ACS Biomaterials Science & Engineering
·
2024
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IF 5.4
Yixiao Chen,Guoqing Li,Yufeng Ge,Su Liu,Jian Weng,Jianjing Lin,Ao Xiong,Hui Zeng,Xinbao Wu,Jun Yang,Fei Yu
In this study, we explore the cartilage defect repair mechanism by phosphocreatine-grafted chitosan hydrogels loaded with berberine-treated ATDC5 cells (CSMP@BBR@ATDC5). Under the optimal concentrations of LPS and BBR ideal conditions, ATDC5 cell toxicity and proliferation were detected with AM/PI and EdU staining. Additionally, qPCR and Western blot were employed to detect the expression of the SIRT1/BMP4 signaling pathway and chondrogenic-related factors in ATDC5 cells. Moreover, BBR-treated ATDC5 was seeded into a phosphocreatine-grafted chitosan hydrogel system. Subsequently, the cartilage defect was established in mice. After 4, 8, and 12 weeks, knee specimens were collected to evaluate the repair of cartilage defects. According to our findings, BBR can increase ATDC5 viability by LPS treatment. Likewise, it upregulates the SIRT1/BMP4 signaling pathway expression and chondrogenic-related factors. Another, it was shown by histological observation that the cartilage defect had been repaired more effectively in the CSMP@BBR@ATDC5 group than in the other groups. Finally, the expressions of chondrogenic-related factors and SIRT1/BMP4 signaling pathway were upregulates in CSMP@BBR@ATDC5 than in other groups. In vitro, BBR protects inflammatory ATDC5 cells and maintains the expression of chondrogenic-related factors. Subsequently, we successfully use CSMP@BBR@ATDC 5 to repair knee cartilage defects in mice.
研究领域:
组织工程
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再生医学
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骨科
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细胞生物学
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药理学
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LIFE SCIENCES
·
2024
·
IF 5.2
Xianzhe Wang,Yanyan Zhu,Huilin Liu,Xiangchuan Wang,Hongjie Zhang,Xiuping Chen
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterized by irreversible lung scarring with a poor prognosis. Emerging evidence has revealed that IPF is an aging-related disease, and the development of cellular senescence plays a pivotal role in persistent remodeling and fibrotic scarring, acting as a key mechanism in the pathophysiology of IPF. Exploring therapeutic strategies for modulating cellular senescence can provide crucial insights into unraveling IPF processes. Here, we have identified Nitazoxanide (NTZ), an FDA-approved antiprotozoal agent, has specific effects on inhibiting cellular senescence development. In the bleomycin and D-galactose-induced senescence model, NTZ effectively inhibits senescence associated-β-gal staining and preserves cell proliferation ability. We also found that NTZ effectively impedes senescence progression in the bleomycin-induced pulmonary fibrosis model, while mitigating the release of senescence-associated secretory phenotype and alleviating pulmonary fibrosis. The anti-senescence effect of NTZ is mechanistically dependent on the preservation of nuclear SIRT1 expression. We observed that PI3K induces a WIPI1-mediated nucleophagic degradation of SIRT1, while NTZ effectively inhibits PI3K and suppresses WIPI1 expression, thereby maintaining SIRT1 expression in the nucleus and exerting its anti-senescence function. Collectively, our research has shown that NTZ can inhibit PI3K in senescence progression, leading to the inhibition of WIPI1-mediated SIRT1 nucleophagic degradation. As a result, NTZ alleviates fibrosis by inhibiting senescence development.
研究领域:
药理学
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肺科学
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细胞生物学
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衰老研究
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FOOD AND CHEMICAL TOXICOLOGY
·
2023
·
IF 4.3
Huiying Huang,Jian Shi,Zhongyi Li,Yifeng Rang,Weiye Li,Xueman Xiao,Congying Chen,Chunhong Liu
Nonylphenol (NP) exposure can trigger neurotoxicity and cause learning and memory impairment. Nicotinamide mononucleotide (NMN) has a therapeutic effect on neurodegenerative diseases , but the role of NMN on NP-induced learning and memory impairment is not known. Here, we examined the mitigative effect of NMN on the impaired learning and memory ability of rats exposed to NP. The NP impaired learning and memory in rats, while the low-dose intervention with NMN significantly prolonged the step-through latency of the PAT and improved the NAMPT and NMNAT1 content in brain tissue. At the same time, the NMN intervention also increased the content of 5-HTR 1A , 5-HTR 4 , and 5-HTR 6 related to learning and memory in the hippocampus. In line with this, we found that the NMN intervention activated the SIRT1/MAO-A pathway in brain tissue. NMN intervention, especially at 125 mg/kg doses, may improve rats’ NP-induced learning and memory impairment via the central 5-HT system and the NAD + /SIRT1/MAO-A pathway in the brain.
