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| 1 | Mechanisms of hepatic ischemia-reperfusion injury and protective effects of nitric oxide显示文摘Hepatic ischemia-reperfusion injury(IRI) is a patho-physiological event post liver surgery or transplantation and significantly influences the prognosis of liver func-tion. The mechanisms of IRI remain unclear, and effec-tive methods are lacking for the prevention and therapy of IRI. Several factors/pathways have been implicated in the hepatic IRI process, including anaerobic metabo-lism, mitochondria, oxidative stress, intracellular cal-cium overload, liver Kupffer cells and neutrophils, and cytokines and chemokines. The role of nitric oxide(NO)in protecting against liver IRI has recently been report-ed. NO has been found to attenuate liver IRI through various mechanisms including reducing hepatocellular apoptosis, decreasing oxidative stress and leukocyte adhesion, increasing microcirculatory flow, and enhanc-ing mitochondrial function. The purpose of this review is to provide insights into the mechanisms of liver IRI, indicating the potential protective factors/pathways that may help to improve therapeutic regimens for control-ling hepatic IRI during liver surgery, and the potential therapeutic role of NO in liver IRI. | Lian-Yue Guan Pei-Yao Fu Pei-Dong Li Zhuo-Nan Li Hong-Yu Liu Min-Gang Xin Wei Li | 2014 | World Journal of Gastrointestinal Surgery2014，6，7： | 44 |
| 2 | Discovery of mitochondrial chimeric-gene associated with cytoplasmic male sterility of HL-rice显示文摘The mitochondrial genome libraries of HL-type sterile line(A) and maintainer line(B) have been constructed. Mitochondrial gene, atp6, was used to screen libraries, due to the different Southern and Northern blot results between sterile and maintainer line. Sequencing analysis of positive clones proved that there were two copies of atp6 gene in sterile line and only one in maintainer line. One copy of atpt6 in sterile line was same to that in maintainer line; the other showed different flanking sequence from the 49th nucleotide downstream of the termination codon of atp6 gene. A new chimeric gene, orfH79, was found in the region. OrfH79 had homology to mitochondrial gene cox Ⅱ and orf107, and was special to HL-sterile cytoplasm. | Yl Ping WANG Li SUN Qingping ZHU Yingguo | 2002 | Chinese Science Bulletin2002，47，9： | 36 |
| 3 | Application and prospects of butylphthalide for the treatment of neurologic diseases显示文摘Objective: The 3-N-butylphthalide (NBP) comprises one of the chemical constituents of celery oil. It has a series of pharmacologic mechanisms including reconstructing microcirculation, protecting mitochondrial function, inhibiting oxidative stress, inhibiting neuronal apoptosis, etc. Based on the complex multi-targets of pharmacologic mechanisms of NBP, the clinical application of NBP is increasing and more clinical researches and animal experiments are also focused on NBP. The aim of this review was to comprehensively and systematically summarize the application of NBP on neurologic diseases and briefly summarize its application to non-neurologic diseases. Moreover, recent progress in experimental models of NBP on animals was summarized. Data sources: Literature was collected from PubMed and Wangfang database until November 2018, using the search terms including '3-N-butylphthalide,''microcirculation,''mitochondria,''ischemic stroke,''Alzheimer disease,''vascular dementia,''Parkinson disease,''brain edema,''CO poisoning,''traumatic central nervous system injury,''autoimmune disease,''amyotrophic lateral sclerosis,''seizures,''diabetes,''diabetic cataract,' and 'atherosclerosis.' Study selection: Literature was mainly derived from English articles or articles that could be obtained with English abstracts and partly derived from Chinese articles. Article type was not limited. References were also identified from the bibliographies of identified articles and the authors’ files. Results: NBP has become an important adjunct for ischemic stroke. In vascular dementia, the clinical application of NBP to treat severe cognitive dysfunction syndrome caused by the hypoperfusion of brain tissue during cerebrovascular disease is also increasing. Evidence also suggests that NBP has a therapeutic effect for neurodegenerative diseases. Many animal experiments have found that it can also improve symptoms in other neurologic diseases such as epilepsy, cerebral edema, and decreased cognitive function caused by severe acute carbon monoxide poisoning. Moreover, NBP has therapeutic effects for diabetes, diabetes-induced cataracts, and non-neurologic diseases such as atherosclerosis. Mechanistically, NBP mainly improves microcirculation and protects mitochondria. Its broad pharmacologic effects also include inhibiting oxidative stress, nerve cell apoptosis, inflammatory responses, and anti-platelet and anti-thrombotic effects. Conclusions: The varied pharmacologic mechanisms of NBP involve many complex molecular mechanisms;however, there many unknown pharmacologic effects await further study. | Xi-Qian Chen Ke Qiu Hui Liu Qiang He Jia-Hui Bai Wei Lu | 2019 | Chinese Medical Journal2019，，12： | 39 |
