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左、右归丸干预pgc-1α/PPARγ对BMSCs线粒体生物发生的影响

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中国实验方剂学杂志 2025年

作者：杨莹冯秀芝陈怡然王智民郭晛任艳玲辽宁中医药大学辽宁中医药大学附属医院

目的：基于“阳化气，阴成形”理论，探讨左、右归丸通过过氧化物酶体增殖激活受体γ共激活因子1α(pgc-1α)及过氧化物酶体增殖物激活受体γ(PPARγ)影响大鼠骨髓间充质干细胞成脂分化过程中线粒体生物发生的分子机制，为左、右归丸防... 详细信息

目的：基于“阳化气，阴成形”理论，探讨左、右归丸通过过氧化物酶体增殖激活受体γ共激活因子1α(pgc-1α)及过氧化物酶体增殖物激活受体γ(PPARγ)影响大鼠骨髓间充质干细胞成脂分化过程中线粒体生物发生的分子机制，为左、右归丸防治绝经后骨质疏松症（PMOP）奠定更多理论依据。方法：将骨髓间充质干细胞（BMSCs）分为成脂诱导组（MX组）、左归丸组（ZGW组）、右归丸组（YGW组）、补佳乐组（BJL组），采用流式细胞仪进行细胞鉴定；噻唑蓝（MTT）法绘制BMSCs的生长曲线，并检测左、右归丸对BMSCs增殖的影响；油红O染色法检测脂滴的形成；蛋白免疫印迹法（Western blot）检测成脂相关因子PPARγ、C/EBPα、C/EBPβ、脂蛋白脂肪酶（LPL）蛋白，棕色脂肪相关蛋白pgc-1α、UCP1、PRDM16蛋白，线粒体生物发生相关pgc-1α、核呼吸因子1（NRF1）、核转录因子红系2相关因子2（NRF2）、TFAM蛋白的表达；RT-qPCR法检测成脂相关因子PPARγ、C/EBPα、C/EBPβ、LPL基因以及CytoB mtDNA拷贝数的表达；透射电镜观察线粒体超微结构。结果：与MX组比较，各给药组BMSCs增殖能力随干预时间增强而增强，药物干预后脂滴明显减少，成脂相关PPARγ、C/EBPα、C/EBPβ、LPL mRNA及蛋白表达水平显著下调（P1）；棕色脂肪相关pgc-1α、UCP1、PRDM16蛋白表达水平显著上调（P1）；线粒体数量增多，肿胀减少，双层膜和嵴结构清晰，同时内嵴断裂减少；线粒体CytoB基因拷贝数显著上调（P1）；线粒体生物发生相关pgc-1α、NRF1、NRF2、TFAM蛋白表达水平显著上调（P1）。结论：左、右归丸均能通过pgc-1α/PPARγ影响BMSCs线粒体生物发生以防治PMOP。

关键词：左归丸右归丸绝经后骨质疏松症 pgc-1α 线粒体生物发生

基于SIRT1/pgc-1α通路探讨氯吡格雷对紫杉醇诱发的周围神经病理性疼痛的干预作用

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新疆医科大学学报 2025年第2期48卷 134-140+148页

作者：郗扬周海滨冯磊周雁首都医科大学附属北京积水潭医院

目的探讨氯吡格雷对紫杉醇诱发的周围神经病理性疼痛大鼠的干预作用及大鼠脊髓腰段背根部神经节(DRG)中沉默信息调节因子2相关酶1/过氧化物酶体增殖物激活受体γ共激活因子1α(SIRT1/pgc-1α)信号通路的影响。方法采用紫杉醇诱发化疗... 详细信息

