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Druggability of lipid metabolism modulation against renal fibrosis

中国药理学报（英文版） 2022年第3期43卷 505-519页

作者： Yuan-yuan Chen Xiao-guang Chen Sen Zhang State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences&Peking Union medical collegeBeijing 100050China

Renal fibrosis contributes to progressive damage to renal structure and *** is a common pathological process as chronic kidney disease develops into kidney failure,irrespective of diverse etiologies,and eventually leads to ***,there are no effective drugs for renal fibrosis treatment at *** aggregation in the kidney and consequent lipotoxicity always accompany chronic kidney disease and *** studies have revealed that restoring the defective fatty acid oxidation in the kidney cells can mitigate renal ***,it is an important strategy to reverse the dysfunctional lipid metabolism in the kidney,by targeting critical regulators of lipid *** this review,we highlight the potential "druggability" of lipid metabolism to ameliorate renal fibrosis and provide current pre-clinical evidence,exemplified by some representative druggable targets and several other metabolic regulators with anti-renal fibrosis ***,we introduce the preliminary progress of noncoding RNAs as promising anti-renal fibrosis drug targets from the perspective of lipid ***,we discuss the prospects and deficiencies of drug targeting lipid reprogramming in the kidney.

关键词： lipid metabolism anti-renal fibrosis drug targets fatty acid oxidation noncoding RNA

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Regulatory T cells in ischemic stroke

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中国药理学报（英文版） 2022年第1期43卷 1-9页

作者： Hong-yun Wang Jun-rui Ye Li-yuan Cui Shi-feng Chu Nai-hong Chen State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica and Neuroscience CenterChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China

Recent evidence shows that when ischemic stroke(IS)occurs,the BBB would be destructed,thereby promoting the immune cells to migrate into the brain,suggesting that the immune responses can play a vital role in the pathology of *** an essential subpopulation of immunosuppressive T cells,regulatory T(Treg)cells are involved in maintaining immune homeostasis and suppressing immune responses in the pathophysiological conditions of *** the past decades,the regulatory role of Treg cells has attracted the interest of numerous ***,whether they are beneficial or detrimental to the outcomes of IS remains ***,Treg cells exert distinctive effects in the different stages of ***,it is urgent to elucidate how Treg cells modulate the immune responses induced by *** this review,we describe how Treg cells fluctuate and play a role in the regulation of immune responses after IS in both experimental animals and humans,and summarize their biological functions and mechanisms in both CNS and *** also discuss how Treg cells participate in poststroke inflammation and immunodepression and the potential of Treg cells as a novel therapeutic approach.

关键词： regulatory T cells ischemic stroke inflammation crosstalk stroke-induced immunodepression ischemic stroke therapy

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Caffeic acid alleviates cerebral ischemic injury in rats by resisting ferroptosis via Nrf2 signaling pathway

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中国药理学报（英文版） 2024年第2期45卷 248-267页

作者： Xin-nan Li Nian-ying Shang Yu-ying Kang Ning Sheng Jia-qi Lan Jing-shu Tang Lei Wu Jin-lan Zhang Ying Peng State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijing 100050China

There are few effective and safe neuroprotective agents for the treatment of ischemic stroke *** acid is a phenolic acid that widely exists in a number of plant *** studies show that caffeic acid ameliorates brain injury in rats after cerebral ischemia/*** this study we explored the protective mechanisms of caffeic acid against oxidative stress and ferroptosis in permanent cerebral *** stroke was induced on rats by permanent middle cerebral artery occlusion(pMCAO).Caffeic acid(0.4,2,10 mg·kg-1·d-1,i.g.)was administered to the rats for 3 consecutive days before or after the *** showed that either pre-pMCAO or post-pMCAO administration of caffeic acid(2 mg·kg-1·d-1)effectively reduced the infarct volume and improved neurological *** therapeutic time window could last to 2 h after *** found that caffeic acid administration significantly reduced oxidative damage as well as neuroinflammation,and enhanced antioxidant capacity in pMCAO rat *** further demonstrated that caffeic acid down-regulated TFR1 and ACSL4,and up-regulated glutathione production through Nrf2 signaling pathway to resist ferroptosis in pMCAO rat brain and in oxygen glucose deprivation/reoxygenation(OGD/R)-treated SK-N-SH cells in *** of ML385,an Nrf2 inhibitor,blocked the neuroprotective effects of caffeic acid in both in vivo and in vitro models,evidenced by excessive accumulation of iron ions and inactivation of the ferroptosis defense *** conclusion,caffeic acid inhibits oxidative stress-mediated neuronal death in pMCAO rat brain by regulating ferroptosis via Nrf2 signaling *** acid might serve as a potential treatment to relieve brain injury after cerebral ischemia.

