significant role in both local and systemic energy metabolism.The current investigation aims to explore the role of the Bambi gene in skeletal muscle,focusing on its implications for muscle hypertrophy and systemic metabolism.We hypothesize that skeletal muscle-specific deletion of Bambi induces muscle hypertrophy,improves metabolic performance,and activates thermogenic adipocytes via the reprogramming of progenitor of iWAT,offering potential therapeutic strategies for metabolic syndromes.Leveraging the Chromatin immunoprecipitation(ChIP)-seq and bioinformatics analysis,Bambi gene is shown to be a direct target of HIF2α,which is further confirmed by ChIP-qPCR and promoter luciferase assay.Skeletal muscle-specific Bambi deletion led to significant muscle hypertrophy and improved metabolic parameters,even under high-fat diet conditions.This deletion induced metabolic reprogramming of stromal vascular fractions(SVFs)into thermogenic adipocytes,contributing to systemic metabolic improvements,potentially through the secretory factor.Notably,mice with skeletal muscle-specific Bambi deletion demonstrate resistance to high-fat diet-induced metabolic disorders,highlighting a potential therapeutic pathway for metabolic syndrome management.Thus,skeletal muscle-specific deletion of Bambi triggers muscle growth,enhances metabolic performance,and activates thermogenic adipocytes.These findings suggest Bambi as a novel therapeutic target for metabolic syndromes,providing new insights into the interaction between muscle hypertrophy and systemic metabolic improvement.The study underscores the potential of manipulating muscle physiology to regulate whole-body metabolism,offering a novel perspective on treating metabolic disorders.
基金supported by the National Basic Research Program of China(2012CB911203)the National Natural Science Foundation of China(31371398,31071200 and 31171320)
文摘Telomerase is a large ribonucleoprotein complex that contains a catalytic telomerase reverse transcriptase(TERT)and an RNA template.Telomerase activity is tightly controlled by TERT expression,which is regulated at both the transcriptional and post-translational levels.However,the detailed molecular mechanisms of telomerase regulation and function are not fully understood.To identify cofactors that contribute to telomerase regulation,we employed a yeast two-hybrid system to screen for hTERT-interacting proteins,using the hTERT T-motif as bait.We identify C53 as a novel hTERT interaction partner.We show that C53 interacts with hTERT both in vivo and in vitro.C53 depletion increases telomerase activity,and C53 overexpression inhibits telomerase activity in MCF7 cells.In addition,the C53 leucine zipper domain(amino acids 301–400)is required for interaction with hTERT.Deleting the leucine zipper domain eliminates C53 interaction with hTERT and abrogates its inhibitory effect on telomerase activity.Taken together,our results demonstrate that C53 is a novel hTERT-associated protein that negatively regulates telomerase activity.
文摘Ataxia telangiectasia mutated （ATM） kinase plays an essential role in the maintenance of genomic stability. ATM-deficient （ATM-/-） mice exhibit hematopoietic stem cell （HSC） dysfunction and a high incidence of lym- phoma. Gadd45a controls cell cycle arrest, apoptosis and DNA repair, and is involved in the ATM-p53 mediated DNA damage response. However, the role of Gadd45a in regulating the functionality of ATM-/- HSCs is unknown. Here we report that Gadd45a deletion did not rescue the defects of T-cells and B-cells development in ATM-/- mice. Instead, ATM and Gadd45a double knockout （ATM-/- Gadd45a-/-） HSCs exhibited an aggravated defect in long-term self-renewal capacity compared to ATM-/- HSCs in HSC transplantation experiments. Fur- ther experiments revealed that the aggravated defect of ATM-/- Gadd45a-/- HSCs was due to a reduction of cell proliferation, associated with an accumulation of DNA damage and subsequent activation of DNA damage response including an up-regulation of p53-p21 signal- ing pathway. Additionally, ATM-/- Gadd45a-/- mice showed an increased incidence of hematopoietic malignancies, as well as an increased rate of metastasis than ATM-/- mice. In conclusion, Gadd45a deletion aggravated the DNA damage accumulation, which sub- sequently resulted in a further impaired self-renewal capacity and an increased malignant transformation in ATM-/- HSCs.
