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| 1 | Ischemia/reperfusion injury and cardioprotective mechanisms:Role of mitochondria and reactive oxygen species显示文摘Reperfusion therapy must be applied as soon as possible to attenuate the ischemic insult of acute myocardial infarction(AMI).However reperfusion is responsible for additional myocardial damage,which likely involves opening of the mitochondrial permeability transition pore(mPTP).In reperfusion injury,mitochondrial damage is a determining factor in causing loss of cardiomyocyte function and viability.Major mechanisms of mitochondrial dysfunction include the long lasting opening of mPTPs and the oxidative stress resulting from formation of reactive oxygen species(ROS).Several signaling cardioprotective pathways are activated by stimuli such as preconditioning and postconditioning,obtained with brief intermittent ischemia or with pharmacological agents.These pathways converge on a common target,the mitochondria,to preserve their function after ischemia/reperfusion.The present review discusses the role of mitochondria in cardioprotection,especially the involvement of adenosine triphosphate-dependent potassium channels,ROS signaling,and the mPTP.Ischemic postconditioning has emerged as a new way to target the mitochondria,and to drastically reduce lethal reperfusion injury.Several clinical studies using ischemic postconditioning during angioplasty now support its protective effects,and an interesting alternative is pharmacological postconditioning.In fact ischemic postconditioning and the mPTP desensitizer,cyclosporine A,have been shown to induce comparable protection in AMI patients. | Maria-Giulia Perrelli Pasquale Pagliaro Claudia Penna | 2011 | World Journal of Cardiology2011，3，6： | 64 |
| 2 | Oxidative stress, cardiolipin and mitochondrial dysfunction in nonalcoholic fatty liver disease显示文摘Nonalcoholic fatty liver disease(NAFLD) is today considered the most common form of chronic liver disease, affecting a high proportion of the population worldwide. NAFLD encompasses a large spectrum of liver damage, ranging from simple steatosis to steatohepatitis, advanced fibrosis and cirrhosis. Obesity, hyperglycemia, type 2 diabetes and hypertriglyceridemia are the most important risk factors. The pathogenesis of NAFLD and its progression to fibrosis and chronic liver disease is still unknown. Accumulating evidence indicates that mitochondrial dysfunction plays a key role in the physiopathology of NAFLD, although the mechanisms underlying this dysfunction are still unclear. Oxidative stress is considered an important factor in producing lethal hepatocyte injury associated with NAFLD. Mitochondrial respiratory chain is the main subcellular source of reactive oxygen species(ROS), which may damage mitochondrial proteins, lipids and mitochondrial DNA. Cardiolipin, a phospholipid located at the level of the inner mitochondrial membrane, plays an important role in several reactions and processes involved in mitochondrial bioenergetics as well as in mitochondrial dependent steps of apoptosis. This phospholipid is particularly susceptible to ROS attack. Cardiolipin peroxidation has been associated with mitochondrial dysfunction in multiple tissues in several physiopathological conditions, including NAFLD. In this review, we focus on the potential roles played by oxidative stress and cardiolipin alterations in mitochondrial dysfunction associated with NAFLD. | Giuseppe Paradies Valeria Paradies Francesca M Ruggiero Giuseppe Petrosillo | 2014 | World Journal of Gastroenterology2014，20，39： | 50 |
| 3 | Arsenic trioxide induces multiple myeloma cell apoptosis via disruption of mitochondrial transmembrane potentials and activation of caspase-3显示文摘investigate the response of multiple myeloma (MM) cells to arsenic trioxide (As 2O 3) and their possible mechanisms Methods Two MM derived cell lines RPMI8226 and U266 cells were used as in vitro models Cell apoptosis was assessed by morphology, flow cytometry, and DNA gel electrophoresis Mitochondrial transmembrane potentials (△Ψm) were evaluated by measuring cellular Rhodamine 123 staining intensity Protein expression was analyzed using Western blot Results Zero point one to 0 5?μmol/L As 2O 3 inhibited cell proliferation and 2.0?μmol/L As 2O 3 induced cell apoptosis, while 1.0?μmol/L As 2O 3 inhibited proliferation with a weak degree of apoptosis induction in RPMI8226 and U266 cell lines As 2O 3 induced apoptosis was accompanied by mitochondrial transmembrane potentials (△Ψm) collapse and caspase 3 activation in the presence of intact membrane Glutathione depleter buthionine sulfoximine enhanced, while disulfide bond reducing agent dithiothreitol partially antagonized As 2O 3 induced △Ψm collapse and apoptosis in MM cells All trans retinoic acid (ATRA) could also induce apoptosis in RPMI8226 cells, but it did not show any cooperative effects with As 2O 3 Conclusion As 2O 3 exerts apoptosis inducing and growth inhibiting effects on MM cells, and mitochondrium is a pivotal and common target of As 2O 3 for apoptosis | 贾培敏 陈国强 黄晓君 蔡循 杨洁 王龙 周宇红 沈玉雷 周励 余韵 陈赛娟 张学光 王振义 | 2001 | Chinese Medical Journal2001，，1： | 36 |