关键词： ischemic stroke caffeic acid oxidative stress neuroinflammation ferroptosis Nrf2

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Diverse Ring-seco Limonoids from Munronia unifoliolata and Their Biological Activities

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Chinese Journal of Chemistry 2022年第1期40卷 123-136页

作者： Yunpeng Sun Qiurong Li Letian Cui Pengfei Tang Yongyi Li Lingyi Kong Jun Luo Jiangsu Key Laboratory of Bioactive Natural Product Research State Key Laboratory of Natural MedicinesDepartment of Natural Medicinal ChemistryChina Pharmaceutical UniversityNanjingJiangsu 210009China

Twenty-two new limonoids,mufolinoids A—V(1—22),including six rings A,B-seco limonoids(1—6),twelve ring A-seco limonoids(7—18),four ring-intact limonoids(19—22),together with thirteen known compounds(23—35)were isolated from Munronia *** structures including absolute configurations were elucidated by combination of NMR,HR-MS,single-crystal X-ray diffraction and calculations of ECD and NMR *** 24,25,33,34 could be significantly reversed the multidrug resistance of MCF-7/doxorubicin(DOX)cells,and the reversal fold(RF)was much higher than that of positive drug *** 24,28,and 29 exhibited significant anti-inflammatory activity with the IC50 values in the range of 17.7—39.4μmol/***,compound 29 could markedly inhibit the release of IL-1βby inhibiting the initiation and assembly of NLRP3 inflammasome,which demonstrates the great potential of limonoids as an anti-inflammatory agent.

关键词： Munronia unifoliolata Limonoids Structure elucidation Inflammatory natural products

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Two types of coumarins-specific enzymes complete the last missing steps in pyran- and furanocoumarins biosynthesis

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Acta Pharmaceutica Sinica B 2024年第2期14卷 869-880页

作者： Yucheng Zhao Yuedong He Liangliang Han Libo Zhang Yuanzheng Xia Fucheng Yin Xiaobing Wang Deqing Zhao Sheng Xu Fei Qiao Yibei Xiao Lingyi Kong Department of Resources Science of Traditional Chinese Medicines School of Traditional Chinese Pharmacyand State Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjing 210009China College of Bioscience and Biotechnology Hunan Agricultural UniversityChangsha 410128China Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines Department of Natural Medicinal ChemistryChina Pharmaceutical UniversityNanjing 210009China Key Laboratory of Crop Gene Resources and Germplasm Enhancement in Southern China Ministry of AgricultureTropical Crops Genetic Resources InstituteChinese Academy of Tropical Agricultural SciencesHaikou 517317China Institute of Botany Jiangsu Province and Chinese Academy of SciencesNanjing 210014China Department of Pharmacology School of Pharmacyand State Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjing 210009China

Pyran-and furanocoumarins are key representatives of tetrahydropyrans and tetrahydrofurans,respectively,exhibiting diverse physiological and medical ***,the biosynthetic mechanisms for their core structures remain poorly *** we combined multiomics analyses of biosynthetic enzymes in Peucedanum praeruptorum and in vitro functional verification and identified two types of key enzymes critical for pyran and furan ring biosynthesis in *** included three distinct *** prenyltransferases(PpPT1e3)responsible for the prenylation of the simple coumarin skeleton 7 into linear or angular precursors,and two novel CYP450 cyclases(PpDC and PpOC)crucial for the cyclization of the linear/angular precursors into either tetrahydropyran or tetrahydrofuran *** analyses of cyclases indicated that acid/base-assisted epoxide ring opening contributed to the enzyme-catalyzed tetrahydropyran and tetrahydrofuran ring *** possible acid/base-assisted catalytic mechanisms of the identified cyclases were theoretically investigated and assessed using site-specific *** identified two possible acidic amino acids Glu303 in PpDC and Asp301 in PpOC as vital in the catalytic *** study provides new enzymatic tools in the epoxide formation/epoxide-opening mediated cascade reaction and exemplifies how plants become chemically diverse in terms of enzyme function and catalytic process.