| 4 | Galangin induces apoptosis of hepatocellular carcinoma cells via the mitochondrial pathway显示文摘AIM:To investigate the mechanism by which galangin,a polyphenolic compound derived from medicinal herbs,induces apoptosis of hepatocellular carcinoma(HCC) cells.METHODS:The 3-(4,5-Dimethyl-thiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay was used to measure cell viability.Apoptosis was evaluated by in situ uptake of propidium iodide and Hoechst 33258 and was then detected by fluorescence microscopy.Protein expressions were detected by Western blotting.To confirm the apoptotic pathway mediated by galangin,cells were transfected by bcl-2 gene to overexpress Bcl-2 or siRNA to down-regulate Bcl-2 expression.RESULTS:Galangin(46.25-370.0 μmol/L) exerted an anti-proliferative effect,induced apoptosis,and decreased mitochondrial membrane potential in a dose and time-dependent manner.Treatment with galangin induced apoptosis by translocating the pro-apoptotic protein Bax to the mitochondria,which released apoptosis-inducing factor and cytochrome c into the cytosol.Overexpression of Bcl-2 attenuated galangin-induced HepG2 cell apoptosis,while decreasing Bcl-2 expression enhanced galangin-induced cell apoptosis.CONCLUSION:Our data suggests that galangin mediates apoptosis through a mitochondrial pathway,and may be a potential chemotherapeutic drug for the treatment of HCC. | Hai-Tao Zhang Liu-Bo Lan Da-Hua Fan Kai-Dan Zhu Xiao-Yi Chen Min Wen Hui-Ming Liu Guangdong Province China Hui Luo | 2010 | World Journal of Gastroenterology2010，16，27： | 32 |
| 5 | Artesunate synergizes with sorafenib to induce ferroptosis in hepatocellular carcinoma显示文摘Sorafenib is the first-line medication for advanced hepatocellular carcinoma(HCC),but it can only extend limited survival.It is imperative to find a combination strategy to increase sorafenib efficacy.Artesunate is such a preferred candidate,because artesunate is clinically well-tolerated and more importantly both drugs can induce ferroptosis through different mechanisms.In this study we investigated the combined effect of sorafenib and artesunate in inducing ferroptosis of HCC and elucidated the involved molecular mechanisms.We showed that artesunate greatly enhanced the anticancer effects of low dose of sorafenib against Huh7,SNU-449,and SNU-182 HCC cell lines in vitro and against Huh7 cell xenograft model in Balb/c nude mice.The combination index method confirmed that the combined effect of sorafenib and artesunate was synergistic.Compared with the treatment with artesunate or sorafenib alone,combined treatment induced significantly exacerbated lipid peroxidation and ferroptosis,which was blocked by N-acetyl cysteine and ferroptosis inhibitors liproxstatin-1 and deferoxamine mesylate,but not by inhibitors of other types of cell death(z-VAD,necrostatin-1 and belnacasan).In Huh7 cells,we demonstrated that the combined treatment induced oxidative stress and lysosome-mediated ferritinophagy,two essential aspects of ferroptosis.Sorafenib at low dose mainly caused oxidative stress through mitochondrial impairments and SLC7A11-invovled glutathione depletion.Artesunate-induced lysosome activation synergized with sorafenib-mediated pro-oxidative effects by promoting sequential reactions including lysosomal cathepsin B/L activation,ferritin degradation,lipid peroxidation,and consequent ferroptosis.Taken together,artesunate could be repurposed to sensitize sorafenib in HCC treatment.The combined treatment can be easily translated into clinical applications. | Zhong-jie Li Hui-qi Dai Xiao-wei Huang Ji Feng Jing-huan Deng Zi-xuan Wang Xiao-mei Yang Yu-jia Liu Yong Wu Pan-hong Chen Huan Shi Ji-gang Wang Jing Zhou Guo-dong Lu | 2021 | Acta Pharmacologica Sinica2021，42，2： | 31 |
| 6 | Impact of hypoxic preconditioning on apoptosis and its possible mechanism in orthotopic liver autotransplantation in rats显示文摘BACKGROUND:Hepatocyte apoptosis is a severe form of cell death after hepatic ischemia-reperfusion injury(HIRI), and its relief is an important issue in liver transplantation. Hypoxic preconditioning(HP)is considered to have protective effects on HIRI.This study was designed to explore the impact of HP on apoptosis and its possible mechanism during orthotopic liver autotransplantation. METHODS:A modified orthotopic liver autotransplantation model was used to simulate HIRI.Sprague-Dawley rats were randomly divided into normal control,autotransplantation (AT)and HP groups.The HP group was subjected to an 8%oxygen atmosphere for 90 minutes before