| 4 | Mitochondrial dysfunction and mitochondrial DNA mutations in atherosclerotic complications in diabetes显示文摘Mitochondrial DNA(mtDNA) is particularly prone to oxidation due to the lack of histones and a deficient mismatch repair system.This explains an increased mutation rate of mtDNA that results in heteroplasmy,e.g.,the coexistence of the mutant and wild-type mtDNA molecules within the same mitochondrion.In diabetes mellitus,glycotoxicity,advanced oxidative stress,collagen cross-linking,and accumulation of lipid peroxides in foam macrophage cells and arterial wall cells may significantly decrease the mutation threshold required for mitochondrial dysfunction,which in turn further contributes to the oxidative damage of the diabetic vascular wall,endothelial dysfunc-tion,and atherosclerosis. | Dimitry A Chistiakov Igor A Sobenin Yuri V Bobryshev Alexander N Orekhov | 2012 | World Journal of Cardiology2012，4，5： | 17 |
| 5 | Neolithic millet farmers contributed to the permanent settlement of the Tibetan Plateau by adopting barley agriculture显示文摘The permanent human settlement of the Tibetan Plateau(TP)has been suggested to have been facilitated by the introduction of barley agriculture^3.6 kilo-years ago(ka).However,how barley agriculture spread onto the TP remains unknown.Given that the lower altitudes in the northeastern TP were occupied by millet cultivators from 5.2 ka,who also adopted barley farming^4 ka,it is highly possible that it was millet farmers who brought barley agriculture onto the TP^3.6 ka.To test this hypothesis,we analyzed mitochondrial DNA(mt DNA)from 8277 Tibetans and 58514 individuals from surrounding populations,including 682 newly sequenced whole mitogenomes.Multiple lines of evidence,together with radiocarbon dating of cereal remains at different elevations,supports the scenario that two haplogroups(M9a1a1c1b1a and A11a1a),which are common in contemporary Tibetans(20.9%)and were probably even more common(40–50%)in early Tibetans prior to historical immigrations to the TP,represent the genetic legacy of the Neolithic millet farmers.Both haplogroups originated in northern China between 10.0–6.0 ka and differentiated in the ancestors of modern Tibetans^5.2–4.0 ka,matching the dispersal history of millet farming.By showing that substantial genetic components in contemporary Tibetans can trace their ancestry back to the Neolithic millet farmers,our study reveals that millet farmers adopted and brought barley agriculture to the TP^3.6–3.3 ka,and made an important contribution to the Tibetan gene pool. | Yu-Chun Li Jiao-Yang Tian Feng-Wen Liu Bin-Yu Yang Kang-Shu-Yun Gu Zia Ur Rahman Li-Qin Yang Fa-Hu Chen Guang-Hui Dong Qing-Peng Kong | 2019 | National Science Review2019，6，5： | 15 |
| 6 | Melittin induces human gastric cancer cell apoptosis via activation of mitochondrial pathway显示文摘AIM: To investigate the apoptotic effects of melittin on SGC-7901 cells via activation of the mitochondrial signaling pathway in vitro.METHODS: SGC-7901 cells were stimulated by melittin, and its effect on proliferation and apoptosis of was investigated by methyl thiazolyl tetrazolium assay, morphologic structure with transmission electron microscopy, annexin-V/propidium iodide double-staining assay, measuring mitochondrial membrane potential(MMP) levels, and analyzing reactive oxygen species(ROS) concentrations were analyzed by flow cytometry. Cytochrome C(Cyt C), apoptosis-inducing factor(AIF), endonuclease G(Endo G), second mitochondria-derived activator of caspases(Smac)/direct IAP binding protein with low isoelectric point(Diablo), and FAS were analyzed by western blot. The expression of caspase-3 and caspase-8 was measured using activity assay kits.RESULTS: Melittin was incubated at 1.0, 2.0, 4.0, or 6.0 μg/m L for 1, 2, 4, 6, or 8 h and showed a timeand concentration-dependent inhibition of SGC-7901 cell growth. Melittin induced SGC-7901 cell apoptosis, which was confirmed by typical morphological changes. Treatment with 4 μg/m L melittin induced early apoptosis of SGC-7901 cells, and