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Amelioration of mitochondrial dysfunction in heart failure through S-sulfhydration of Ca2Vcalmodulin-dependent protein kinase II

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中国药理学与毒理学杂志 2017年第10期31卷 1025-1026页

作者： Dan WU Qing-xun HU De-qiu zhu yi-zhun zhu Department of Pharmacy Tongji Hospital Tongji University School of Medicine Shanghai 200065China School of Pharmacy Macao University of Science and Technology Macao China Mitochondria and Metabolism Center Department of Anesthesiology & Pain Medicine University of Washington Seattle WA 98109 USA

OBJECTIVE To determine the functional role of hydrogen sulfide (H2S) in protecting against mitochondrial dysfunction in heart failure through the inhibition of Ca2 +/calmodulin-dependent protein kinaseⅡ (CaMKⅡ) using wild type and CSE knockout mouse models. METHODS Continuous subcutaneous injection isoprenaline (7.5 mg·kg-1·d-1), once a day for 4 weeks to induce heart failure in Male C57BL/6 (6-8 weeks old) mice and CSE-/- mice. 150 μmol·L-1 H2O2 was used to induce oxidative stress in H9c2 cells. Echocardiograph was used to detect cardiac parameters. H&E stain and Masson stain was to observation histopathological changes. Western blot was used to detect protein expression and activity. The siRNA was used to silence protein expression. HPLC was used to detect H2S level. Biotin assay was used to detect the level of S- sulfhydration protein. RESULTS Treatment with S-propyl-L-cysteine (SPRC) or sodium hydrosulfide (NaHS), modulators of blood H2S levels, attenuated the development of heart failure in animals, reduced lipid peroxidation, and preserved mitochondrial function. The inhibition CaMKⅡ phosphorylation by SPRC and NaHS as demonstrated using both in vivo and in vitro models corresponded with the cardioprotective effects of these compounds. Interestingly, CaMKⅡ activity was found to be elevated in CSE-/- mice as compared to wild type animals and the phosphorylation status of CaMKⅡ appeared to relate to the severity of heart failure. Importantly, in wild type mice SPRC was found to promote S-sulfhydration of CaMKII leading to reduced activity of this protein however, in CSE-/- mice S-sulfhydration was abolished following SPRC treatment. CONCLUSION A novel mechanism depicting a role of S-sulfhydration in the regulation of CaMKⅡ is presented. SPRC mediated S-sulfhydration of CaMKII was found to inhibit CaMKⅡ activity and to preserve cardiovascular homeostasis.

关键词： hydrogen sulfide mitochondria heart failure Ca2 +/calmodulin- dependent protein kinaseⅡ S-sulfhydration

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Signaling pathways in rheumatoid arthritis:implications for targeted therapy

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Signal Transduction and Targeted Therapy 2023年第3期8卷 983-1006页

作者： Qian Ding Wei Hu Ran Wang Qinyan Yang Menglin zhu Meng Li Jianghong Cai Peter Rose Jianchun Mao yi zhun zhu State Key Laboratory of Quality Research in Chinese Medicine&School of Pharmacy Macao University of Science and TechnologyMacao SAR 999078China School of Basic Medicine Guizhou University of Traditional Chinese MedicineGuiyangChina Affiliated Hospital of Guangdong Medical University ZhanjiangChina School of Biosciences University of NottinghamLoughboroughUnited Kingdom Department of Rheumatology Longhua Hospital of Shanghai University of Traditional Chinese MedicineShanghai 201203China Shanghai Key Laboratory of Bioactive Small Molecules Department of PharmacologySchool of PharmacyFudan UniversityShanghai 201203China

Rheumatoid arthritis(RA)is an incurable systemic autoimmune *** progression leads to joint deformity and associated loss of function,which significantly impacts the quality of life for sufferers and adds to losses in the labor *** the past few decades,RA has attracted increased attention from researchers,the abnormal signaling pathways in RA are a very important research field in the diagnosis and treatment of RA,which provides important evidence for understanding this complex disease and developing novel RA-linked intervention *** current review intends to provide a comprehensive overview of RA,including a general introduction to the disease,historical events,epidemiology,risk factors,and pathological process,highlight the primary research progress of the disease and various signaling pathways and molecular mechanisms,including genetic factors,epigenetic factors,summarize the most recent developments in identifying novel signaling pathways in RA and new inhibitors for treating *** interventions including approved drugs,clinical drugs,pre-clinical drugs,and cutting-edge therapeutic *** developments will hopefully drive progress in new strategically targeted therapies and hope to provide novel ideas for RA treatment options in the future.