surgery.At 1,6 and 24 hours after surgery,the rats were killed and their liver tissue was sampled to assess the expression of Bcl-2 protein.The samples were subjected to blood chemistry study,morphological study under a light or transmission electron microscope,and quantitative study of mitochondria. RESULTS:The serum levels of ALT and AST in the HP group were lower than those in the AT group at 1,6 and 24 hours after orthotopic liver autotransplantation(P<0.05).Bcl-2 protein expression was increased in the HP group at each measurement point(P<0.05).Light microscopy showed that hepatic injury in the AT group was much more severe than in the HP group.Hepatocytes in the AT group showed typical apoptosis signs under a transmission electron microscope.The ultrastructural appearance of hepatocytes in the HP group was much better than in the AT group,and the area,perimeter and diameter of the mitochondria were smaller in the HP group than in the AT group(P<0.05). CONCLUSIONS:Hepatocytes sense and respond to decreased tissue oxygenation.Stimulation by HP relieves apoptosis by upregulating expression of Bcl-2 protein and its protection of mitochondria after orthotopic liver autotransplantation. | Jin, Cheng Zhang, Pei-Jian Wu, Xiao-Min Zhou, Bin Li, Yong Liu, Xin-Yan Feng, Min Tao, Li-De | 2009 | Hepatobiliary & Pancreatic Diseases International2009，8，1： | 26 |
| 7 | Impaired PI3K/Akt signal pathway and hepatocellular injury in high-fat fed rats显示文摘AIM:To determine whether mitochondrial dysfunction resulting from high-fat diet is related to impairment of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt,also known as PKB) pathway. METHODS:Rat models of nonalcoholic fatty liver were established by high-fat diet feeding. The expression of total and phosphorylated P13K and Akt proteins in hepatocytes was determined by Western blotting. Degree of fat accumulation in liver was measured by hepatic triglyceride. Mitochondrial number and size were determined using quantitative morphometric analysis under transmission electron microscope. The permeability of the outer mitochondrial membrane was assessed by determining the potential gradient across this membrane.RESULTS:After Wistar rats were fed with high-fat diet for 16 wk,their hepatocytes displayed an accumulation of fat (103.1 ± 12.6 vs 421.5 ± 19.7,P < 0.01),deformed mitochondria (9.0% ± 4.3% vs 83.0% ± 10.9%,P < 0.05),and a reduction in the mitochondrial membrane potential (389.385% ± 18.612% vs 249.121% ± 13.526%,P < 0.05). In addition,the expression of the phosphorylated P13K and Akt proteins in hepatocytes was reduced,as was the expression of the anti-apoptotic protein Bcl-2,while expression of the pro-apoptotic protein caspase-3 was increased. When animals were treated with pharmacological inhibitors of P13K or Akt,instead of high-fat diet,a similar pattern of hepatocellular fat accumulation,mitochondrial impairment,and change in the levels of PI3K,Akt,Bcl-2 was observed. CONCLUSION:High-fat diet appears to inhibit the PI3K/Akt signaling pathway,which may lead to hepa-tocellular injury through activation of the mitochondrial membrane pathway of apoptosis. | Ji-Wu Han,Department of Gastroenterology,The 4th Hospital of Harbin Medical University,Harbin 150001,Heilongjiang Province,China Xiao-Rong Zhan,Xin-Yu Li,Bing Xia,Yue-Ying Wang,Jing Zhang,Department of Endocrinology,First Hospital of Harbin Medical University,Harbin 150001,Heilongjiang Province,China Bao-Xin Li,Department of Pharmacology,State Key Laboratory of Biomedicine and Pharmacology,Harbin Medical University,Harbin 150001,Heilongjiang Province,China | 2010 | World Journal of Gastroenterology2010，16，48： | 22 |
| 8 | Mitochondrial ROS promote macrophage pyroptosis by inducing GSDMD oxidation显示文摘Disrupted mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) generation are often associated with macrophage pyroptosis. It remains unclear how these forms of mitochondrial dysfunction relate to inflammasome activation and gasdermin-D (Gsdmd) cleavage, two central steps of the pyroptotic process. Here, we also found MMP collapse and ROS generation induced by Nlrp3 inflammasome activation as previous studies reported. The elimination of ROS alleviated the cleavage of Gsdmd, suggesting that Gsdmd cleavage occurs downstream of ROS release. Consistent with this result, hydrogen peroxide treatment augmented the cleavage of Gsdmd by caspase-1. Indeed, four amino acid residues of Gsdmd were oxidized under oxidative stress in macrophages. The efficiency of Gsdmd cleavage by inflammatory caspase-1 was dramatically reduced when oxidative modification was blocked by mutation of these amino acid residues. These results demonstrate that Gsdmd oxidation serves as a de novo mechanism by which mitochondrial ROS promote Nlrp3 inflammasome-dependent pyroptotic cell death. | Yufang Wang Peiliang Shi Qin Chen Zan Huang Dayuan Zou Jingzi Zhang Xiang Gao Zhaoyu Lin | 2019 | Journal of Molecular Cell Biology2019，11，12： | 23 |