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Oxidative Medicine and Cellular Longevity
·
2022
·
IF 7.31
Zhihui Yin,Demin Gao,Ke Du,Chen Han,Yuhan Liu,Ying Wang,Xiaoyan Gao
Mitochondrial oxidative stress plays an important role in the pathogenesis of Alzheimer’s disease (AD). Recently, antioxidant therapy has been considered an effective strategy for the treatment of AD. Our previous work discovered that rhein relieved mitochondrial oxidative stress in β-amyloid (Aβ) oligomer-induced primary neurons by improving the sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha- (PGC-1α-) regulated mitochondrial biogenesis. While encouraging results have been provided, mechanisms underlying the beneficial effect of rhein on AD are yet to be elucidated in vivo. In this study, we evaluated the therapeutic effect of rhein on an APP/PS1 transgenic (APP/PS1) mouse model of AD and explored its antioxidant mechanisms. As a result, rhein significantly reduced Aβ burden and neuroinflammation and eventually ameliorated cognitive impairment in APP/PS1 mice. Moreover, rhein reversed oxidative stress in the brain of APP/PS1 mice and protected neurons from oxidative stress-associated apoptosis. Further study revealed that rhein promoted mitochondrial biogenesis against oxidative stress by upregulating SIRT1 and its downstream PGC-1α as well as nuclear respiratory factor 1. Improved mitochondrial biogenesis not only increased the activity of superoxide dismutase to scavenge excess reactive oxygen species (ROS) but also repaired mitochondria by mitochondrial fusion to inhibit the production of ROS from the electron transport chain. Notably, the exposure of rhein in the brain analyzed by tissue distribution study indicated that rhein could permeate into the brain to exert its therapeutic effects. In conclusion, these findings drive rhein to serve as a promising therapeutic antioxidant for the treatment of AD. Our research highlights the therapeutic efficacy for AD through regulating mitochondrial biogenesis via the SIRT1/PGC-1α pathway.
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Frontiers in Pharmacology
·
2022
·
IF 5.988
Liao Wenli,Rao Zhiwei,Wu Lingling,Chen Yong,Li Cairong
Background: Doxorubicin (DOX) is a potent chemotherapeutic agent with limited usage due to its cumulative cardiotoxicity. The Na+/H+ exchanger isoform 1 (NHE1) is a known regulator of oxidative stress, inflammation, and apoptosis. The present study was designed to investigate the possible protective effect of cariporide (CAR), a selective inhibitor of NHE1, against DOX-induced cardiotoxicity in rats.Methods: Male Sprague-Dawley rats were intraperitoneally injected with DOX to induce cardiac toxicity and CAR was given orally for treatment. The injured H9c2 cell model was established by incubation with DOX in vitro. Echocardiography, as well as morphological and ultra-structural examination were performed to evaluate cardiac function and histopathological changes. The biochemical parameters were determined according to the manufacturer’s guideline of kits. ROS were assessed by using an immunofluorescence assay. The serum levels and mRNA expressions of inflammatory cytokines were measured by using ELISA or qRT-PCR. Cardiac cell apoptosis and H9c2 cell viability were tested by TUNEL or MTT method respectively. The protein expressions of Cleaved-Caspase-3, Bcl-2, Bax, Akt, GSK-3β, and Sirt1 were detected by western blot.Results: Treatment with CAR protected against DOX-induced body weight changes, impairment of heart function, leakage of cardiac enzymes, and heart histopathological damage. In addition, CAR significantly attenuated oxidative stress and inhibited the levels and mRNA expressions of inflammatory cytokines (TNF-α, IL-6, IL-18, and IL-1β), which were increased by DOX treatment. Moreover, CAR significantly suppressed myocardial apoptosis and Cleaved-Caspase-3 protein expression induced by DOX, which was in agreement with the increased Bcl-2/Bax ratio. Also, DOX suppressed phosphorylation of Akt and GSK-3β, which was significantly reversed by administration of CAR. Furthermore, CAR treatment prevented DOX-induced down-regulation of Sirt1 at the protein level in vitro and in vivo. Finally, Sirt1 inhibitor reversed the protective effects of CAR, as evidenced by reduced cell viability and Sirt1 protein expression in vitro.Conclusion: Taken together, we provide evidence for the first time in the current study that CAR exerts potent protective effects against DOX-induced cardiotoxicity in rats. This cardio-protective effect is attributed to suppressing oxidative stress, inflammation, and apoptosis, at least in part, through regulation of Akt/GSK-3β and Sirt1 signaling pathway, which has not been reported to date.