关键词： drugs targeted epidemiology

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Neuron navigator 2 is a novel mediator of rheumatoid arthritis

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Cellular & Molecular Immunology 2021年第9期18卷 2288-2289页

作者： Ran Wang Meng Li Qian Ding Jianghong Cai Yue Yu Xinhua Liu Jianchun Mao yi zhun zhu State Key Laboratory of Quality Research in Chinese Medicine School of PharmacyMacao University of Science and TechnologyAvenida Wai LongTaipaMacaoChina Shanghai Key Laboratory of Bioactive Small Molecules Department of PharmacologySchool of PharmacyFudan UniversityShanghaiChina Department of Rheumatology Longhua Hospital of Shanghai University of Traditional Chinese MedicineShanghai 200030China

Rheumatoid arthritis(RA)is a systemic autoimmune disease mainly characterized by synovial tumor-like hyperplasia,synovial inflammation,and damage to adjacent cartilage and bones.^(1) Our previous study provided evidence that cystathionine-γ-lyase(CSE)and the histone demethylase JMJD3 are significantly increased in RA,and CSE was found to negatively regulate the inflammatory response in fibroblast-like synoviocytes(FLSs),which was mainly attributed to JMJD3 inhibition,in RA.

关键词： Neuron inflammation damage

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STAT3-NAV2 axis as a new therapeutic target for rheumatoid arthritis via activating SSH1L/Cofilin-1 signaling pathway

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Signal Transduction and Targeted Therapy 2022年第8期7卷 2690-2693页

作者： Ran Wang Jianghong Cai Keyuan Chen Menglin zhu Zhaoyi Li Hua Liu Tiantian Liu Jianchun Mao Qian Ding yi zhun zhu State Key Laboratory of Quality Research in Chinese Medicine School of PharmacyMacao University of Science and TechnologyAvenida Wai LongTaipaMacaoChina School of Pharmacy Minzu University of ChinaBeijing 100081China Department of Pharmacy Aerospace Center HospitalBeijing 100049China Department of Rheumatology Longhua Hospital of Shanghai University of Traditional Chinese MedicineShanghai 200032China Shanghai Key Laboratory of Bioactive Small Molecules Department of PharmacologySchool of PharmacyFudan UniversityShanghai 201203China

Dear Editor,Rheumatoid arthritis(RA),which is the most common inflammatory arthritis disease,as well as a kind of most prevalent autoimmune disease,affects 1–3%population all over the world.1 Currently available treatments can reduce the disability rate of patients with RA to some extent,but they cannot completely block the inflammatory joint destruction and relieve the pain that comes with *** previous study found that Neuron Navigator 2(NAV2)increased significantly in RA and was regulated by transcription factor E2F1.2 However,it is still unclear why NAV2 is elevated at the genetic level in RA fibroblast-like synoviocytes(FLS).Additionally,RA’s exact pathological mechanisms and therapeutic targets are also not fully ***,an indepth study of the pathogenesis of RA is urgently needed.

关键词： therapeutic STAT3 elevated

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ZYZ451 Protects cardiomyocytes from hypoxia-induced apoptosis by enhancing MnSOD and STAT3 interaction

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中国药理学与毒理学杂志 2015年第S1期29卷 27-28页

作者： Shan-shan LUO Ya-qi SHEN Li-ming MA Xian-feng GU yi-zhun zhu Department of Pharmacology School of Pharmacy Fudan University Shanghai 201203 China Department of Medicinal Chemistry School of Pharmacy Fudan University Shanghai 201203 China Department of Pharmacology Loo Yong Lin School of Medicine National University of Singapore Singapore