关键词： Tetrahydropyrans Tetrahydrofurans Baldwin rules Coumarins CYP450cyclase

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Rg1 exerts protective effect in CPZ-induced demyelination mouse model via inhibiting CXCL10-mediated glial response

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中国药理学报（英文版） 2022年第3期43卷 563-576页

作者： Yi-xiao Dong Shi-feng Chu Sha-sha Wang Ya-juan Tian Wen-bin He Yu-sheng Du Zhen-zhen Wang Xu Yan Zhao Zhang Nai-hong Chen State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica&Neuroscience CenterChinese Academy of Medical SciencesPeking Union Medical CollegeBeijing 100050China Tianjin University of Traditional Chinese Medicine Tianjin 301617China State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica&Neuroscience CenterChinese Academy of Medical SciencesPeking Union Medical CollegeBeijing 100050China State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica&Neuroscience CenterChinese Academy of Medical SciencesPeking Union Medical CollegeBeijing 100050China Shanxi Key Laboratory of Chinese Medicine Encephalopathy Shanxi University of Chinese MedicineJinzhong 030619China Shanxi Key Laboratory of Chinese Medicine Encephalopathy Shanxi University of Chinese MedicineJinzhong 030619China State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica&Neuroscience CenterChinese Academy of Medical SciencesPeking Union Medical CollegeBeijing 100050China Tianjin University of Traditional Chinese Medicine Tianjin 301617China Shanxi Key Laboratory of Chinese Medicine Encephalopathy Shanxi University of Chinese MedicineJinzhong 030619China

Myelin damage and abnormal remyelination processes lead to central nervous system *** activation-induced microenvironment changes are characteristic features of the diseases with myelin *** previously showed that ginsenoside Rg1,a main component of ginseng,ameliorated MPTP-mediated myelin damage in mice,but the underlying mechanisms are *** this study we investigated the effects of Rg1 and mechanisms in cuprizone(CPZ)-induced demyelination mouse *** were treated with CPZ solution(300mg·kg-1·d-1,ig)for 5 weeks;from week 2,the mice received Rg1(5,10,and 20 mg·kg-1·d-1,ig)for 4 *** showed that Rg1 administration dose-dependently alleviated bradykinesia and improved CPZ-disrupted motor coordination ability in CPZ-treated ***,Rg1 administration significantly decreased demyelination and axonal injury in pathological *** further revealed that the neuroprotective effects of Rg1 were associated with inhibiting CXCL10-mediated modulation of glial response,which was mediated by NF-KB nuclear translocation and CXCL10 promoter *** microglial cell line BV-2,we demonstrated that the effects of Rg1 on pro-inflammatory and migratory phenotypes of microglia were related to CXCL10,while Rg1-induced phagocytosis of microglia was not directly related to *** CPZ-induced demyelination mouse model,injection of AAV-CXCL10 shRNA into mouse lateral ventricles 3 weeks prior CPZ treatment occluded the beneficial effects of Rg1 administration in behavioral and pathological *** conclusion,CXCL10 mediates the protective role of Rg1 in CPZ-induced demyelination mouse *** study provides new insight into potential disease-modifying therapies for myelin abnormalities.