| 9 | Asiatic acid inhibits lung cancer cell growth in vitro and in vivo by destroying mitochondria显示文摘Asiatic acid(AA), a pentacyclic triterpene found in Centella asiatica, displays significant antiproliferative effects on cancer cells in vitro although the underlying mechanism of this effect remains unknown. This study investigated the efficacy and mechanism of action of AA against lung cancer both in vivo and in vitro. Using the MTT assay, AA was found to induce apoptosis in a dose- and timedependent manner, an effect enhanced by pretreatment with an autophagy inhibitor. It also elevated expression of microtubule-associated protein 1 light chain 3(LC3) and decreased the expression of p62.Furthermore, exposure to AA resulted in collapse of the mitochondrial membrane potential and generation of reactive oxygen species(ROS), suggesting mitochondria are the target of AA. In the mouse lung cancer xenograft model, oral administration of AA significantly inhibited tumor volume and weight accompanied by significant apoptosis of lung cancer cells. In addition, it led to a significant decrease in the expression of proliferating cell nuclear antigen(PCNA). In summary, the results show that AA significantly reduces lung cancer cell growth both in vitro and in vivo and that the associated apoptosis is mediated through mitochondrial damage. | Tiancong Wu Ji Geng Wenjie Guo Jing Gao Xixu Zhu | 2017 | Acta Pharmaceutica Sinica B2017，7，1： | 19 |
| 10 | The cGAS-STING signaling in cardiovascular and metabolic diseases: Future novel target option for pharmacotherapy显示文摘The cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING) signaling exert essential regulatory function in microbial-and onco-immunology through the induction of cytokines, primarily type I interferons. Recently, the aberrant and deranged signaling of the cGAS-STING axis is closely implicated in multiple sterile inflammatory diseases, including heart failure,myocardial infarction, cardiac hypertrophy, nonalcoholic fatty liver diseases, aortic aneurysm and dissection, obesity, etc. This is because of the massive loads of damage-associated molecular patterns(mitochondrial DNA, DNA in extracellular vesicles) liberated from recurrent injury to metabolic cellular organelles and tissues, which are sensed by the pathway. Also, the cGAS-STING pathway crosstalk with essential intracellular homeostasis processes like apoptosis, autophagy, and regulate cellular metabolism.Targeting derailed STING signaling has become necessary for chronic inflammatory diseases. Meanwhile, excessive type I interferons signaling impact on cardiovascular and metabolic health remain entirely elusive. In this review, we summarize the intimate connection between the cGAS-STING pathway and cardiovascular and metabolic disorders. We also discuss some potential small molecule inhibitors for the pathway. This review provides insight to stimulate interest in and support future research into understanding this signaling axis in cardiovascular and metabolic tissues and diseases. | Patrick Kwabena Oduro Xianxian Zheng Jinna Wei Yanze Yang Yuefei Wang Han Zhang Erwei Liu Xiumei Gao Mei Du Qilong Wang | 2022 | Acta Pharmaceutica Sinica B2022，12，1： | 18 |
| 11 | Role of mitochondria in alcoholic liver disease显示文摘Alcohol abuse is the leading cause of liver related morbidity and mortality.Chronic or binge alcohol drinking causes hepatic steatosis which can develop to steatohepatitis,cirrhosis and ultimately hepatocellular carcinoma.The pathogenesis of alcoholic liver disease(ALD)is poorly characterized,however several recent studies point to a major role of mitochondria in this process.Mitochondria play a crucial role in cellular energy metabolism and in reactive species formation.Alcohol treatment causes mitochondrial DNA damage,lipid accumulation and oxidative stress.Studies in both animal models and in humans showed that alcohol administration causes changes in the mitochondrial morphology and function suggesting a role of these changes in the pathogenesis of ALD.We review recent findings on mechanisms by which alcohol negatively impacts mitochondrial biogenesis and function and we will discuss the specific intracellular pathways affected by alcohol consumption.Interestingly,recent findings indicate that a large number of mitochondrial proteins are acetylated and that mitochondrial proteins acetylation and sirtuins are modulated by alcohol.Un-derstanding the mechanisms behind alcohol mediated impaired mitochondrial biogenesis and function may help identify potential therapeutic targets for treating ALD in humans. | Fatiha Nassir Jamal A Ibdah | 2014 | World Journal of Gastroenterology2014，20，9： | 18 |