the early apoptosis rates were 39.97% ± 3.19%, 59.27% ± 3.94%, and 71.50% ± 2.87% vs 32.63% ± 2.75% for 1, 2, and 4 h vs 0 h(n = 3, P < 0.05); the ROS levels were 616.53% ± 79.78%, 974.81% ± 102.40%, and 1330.94% ± 93.09% vs 603.74% ± 71.99%(n = 3, P < 0.05); the MMP values were 2.07 ± 0.05, 1.78 ± 0.29, and 1.16 ± 0.25 vs 2.55 ± 0.42(n = 3, P < 0.05); caspase-3 activity was significantly higher compared to the control(5492.3 ± 321.1, 6562.0 ± 381.3, and 8695.7 ± 449.1 vs 2330.0 ± 121.9), but the caspase activity of the non-tumor cell line L-O2 was not different from that of the control. With the addition of the caspase-3 inhibitor(Ac-DEVD-CHO), caspase-3 activity was significantly decreased compared to the control group(1067.0 ± 132.5 U/g vs 8695.7 ± 449.1 U/g). The expression of the Cyt C, Endo G, and AIF proteins in SGC-7901 cells was significantly higher than those in the control(P < 0.05), while the expression of the Smac/Diablo protein was significantly lower than the control group after melittin exposure(P < 0.01). Ac-DEVD-CHO did not, however, have any effect on the expression of caspase-8 and FAS in the SGC-7901 cells.CONCLUSION: Melittin can induce apoptosis of human gastric cancer(GC) cells through the mitochondria pathways, and it may be a potent agent in the treatment of human GC. | Gui-Mei Kong Wen-Hua Tao Ya-Li Diao Peng-Hua Fang Ji-Jun Wang Ping Bo Feng Qian | 2016 | World Journal of Gastroenterology2016，22，11： | 15 |
| 7 | Molecular phylogenetic relationships of China Seas groupers based on cytochrome b gene fragment sequences显示文摘The classification and evolutionary relationships are important issues in the study of the groupers. Cytochrome b gene fragment of twenty-eight grouper species within six genera of subfamily Epinephelinae was amplified using PCR techniques and the sequences were analyzed to derive the phylogenetic relationships of the groupers from the China Seas. Genetic information indexes, including Kimura-2 parameter genetic distance and Ts/Tv ratios, were generated by using a variety of biology softwares. With Niphon spinosus, Pagrus major and Pagrus auriga as the designated outgroups, phylogenetic trees, which invoke additional homologous sequences of other Epinephelus fishes from GenBank, were constructed based on the neighbor-joining (NJ), maximum-parsimony (MP), maximum-likelihood (ML) and minimum-evolution (ME) methods. Several conclusions were drawn from the DNA sequences analysis: (1) genus Plectropomus, which was early diverged, is the most primitive group in the subfamily Epinephelinae; (2) genus Variola is more closely related to genus Cephalopolis than the other four genera; (3) genus Cephalopolis is a monophyletic group and more primitive than genus Epinephelus; (4) Promicrops lanceolatus and Cromileptes altivelis should be included in genus Epinephelus; (5) there exist two sister groups in genus Epinephelus. | DING Shaoxiong, ZHUANG Xuan, GUO Feng, WANG Jun, SU Yongquan, ZHANG Qiyong & LI Qifu Department of Oceanography and Institute of Subtropical Oceanography, Xiamen University, Xiamen 361005, China Department of Biology, Xiamen University, Xiamen 361005, China | 2006 | Science China(Life Sciences)2006，49，3： | 14 |
| 8 | 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 |
| 9 | Shuxuetong injection protects cerebral microvascular endothelial cells against oxygen-glucose deprivation reperfusion显示文摘Shuxuetong injection composed of leech(Hirudo nipponica Whitman) and earthworm(Pheretima aspergillum) has been used for the clinical treatment of acute stroke for many years in China. However, the precise neuroprotective mechanism of Shuxuetong injection remains poorly understood. Here, cerebral microvascular endothelial cells(bEnd.3) were incubated in glucose-free Dulbecco's modified Eagle's medium containing 95% N_2/5% CO_2 for 6 hours, followed by high-glucose medium containing 95% O_2 and 5% CO_2 for 18 hours to establish an oxygen-glucose deprivation/reperfusion model. This in vitro cell model was administered Shuxuetong injection at 1/32, 1/64, and 1/128 concentrations(diluted 32-, 64-, and 128-times). Cell Counting Kit-8 assay was used to evaluate cell viability. A fluorescence method was used to measure lactate dehydrogenase, and a fluorescence microplate reader used to detect intracellular reactive oxygen species. A fluorescent probe was also used to measure mitochondrial superoxide production. A cell resistance meter was used to measure transepithelial resistance and examine integrity of monolayer cells. The fluorescein isothiocyanate-dextran test was performed to examine blood-brain