基金We thank Claude Labrie for the plasmid construct encoding BMPRII truncation and Peter Lansdorp for the TFL-Telo 2.2 software program for telomere analysis. This work was supported by grants from the National Basic Research Program （973 Program） （No. 2012CB911204）, National Natural Science Foundation of China （Grant Nos. 81170313 and 81272889）, the National Health and Medical Research Council of Australia and Australia Research Council. Cancer Council of Victoria, Australia.
文摘Human telomerase reverse transcriptase （hTERT） plays a central role in telomere lengthening for continuous cell proliferation, but it remains unclear how extracellular cues regulate telomerase lengthening of telomeres. Here we report that the cytokine bone morphogenetic protein-7 （BMP7） induces the hTERT gene repression in a BMPRII receptor- and Smad3-dependent manner in human breast cancer cells. Chonic exposure of human breast cancer cells to BMP7 results in short telomeres, cell senescence and apoptosis. Mutation of the BMPRII receptor, but not TGFbRII, ACTRIIA or ACTRIIB receptor, inhibits BMP7-induced repression of the hTERT gene promoter activity, leading to increased telomerase activity, lengthened telomeres and continued cell proliferation. Expression of hTERT prevents BMP7-induced breast cancer cell senescence and apoptosis. Thus, our data suggest that BMP7 induces breast cancer cell aging by a mechanism involving BMPRII receptor- and Smad3-mediated repression of the hTERT gene.
基金Supported by Natural Science Foundation of Zhejiang Province(No.LY20C060002)。
文摘Objective:To investigate the therapeutic effect of Sanhuang Xiexin Decoction(SXD)on triplenegative breast cancer(TNBC)in mice and its underlying mechanism.Methods:The high-performance liquid chromatography(HHLC)was used to quantitate and qualify SXD.A total of 15 female BALB/c mice were inoculated subcutaneously on the right hypogastrium with 3×10^(5) of 4T1-Luc cells to establish TNBC mouse model.All mice were divided randomly into 3 groups,including phosphate buffered solution(PBS),SXD and doxorubicin(DOX)groups(positive drug).Additionally,tumor growth,pathological changes,serum lipid profiles,expression of Janus kinase 2(JAK2)-signal transducer and activator of transcription 3(STAT3)signaling pathway and its key targets including inflammatory factors,cell cycle and epithelial-mesenchymal transition(EMT)markers were investigated.Besides,the biosafety of SXD was also evaluated in mice.Results:Rhein,coptisine,berberine hydrochloride and baicalin were all found in SXD,and the concentrations of these 4 components were 0.57,2.61,2.93,and 46.04 mg/g3respectively.The mouse experiment showed that SXD could notably suppress the development of tumors and reduce the density of tumor cells(P<0.01).The serum lipid analysis and Oil-Red-O staining both showed the differences,SXD group exhibited higher serum adiponectin and HDL-C levels with lower TC and LDL-C levels compared to the PBS and DOX groups(P<0.05 or P<0.01),respectively.SXD also decreased the levels of phospho-JAK2(p-JAK2),phospho-STAT3(p-STAT3)expressions and its downstream factors,including mostly inflammatory cytokine,EMT markers,S phase of tumor cells and vascular endothelial growth factor(VEGF)expression(P<.05 or P<0.01),respectively.The biosafety assessment of SXD revealed low levels of toxicity in mice.Conclusion:SXD could inhibit TNBC by suppressing JAK2-STAT3 phosphorylation which may be associated with modulation of lipid metabolism.