目的探讨氯吡格雷对紫杉醇诱发的周围神经病理性疼痛大鼠的干预作用及大鼠脊髓腰段背根部神经节(DRG)中沉默信息调节因子2相关酶1/过氧化物酶体增殖物激活受体γ共激活因子1α(SIRT1/pgc-1α)信号通路的影响。方法采用紫杉醇诱发化疗后周围神经病理性疼痛大鼠模型，将40只雄性SD大鼠随机分为正常组、模型组、6 mg/kg氯吡格雷组和12 mg/kg氯吡格雷组，每组10只。在实验前1天(T0)、实验第8天(T1)和实验第14天(T2)分别测定大鼠的50%机械缩足阈值(50%MWT)和热缩足潜伏期(TWL)。取大鼠DRG,原位末端转移酶标记实验(TUNEL)检测DRG中细胞凋亡。酶联免疫吸附试验(ELISA)测定DRG中炎症因子白介素-6(IL-6)、IL-1β以及肿瘤坏死因子-α(TNF-α)水平。采用丙二醛(MDA)和超氧化物歧化酶(SOD)试剂盒测定DRG中MDA和SOD水平。Western blot测定DRG组织中SIRT1和pgc-1α蛋白表达水平。结果与正常组相比，模型组在T1和T2时间点的50%MWT和TWL值均显著降低(P1)。与模型组相比，6 mg/kg和12 mg/kg氯吡格雷组在T1和T2时间点的50%MWT和TWL值均显著升高(P1～0.05)。与正常组相比，模型组DRG组织中细胞凋亡水平，IL-6、IL-1β、TNF-α以及MDA水平均升高，SOD水平降低，SIRT1和pgc-1α蛋白表达显著下调(P1)。与模型组相比，6 mg/kg和12 mg/kg氯吡格雷组DRG组织中上述指标被逆转(P1～0.05)。与6 mg/kg氯吡格雷组相比，12 mg/kg氯吡格雷组对周围神经病理性疼痛大鼠中上述指标的改善更显著。结论氯吡格雷能减轻紫杉醇诱发的周围神经病理学疼痛，抑制DRG中炎症反应，减少细胞凋亡及氧化应激水平，其机制可能与激活SIRT1/pgc-1α信号通路相关。

关键词： SIRT1 pgc-1α 氯吡格雷紫杉醇周围神经病理性疼痛

pgc-1α-mediated imbalance of mitochondria-lipid droplet homeostasis in neomycin-induced ototoxicity and nephrotoxicity

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Acta Pharmaceutica Sinica B 2024年第10期14卷 4413-4430页

作者： Bin Chen Cheng Cheng Yunhao Wu Siyu Li Mo Han Le Zhen Ying Peng Suhan Guo Kaidi Shen Xia Gao Renjie Chai Guangji Wang Fang Zhou Key Laboratory of Drug Metabolism and Pharmacokinetics State Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjing 210009China Department of Otolaryngology Head and Neck Surgery Nanjing Drum Tower HospitalAffiliated Hospital of Medical SchoolNanjing UniversityNanjing 210096China Co-Innovation Center of Neuroregeneration Nantong UniversityNantong 226001China Medical Science and Technology Innovation Center Shandong First Medical University&Shandong Academy of Medical SciencesJinan 250117China State Key Laboratory of Digital Medical Engineering Department of Otolaryngology Head and Neck SurgeryZhongda HospitalSchool of Life Sciences and TechnologyAdvanced Institute for Life and HealthJiangsu Province High-Tech Key Laboratory for Bio-Medical ResearchSoutheast UniversityNanjing 210096China Department of Neurology Aerospace Center HospitalSchool of Life ScienceBeijing Institute of TechnologyBeijing 100081China