barrier permeability. Real-time reverse transcription polymerase chain reaction was performed to analyze mRNA expression levels of tumor necrosis factor alpha, interleukin-1β, interleukin-6, and inducible nitric oxide synthase. Western blot assay was performed to analyze expression of caspase-3, intercellular adhesion molecule 1, vascular cell adhesion molecule 1, occludin, vascular endothelial growth factor, cleaved caspase-3, B-cell lymphoma 2, phosphorylated extracellular signal-regulated protein kinase, extracellular signal-regulated protein kinase, nuclear factor-κB p65, I kappa B alpha, phosphorylated I kappa B alpha, I kappa B kinase, phosphorylated I kappa B kinase, claudin-5, and zonula occludens-1. Our results show that Shuxuetong injection increases bEnd.3 cell viability and B-cell lymphoma 2 expression, reduces cleaved caspase-3 expression, inhibits production of reactive oxygen species and mitochondrial superoxide, suppresses expression of tumor necrosis factor alpha, interleukin-1β, interleukin-6, inducible nitric oxide synthase mRNA, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1, markedly increases transepithelial resistance, decreases blood-brain barrier permeability, upregulates claudin-5, occludin, and zonula occludens-1 expression, reduces nuclear factor-κB p65 and vascular endothelial growth factor expression, and reduces I kappa B alpha, extracellular signal-regulated protein kinase 1/2, and I kappa B kinase phosphorylation levels. Overall, these findings suggest that Shuxuetong injection has protective effects on brain microvascular endothelial cells after oxygen-glucose deprivation/reperfusion. Moreover, its protective effect is associated with reduction of mitochondrial superoxide production, inhibition of the inflammatory response, and inhibition of vascular endothelial growth factor, extracellular signal-regulated protein kinase 1/2, and the nuclear factor-κB p65 signaling pathway. | Zuo-Yan Sun Fu-Jiang Wang Hong Guo Lu Chen Li-Juan Chai Rui-Lin Li Li-Min Hu Hong Wang Shao-Xia Wang | 2019 | Neural Regeneration Research2019，14，5： | 12 |
| 10 | 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 |
| 11 | Regulation of AMP-activated protein kinase by natural and synthetic activators显示文摘The AMP-activated protein kinase(AMPK)is a sensor of cellular energy status that is almost universally expressed in eukaryotic cells.While it appears to have evolved in single-celled eukaryotes to regulate energy balance in a cell-autonomous manner,during the evolution of multicellular animals its role has become adapted so that it also regulates energy balance at the whole body level,by responding to hormones that act primarily on the hypothalamus.AMPK monitors energy balance at the cellular level by sensing the ratios of AMP/ATP and ADP/ATP,and recent structural analyses of the AMPK heterotrimer that have provided insight into the complex mechanisms for these effects will be discussed.Given the central importance of energy balance in diseases that are major causes of morbidity or death in humans,such as type 2 diabetes,cancer and inflammatory disorders,there has been a major drive to develop pharmacological activators of AMPK.Many such activators have been described,and the various mechanisms by which these activate AMPK will be discussed.A particularly large class of AMPK activators are natural products of plants derived from traditional herbal medicines.While the mechanism by which most of these activate AMPK has not yet been addressed,I will argue that many of them may be defensive compounds produced by plants to deter infection by pathogens or grazing by insects or herbivores,and that many of them will turn out to be inhibitors of mitochondrial function. | David Grahame Hardie | 2016 | Acta Pharmaceutica Sinica B2016，6，1： | 11 |
| 12 | Arsenic trioxide promotes mitochondrial DNA mutation and cell apoptosis in primary APL cells and NB4 cell lines显示文摘This study aimed to investigate the effects of arsenic trioxide(As2O3) on the mitochondrial DNA(mtDNA) of acute promyelocytic leukemia(APL) cells.The NB4 cell line was treated with 2.0 μmol/L As2O3 in vitro,and the primary APL cells were treated with 2.0 μmol/L As2O3 in vitro and 0.16 mg kg-1 d-1 As2O3 in vivo.The mitochondrial DNA of all the cells above was amplified by PCR,directly sequenced and analyzed by Sequence Navigatore and Factura software.The apoptosis rates were assayed by flow cytometry.Mitochondrial DNA mutation in the D-loop region was found in NB4 and APL cells before As2O3 use,but the mutation spots were remarkably increased after As2O3 treatment,which was