| 12 | BMAL1 regulates mitochondrial fission and mitophagy through mitochondrial protein BNIP3 and is critical in the development of dilated cardiomyopathy显示文摘Dysregulation of circadian rhythms associates with cardiovascular disorders.It is known that deletion of the core circadian gene Bma/1 in mice causes dilated car-diomyopathy.However,the biological rhythm regulation system in mouse is very different from that of humans.Whether BMAL1 plays a role in regulating human heart function remains unclear.Here we generated a BMAL1 knockout human embryonic stem cell(hESC)model and further derived human BMAL1 deficient cardiomy-ocytes.We show that BMAL1 deficient hESC-derived cardiomyocytes exhibited typical phenotypes of dilated cardiomyopathy including attenuated contractility,cal-cium dysregulation,and disorganized myofilaments.In addition,mitochondrial fission and mitophagy were suppressed in BMAL1 deficient hESC-cardiomyocytes,which resulted in significantly attenuated mitochondrial oxidative phosphorylation and compromised cardiomy-ocyte function.We also found that BMAL1 binds to the E-box element in the promoter region of BNIP3 gene and specifically controls BNIP3 protein expression.BMAL1 knockout directly reduced BNIP3 protein level,causing compromised mitophagy and mitochondria dysfunction and thereby leading to compromised cardiomyocyte function.Our data indicated that the core circadian gene S/VMLf is critical for normal mitochondria activities and cardiac function.Circadian rhythm disruption may directly link to compromised heart function and dilated cardiomyopathy in humans. | Ermin Li Xiuya Li Jie Huang Chen Xu Qianqian Liang Kehan Ren Aobing Bai Chao Lu Ruizhe Qian Ning Sun | 2020 | Protein & Cell2020，11，9： | 17 |
| 13 | Curcumin attenuates Nrf2 signaling defect, oxidative stress in muscle and glucose intolerance in high fat diet-fed mice显示文摘AIM: To investigate the signaling mechanism of antioxidative action by curcumin and its impact on glucose disposal. METHODS: Male C57BL/6J mice were fed with either a normal diet (n = 10) or a high fat diet (HFD) (n = 20) to induce obesity and insulin resistance. After 16 wk, 10 HFD-fed mice were further treated with daily curcumin oral gavage at the dose of 50 mg/kg body weight (BW) (HFD + curcumin group). After 15 d of the curcumin supplementation, an intraperitoneal glucose tolerance test was performed. Fasting blood samples were also collected for insulin and glucose measurements. Insulin-sensitive tissues, including muscle, adipose tissue and the liver, were isolated for the assessments of malondialdehyde (MDA), reactive oxygen species (ROS)and nuclear factor erythroid-2-related factor-2 (Nrf2) signaling. RESULTS: We show here that in a HFD mouse model, short-term curcumin gavage attenuated glucose intolerance without affecting HFD-induced BW gain. Curcumin also attenuated HFD-induced elevations of MDA and ROS in the skeletal muscle, particularly in its mitochondrial fraction, but it had no such an effect in either adipose tissue or the liver of HFD-fed mice. Correspondingly, in skeletal muscle, the levels of total or nuclear content of Nrf2, as well as its downstream target, heme oxygenase-1, were reduced by HFD-feeding. Curcumin intervention dramatically reversed these defects in Nrf2 signaling. Further analysis of the relationship of oxidative stress with glucose level by a regression analysis showed a positive and significant correlation between the area under the curve of a glucose tolerance test with MDA levels either in muscle or muscular mitochondria. CONCLUSION: These findings suggest that the shortterm treatment of curcumin in HFD-fed mice effectively ameliorates muscular oxidative stress by activating Nrf2 function that is a novel mechanism for its effect in improving glucose intolerance. | Hui-Jun He Guo-Yu Wang Yuan Gao Wen-Hua Ling Zhi-Wen Yu Tian-Ru Jin | 2012 | World Journal of Diabetes2012，3，5： | 15 |
| 14 | Identification of mecciRNAs and their roles in the mitochondrial entry of proteins显示文摘Mammalian mitochondria have small genomes encoding very limited numbers of proteins.Over one thousand proteins and noncoding RNAs encoded by the nuclear genome must be imported from the cytosol into the mitochondria.Here,we report the identification of hundreds of circular RNAs(mecciRNAs)encoded by the mitochondrial genome.We provide both in vitro and in vivo evidence to show that mecciRNAs facilitate the mitochondrial entry of nuclear-encoded proteins by serving as molecular chaperones in the folding of imported proteins.Known components involved in mitochondrial protein and RNA importation,such as TOM40 and PNPASE,interact with mecciRNAs and regulate protein entry.The expression of mecciRNAs is regulated,and these transcripts are critical for the adaption of mitochondria to physiological conditions and diseases such as stresses and cancers by modulating mitochondrial protein importation.mecciRNAs and their associated physiological roles add categories and functions to the known eukaryotic circular RNAs and shed novel light on the communication between mitochondria and the nucleus. | Xu Liu Xiaolin Wang Jingxin Li Shanshan Hu Yuqi Deng Hao Yin Xichen Bao Qiangfeng Cliff Zhang Geng Wang Baolong Wang Qinghua Shi Ge Shan | 2020 | Science China(Life Sciences)2020，63，10： | 15 |