基金supported by the National Natural Science Foundation of China(Grant No.81571380)the Natural Science Foundation of Zhejiang Province–China(Grant No.LY16H080009)+2 种基金supported by the National Natural Science Foundation of China(Grant Nos.81130074,81420108017,and 81525010)funded by the National Key R&D Plan from the Ministry of Science and Technology of China(Grant No.SQ2016ZY05002341)partially supported by the Deutsche Forschungsgemeinschaft(DFG),Germany
文摘Maintenance of tissue-specific stem cells is vital for organ homeostasis and organismal longevity.Hematopoietic stem cells（HSCs） are the most primitive cell type in the hematopoietic system.They divide asymmetrically and give rise to daughter cells with HSC identity（selfrenewal） and progenitor progenies（differentiation）,which further proliferate and differentiate into full hematopoietic lineages.Mammalian ageing process is accompanied with abnormalities in the HSC self-renewal and differentiation.Transcriptional changes and epigenetic modulations have been implicated as the key regulators in HSC ageing process.The DNA damage response（DDR）in the cells involves an orchestrated signaling pathway,consisting of cell cycle regulation,cell death and senescence,transcriptional regulation,as well as chromatin remodeling.Recent studies employing DNA repair-deficient mouse models indicate that DDR could intrinsically and extrinsically regulate HSC maintenance and play important roles in tissue homeostasis of the hematopoietic system.In this review,we summarize the current understanding of how the DDR determines the HSC fates and finally contributes to organismal ageing.
基金This work is supported by National Natural Science Foundation of China(91749203,81525010,91949125,81801372,82030039)Program for Guangdong Introducing Innovative and Enterpreneurial Teams(2017ZT07S347)+2 种基金Innovative Team Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory(2018GZR110103002)Natural Science Foundation of Zhejiang Province(LGD19H030001)Key Laboratory of Aging and Cancer Biology of Zhejiang province,School of medicine,Hangzhou Normal University.
文摘Dear Editor,Emerging evidences show close associations between miRNAs and liver regeneration.MiR-126 is known as a governor of vascular integrity and angiogenesis.MiR-126 is involved in the self-renewal of hematopoietic stem cells(HSCS)and leukemia stem cells.1,2 MiR-126 also plays a vital role in hepatocellular carcinogenesis,however,the functions of miR-126 in liver regeneration were still unclear.
基金supported in part by grants from the National Basic Research Program of China 973 Program(2015CB943301)the National Natural Science Foundation of China(81830006,31670887,31870874,and 31800734)+2 种基金the Zhejiang provincial Key Project of Research and Development(2019C0304)the Zhejiang Natural Science Foundation(LQ16H030003)the Zhejiang Science and Technology Program(2017C37117 and 2017C37170).
文摘The expression of coinhibitory receptors,such as CTLA-4,on effector T cells is a key mechanism for the negative regulation of T-cell activation.However,the transcriptional regulation of CTLA-4 is not well understood.Zfp281,a C2H2 zinc finger protein,is a negative regulator of pluripotency maintenance of embryonic stem cells.Nevertheless,the function of Zfp281 in differentiated cells has not been studied.We generated Zfp281 conditional knockout mice in which the function of the Zfp281 gene was conditionally disrupted by the Cd4^(Cre) transgene to study its impact on T cell function.Zfp281 had no effect on T-cell development,but CD4^(+)T cell activation and cytokine production were impaired due to diminished T-cell receptor signaling.Furthermore,Zfp281 deficiency inhibited in vivo T cell responses to Listeria monocytogenes infection.Using genome-wide expression profiling assays,we determined that Zfp281 repressed Ctla-4 expression by directly binding to GC-rich sites in its promoter,which inhibited the negative feedback of T cell activation.In line with this result,CTLA-4 blockade and shRNA knockdown partly rescued the reduced cytokine production caused by Zfp281 deficiency.These findings indicate that Zfp281 sustains CD4^(+)T lymphocyte activation by directly repressing Ctla-4 transcription.