positively correlated to the rates of cellular apoptosis,the correlation coefficient:rNB4-As2O3=0.973818,and rAPL-As2O3=0.934703.The mutation types include transition,transversion,codon insertion or deletion,and the mutation spots in all samples were not constant and regular.It is revealed that As2O3 aggravates mtDNA mutation in the D-loop region of acute promyelocytic leukemia cells both in vitro and in vivo.Mitochondrial DNA might be one of the targets of As2O3 in APL treatment. | MENG Ran1,ZHOU Jin2,SUI Meng3,LI ZhiYong4,FENG GuoSheng1 & YANG BaoFeng2 1 Division of Neurology,the Ninth Clinical Medical College of Beijing University(Shijitan Hospital),Beijing 100038,China 2 The First Hospital of Harbin Medical University,Harbin 150001,China 3 Management Information System,University of International Business and Economics,Beijing 100029,China 4 Department of Radiology,Cambridge University Hospitals NHS Foundation Trust Box 219 Level 5,Addenbrooke’s Hospital Cambridge CB2 0QQ,UK | 2010 | Science China(Life Sciences)2010，53，1： | 10 |
| 13 | Regulatory role of mitochondria in oxidative stress and atherosclerosis显示文摘Mitochondrial physiology and biogenesis play a crucial role in the initiation and progression of cardiovascular disease following oxidative stress-induced damage such as atherosclerosis(AST).Dysfunctional mitochondria caused by an increase in mitochondrial reactive oxygen species(ROS)production,accumulation of mitochondrial DNA damage,and respiratory chain deficiency induces death of endothelial/smooth muscle cells and favors plaque formation/rupture via the regulation of mitochondrial biogenesis-related genes such as peroxisome proliferator-activated receptorγcoactivator(PGC-1),although more detailed mechanisms still need further study.Based on the effect of healthy mitochondria produced by mitochondrial biogenesis on decreasing ROS-mediated cell death and the recent finding that the regulation of PGC-1 involves mitochon- drial fusion-related protein(mitofusin),we thus infer the regulatory role of mitochondrial fusion/fission balance in AST pathophysiology.In this review,the first section discusses the possible association between AST-inducing factors and the molecular regulatory mechanisms of mitochondrial biogenesis and dynamics,and explains the role of mitochondria-dependent regulation in cell apoptosis during AST development. Furthermore,nitric oxide has the Janus-faced effect by protecting vascular damage caused by AST while being a reactive nitrogen species(RNS)which act together with ROS to damage cells.Therefore,in the second section we discuss mitochondrial ATP-sensitive K+ channels,which regulate mitochondrial ion transport to maintain mitochondrial physiology,involved in the regulation of ROS/RNS production and their influence on AST/cardiovascular diseases(CVD).Through this review,we can further appreciate the multi-regulatory functions of the mitochondria involved in AST development.The understanding of these related mechanisms will benefit drug development in treating AST/CVD through targeted biofunctions of mitochondria. | Jui-Chih Chang Shou-Jen Kou Chin-San Liu | 2010 | World Journal of Cardiology2010，2，6： | 10 |
| 14 | Ganoderma lucidum extract ameliorates MPTP-induced parkinsonism and protects dopaminergic neurons from oxidative stress via regulating mitochondrial function, autophagy, and apoptosis显示文摘Neuroprotection targeting mitochondrial dysfunction has been proposed as an important therapeutic strategy for Parkinson's disease. Ganoderma lucidum (GL) has emerged as a novel age nt that protects neurons from oxidative stress. However, the detailed mechanisms underlying GL-induced neuroprotection have not been documented. In this study, we investigated the neuroprotective effects of GL extract (GLE) and the underlying mechanisms in the classic MPTP(1 -methyl-4-phenyl-1,2,3,6- tetrahydropyridine)-induced mouse model of PD. Mice were injected with MPTP to in duce parkins on ism. The n the mice were administered GLE (400 mg kg^-1 d^-1,ig) for 4 weeks. We observed that GLE administration significantly improved locomotor performanee and increased tyrosine hydroxylase expression in the substantia nigra pars compact (SNpc) of MPTP-treated mice. In in vitro study, treatment of neuroblastoma neuro-2a cells with 1 -methyl-4-phenyIpyridinium (MPP^+, 1 mmol/L) caused mitochondrial membrane potential collapse, radical oxygen species accumulation, and ATP depletion. Application of GLE (800 pg/mL) protected n euroblastoma neu ro-2a cells agai nst MPP in suit. Application of GLE also improved mitochondrial movement dysfunction in