| 15 | Mitochondrial inhibitor as a new class of insulin sensitizer显示文摘Insulin resistance is a major risk factor for type 2 diabetes.AMP-activated protein kinase(AMPK)is a drug target in the improvement of insulin sensitivity.Several insulin-sensitizing medicines are able to activate AMPK through inhibition of mitochondrial functions.These drugs,such as metformin and STZ,inhibit ATP synthesis in mitochondria to raise AMP/ATP ratio in the.process of A MPK activation.However,chemicals that activate AMPK directly or by activating its upstream kinases have not been approved for treatment of type 2 diabetes in humans.In an early study,we reported that berberine inhibited oxygen consumption in mitochondria,and increased AMP/ATP ratio in cells.The observation suggests an indirect mechanism for AMPK activation by berberine.Berberine stimulates glycolysis for ATP production that offsets the cell toxicity after mitochondria inhibition.The study suggests that mitochondrial inhibition is an approach for AMPK activation.In this review article,literature is critically reviewed to interpret the role of mitochondria function in the mechanism of insulin resistance,which supports that mitochondria inhibitors represent a new class of AMPK activator.The inhibitors are promising candidates for insulin sensitizers.This review provides a guideline in search for small molecule AMPK activators in the drug discovery for type 2 diabetes. | Yong Zhang Jianping Ye | 2012 | Acta Pharmaceutica Sinica B2012，2，4： | 15 |
| 16 | Sirtuin 3 deficiency exacerbates diabetic cardiomyopathy via necroptosis enhancement and NLRP3 activation显示文摘Sirtuin 3(SIRT3)is a potential therapeutic target for cardiovascular,metabolic,and other aging-related diseases.In this study,we investigated the role of SIRT3 in diabetic cardiomyopathy(DCM).Mice were injected with streptozotocin(STZ,60 mg/kg,ip)to induce diabetes mellitus.Our proteomics analysis revealed that SIRT3 expression in the myocardium of diabetic mice was lower than that of control mice,as subsequently confirmed by real-time PCR and Western blotting.To explore the role of SIRT3 in DCM,SIRT3-knockout mice and 129S1/SvImJ wild-type mice were injected with STZ.We found that diabetic mice with SIRT3 deficiency exhibited aggravated cardiac dysfunction,increased lactate dehydrogenase(LDH)level in the serum,decreased adenosine triphosphate(ATP)level in the myocardium,exacerbated myocardial injury,and promoted myocardial reactive oxygen species(ROS)accumulation.Neonatal rat cardiomyocytes were transfected with SIRT3 siRNA,then exposed to high glucose(HG,25.5 mM).We found that downregulation of SIRT3 further increased LDH release,decreased ATP level,suppressed the mitochondrial membrane potential,and elevated oxidative stress in HG-treated cardiomyocytes.SIRT3 deficiency further raised expression of necroptosis-related proteins including receptor-interacting protein kinase 1(RIPK1),RIPK3,and cleaved caspase 3,and upregulated the expression of inflammation-related proteins including NLR family pyrin domain-containing protein 3(NLRP3),caspase 1 p20,and interleukin-1βboth in vitro and in vivo.Collectively,SIRT3 deficiency aggravated hyperglycemia-induced mitochondrial damage,increased ROS accumulation,promoted necroptosis,possibly activated the NLRP3 inflammasome,and ultimately exacerbated DCM in the mice.These results suggest that SIRT3 can be a molecular intervention target for the prevention and treatment of DCM. | Shu Song Yue Ding Guo-liang Dai Yue Zhang Meng-ting Xu Jie-ru Shen Ting-ting Chen Yun Chen Guo-liang Meng | 2021 | Acta Pharmacologica Sinica2021，42，2： | 14 |
| 17 | Selective brain hypothermia-induced neuroprotection against focal cerebral ischemia/reperfusion injury is associated with Fis1 inhibition显示文摘Selective brain hypothermia is considered an effective treatment for neuronal injury after stroke,and avoids the complications of general hypothermia.However,the mechanisms by which selective brain hypothermia affects mitochondrial fission remain unknown.In this study,we investigated the effect of selective brain hypothermia on the expression of fission 1 (Fis1) protein,a key factor in the mitochondrial fission system,during focal cerebral ischemia/reperfusion injury.Sprague-Dawley rats were divided into four groups.In the sham group,the carotid arteries were exposed only.In the other three groups,middle cerebral artery occlusion was performed using the intraluminal