关键词： Biomedicine general Pharmacology/Toxicology Medical Microbiology Immunology Internal Medicine Vaccine

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Pyk2 inhibition attenuates hypoxic-ischemic brain injury in neonatal mice

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中国药理学报（英文版） 2022年第4期43卷 797-810页

作者： Jie Zhu Shi-feng Chu Ye Peng Dan-dan Liu Chen Chen Wen-xuan Jian Hong-shuo Sun Zhong-ping Feng Zhao Zhang Nai-hong Chen State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica&Neuroscience CenterChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica&Neuroscience CenterChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China College of Pharmacy Hunan University of Chinese MedicineChangsha 410208China State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica&Neuroscience CenterChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China Institute of Clinical Pharmacology Guangzhou University of Chinese MedicineGuangzhou 510720China Department of Physiology Faculty of MedicineUniversity of TorontoTorontoONCanada State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica&Neuroscience CenterChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China College of Pharmacy Hunan University of Chinese MedicineChangsha 410208China Institute of Clinical Pharmacology Guangzhou University of Chinese MedicineGuangzhou 510720China

Newborns suffering from hypoxia-ischemia(HI)brain injury still lack effective ***-rich tyrosine kinase 2(Pyk2)is a non-receptor tyrosine kinase,which is highly correlated with transient ischemic brain injury in *** this study,we investigated the role of Pyk2 in neonatal HI brain *** was induced in postnatal day 7 mouse pups by unilateral common carotid artery ligation followed by hypoxic ***2 interference lentivirus(LV-Pyk2 shRNA)was constructed and injected into unilateral cerebral ventricle of neonatal mice before *** volume,pathological changes,and neurological behaviors were assessed on postnatal day *** showed that the phosphorylation level of Pyk2 was significantly increased in neonatal brain after HI,whereas LV-Pyk2 shRNA injection significantly attenuated acute HI brain damage and improved neurobehavioral *** oxygen-glucose deprivation-treated cultured cortical neurons,Pyk2 inhibition significantly alleviated NMDA receptor-mediated excitotoxicity;similar results were also observed in neonatal HI brain *** demonstrated that Pyk2 inhibition contributes to the long-term cerebrovascular recovery assessed by laser speckle contrast imaging,but cognitive function was not obviously improved as evaluated in Morris water maze and novel object recognition ***,we constructed lentiviral LV-HIF-Pyk2 shRNA,through which HIF-1 α promoter-mediated interference of Pyk2 would occur during the anoxic *** injection of LV-HIF-Pyk2 shRNA significantly improved long-term recovery of cognitive function in HI-treated neonatal *** conclusion,this study demonstrates that Pyk2 interference protects neonatal brain from hypoxic-ischemic ***-1 α promoter-mediated hypoxia conditional control is a useful tool to distinguish between hypoxic period and normal ***2 is a promising drug target for potential treatment of neonatal HI brain injury.

关键词： neonatal mice hypoxic-ischemic brain injury Pyk2 NMDA receptor excitotoxicity HIF-1α

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Dynamic gut microbiome-metabolome in cationic bovine serum albumin induced experimental immune-complex glomerulonephritis and effect of losartan and mycophenolate mofetil on microbiota modulation

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Journal of Pharmaceutical Analysis 2024年第4期14卷 562-577页

作者： Wenying Shi Zhaojun Li Weida Wang Xikun Liu Haijie Wu Xiaoguang Chen Xunrong Zhou Sen Zhang State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing100050China State Key Laboratory of Functions and Applications of Medicinal Plants College of PharmacyGuizhou Provincial Engineering Technology Research Center for Chemical Drug R&DGuizhou Medical UniversityGuiyang550004China Department of Medicine Solna Center for Molecular MedicineKarolinska University Hospital and Karolinska InstituteStockholm17176Sweden Department of Pharmacy The Second Affiliated Hospital of Guizhou University of Traditional Chinese MedicineGuiyang550001China