OBJECTIVE 3,5-Dimethoxy-4-(2-amino-3-prop-2-ynylsulfanyl-propionyl)-benzoic acid 4-guanidino-butyl ester(ZYZ451)showed excellent cardio-protective effects in our previous ***,its therapeutic potential in vivo and the mechanism remained to be ***,we evaluated cardiac protective role of ZYZ451 in post-myocardial infarction(post-MI)rats,and elucidated the underlying *** Neonatal rat ventricular cardiomyoctys(NRVCs)were separated and subjected to pre-deoxidized(1%O2,5%CO2),and serum-free medium for 4h to obtain ischemic *** ROS,MnSOD activity and cell apoptosis were tested to verify the cardiac protective effects of *** and siRNA for Stat3 were used to determine role of Stat3 played in cardio-protective effectes of *** were isolated from NRVCs to determine expression of Stat3 and *** and coimmunoprecipitation were conducted to determine the interaction between MnSOD and *** apply post-MI model in rats,the rats were subjected to ligation of LAD except for control *** vehicle or ZYZ451(1,2or 5mg·kg-1)or mixture of Leonurine and SPRC(15mg·kg-1)was administered 7dbefore and 3more days after the *** at risk(AAR),apoptosis in AAR,LDH and MDA levels,and MnSOD activity and expression were detected to evaluate the cardiac *** mitochondria were isolated to determine MnSOD and Stat3 expression in ischemia,and coimmunoprecipitaion was performed to verify the interaction between MnSOD and Stat3 in *** ZYZ451 prevented hypoxia induced NRVCs apoptosis via increasing MnSOD activity and inhibiting mitochondrial ROS ***,5,15-DPP(STAT3phosphorylation inhibitor)failed to inhibit MnSOD activity,while knockout of STAT3 resulted in significant reduction of MnSOD activity,followed by increased mitochondrial ROS production and cardiomyocytes apoptosis in ***,protective effects of ZYZ451 were blunted in Stat3 deficient

关键词： hypoxia acute myocardial infarction ROS MnSOD apop

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Cystathionine-γ-lyase ameliorates the histone demethylase JMJD3-mediated autoimmune response in rheumatoid arthritis

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Cellular & Molecular Immunology 2019年第8期16卷 694-705页

作者： Weijun Wu Ming Qin Wanwan Jia Zheng Huang Zhongzheng Li Di Yang Mengwei Huang Chenxi Xiao Fen Long Jianchun Mao Philip K.Moore Xinhua Liu yi zhun zhu Department of Pharmacology Shanghai Key Laboratory of Bioactive Small MoleculesSchool of PharmacyFudan UniversityShanghai 201203China State Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy Macao University of Science and TechnologyMacaoChina Institute of Arthritis Research Shanghai Academy of Chinese Medical SciencesGuanghua Integrative Medicine Hospital/Shanghai University of T.C.MShanghaiChina Ningbo The 9th Hospital Ningbo 315000China Department of Rheumatology Shanghai Longhua HospitalShanghaiChina Department of Pharmacology National University of SingaporeSingaporeSingapore

Cystathionine-γ-lyase(CSE),an enzyme associated with hydrogen sulfide(H2S)production,is an important endogenous regulator of *** domain-containing protein 3(JMJD3)is implicated in the immune response and ***,we investigated the potential contribution of JMJD3 to endogenous CSE-mediated inflammation in rheumatoid arthritis(RA).Upregulated CSE and JMJD3 were identified in synovial fibroblasts(SFs)from RA patients as well as in the joints of arthritic *** down CSE augmented inflammation in IL-1β-induced SFs by increasing JMJD3 *** addition,CSE−/−mice with collagen-induced arthritis(CIA)developed severe joint inflammation and bone ***,overexpressing CSE inhibited JMJD3 expression by the transcription factor Sp-1 and was accompanied by reduced inflammation in IL-1β-treated ***,JMJD3 silencing or the administration of the JMJD3 inhibitor GSK-J4 significantly decreased the inflammatory response in IL-1β-treated SFs,mainly by controlling the methylation status of H3K27me3 at the promoter of its target ***-J4 markedly attenuated the severity of arthritis in CIA *** conclusion,suppressing JMJD3 expression by the transcription factor Sp-1 is likely responsible for the ability of CSE to negatively modulate the inflammatory response and reduce the progression of RA.

关键词： cystathionine-γ-lyase rheumatoid arthritis Jumonji domain-containing protein 3 Sp-1 Toll like receptor 2

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Salvia miltiorrhiza and ischemic diseases

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Acta Pharmacologica Sinica 2000年第12期 34-39页

作者： Xin-Yan JI, Benny K-H TAN, yi-zhun zhu (Department of Pharmacology, Faculty of Medicine, National University of Singapore, Singapore 119260, Singapore) Department of Pharmacology Faculty of Medicine National University of Singapore Singapore 119260

The demonstration of beneficial effects of salvia miltiorrhiza (DanShen) on ischemic diseases has revolutionized the management of angina pectoris, myocardial infarction (MI) or stroke in Chinese society. Experimental studies have shown that DanShen dilated coronary arteries, increased coronary blood flow, and scavenged free radicals in ischemic diseases, so that it reduced the cellular damage from ischemia and improved heart functions. Clinical trials also indicated that DanShen was an effective medicine for angina pectoris, MI, and stroke. This review will focus on DanShen’s effects in angina pectoris, MI and stroke.