filament technique.After 2 hours of occlusion,the filament was slowly removed to allow blood reperfusion in the ischemia/reperfusion group.Saline,at 4℃ and 37℃,were perfused through the carotid artery in the hypothermia and normothermia groups,respectively,followed by restoration of blood flow.Neurological function was assessed with the Zea Longa 5-point scoring method.Cerebral infarct volume was assessed by 2,3,5-triphenyltetrazolium chloride staining,and apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining.Fis1 and cytosolic cytochrome c levels were assessed by western blot assay.Fis1 mRNA expression was assessed by quantitative reverse transcription-polymerase chain reaction.Mitochondrial ultrastructure was evaluated by transmission electron microscopy.Compared with the sham group,apoptosis,Fis1 protein and mRNA expression and cytosolic cytochrome c levels in the cortical ischemic penumbra and cerebral infarct volume were increased after reperfusion in the other three groups.These changes caused by cerebral ischemia/reperfusion were inhibited in the hypothermia group compared with the normothermia group.These findings show that selective brain hypothermia inhibits Fis1 expression and reduces apoptosis,thereby ameliorating focal cerebral ischemia/reperfusion injury in rats.Experiments were authorized by the Ethics Committee of Qingdao Municipal Hospital of China (approval No.2019008). | Ya-Nan Tang Gao-Feng Zhang Huai-Long Chen Xiao-Peng Sun Wei-Wei Qin Fei Shi Li-Xin Sun Xiao-Na Xu Ming-Shan Wang | 2020 | Neural Regeneration Research2020，15，5： | 13 |
| 18 | Glycyrrhizic acid attenuates CCl_4-induced hepatocyte apoptosis in rats via a p53-mediated pathway显示文摘AIM: To investigate the effect of glycyrrhizic acid (GA) on carbon tetrachloride (CCl4)-induced hepatocyte apo-ptosis in rats via a p53-dependent mitochondrial path-way. METHODS: Forty-five male Sprague-Dawley rats were randomly and equally divided into three groups, the control group, the CCl4 group, and the GA treatment group. To induce liver fibrosis in this model, rats were given a subcutaneous injection of a 40% solution of CCl4 in olive oil at a dose of 0.3 mL/100 g body weight biweekly for 8 wk, while controls received the same isovolumetric dose of olive oil by hypodermic injection, with an initial double-dose injection. In the GA group,rats were also treated with a 40% solution of CCl4 plus 0.2% GA solution in double distilled water by the intraperitoneal injection of 3 mL per rat three times a week from the first week following previously published methods, with modifications. Controls were given the same isovolumetric dose of double distilled water. Liver function parameters, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were de-termined. Pathologic changes in the liver were detected by hematoxylin and eosin staining. Collagen fibers were evaluated by Sirius red staining. Hepatocyte apoptosis was investigated using the terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphosphate nick end labeling (TUNEL) assay and the cleaved caspase-3 immunohistochemistry assay. The expression levels of p53 and apoptosis-related proteins were evaluated by immunohistochemistry or Western blotting analysis. RESULTS: After 8 wk of treatment, GA significantly re-duced serum activity of ALT (from 526.7 ± 57.2 to 342 ± 44.8, P<0.05) and AST (from 640 ± 33.7 to 462.8 ± 30.6, P<0.05), attenuated the changes in liver his-topathology and reduced the staging score (from 3.53 ± 0.74 to 3.00 ± 0.76, P<0.05) in CCl4 -treated rats. GA markedly reduced the positive area of Sirius red and the ratio of the hepatic fibrotic region (from 7.87% ± 0.66% to 3.68% ± 0.32%, P<0.05) compared with the CCl4 group. GA also decreased the expression level of cleaved caspase-3 compared to the CCl4 group. TU-NEL assay indicated that GA significantly diminished the number of TUNEL-positive cells compared with the CCl4 group (P<0.05). GA treatment clearly decreased the level of p53 (P<0.05) detected by immunohis-tochemistry and Western blotting analysis. Compared with the CCl4 group, we also found that GA reduced the Bax/Bcl-2 ratio (P<0.05), the expression of cleaved caspase-3 (P<0.05), cleaved caspase-9 (P<0.05), and inhibited cytochrome C and second mitochondria-derived activator of caspases (Smac) release from mito-chondria to cytoplasm, i.e. , GA reduced the expressionlevel of Smac, which inhibited c-IAP1 activity (P<0.05), ultimately inhibiting the activity of caspase-3, according to Western blotting analysis. As a result, GA suppressed activation of the caspase cascades and prevented he-patocyte apoptosis. | Xiao-Ling Guo Bo Liang Xue-Wei Wang Fu-Gang Fan Jing Jin Rui Lan Jing-Hui Yang Xiao-Chun Wang Lei Jin Qin Cao | 2013 | World Journal of Gastroenterology2013，19，24： | 12 |
