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Salidroside Ameliorates Vascular Endothelial cell senescence through Downregulation of KLF4

Journal of Biosciences and Medicines 2021年第2期9卷 21-32页

作者： Yanyan Zhang Li He Mengxin Tu Yongpan Huang Xiangchun Shen The Key Laboratory of Optimal Utilization of Natural Medicine Resources School of Pharmaceutical Sciences Guizhou Medical University Guiyang China Department of Clinical Pharmacy School of Pharmaceutical Sciences Guizhou Medical University Guiyang China School of Medicine Changsha Social Work College Changsha China

Salidroside is extensively used as a herbal medicine worldwide, and it has been shown to protect against disruption of endothelial homeostasis and act as an anti-aging agent. The present study aimed to investigate the ameliorative effects of salidroside on homocysteine (Hcy)-induced cell senescence in human umbilical vein endothelial cells (HUVECs) that were mediated via inhibition of Krüppel-like factor 4 (KLF4). An endothelial cell senescence model was induced by Hcy. The cell viability, activities of telomerase and lactate dehydrogenase (LDH), and the level of reactive oxygen species were determined using commercial kits. The expression levels of KLF4, p53 and p21 were determined via western blot analysis, whereas the mRNA expression levels of KLF4 were detected by reverse transcription-quantitative PCR. Small interfering RNA-mediated knockdown of KLF4 was found to reverse Hcy-induced cell senescence. Hcy treatment led to an accelerated cell senescence, as evidenced by decreases in both cell viability and telomerase activity, whereas increases were noted in the leakage of LDH and the level of reactive oxygen species, in addition to an up-regulation of the protein levels of p53 and p21, and up-regulation of KLF4 at both the mRNA and protein level. Treatment with salidroside ameliorated Hcy-induced cell senescence in a dose-dependent manner. Taken together, these results suggested that Hcy may induce cell senescence through upregulation of KLF4, and this may be reversed by treatment with salidroside. Therefore, salidroside was shown to inhibit Hcy-induced cell senescence through KLF4 inhibition.

关键词： cell senescence Salidroside HUVECs Human Umbilical Vein Endothelial cells Krüppel-Like Factor 4 KLF4 Homocysteine

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Over-expression of wild type UCP2,but not its mutant form UCP2 (D212N),induces mitochondrial dysfunctions and cell senescence of hepatocarcinoma cells

Over-expression of wild type UCP2,but not its mutant form UC...

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第六届全国自由基生物学与自由基医学学术会议和海峡两岸自由基生物学与自由基医学学术会议

作者： Lei Gao, Yingli Shang, Fang Yang, Honggang Wang, Shusen Liu and Quan Chen The State Key Laboratory of Biomembrane and Membrane Biotechnology, Chinese Academy of Sciences, Beijing 100080, P.R. China, chenq@*** Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA

Uncoupling protein 2 (UCP2), discovered in 1997, belongs to a family of inner mitochondrial membrane proteins that, in general, function as proton transporter. The physiological function of UCP2 is to uncouple respiration from ATP synthesis and thus, to dissipate the energy stored in the proton electrochemical gradient as heat. In addition to functioning as a thermogen, the ubiquitously expressed uncoupling protein-2 (UCP2) was suggested to play critical roles in regulating cellular reactive oxygen species (ROS) production and modulating cellular stress responses. However, the underlying mechanisms of how this mitochondrial inner membrane protein achieves such diverse functions are not *** this study, we found that, when stably over-expressed in HepG 2 cells, wild type (wt) UCP2 induced significant proportion of the cells to have a senescent-like phenotype characterized by growth retardation, increased cell size, and positive p-Galactosidase (β-gal) staining. Over-expression of wtUCP2 caused significant reduction of mitochondrial membrane potential (ΔΨm), increased mitochondrial mass enhanced cellular oxygen consumption and intracellular ROS production, indicating impaired mitochondrial functions. In contrast, cells over-expressing identical levels of mutant UCP2 (D212N), which lack proton translocation activity, or cells treated with siRNA that specifically knock down the expression of UCP2, did not show senescent-like phenotypes and associated mitochondrial abnormalities. Furthermore, we found telomere shortening, mitochondrial DNA (mtDNA) mutations and rearrangements in cells that over-expressed wtUCP2, but not in siRNA treated cells or in cells that over-expressed mutant UCP2 (D212N). Our data suggest that the over-expression of wtUCP2 in HepG2 cells causes abnormal mitochondrial physiology that lead to mtDNA and telomere damage and ultimately cellular senescence. Taken together, UCP2 may be a potential regulator of cell senescence through regulating cellul