cultured primary mesencephalic neurons. In addition, GLE counteracted the decline in NIX (also called BNIP3L) expression and increase in the LC3-II/LC3-I ratio evoked by MPP I Moreover, GLE reactivated MPP^+-inhibited AMPK, mTOR, and ULK1. Similarly, GLE was sufficient to counteract MPP1 -induced inhibition of PINK1 and Parkin expression. GLE suppressed MPP^+-induced cytochrome C release and activation of caspase-3 and caspase-9. In summary, our results provide evidence that GLE ameliorates parkinsonism pathology via regulating mitochondrial function, autophagy, and apoptosis, which may involve the activation of both the AMPK/mTOR and PINK1/Parkin signaling pathway. | Zhi-li Ren Chao-dong Wang Tao Wang Hui Ding Ming Zhou Nan Yang Yan-yong Liu Piu Chan | 2019 | Acta Pharmacologica Sinica2019，40，4： | 10 |
| 15 | The role of RIP3 in cardiomyocyte necrosis induced by mitochondrial damage of myocardial ischemia-reperfusion显示文摘Myocardial damage caused by myocardial ischemia-reperfusion injury (MIRI)is difficult to be alleviated because cardiomyocyte necrosis is an irreversible and unregulated death form.Recently, necroptosis,a necrosis form caused by tumor necrosis factor-α (TNF-α)and Fas ligand (FasL),was found to be regulated by receptor interacting protein 3 (RIP3)and RIP3-receptor interacting protein 1 (RIP1)-mixed lineage kinase domain like protein (MLKL)pathway.But it is unclear whether they also play a regulatory role in MIRI-induced necroptosis.Our previous results showed that in rat MIRI,RIP3 could translocate and express highly in mitochondria.Therefore,it is important to explore proteins that interact with RIP3 which was translocated to mitochondria.The aim of this study was to explore the role of RIP3 in cardiomyocyte necrosis induced by mitochondrial damage of hypoxia/reoxygenation (H/R).Our results showed that H/R could cause RIP3-depended mitochondrial fragmentation and necrosis-based death;and RIP3-promoted H/R-induced necroptosis in H9c2 cells through increasing lactate dehydrogenase release and inhibiting cell viability.This process did not require RIP1 or MLKL but dynamin-related protein 1 (Drp1),which was related to Drpl activation,reactive oxygen species elevation,and △Ψm decline.This study provides novel insights into the role of RIP3 in cardiomyocyte injury during H/R.RIP3 may serve as a potential target for the treatment of MIRI. | Huifang Hou Yongling Wang Qiong Li Zaibing Li Yan Teng Jingyu Li Xiaoying Wang Junli Chen Ning Huang | 2018 | Acta Biochimica et Biophysica Sinica2018，50，11： | 10 |
| 16 | Mitochondrial uncoupling protein 2 expression in colon cancer and its clinical significance显示文摘AIM: To detect the expression of mitochondrial uncoupling protein 2 (UCP2) in colon cancer and analyze the relation between UCP2 expression and clinical pathological features of colon cancer.METHODS: Fifteen colon tissue samples and 15 its adjacent tissue samples were obtained from colon cancer patients during surgical interventions. UCP2 expression was detected with immunohistochemical method in 10 normal controls, 10 hyperplastic polyp patients, 20 tubular adenoma patients and 78 colon cancer patients. Patients with rectal cancer were excluded. Quantitative reverse transcription polymerase chain reaction and Western blotting were used to detect UCP2 expressions in colon cancer tissue samples and its adjacent tissue samples. Relation between UCP2 expression and clinical pathological features of colon cancer was also analyzed. RESULTS: The UCP2 mRNA expression level was fourfold higher in colon cancer tissue samples than in its adjacent tissue samples. The UCP2 protein expression level was three-fold higher in colon cancer tissue samples than in its adjacent normal tissue samples. The UCP2 was mainly expressed in cytoplasm. The UCP2 was not expressed in normal colon mucosa. Strong positive staining for UCP2 with a diffuse distribution pattern was identified throughout the mucosa in colon cancer tissue samples with a positive expression rate of 85.9%. The UCP2 expression level was higher in colon cancer tissue samples at clinical stages Ⅲ and Ⅳ than in those at stageⅠ+ Ⅱ. Univariate analysis showed that the high UCP2 expression level was significantly correlated to colon cancer metastasis (hazard ratio = 4.321, confidence interval = 0.035-0.682, P = 0.046). CONCLUSION: UCP2 is highly expressed in human colon cancer tissue and may be involved in colon cancer metastasis. | Xiao-Yi Kuai, Ze-Yu Ji, Hong-Jie Zhang,Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China | 2010 | World Journal of Gastroenterology2010，16，45： | 9 |