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TOXICOLOGY LETTERS
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2020
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IF 3.569
Jianxin Ye,Kangnan Zhang,Xindi Yuan,Haosen Ji,Miner Hu,Tongliang Huang,Ren-Shan Ge
Di -n- hexyl phthalate (DNHP) is commonly used as a plasticizer. However, whether DNHP influences Leydig cell development during puberty remains unexplored. In this study, DNHP (0, 10, 100, and 1000 mg/kg) was administered via gavage to 35-day-old male Sprague-Dawley rats for 21 days. Serum levels of testosterone, luteinizing hormone, follicle-stimulating hormone, Leydig cell number, the expression of Leydig and Sertoli cell genes and proteins were investigated. DNHP significantly increased serum testosterone levels at 10 mg/kg but lowered its level at 1000 mg/kg. DNHP significantly increased luteinizing hormone levels at 1000 mg/kg without affecting follicle-stimulating hormone levels. DNHP increased Leydig cell number at all doses but down-regulated the expression of Lhcgr , Hsd3b1 , Hsd17b3 , and Hsd11b1 in Leydig cell per se at 1000 mg/kg. DNHP elevated phosphorylation of ERK1/2 and GSK-3β at 10 mg/kg but decreased SIRT1 and PGC-1α levels at 1000 mg/kg. In conclusion, DNHP exposure causes Leydig cell hyperplasia possibly via stimulating phosphorylation of ERK1/2 and GSK-3β signaling pathways.
研究领域:
毒理学
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内分泌学
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生殖生物学
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BIOCHEMICAL PHARMACOLOGY
·
2018
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IF 4.235
Zhihua Wang,Sheng Yuan,Yanbing Li,Zhe Zhang,Wei Xiao,Dan Tang,Kaihe Ye,Zhijun Liu,Congcong Wang,Yixiong Zheng,Hong Nie,Heru Chen
( R , E )- N -(3-(2-acetamido-3-(benzyloxy) propanamido)propyl)-2-cyano-3-(4-hydroxy phenyl)acrylamide ( hr5F ) was design-synthesized based on bioactivity focus strategy as a potential agent to treat diabetic complicates. With in vitro enzyme assay, it is confirmed that hr5F is an effective ALR2 inhibitor with IC 50 value of 2.60 ± 0.15 nM, and selectivity index of 86.0 over ALR1, which is a little bit better than the reference Epalrestat (Epa). hr5F inhibits the increase of ALR2 enzyme activity and expression in human lens epithelial cells (HLECs) induced by high glucose. By applying western blot , it was found that hr5F alleviates the high glucose-induced superoxide overproduction insults by regulating SIRT1-PGC-1α/Nrf2 pathway, together with regulating NRF-1, mtTFA , Bax/Bcl-2 to ameliorate cell apoptosis . The in vivo effects of hr5F on short term streptozocin (STZ)-induced diabetic mice confirm the same functions disclosed in vitro . All the evidences support that hr5F may serve as a promising agent in the treatment of diabetic complications with close efficacy and broader indication than the reference Epa.