Ototoxicity and nephrotoxicity are the most prevalent side effects of aminoglycoside antibiotics(gentamicin,amikacin,neomycin)and platinum anti-tumor drugs(cisplatin,carboplatin).The inner ear and kidney share similarities in drug deposition and toxicity,but the underlying pathophysiological mechanisms remain *** the shared mechanisms and metabolic alterations in these distinct organs will provide valuable insights for clinical therapy.A strong correlation has been identified between the spatiotemporal accumulation patterns of neomycin and the specific occurrence of lipid metabolism disorders in these two *** primary allocation of neomycin to mitochondria results in a notable escalation in the accumulation of lipid droplets(LDs)and more interactions between mitochondria and LDs,leading to a sequence of disturbances in lipid metabolism,such as increased lipid ROS and the blocked transfer of fatty acids from LDs to ***-1αdeficiency worsens the neomycin-induced disorders in lipid metabolism and intensifies the pathological interactions between mitochondria and LDs,as indicated by the exacerbated disturbance of dynamic LD turnover,increased level of oxidized lipids and decreased use of fatty *** investigation provides a fresh perspective on the lipid metabolic dysfunction related to mitochondria-LD interactions in drug-induced ototoxicity and nephrotoxicity,potentially providing novel avenues for intervention strategies.

关键词： Mitochondria Neomycin Nephrotoxicity Ototoxicity Lipid metabolism Triacylglycerol pgc-1α PLIN3

Enforced pgc-1α expression promotes CD8 T cell fitness, memory formation and antitumor immunity

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Cellular & Molecular Immunology 2021年第7期18卷 1761-1771页

作者： Nina Dumauthioz Benjamin Tschumi Mathias Wenes Bastien Marti Haiping Wang Fabien Franco Wenhui Li Isabel CLopez-Mejia Lluis Fajas Ping-Chih Ho Alena Donda Pedro Romero Lianjun Zhang Translational Tumor Immunology Group Ludwig Cancer ResearchUniversity of LausanneEpalingesSwitzerland Department of Fundamental Oncology University of LausanneEpalingesSwitzerland Department of Fundamental Oncology University of LausanneEpalingesSwitzerland Ludwig Cancer Research Institute Lausanne BranchEpalingesSwitzerland Center for Systems Medicine Institute of Basic Medical SciencesChinese Academy of Medical Sciences and Peking Union Medical College100005BeijingChina Suzhou Institute of Systems Medicine SuzhouJiangsu215123China Center for Integrative Genomics University of LausanneLausanneSwitzerland

Memory CD8 T cells can provide long-term protection against tumors,which depends on their enhanced proliferative capacity,self-renewal and unique metabolic rewiring to sustain cellular ***,memory CD8 T cells engage oxidative phosphorylation and fatty acid oxidation to fulfill their metabolic *** contrast,tumor-infiltrating lymphocytes(TILs)display severe metabolic defects,which may underlie their functional ***,we show that overexpression of proliferator-activated receptor gamma coactivator 1-alpha(pgc-1α),the master regulator of mitochondrial biogenesis(MB),favors CD8 T cell central memory formation rather than resident memory ***-1α-overexpressing CD8 T cells persist and mediate more robust recall responses to bacterial infection or peptide ***,CD8 T cells with enhanced pgc-1αexpression provide stronger antitumor immunity in a mouse melanoma ***,TILs overexpressing pgc-1αmaintain higher mitochondrial activity and improved expansion when rechallenged in a tumor-free ***,our findings indicate that enforcing mitochondrial biogenesis promotes CD8 T cell memory formation,metabolic fitness,and antitumor immunity in vivo.

关键词： pgc-1α Mitochondria CD8 Memory Anti-tumor immunity

pgc-1α promotes mitochondrial respiration and biogenesis during the differentiation of hiPSCs into cardiomyocytes

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Genes & Diseases 2021年第6期8卷 891-906页

作者： Qin Zhou Hao Xu Liang Yan Liang Ye Xinyuan Zhang Bin Tan Qin Yi Jie Tian Jing Zhu Department of Pediatric Research Institute Ministry of Education Key Laboratory of Child Development and Disorders National Clinical Research Center for Child Health and Disorders(Chongqing)China International Science and Technology Cooperation Base of Child Development and Critical Disorders Children’s Hospital of Chongqing Medical UniversityChongqing400000PR China Chongqing Key Laboratory of Pediatrics Chongqing400000PR China Department of Clinical Laboratory Ministry of Education Key Laboratory of Child Development and Disorders National Clinical Research Center for Child Health and Disorders(Chongqing)China International Science and Technology Cooperation Base of Child Development and Critical Disorders Children’s Hospital of Chongqing Medical University Chongqing400000PR China Department of Cardiovascular(Internal Medicine) Ministry of Education Key Laboratory of Child Development and Disorders National Clinical Research Center for Child Health and Disorders(Chongqing)China International Science and Technology Cooperation Base of Child Development and Critical Disorders Children’s Hospital of Chongqing Medical UniversityChongqing400000PR China Chengdu Women’s and Children’s Central Hospital School of MedicineUniversity of Electronic Science and Technology of ChinaChengduSichuan Province610073PR China