| 19 | Polydatin prevents the induction of secondary brain injury after traumatic brain injury by protecting neuronal mitochondria显示文摘Polydatin is thought to protect mitochondria in different cell types in various diseases.Mitochondrial dysfunction is a major contributing factor in secondary brain injury resulting from traumatic brain injury.To investigate the protective effect of polydatin after traumatic brain injury,a rat brain injury model of lateral fluid percussion was established to mimic traumatic brain injury insults.Rat models were intraperitoneally injected with polydatin(30 mg/kg)or the SIRT1 activator SRT1720(20 mg/kg,as a positive control to polydatin).At 6 hours post-traumatic brain injury insults,western blot assay was used to detect the expression of SIRT1,endoplasmic reticulum stress related proteins and p38 phosphorylation in cerebral cortex on the injured side.Flow cytometry was used to analyze neuronal mitochondrial superoxide,mitochondrial membrane potential and mitochondrial permeability transition pore opened.Ultrastructural damage in neuronal mitochondria was measured by transmission electron microscopy.Our results showed that after treatment with polydatin,release of reactive oxygen species in neuronal mitochondria was markedly reduced;swelling of mitochondria was alleviated;mitochondrial membrane potential was maintained;mitochondrial permeability transition pore opened.Also endoplasmic reticulum stress related proteins were inhibited,including the activation of p-PERK,spliced XBP-1 and cleaved ATF6.SIRT1 expression and activity were increased;p38 phosphorylation and cleaved caspase-9/3 activation were inhibited.Neurological scores of treated rats were increased and the mortality was reduced compared with the rats only subjected to traumatic brain injury.These results indicated that polydatin protectrd rats from the consequences of traumatic brain injury and exerted a protective effect on neuronal mitochondria.The mechanisms may be linked to increased SIRT1 expression and activity,which inhibits the p38 phosphorylation-mediated mitochondrial apoptotic pathway.This study was approved by the Animal Care and Use Committee of the Southern Medical University,China(approval number:L2016113)on January 1,2016. | Li Li Hong-Ping Tan Cheng-Yong Liu Lin-Tao Yu Da-Nian Wei Zi-Chen Zhang Kui Lu Ke-Sen Zhao Marc Maegele Dao-Zhang Cai Zheng-Tao Gu | 2019 | Neural Regeneration Research2019，14，9： | 12 |
| 20 | Mitochondrial pathway mediated by reactive oxygen species involvement in α-hederin-induced apoptosis in hepatocellular carcinoma cells显示文摘AIM To investigate the antitumor activity of α-hederin in hepatocellular carcinoma(HCC) cells and its underlying mechanisms in vitro and in vivo.METHODS SMMC-7721, Hep G-2 and Huh-7 HCC cells were cultured in vitro and treated with α-hederin(0, 5 μmol/L, 10 μmol/L, 15 μmol/L, 20 μmol/L, 25 μmol/L, 30 μmol/L, 35 μmol/L, 40 μmol/L, 45 μmol/L, 50 μmol/L, 55 μmol/L, or 60 μmol/L) for 12 h, 24 h, or 36 h, and cell viability was then detected by the Cell Counting Kit-8. SMMC-7721cells were treated with 0, 5 μmol/L, 10 μmol/L, or 20 μmol/L α-hederin for 24 h with or without DL-buthionineS,R-sulfoximine(2 mmol/L) or N-acetylcysteine(5 mmol/L) pretreatment for 2 h, and additional assays were subsequently performed. Apoptosis was observed after Hoechst staining. Glutathione(GSH) and adenosine triphosphate(ATP) levels were measured using GSH and ATP Assay Kits. Intracellular reactive oxygen species(ROS) levels were determined by measuring the oxidative conversion of 2',7'-dichlorofluorescin diacetate. Disruption of the mitochondrial membrane potential was evaluated using JC-1 staining. The protein levels of Bax, Bcl-2, cleaved caspase-3, cleaved caspase-9, apoptosis-inducing factor and cytochrome C were detected by western blotting. The antitumor efficacy of α-hederin in vivo was evaluated in a xenograft tumor model.RESULTS The α-hederin treatment induced apoptosis of HCC cells. The apoptosis rates in the control, low-dose α-hederin(5 μmol/L), mid-dose α-hederin(10 μmol/L) and highdose α-hederin(20 μmol/L) groups were 0.90% ± 0.26%, 12% ± 2.0%, 21% ± 2.1% and 37% ± 3.8%, respectively(P < 0.05). The α-hederin treatment reduced intracellular GSH and ATP levels, induced ROS, disrupted the mitochondrial membrane potential, increased the protein levels of Bax, cleaved caspase-3, cleaved caspase-9, apoptosis-inducing factor and cytochrome C, and decreased Bcl-2 expression. The α-hederin treatment also inhibited xenograft tumor growth in vivo. CONCLUSION The α-hederin saponin induces apoptosis of HCC cells via the mitochondrial pathway mediated by increased intracellular ROS and may be an effective treatment for human HCC. | Jiao Li Dan-Dan Wu Ji-Xiang Zhang Jing Wang Jing-Jing Ma Xue Hu Wei-Guo Dong | 2018 | World Journal of Gastroenterology2018，24，17： | 11 |
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