研究领域:
药理学
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糖尿病
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
International Journal of Chronic Obstructive Pulmonary Disease
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2022
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IF 2.893
Xiao Sun,Zhonghua Dong,Nan Li,Xiuli Feng,Yan Liu,Ang Li,Xiaosong Zhu,Chunyan Li,Zhongxi Zhao
Background Ophiocordyceps sinensis (C. sinensis) extracts have been found to have a therapeutic effect on patients with chronic obstructive pulmonary disease (COPD). Silent information regulator 1 (SIRT1) plays an important role in the regulation of inflammatory mediators and correlates with lung function and COPD exacerbations. The objective of this work was to explore the anti-inflammatory effect and preliminary pathways of nucleosides from cultured C. sinensis on RAW264.7 macrophages and COPD mice.Materials and methods The nucleosides were extracted from cultured C. sinensis powder and further purified by macroporous resin D101 and glucan G10 columns. Inflammation and oxidative stress models in RAW264.7 macrophages and in mice were established by injection of cigarette smoke extract (CSE). We then examined how the isolated nucleosides regulated the production of the associated inflammatory mediators in vitro and in vivo by enzyme-linked immunosorbent assay, reverse transcription polymerase chain reaction, and Western blot.Results The nucleosides inhibited inflammatory mediator expression of tumor necrosis factor-α, interleukin-6, interleukin-1β, and nitric oxide in both the CSE-stimulated RAW264.7 macrophages and mice. Moreover, the nucleosides elevated SIRT1 activation and suppressed nuclear factor-κB (NF-κB)/p65 activation in vitro and in vivo. Nucleoside treatment significantly decreased the levels of the inflammatory mediators in the bronchoalveolar lavage fluid (BALF) and serum of the CSE-induced mice. The nucleosides also altered the recruitment of inflammatory cells in BALF and improved characteristic features of the lungs in the CSE-induced mice.Conclusion These results show that the nucleosides suppressed COPD inflammation through the SIRT1–NF-κB/p65 pathway, suggesting that the nucleosides may be partly responsible for the therapeutic effects of cultured C. sinensis on COPD patients.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2019
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IF 4.784
Qiang Chu,Shuang Zhang,Lushuang Yu,Yonglu Li,Yangyang Liu,Xiang Ye,Xiaodong Zheng
The tubers of Apios americana Medikus possess high nutritional value and have been used as food in many countries for a long time. However, few researches have focused on the tuber polysaccharides. In the present study, a purified polysaccharide (ATP-1) was isolated with the average molecular weights of 12.16 kDa. ATP-1 significantly suppressed the release of nitric oxide (NO) and inflammatory cytokines from LPS-induced RAW 264.7 cells, as well as oxidative stress and mitochondrial dysfunction. Meanwhile, ATP-1 reduced oxidative damage via the NF-κB, MAPKs and Nrf2-Keap1 signaling pathways in RAW264.7 macrophages. Furthermore, autophagy was activated by HMGB1-Beclin1, Sirt1-FoxO1 and Akt-mTOR signaling pathways, leading to a relief of oxidative stress, mitochondrial dysfunction, inflammation and an expression enhancement of autophagy-related proteins, such as LC3, Beclin1, Atg4, Atg5, and Atg7. In summary, our results suggested that ATP-1 might help to activate the anti-inflammation system，resulting in prevention of LPS-induced damage in RAW264.7 cells.
研究领域:
药理学
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免疫学
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细胞生物学
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生物化学
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高影响因子
INFLAMMATION
·
2021
·Vol. 44
·期 5
·1993-2005
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IF 4.092
Wu Yuqin,Fan Lin,Wang Yun,Ding Jing,Wang Rongfu
This study is aimed at exploring the potential of isorhamnetin in protection against diabetes-exacerbated ischemia/reperfusion-induced brain injury and elucidating its action mechanism. After establishment of the model of high glucose (HG)-aggravated oxygen-glucose deprivation and reoxygenation (OGD/R), HT22 cell viability was detected by CCK-8. Lactate dehydrogenase (LDH) activity, casapase-3 activity, and oxidative stress-related markers in HT22 cells were detected by corresponding commercial kits. The apoptosis of HG-treated HT22 cells following OGD/R was observed with TUNEL staining. The level of pro-inflammatory cytokines was examined by ELISA. The expression of Akt/SIRT1/Nrf2/HO-1 signaling-related proteins was assayed by Western blot. The results showed that HG noticeably worsened the OGD/R-induced apoptosis of HT22 cells. Isorhamnetin relieved the HG-aggravated OGD/R-induced apoptosis, inflammatory response, and oxidative stress of HT22 cells. Isorhamnetin alleviated the HG-aggravated OGD/R injury in HT22 cells through Akt/SIRT1/Nrf2/HO-1 signaling pathway. Meanwhile, treatment with Akt inhibitor LY294002 reversed the protective effects of isorhamnetin against HG-aggravated OGD/R injury in HT22 cells. In a conclusion, Isorhamnetin alleviates HG-aggravated OGD/R in HT22 hippocampal neurons through Akt/SIRT1/Nrf2/HO-1 signaling pathway.