Although it is widely accepted that human induced pluripotent stem cell-derived cardiomyocytes(hiPSC-CMs)are readily available,robustly reproducible,and physiologically appropriate human cells for clinical applications and research in the cardiovascular field,hiPSC-CMs cultured in vitro retain an immature metabolic phenotype that limits their application,and little is known about the underlying molecular mechanism controlling mitochondrial metabolic maturation during human induced pluripotent stem cells(hiPSCs)differentiation into *** this study,we found that peroxisome proliferator-activated receptor g coactivator-1α(pgc-1α)played an important role in inducing mitochondrial biogenesis and establishing oxidative phosphorylation(OXPHOS)during the cardiac differentiation of *** down pgc-1α by siRNA impaired mitochondrial respiration,while upregulating pgc-1α by ZLN005 promoted mitochondrial biosynthesis and function by regulating the expression of downstream genes involved in mitochondrial dynamics and oxidative metabolism in ***,we found that estrogen-related receptor a(ERRa)was required for the induction of pgc-1α stimulatory effects in *** findings provide key insights into the molecular control of mitochondrial metabolism during cardiac differentiation and may be used to generate more metabolically mature cardiomyocytes for application.

关键词： Cardiac differentiation hiPSCs Mitochondrial metabolism pgc-1α Maturation

Deciphering the role of pgc-1α in neurological disorders: from mitochondrial dysfunction to synaptic failure

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Neural Regeneration Research 2022年第2期17卷 237-245页

作者： Jessica D.Panes Aline Wendt Oscar Ramirez-Molina Patricio A.Castro Jorge Fuentealba Laboratorio de Screening de Compuestos Neuroactivos(LSCN) Departamento de FisiologiaFacultad de Ciencias BiologicasUniversidad de ConcepcionConcepcionChile Centro de Investigaciones Avanzadas en Biomedicina(CIAB-UdeC) Facultad de Ciencias BiologicasUniversidad de ConcepcionConcepcionChile Departamento de Fisiologia Facultad de Ciencias BiologicasUniversidad de ConcepcionConcepcionChile

The onset and mechanisms underlying neurodegenerative diseases remain uncertain. The main features of neurodegenerative diseases have been related with cellular and molecular events like neuronal loss, mitochondrial dysfunction and aberrant accumulation of misfolded proteins or peptides in specific areas of the brain. The most prevalent neurodegenerative diseases belonging to age-related pathologies are Alzheimer's disease, Huntington's disease, Parkinson's disease and amyotrophic lateral sclerosis. Interestingly, mitochondrial dysfunction has been observed to occur during the early onset of several neuropathological events associated to neurodegenerative diseases. The master regulator of mitochondrial quality control and energetic metabolism is the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha(pgc-1α). Additionally, it has been observed that pgc-1α appears to be a key factor in maintaining neuronal survival and synaptic transmission. In fact, pgc-1α downregulation in different brain areas(hippocampus, substantia nigra, cortex, striatum and spinal cord) that occurs in function of neurological damage including oxidative stress, neuronal loss, and motor disorders has been seen in several animal and cellular models of neurodegenerative diseases. Current evidence indicates that pgc-1α upregulation may serve as a potent therapeutic approach against development and progression of neuronal damage. Remarkably, increasing evidence shows that pgc-1α deficient mice have neurodegenerative diseases-like features, as well as neurological abnormalities. Finally, we discuss recent studies showing novel specific pgc-1α isoforms in the central nervous system that appear to exert a key role in the age of onset of neurodegenerative diseases and have a neuroprotective function in the central nervous system, thus opening a new molecular strategy for treatment of neurodegenerative diseases. The purpose of this review is to provide an up-t