Dynamic changes in gut dysbiosis and metabolomic dysregulation are associated with immune-complex glomerulonephritis(ICGN).However,an in-depth study on this topic is currently ***,we report an ICGN model to address this *** was induced via the intravenous injection of cationized bovine serum albumin(c-BSA)into Sprague-Dawley(SD)rats for two weeks,after which mycophenolate mofetil(MMF)and losartan were administered *** and six weeks after ICGN establishment,fecal samples were collected and 16S ribosomal DNA(rDNA)sequencing and untargeted metabolomic were *** microbiota transplantation(FMT)was conducted to determine whether gut normali-zation caused by MMF and losartan contributed to their renal protective effects.A gradual decline in microbial diversity and richness was accompanied by a loss of renal *** 18 genera were found to have significantly different relative abundances between the early and later stages,and Marvinbryantia and Allobaculum were markedly upregulated in both *** metabolomics indicated that the tryptophan metabolism was enhanced in ICGN,characterized by the overproduction of indole and kynurenic acid,while the serotonin pathway was *** of losartan and MMF ameliorated microbial dysbiosis and reduced the accumulation of indoxyl conjugates in *** using feces from animals administered MMF and losartan improved gut dysbiosis by decreasing the Firmicutes/Bacteroidetes(F/B)ratio but did not improve renal *** findings indicate that ICGN induces serous gut dysbiosis,wherein an altered tryptophan metabolism may contribute to its *** and losartan significantly reversed the gut microbial and metabolomic dysbiosis,which partially contributed to their renoprotective effects.

关键词： Immune-complex glomerulonephritis Gut microbiome Metabolomics Fecal microbiota transplant Tryptophan metabolism

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Connexin 43:insights into candidate pathological mechanisms of depression and its implications in antidepressant therapy

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中国药理学报（英文版） 2022年第10期43卷 2448-2461页

作者： Ning-ning Zhang Yi Zhang Zhen-zhen Wang Nai-hong Chen State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica&Neuroscience CenterChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China Department of Anatomy School of Chinese MedicineBeijing University of Chinese MedicineBeijing 102488China

Major depressive disorder(MDD),a chronic and recurrent disease characterized by anhedonia,pessimism or even suicidal thought,remains a major chronic mental concern *** 43(Cx43)is the most abundant connexin expressed in astrocytes and forms the gap junction channels(GJCs)between astrocytes,the most abundant and functional glial cells in the *** regulate neurons'synaptic strength and function by expressing receptors and regulating various *** dysfunction causes synaptic abnormalities,which are related to various mood disorders,e.g.,*** evidence suggests a crucial role of Cx43 in the pathogenesis of *** down-regulates Cx43 expression in humans and rats,and dysfunction of Cx43 also induces depressive behaviors in rats and *** Cx43 has received considerable critical attention and is highly implicated in the onset of ***,the pathological mechanisms of depression-like behavior associated with Cx43 still remain *** this review we summarize the recent progress regarding the underlying mechanisms of Cx43 in the etiology of depression-like behaviors including gliotransmission,metabolic disorders,and *** also discuss the effects of antidepressants(monoamine antidepressants and ketamine)on *** clarity of the candidate pathological mechanisms of depression-like behaviors associated with Cx43 and its potential pharmacological roles for antidepressants will benefit the exploration of a novel antidepressant target.

关键词： depression Connexin 43 astrocyte prefrontal cortex hippocampus Ca2+ wave ATP antidepressant target

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Long non-coding RNAs: From disease code to drug role

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Acta Pharmaceutica Sinica B 2021年第2期11卷 340-354页

作者： Yuanyuan Chen Zhaojun Li Xiaoguang Chen Sen Zhang State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia MedicaChinese Academy of Medical SciencesPeking Union Medical CollegeBeijing 100050China

Enormous studies have corroborated that long non-codig RNAs(LncRNAs)extensively participate in crucial physiological processes such as metabolism and immunity,and are closely related to the occurrence and development of tumors,cardiovascular diseases,nervous system disorders,nephropathy,and other *** application of lncRNAs as biomarkers or intervention targets can provide new insights into the diagnosis and treatment of *** paper has focused on the emerging research into lncRNAs as pharmacological targets and has reviewed the transition of IncRNAs from the role of disease coding to acting as drug candidates,including the current status and progress in preclinical ***-edge strategies for lncRNA modulation have been summarized,including the sources of LncRNA-related drugs,such as genetic technology and small-molecule compounds,and related delivery *** current progress of clinical trials of lncRNA-targeting drugs is also *** information will form a latest updated reference for research and development of lncRNA-based drugs.

关键词： LncRNAs Targeted drug Gene therapy Small molecules Delivery ASncmtRNA Translational medicine Clinical trials

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