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JOURNAL OF BIOLOGICAL CHEMISTRY
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2025
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IF 3.9
Juncheng Zhong,Xuebo Liu,Jiawei Wang,Huaming Liu,Geng Liu,Xiaobo Wen,Kun Wu
Very-long-chain fatty acids (VLCFAs), are vital for growth, development, and overall health. Zinc oxide nanoparticles (ZnO NPs), recognized for their high bioavailability and wide use in medicine and nutrition, have an unclear impact on lipid metabolism. This study explores how ZnO NPs impact VLCFA metabolism using yellow catfish ( Pelteobagrus fulvidraco ) as a model organism. In vivo , 240 yellow catfish were divided into a control group and a group fed 10 mg/kg ZnO NPs diet for 10 weeks. ZnO NPs administration significantly increased hepatic VLCFA content, accompanied by elevated triglyceride (TG) and total cholesterol (T-CHO) levels. Additionally, ZnO NPs reduced peroxisomal β-oxidation and peroxisome-ER (Po-ER) contacts. In vitro studies with yellow catfish hepatocytes confirmed these findings and explored the underlying mechanisms. ZnO NPs reduced Po-ER attachment and significantly decreased peroxisomal β-oxidation levels. ZnO NPs markedly decreased the expression and localization of ACBD5, a key protein involved in Po-ER interactions and VLCFA degradation. Overexpression of ACBD5 counteracted these effects, whereas knockdown mimicked them. Further experiments revealed that FOXO3 directly regulates ACBD5 by binding to its promoter. ZnO NPs increased the acetylation level of hepatocytes, inhibited the nuclear entry of FOXO3, and reduced the protein level of SIRT1. SIRT1 directly regulates FOXO3 deacetylation at lysine 243. Overall, ZnO NPs disrupt lipid homeostasis by downregulating ACBD5 via the SIRT1/FOXO3 axis, impairing peroxisomal function and Po-ER contacts. This study highlights the significance of the SIRT1 - FOXO3 - ACBD5 axis in managing VLCFA-related metabolic disorders.
研究领域:
纳米毒理学
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脂质代谢
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细胞生物学
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分子生物学
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环境毒理学
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营养科学
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Molecular Medicine Reports
·
2025
·Vol. 31
·期 3
·1-12
·
IF 3.5
Xiangli Yan,Siqi Quan,Roujia Guo,Zibo Li,Ming Bai,Baoying Wang,Pan Su,Erping Xu,Yucheng Li
Calycosin‑7‑O‑β‑D‑glucoside (CG), a major active ingredient of Astragali Radix, exerts neuroprotective effects against cerebral ischemia; however, whether the effects of CG are associated with mitochondrial protection remains unclear. The present study explored the role of CG in improving mitochondrial function in a HT22 cell model of oxygen‑glucose deprivation/reperfusion (OGD/R). The Cell Counting Kit‑8 assay, flow cytometry, immunofluorescence and western blotting were performed to investigate the effects of CG on mitochondrial function. The results demonstrated that mitochondrial function was restored after treatment with CG, as indicated by reduced mitochondrial reactive oxygen species levels, increased mitochondrial membrane potential and improved mitochondrial morphology. Overactivated mitophagy was revealed to be inhibited by the regulation of proteins involved in fission [phosphorylated‑dynamin‑related protein 1 (Drp1) and Drp1] and mitophagy (LC3, p62 and translocase of outer mitochondrial membrane 20), and mitochondrial biogenesis was demonstrated to be enhanced by increased levels of sirtuin 1 (SIRT1) and peroxisome proliferator‑activated receptor γ coactivator‑1α (PGC‑1α). In addition, neuronal apoptosis was ameliorated by CG, as determined by a decreased rate of apoptosis, and levels of caspase‑3 and Bcl‑2/Bax. In conclusion, the present study demonstrated that CG may alleviate OGD/R‑induced injury by upregulating SIRT1 and PGC‑1α protein expression, and reducing excessive mitochondrial fission and overactivation of mitophagy.
研究领域:
神经科学
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细胞生物学
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药理学
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