关键词： Alzheimer's disease amyotrophic lateral sclerosis Huntington's disease mitochondrial dysfunction Parkinson's disease pgc-1α synaptic function vascular dementia

Vitamin A regulates mitochondrial biogenesis and function through p38 MAPK‑pgc‑1α signaling pathway and alters the muscle fiber composition of sheep

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Journal of Animal Science and Biotechnology 2024年第2期15卷 898-910页

作者： Pengkang Song Jiamin Zhao Fanqinyu Li Xiaoyi Zhao Jinxin Feng Yuan Su Bo Wang Junxing Zhao College of Animal Science Shanxi Agricultural UniversityTaiguShanxi 030801People’s Republic of China State Key Laboratory of Animal Nutrition and Feeding Department of Animal Nutrition and Feed ScienceCollege of Animal Science and TechnologyChina Agricultural UniversityBeijing 100193People’s Republic of China

Background Vitamin A(VA)and its metabolite,retinoic acid(RA),are of great interest for their wide range of physiological ***,the regulatory contribution of VA to mitochondrial and muscle fiber composition in sheep has not been *** Lambs were injected with 0(control)or 7,500 IU VA palmitate into the biceps femoris muscle on d 2 after *** the age of 3 and 32 weeks,longissimus dorsi(LD)muscle samples were obtained to explore the effect of VA on myofiber type *** vitro,we investigated the effects of RA on myofiber type composition and intrinsic *** The proportion of type I myofiber was greatly increased in VA-treated sheep in LD muscle at *** greatly promoted mitochondrial biogenesis and function in LD muscle of *** exploration revealed that VA elevated pgc-1αmRNA and protein contents,and enhanced the level of p38 MAPK phosphorylation in LD muscle of *** addition,the number of type I myofibers with RA treatment was significantly increased,and type IIx myofibers was significantly decreased in primary *** with in vivo experiment,RA significantly improved mitochondrial biogenesis and function in primary myoblasts of *** then used si-pgc-1αto inhibit pgc-1αexpression and found that si-pgc-1αsignificantly abrogated RA-induced the formation of type I myofibers,mitochondrial biogenesis,MitoTracker staining intensity,UQCRC1 and ATP5A1 expression,SDH activity,and enhanced the level of type IIx muscle *** data suggested that RA improved mitochondrial biogenesis and function by promoting pgc-1αexpression,and increased type I *** order to prove that the effect of RA on the level of pgc-1αis caused by p38 MAPK signaling,we inhibited the p38 MAPK signaling using a p38 MAPK inhibitor,which significantly reduced RA-induced pgc-1αand MyHC I *** VA promoted pgc-1αexpression through the p38 MAPK signaling pathway,improved mitochondrial biogenesis,and altered

关键词： Mitochondria Muscle fiber type pgc-1α p38 MAPK Retinoic acid Vitamin A

lncRNA Gm20257 alleviates pathological cardiac hypertrophy by modulating the pgc-1α–mitochondrial complexⅣaxis

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Frontiers of Medicine 2024年第4期18卷 664-677页

作者： Tong Yu Qiang Gao Guofang Zhang Tianyu Li Xiaoshan Liu Chao Li Lan Zheng Xiang Sun Jianbo Wu Huiying Cao Fangfang Bi Ruifeng Wang Haihai Liang Xuelian Li Yuhong Zhou Lifang Lv Hongli Shan Department of Physiology School of Basic MedicineHarbin Medical UniversityHarbin150081China State Key Laboratory of Frigid Zone Cardiovascular Disease Department of Pharmacology(State-Province Key Laboratories of Biomedicine-Pharmaceutics of China Key Laboratory of Cardiovascular Research Ministry of Education)College of PharmacyHarbin Medical UniversityHarbin150081China The Center of Functional Experiment Teaching School of Basic MedicineHarbin Medical UniversityHarbin150081China