关键词： Uncoupling protein 2 (UCP2) Reactive Oxygen Species (ROS) cell senescence Mitochondria

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Reductive stress induced by Ero1α S-nitrosation in endoplasmic reticulum accelerates cell senescence

Reductive stress induced by Ero1α S-nitrosation in endoplas...

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中国生物化学与分子生物学会2019年全国学术会议暨学会成立四十周年

作者： Xinhua Qiao Chang Chen National Laboratory of Biomacromolecules CAS Center for Excellence in Biomacromolecules Institute of Biophysics Chinese Academy of Sciences University of Chinese Academy of Sciences

Redox homeostasis in cells is crucial for the function of biomacromolecules. Oxidative stress is known to mediate many cellular signal transduction in physiological and pathological processes, however, the biological effects and mechanisms of reductive stress(RS, an abnormal increase in electron pressure or reducing equivalents(GSH/GSSG;NADH/NAD;NADPH/NADP) are still poorly understood. In this study, we found that the ER exhibited reductive stress in senescent cells, and reductive stress accelerated senescence. Further study showed that the decrease of Ero1α activity is an important cause of ER reductive stress in the process of aging, and delaying aging was successfully achieved by increasing the oxidative power in the ER. For mechanism study, we found the Ero1α S-nitrosation increased in senescence cells. Ero1α C166 and C131 were identified as the site of S-nitrosation and result in decreasing of Ero1α activity. Moreover, we found that ER reductive stress led to protein homeostatic imbalance and decreased ER folding ability which accelerated aging. Our results suggested a new mechanism of aging caused by insufficient oxidation in the ER.

关键词： Reductive Stress ER Ero1α S-nitrosation cell senescence

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Bazi Bushen alleviates reproductive aging in aged male mice

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Chinese Journal of Natural Medicines 2024年第5期22卷 416-425页

作者： MA Kun LI Mengnan SONG Yahui MAO Xinjing ZHANG Shaolan ZHANG Yaping JIANG Yuning JI Chuanyuan NIU Kunxu LI Hongrong HOU Yunlong WEI Cong Graduate School Hebei University of Chinese MedicineShijiazhuang 050091China State Key Laboratory for Innovation and Transformation of Luobing Theory Shijiazhuang 050035China Key Laboratory of State Administration of TCM(Cardio-Cerebral Vessel Collateral Disease) Shijiazhuang 050035China College of Traditional Chinese Medicine·College of Integrated Traditional Chinese and Western Medicine Nanjing University of Chinese MedicineNanjing 210023China Hebei Provincial Key Laboratory of Luobing Shijiazhuang 050035China Key Disciplines of State Administration of TCM for Luobing Shijiazhuang 050035China

Bazi Bushen(BZBS),a traditional Chinese medicine(TCM),has demonstrated therapeutic efficacy in testicular dysfunction within D-galactose and NaNO_(2)mouse *** study aimed to ascertain if BZBS could also mitigate the decline in testicular function associated with natural ***,male aged mice were employed to evaluate the preventive effects of BZBS on male reproductive *** was achieved by assessing sex hormone production,testicular histomorphology,and *** to the untreated aged control group,BZBS administration elevated the levels of sex hormones and spermatocyte populations and preserved normal testicular structure in aged ***,spermatogenesis was *** analyses,including malondialdehyde(MDA)assays and real-time PCR,indicated that BZBS diminished testicular oxidative stress and the inflammatory *** these findings,mice treated with BZBS exhibited reductions in the populations of senescent and apoptotic cells within the seminiferous tubules,suggesting alleviated cellular *** contrast,we observed that rapamycin,a drug known for its longevity benefits,induced excessive testicular apoptosis and did not decrease lipid ***,our results highlight BZBS’s promising clinical potential in counteracting male reproductive aging,underlining its mechanisms of action.