关键词： Salvia miltiorrhiza myocardial infarc-tion cardiovascular system cerebrovascular disorders antioxidants free radicls myocarodial ischemia

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Hydrogen sulfide:third gaseous transmitter,but with great pharmacological potential

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Acta Pharmacologica Sinica 2007年第11期28卷 1709-1716页

作者： Chang-qing CHEN Hong XIN yi-zhun zhu Department Of Pharmacology,School of Pharmacy,Fudan University Shanghai 200032,China ment of Pharmacology School of Pharmacy Fudan University Shanghai 200032 China. zhuyz@***.

Hydrogen sulfide (H2S),which is well known traditionally as a toxic gas,has beenproven to be produced endogenously by 3 enzymes in mammalian tissues andplays important roles in physiological and pathophysiological *** thecentral nervous system,H2S functions as not only a neuromodulator,but also aneuroprotectant against oxidative *** the cardiovascular system,H2S re-laxes vascular smooth muscles by the activation of KATPchannels and inhibitssmooth muscle cell proliferation via the mitogen-activated protein kinase signal-ing *** effects are important for maintaining blood pressure andpreventing vessel structural remodeling,and identifies H2S as an important factorin the development of some vascular diseases,such as hypertension.H2S alsoshows cardioprotective effects in ischemic myocardium and septic and *** studies have demonstrated a new mechanism to explain the motoreffect of H2S on the rat detrusor muscle,which is through the activation of thecapsaicin-sensitive primary *** review focuses on the recent researchachievements on H2S and discloses the great potential of H2S as the third gaseoustransmitter in cardiac protection.

关键词： hydrogen sulfide cystathionine β-synthetase cystathionine γ-lyase KATP channels capsaicin

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The therapeutic effects of S-allylcysteine and S-propargyl-cysteine on myocardial ischemia is mediated via modulation of endogenous H2S

The therapeutic effects of S-allylcysteine and S-propargyl-c...

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中国科协第二十三届新观点新学说学术沙龙

作者： QIAN WANG yi-zhun zhu Department of Pharmacology,School of Pharmacy,Fudan University,Shanghai 200433

Garlic Allium sativum has been used as a traditional medicine for cardiovascular diseases. To date however,the molecular mechanisms ascribed to garlics pharmacological actions have not been fully *** this study,we determined the cytoprotective properties of S- allylcysteine(SAC),a component of garlic,and S-propargyl-cysteine(SPRC),a structure

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Leonurine(4-guanidino-n-butyl Syringate)protects the middle cerebral artery occluded rats through antioxidant mechanisms and regulation of mitochondrial function

Leonurine(4-guanidino-n-butyl Syringate)protects the middle ...

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中国药理学会第十次全国学术会议

作者： Jia Qi,yi-zhun zhu (Department of Pharmacology,School of Pharmacy and Institute of Biomedical Sciences,Fudan University,Shanghai,China)

Oxidative stress is known to be involved in ischemic *** interest is drawn to the therapeutic potential of Chinese herbs on ischemic stroke as many of them contain antioxidant *** recently reported that purified Herba Leonuri(pHL) could be cerebral protective for ischemic ***,one of the key active compounds from pHL was further studied to evaluate its possible therapeutic effects on ischemic *** was pretreated with Leonurine orally for 7 days before the middle cerebral artery occlusion(MCAO) was *** day after surgery,Leonurine pretreatment could significantly reduce 40%of infarct volume from 40%,improve neurological deficit from stroke groups,increase activities of antioxidant enzymes SOD and GPx to 131%and 154%,respectively as compared to vehicle,and decrease 50%in level of lipid peroxidation marker MDA from(P<0.05).Leonurine also inhibited mitiochondrial ROS production and ATP biosynthesis dose-dependently in isolated *** studies demonstrated that the mitochondrial function(mitochondrial oxygen consumption and respiratory control ratio) was restored by Leonurine ***,Leonurine has neuroprotective effects and carries a therapeutic potential for treatment of stroke.

关键词： Ischemic stroke MCAO Leonurine antioxidant mitochondrial modulation

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