Pathological cardiac hypertrophy,a major contributor to heart failure,is closely linked to mitochondrial *** roles of long noncoding RNAs(lncRNAs),which regulate mitochondrial function,remain largely unexplored in this ***,a previously unknown lncRNA,Gm20257,was *** markedly increased under hypertrophic stress in vivo and in *** suppression of Gm20257 by using small interfering RNAs significantly induced cardiomyocyte ***,the overexpression of Gm20257 through plasmid transfection or adeno-associated viral vector-9 mitigated angiotensinⅡ-induced hypertrophic phenotypes in neonatal mouse ventricular cells or alleviated cardiac hypertrophy in a mouse TAC model respectively,thus restoring cardiac ***,Gm20257 restored mitochondrial complexⅣlevel and enhanced mitochondrial *** prediction showed that Gm20257 had a high binding score with peroxisome proliferator–activated receptor coactivator-1(pgc-1α),which could increase mitochondrial complex ***,Western blot analysis results revealed that Gm20257 substantially affected the expression of pgc-1α.Further analyses through RNA immunoprecipitation and immunoblotting following RNA pull-down indicated that pgc-1αwas a direct downstream target of *** interaction was demonstrated to rescue the reduction of mitochondrial complex IV induced by hypertrophic stress and promote the generation of mitochondrial *** findings suggest that Gm20257 improves mitochondrial function through the pgc-1α-mitochondrial complexⅣaxis,offering a novel approach for attenuating pathological cardiac hypertrophy.

关键词： lncRNA Gm20257 cardiac hypertrophy pgc-1α mitochondrial complexⅣ ATP

Effects of pgc-1αoverexpression on the myogenic response during skeletal muscle regeneration

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Sports Medicine and Health Science 2022年第3期4卷 198-208页

作者： Tyrone A.Washington Wesley S.Haynie Eleanor R.Schrems Richard A.Perry Jr. Lemuel A.Brown Breanna M.Williams Megan E.Rosa-Caldwell David E.Lee Jacob L.Brown Exercise Muscle Biology Laboratory Exercise Science Research CenterDepartment of HealthHuman Performance and RecreationUniversity of ArkansasFayettevilleAR72701USA Cachexia Research Laboratory Exercise Science Research CenterDepartment of HealthHuman Performance and RecreationUniversity of ArkansasFayettevilleAR72701USA

The ability of skeletal muscle to regenerate from injury is crucial for locomotion,metabolic health,and quality of *** proliferator-activated receptor-γcoactivator-1α(pgc1A)is a transcriptional coactivator required for mitochondrial *** mitochondrial biogenesis is associated with improved muscle cell differentiation,however pgc1A's role in skeletal muscle regeneration following damage requires further *** purpose of this study was to investigate the role of skeletal muscle-specific pgc1A overexpression during regeneration following damage.22 C57BL/6J(WT)and 26 pgc1A muscle transgenic(A1)mice were injected with either phosphate-buffered saline(PBS,uninjured control)or Bupivacaine(MAR,injured)into their tibialis anterior(TA)muscle to induce skeletal muscle *** muscles were extracted 3-or 28-days postinjury and analyzed for markers of regenerative myogenesis and protein ***1a mRNA was~10–20 fold greater in A1 *** of protein synthesis,AKT and 4EBP1,displayed decreases in A1 mice compared to WT at both timepoints indicating a decreased protein synthetic *** mRNA was~75%lower compared to WT 3 days *** mice exhibited decreased cross-sectional area of the TA muscle at 28 days post-injection with bupivacaine compared to all other ***1A overexpression modifies the myogenic response during regeneration.

关键词： pgc-1α Skeletal muscle Muscle regeneration Satellite cells Protein turnover p38 MAPK