关键词： Traditional Chinese medicine Male reproductive aging Spermatogenic cells cell senescence Apoptosis

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Conditionally Reprogrammed Human Normal Airway Epithelial cells at ALI: A Physiological Model for Emerging Viruses

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Virologica Sinica 2020年第3期35卷 280-289页

作者： Xuefeng Liu Yuntao Wu Lijun Rong Department of Pathology Center for Cell ReprogrammingGeorgetown University Medical CenterWashingtonDCUSA Department of Oncology Lombardi Comprehensive Cancer CenterGeorgetown University Medical CenterWashingtonDCUSA National Center for Biodefense and Infectious Diseases School of Systems BiologyGeorge Mason UniversityManassasVA 20110USA Department of Microbiology and Immunology University of Illinoi at ChicagoChicagoIL 60612USA

Cancer cell lines have been used widely in cancer biology, and as biological or functional cell systems in many biomedical research fields. These cells are usually defective for many normal activities or functions due to significant genetic and epigenetic changes. Normal primary cell yields and viability from any original tissue specimens are usually relatively low or highly variable. These normal cells cease after a few passages or population doublings due to very limited proliferative capacity. Animal models(ferret, mouse, etc.) are often used to study virus-host interaction. However, viruses usually need to be adapted to the animals by several passages due to tropism restrictions including viral receptors and intracellular restrictions. Here we summarize applications of conditionally reprogrammed cells(CRCs), long-term cultures of normal airway epithelial cells from human nose to lung generated by conditional cell reprogramming(CR) technology, as an ex vivo model in studies of emerging viruses. CR allows to robustly propagate cells from non-invasive or minimally invasive specimens, for example, nasal or endobronchial brushing. This process is rapid(2 days) and conditional. The CRCs maintain their differentiation potential and lineage functions, and have been used for studies of adenovirus, rhinovirus, respiratory syncytial virus, influenza viruses, parvovirus, and SARS-CoV. The CRCs can be easily used for airliquid interface(ALI) polarized 3 D cultures, and these coupled CRC/ALI cultures mimic physiological conditions and are suitable for studies of viral entry including receptor binding and internalization, innate immune responses, viral replications, and drug discovery as an ex vivo model for emerging viruses.

关键词： Normal cells cell senescence Conditional reprogramming Physiological conditions Functional models Air-liquid interface(ALI) Emerging viruses SARS-CoVs

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DNA-PK inhibition by M3814 enhances chemosensitivity in non-small cell lung cancer

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Acta Pharmaceutica Sinica B 2021年第12期11卷 3935-3949页

作者： Manni Wang Siyuan Chen Yuquan Wei Xiawei Wei Laboratory of Aging Research and Cancer Drug Target State Key Laboratory of Biotherapy and Cancer CenterNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengdu 610000China

A significant proportion of non-small cell lung cancer(NSCLC) patients experience accumulating chemotherapy-related adverse events,motivating the design of chemosensitizating *** main cytotoxic damage induced by chemotherapeutic agents is DNA double-strand breaks(DSB).It is thus conceivable that DNA-dependent protein kinase(DNA-PK) inhibitors which attenuate DNA repair would enhance the anti-tumor effect of *** present study aims to systematically evaluate the efficacy and safety of a novel DNA-PK inhibitor M3814 in synergy with chemotherapies on *** identified increased expression of DNA-PK in human NSCLC tissues which was associated with poor prognosis.M3814 potentiated the anti-tumor effect of paclitaxel and etoposide in A549,H460 and H1703 NSCLC cell *** the four combinations based on two NSCLC xenograft models and two chemotherapy,we also observed tumor regression at tolerated doses in ***,we identified a P53-dependent accelerated senescence response by M3814 following treatment with paclitaxel/*** present study provides a theoretical basis for the use of M3814 in combination with paclitaxel and etoposide in clinical practice,with hope to aid the optimization of NSCLC treatment.