| 17 | Protective effect of hydrogen sulfide on oxidative stress-induced neurodegenerative diseases显示文摘Hydrogen sulfide is an antioxidant molecule that has a wide range of biological effects against oxidative stress. Balanced oxidative stress is also vital for maintaining cellular function in biological system, where reactive oxygen species are the main source of oxidative stress. When the normal redox balance is disturbed, deoxyribonucleic acid, lipid, and protein molecules are oxidized under pathological conditions, like diabetes mellitus that leads to diabetic peripheral neuropathy. In diabetes mellitus-induced diabetic peripheral neuropathy, due to hyperglycemia, pancreatic beta cell(β cell) shows resistance to insulin secretion. As a consequence, glucose metabolism is disturbed in neuronal cells which are distracted from providing proper cell signaling pathway. Not only diabetic peripheral neuropathy but also other central damages occur in brain neuropathy. Neurological studies regarding type 1 diabetes mellitus patients with Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis have shown changes in the central nervous system because high blood glucose levels(HbA1 c) appeared with poor cognitive function. Oxidative stress plays a role in inhibiting insulin signaling that is necessary for brain function. Hydrogen sulfide exhibits antioxidant effects against oxidative stress, where cystathionine β synthase, cystathionine γ lyase, and 3-mercaptopyruvate sulfurtransferase are the endogenous sources of hydrogen sulfide. This review is to explore the pathogenesis of diabetes mellitus-induced diabetic peripheral neuropathy and other neurological comorbid disorders under the oxidative stress condition and the anti-oxidative effects of hydrogen sulfide. | Rubaiya Tabassum Na Young Jeong Junyang Jung | 2020 | Neural Regeneration Research2020，15，2： | 9 |
| 18 | Inhibition of phosphodiesterase 4 by FCPR16 protects SH-SY5Y cells against MPP^+ -induced decline of mitochondrial membrane potential and oxidative stress显示文摘Parkinson disease(PD) is a chronic neurodegenerative disorder caused by progressive dopaminergic neuronal death in the substantia nigra pars compacta within the midbrain.There still is no cure,effective treatments for PD,available therapies are only capable of offering temporary and symptomatic relief to the patients.There are certain patents that claim phosphodiesterase(PDE) inhibitors as possible anti-PD drugs,PDE4 is a promising target for the treatment of PD and the underlying mechanism has not yet been well elucidated.PDE4 is an enzyme that specifically hydrolyzes intracellular cyclic adenosine monophosphate(cAMP)throughout the body,including the brain.Most of the available PDE4 inhibitors exert unpleasant and serious side effects,such as emesis and nausea,which hinder its clinical application.Therefore,more efforts are needed before PDE4 inhibitors with high therapeutic indices are available for treatment of PD.FCPR16 is a novel PDE4 inhibitor with little emetic potential,which exhibits excellent enzyme inhibition activity(IC50=90 nmol·L^(-1)).METHODS SH-SY5 Y cell was induced with 1-methyl-4-phenylpyridinium(MPP+)to mimic PD cell injury in vitro,and CCK-8 assay was used to investigate the viability effects of different concentration of FCPR16(3.1-50 μmol·L^(-1)) on MPP+-injured SH-SY5 Y cells.Detection of apoptosis was performed by flow cytometry.The level of ntracellular reactive oxygen species was detected with the fluorescent probe DCFH-DA,and the mitochondrial membrane potential of cells in different experimental groups was detected with the JC-1 fluorescent probe.AO staining and Lysotracker Red staining were used to detect the intracellular antophagy changes.The expression of apoptosis related proteins,autophagy and other related signal molecules were demonstrated by Western blotting.Different cellular signaling pathway inhibitors were used to invesitigate the specific cellular mechanisms of FCPR16 protecting MPP+-induced cell injury.RESULTS FCPR16(12.5-50 μmol·L^(-1)) dose-dependently reduced MPP+-induced decline of cell viability,accompanied by reductions in nuclear condensation and lactate dehydrogenase release.The level of cleaved caspase 3 and the ratio of Bax/Bcl-2 were also decreased after treatment with FCPR16 in MPP+-treated cells.Furthermore,FCPR16(25 μmol·L^(-1)) significantly suppressed the accumulation of reactive oxygen species(ROS),prevented the decline of mitochondrial membrane potential(Δψm) and attenuated the expression of malonaldehyde level.Further studies disclosed that FCPR16 enhanced the levels of cA MP and the