关键词： M3814 Paclitaxel Etoposide DNA-dependent protein kinase Non-small cell lung cancer DNA repair cell senescence Chemosensitization

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Mechanisms of neuroplasticity and brain degeneration: strategies for protection during the aging process

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Neural Regeneration Research 2021年第1期16卷 58-67页

作者： Mariana Toricelli Arthur Antonio Ruiz Pereira Guilherme Souza Abrao Helena Nascimento Malerba Julia Maia Hudson Sousa Buck Tania Araujo Viel Department of Physiological Sciences Santa Casa de Sao Paulo School of Medical SciencesSao PauloBrazil Laboratory of Neurobiology of Aging School of ArtsSciences and HumanitiesUniversidade de São PauloSao PauloBrazil

Aging is a dynamic and progressive process that begins at conception and continues until *** process leads to a decrease in homeostasis and morphological,biochemical and psychological changes,increasing the individual’s vulnerability to various *** growth in the number of aging populations has increased the prevalence of chronic degenerative diseases,impairment of the central nervous system and dementias,such as Alzheimer’s disease,whose main risk factor is age,leading to an increase of the number of individuals who need daily support for life *** theories about aging suggest it is caused by an increase of cellular senescence and reactive oxygen species,which leads to inflammation,oxidation,cell membrane damage and consequently neuronal ***,mitochondrial mutations,which are generated throughout the aging process,can lead to changes in energy production,deficiencies in electron transport and apoptosis induction that can result in decreased ***,increasing cellular senescence and the release of proinflammatory cytokines can cause irreversible damage to neuronal *** reports point to the importance of changing lifestyle by increasing physical exercise,improving nutrition and environmental enrichment to activate neuroprotective defense ***,this review aims to address the latest information about the different mechanisms related to neuroplasticity and neuronal death and to provide strategies that can improve neuroprotection and decrease the neurodegeneration caused by aging and environmental stressors.

关键词： cell senescence cell signaling cholinergic enriched environment long-term potentiation neurodegeneration neurogenesis neuroinflammatory neuronal death neuroprotection neurotophin

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Determining the in vitro Anti-Aging Effect of the Characteristic Components from Eucommia ulmoides

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Journal of Renewable Materials 2022年第12期10卷 3131-3145页

作者： Xuesong Wang Zhihong Wang Qiuling Yang Sheng Peng Mijun Peng Guangdong Provincial Key Laboratory of Chemical Measurement and Emergency Test Technology Guangdong Provincial Engineering Research Center for Ambient Mass SpectrometryInstitute of AnalysisGuangdong Academy of Sciences(China National Analytical CenterGuangzhou)Guangzhou510070China Guangdong Provincial Key Laboratory of Silviculture Protection and UtilizationGuangdong Academy of ForestryGuangzhou510520China National&Local United Engineering Laboratory of Integrative Utilization Technology of Eucommia ulmoides Jishou University Jishou427000China

To evaluate the potential anti-aging ability of Eucommia ulmoides,four characteristic components(chlorogenic acid,geniposidic acid,aucubin,quercetin)were selected to assess their effects on H_(2)O_(2)-induced oxidative damage model of human umbilical vein endothelial cell(HUVEC).Oxidative damage indexes,inflammatory factors,cell cycle,cell apoptosis,cell senescence,and their related proteins were analyzed by methyl thiazolyl tetrazolium(MTT)assay,enzyme-linked immunosorbent assay(ELISA),propidium iodide(PI)staining,annexin V-FITC/PI double staining,SAβ-galactosidase staining,and western blotting(WB).The results showed that H_(2)O_(2)-induced cell growth inhibition rate decreased as supplementation with characteristic components when compared to H_(2)O_(2) ***,the contents of antioxidant indexes(reactive oxygen species,lactate dehydrogenase,molondialdehyde,superoxide dismutase,glutathione),inflammatory factors(nuclear factor kappa-B,intercellular cell adhesion molecule-1,vascular cell adhesion protein 1),and functional factors(NO,Endothelin-1)in characteristic components treated groups improved if comparison with H_(2)O_(2) group,suggesting the characteristic components of *** could alleviate H_(2)O_(2)-induced oxidative ***,cell cycle,cell apoptosis,cell senescence,and their related proteins under characteristic components treatment exhibited a better effect than under H_(2)O_(2) treatment,implying the characteristic components could participate in anti-aging via multiple *** results manifested that the characteristic components of *** posses the capacity of anti-aging,which provided a basis for investigating the anti-aging ability of *** itself.

关键词： Anti-aging Eucommia ulmoides characteristic components oxidative damage cell senescence

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The cell cycle inhibitor P21 promotes the development of pulmonary fibrosis by suppressing lung alveolar regeneration

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Acta Pharmaceutica Sinica B 2022年第2期12卷 735-746页

作者： Xiaoxi Lv Chang Liu Shanshan Liu Yunxuan Li Wanyu Wang Ke Li Fang Hua Bing Cui Xiaowei Zhang Jiaojiao Yu Jinmei Yu ZhuoWei Hu Immunology and Cancer Pharmacology Group State Key Laboratory of Bioactive Substance and Function of Natural MedicinesInstitute of Materia MedicaChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China Drug Clinical Trial Institution Children’s HospitalCapital Institute of PediatricsBeijing 100020China Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China

The cell cycle inhibitor P21 has been implicated in cell senescence and plays an important role in the injury-repair process following lung *** fibrosis(PF)is a fibrotic lung disorder characterized by cell senescence in lung alveolar epithelial *** this study,we report that P21 expression was increased in alveolar epithelial type 2 cells(AEC2 s)in a time-dependent manner following multiple bleomycin-induced *** injury of AEC2 s resulted in telomere shortening and triggered P21-dependent cell ***2 s with elevated expression of P21 lost their self-renewal and differentiation *** particular,elevated P21 not only induced cell cycle arrest in AEC2 s but also bound to P300 andβ-catenin and inhibited AEC2 differentiation by disturbing the P300-β-catenin ***,senescent AEC2 s triggered myofibroblast activation by releasing profibrotic *** of P21 restored AEC2-mediated lung alveolar regeneration in mice with chronic *** results of our study reveal a mechanism of P21-mediated lung regeneration failure during PF development,which suggests a potential strategy for the treatment of fibrotic lung diseases.

关键词： P21 cell senescence Alveolar epithelial type 2 cells Pulmonary fibrosis Alveolar regeneration Bleomycin cell cycle arrest P300-β-catenin complex

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cellular senescence is a promising target for chronic wounds:a comprehensive review

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Burns & Trauma 2020年第1期8卷 277-284页

作者： Ziwen Wang Chunmeng Shi Institute of Rocket Force Medicine State Key Laboratory of TraumaBurns and Combined InjuryThird Military Medical University(Army Medical University)No.30 Gaotanyan StreetChongqing400038China

Chronic wounds include,but are not limited to,radiation ulcers,pressure ulcers,vascular ulcers and diabetic foot *** chronic wounds can persist for years without healing and severe ulcers may lead to ***,the underlying pathologies of refractory chronic wounds are not fully characterized,and new treatments are urgently ***,increasing evidence has indicated that cell senescence plays an important role in the development of chronic wounds,and preventing cell senescence or removing senescent cells holds promise as a new therapeutic *** this review,we aim to probe these latest findings to promote the understanding of cellular senescence in the pathological process and potential management of chronic wounds.

关键词： Chronic wounds cell senescence Therapeutic agent Skin Mucosa

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