exchange protein directly activated by cA MP(Epac) in SHSY5 Y cel s.Western blotting analysis revealed that FCPR16 increased the phosphorylation of c AMP response element-binding protein(CREB) and protein kinase B(Akt)down-regulated by MPP+in SHSY5 Y cells.Moreover,the inhibitory effects of FCPR16 on the production of ROS and Δψm loss could be blocked by PKA inhibitor H-89 and Akt inhibitor KRX-0401.CONCLUSION The novel PDE4 inhibitor FCPR16 can protect against damaging pathways including oxidative stress,mitochondrial dysfunction and apoptosis in SH-SY5 Y cells.FCPR16 preventes MPP+-induced neurotoxicity through activation of cAMP/PKA/CREB and Epac/Akt signaling pathways.These may lead to develop mechanism based therapeutics and improved pharmacotherapy for PD.It is reasonable to assume that FCPR16 is a potential candidate for the prevention and treatment of PD. | ZHONG Jia-hong XIE Jin-feng XIAO Jiao LI Dan ZHOU Zhong-zhen WANG Hai-tao XU Jiang-ping | 2018 | 中国药理学与毒理学杂志2018，32，9： | 9 |
| 19 | Benzoylaconine induces mitochondrial biogenesis in mice via activating AMPK signaling cascade显示文摘The traditional Chinese medicine “Fuzi”(Aconiti Lateralis Radix Praeparata) and its three representative alkaloids, aconitine (AC), benzoylaconine (BAC), and aconine, have been shown to increase mitochondrial mass. Whether Fuzi has effect on mitochondrial biogenesis and the underlying mechanisms remain unclear. In the present study, we focused on the effect of BAC on mitochondrial biogenesis and the underlying mechanisms. We demonstrated that Fuzi extract and its three components AC, BAC, and aconine at a concentration of 50 μM signi?cantly increased mitochondrial mass in HepG2 cells. BAC (25, 50, 75 μM) dose-dependently promoted mitochondrial mass, mtDNA copy number, cellular ATP production, and the expression of proteins related to the oxidative phosphorylation (OXPHOS) complexes in HepG2 cells. Moreover, BAC dose-dependently increased the expression of proteins involved in AMPK signaling cascade;blocking AMPK signaling abolished BAC-induced mitochondrial biogenesis. We further revealed that BAC treatment increased the cell viability but not the cell proliferation in HepG2 cells. These in vitro results were verified in mice treated with BAC (10 mg/kg per day, ip) for 7 days. We showed that BAC administration increased oxygen consumption rate in mice, but had no significant effect on intrascapular temperature. Meanwhile, BAC administration increased mtDNA copy number and OXPHOS-related protein expression and activated AMPK signaling in the heart, liver, and muscle. These results suggest that BAC induces mitochondrial biogenesis in mice through activating AMPK signaling cascade. BAC may have the potential to be developed as a novel remedy for some diseases associated with mitochondrial dysfunction. | Xiao-hong Deng Jing-jing Liu Xian-jun Sun Jing-cheng Dong Jian-hua Huang | 2019 | Acta Pharmacologica Sinica2019，40，5： | 9 |
| 20 | Somatic alterations in mitochondrial DNA and mitochondrial dysfunction in gastric cancer progression显示文摘Energy metabolism reprogramming was recently identified as one of the cancer hallmarks.One of the underlying mechanisms of energy metabolism reprogramming is mitochondrial dysfunction caused by mutations in nuclear genes or mitochondrial DNA(mtDNA).In the past decades,several types of somatic mtDNA alterations have been identified in gastric cancer.However,the role of these mtDNA alterations in gastric cancer progression remains unclear.In this review,we summarize recently identified somatic mtDNA alterations in gastric cancers as well as the relationship between these alterations and the clinicopathological features of gastric cancer.The causative factors and potential roles of the somatic mtDNA alterations in cancer progression are also discussed.We suggest that point mutations and mtDNA copy number decreases are the two most common mtDNA alterations that result in mitochondrial dysfunction in gastric cancers.The two primary mutation types(transition mutations and mononucleotide or dinucleotide repeat instability)imply potential causative factors.Mitochondrial dysfunction-generated reactive oxygen species may be involved in the malignant changes of gastric cancer.The search for strategies to prevent mtDNA alterations and inhibit the mitochondrial retrograde signaling will benefit the development of novel treatments for gastric cancer and other malignancies. | Hsin-Chen Lee Kuo-Hung Huang Tien-Shun Yeh Chin-Wen Chi | 2014 | World Journal of Gastroenterology2014，20，14： | 9 |
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