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New insights for infection mechanism and potential targets of COVID-19:Three Chinese patent medicines and three Chinese medicine formulas as promising therapeutic approaches

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Chinese Herbal Medicines 2023年第2期15卷 157-168页

作者： Kexin Jia Yijie li Tiegang liu Xiaohong Gu Xiaojiaoyang Li School of life Sciences Beijing University of Chinese MedicineBeijing 100029China Institute of Chinese Epidemic Disease Beijing University of Chinese MedicineBeijing 100029China School of Traditional Chinese Medicine Beijing University of Chinese MedicineBeijing 100029China

The coronavirus disease 2019(COVID-19)caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)with high pathogenicity and infectiousness has become a sudden and lethal pandemic worldwide.Currently,there is no accepted specific drug for COVID-19 treatment.Therefore,it is extremely urgent to clarify the pathogenic mechanism and develop effective therapies for patients with COVID-19.According to several reliable reports from China,traditional Chinese medicine(TCM),especially for three Chinese patent medicines and three Chinese medicine formulas,has been demonstrated to effectively alleviate the symptoms of COVID-19 either used alone or in combination with Western medicines.In this review,we systematically summarized and analyzed the pathogenesis of COVID-19,the detailed clinical practice,active ingredients investigation,network pharmacology prediction and underlying mechanism verification of three Chinese patent medicines and three Chinese medicine formulas in the COVID-19 combat.Additionally,we summarized some promising and high-frequency drugs of these prescriptions and discussed their regulatory mechanism,which provides guidance for the development of new drugs against COVID-19.Collectively,by addressing critical challenges,for example,unclear targets and complicated active ingredients of these medicines and formulas,we believe that TCM will represent promising and efficient strategies for curing COVID-19 and related pandemics.

关键词： COVID-19 Huashi Baidu Formula Jinhua Qinggan Granules lianhua Qingwen Capsule Qingfei Paidu Decoction SARS-CoV-2 traditional Chinese medicine Xuanfei Baidu Formula Xuebijing Injection

Integrating systematic pharmacology-based strategy and experimental validation to explore mechanism of Tripterygium glycoside on cholangiocyte-related liver injury

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Chinese Herbal Medicines 2022年第4期14卷 563-575页

作者： Yajing li Sen li Xiaoyong Xue Ting Wang Xiaojiaoyang Li School of life Sciences Beijing University of Chinese MedicineBeijing 100029China Beijing Research Institute of Chinese Medicine Beijing University of Chinese MedicineBeijing 100029China

Objective:Tripterygium glycoside(TG)is widely used in clinical practice for its multiple bioactivities including anti-inflammatory and immunosuppressive effects.However,emerging studies have frequently reported TG-induced adverse reactions to multiple organs,especially liver.Here,this study aimed to investigate the mechanism of liver damage induced by TG and explore representative components to reflect TG hepatotoxicity.Methods:Network pharmacology was used to determine the potential targets of bile duct injury caused by TG.Next,the hepatotoxic effects of TG,triptolide(TP)and celastrol(CEL)were investigated and compared in vivo and in vitro.liver function was determined by measuring serum transaminase and histopathology staining.The cell proliferation and apoptosis were determined by cell viability assay,scratch assay and flow cytometry.The expression of gene of interest was determined by qPCR and Western blot.Results:Based on the network pharmacological analysis of 12 bioactive ingredients found in TG,a total of35 targets and 15 pathways related to bile duct injury were obtained.Both TG and TP resulted in cholangiocyte damage and liver injury,as illustrated by increased levels of serum transaminase and oxidative stress,stimulated portal edema and lymphocytic infiltration and decreased expression of cholangiocyte marker,cytoskeletal 19.In addition,TG and TP inhibited cell proliferation and migration,arrested cell cycle and promoted Caspase-dependent apoptosis of cholangiocytes via suppressing the phosphorylation of extracellular regulated protein kinases 1/2(ERK1/2)and protein kinase B(AKT).While,CEL at equivalent dosage had no obvious hepatotoxicity.Conclusion:We revealed that TG-stimulated liver injury was specifically characterized by cholangiocyte damage and TP might be the decisive ingredient to reflect TG hepatotoxicity.Our results not only provide novel insights into the mechanism underlying the hepatotoxicity effects of TG but also offer reference for clinical rational use of TG.

关键词： cell apoptosis cholangiocyte liver injury Tripterygium glycoside triptolide

Modulation of type I interferon signaling by natural products in the treatment of immune-related diseases

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Chinese Journal of Natural Medicines 2023年第1期21卷 3-18页

作者： li Shuo FAN Guifang li xiaojiaoyang CAI Yajie liU Runping School of Chinese Materia Medica Beijing University of Chinese MedicineBeijing 100029China School of life Sciences Beijing University of Chinese MedicineBeijing 102488China

Type I interferon(IFN)is considered as a bridge between innate and adaptive immunity.Proper activation or inhibition of type I IFN signaling is essential for host defense against pathogen invasion,tumor cell proliferation,and overactive immune responses.Due to intricate and diverse chemical structures,natural products and their derivatives have become an invaluable source inspiring innovative drug discovery.In addition,some natural products have been applied in clinical practice for infection,cancer,and autoimmunity over thousands of years and their promising curative effects and safety have been well-accepted.However,whether these natural products are primarily targeting type I IFN signaling and specific molecular targets involved are not fully elucidated.In the current review,we thoroughly summarize recent advances in the pharmacology researches of natural products for their type I IFN activity,including both agonism/activation and antagonism/inhibition,and their potential application as therapies.Furthermore,the source and chemical nature of natural products with type I IFN activity are highlighted and their specific molecular targets in the type I IFN pathway and mode of action are classified.In conclusion,natural products possessing type I IFN activity represent promising therapeutic strategies and have a bright prospect in the treatment of infection,cancer,and autoimmune diseases.

关键词： Type I interferons Natural products Infection Cancer Autoimmune diseases

A novel pulmonary fibrosis murine model with immune-related liver injury

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Animal Models and Experimental Medicine 2023年第3期6卷 274-282页

作者： Kexin Jia Jianzhi Wu Yijie li Jia liu Runping liu Yajie Cai Yinhao Zhang Xiaojiaoyang Li School of life Sciences Beijing University of Chinese MedicineBeijingChina School of Chinese Materia Medica Beijing University of Chinese MedicineBeijingChina

Idiopathic pulmonary fibrosis(IPF),characterized by aggravated alveolar destruc-tion and fibrotic matrix deposition,tendentiously experiences the stage called acute exacerbation IPF(AE-IPF)and progresses to multiple organ damage,especially liver injury.Recent studies have found a variety of immune microenvironment disorders associated with elevated IPF risk and secondary organ injury,whereas current animal models induced with bleomycin(BLM)could not completely reflect the pathologi-cal manifestations of AE-IPF patients in clinic,and the exact underlying mechanisms are not yet fully explored.In the current study,we established an AE-IPF model by tracheal administration of a single dose of BLM and then repeated administrations of lipopolysaccharide in mice.This mouse model successfully recapitulated the clinical features of AE-IPF,including excessive intrapulmonary inflammation and fibrosis and extrapulmonary manifestations,as indicated by significant upregulation of Il6,Tnfa,Il1b,Tgfb,fibronectin,and Col1a1 in both lungs and liver and elevated serum aspartate transaminase and alanine transaminase levels.These effects might be attributed to the regulation of Th17 cells.By sharing this novel murine model,we expect to pro-vide an appropriate experimental platform to investigate the pathogenesis of AE-IPF coupled with liver injury and contribute to the discovery and development of targeted interventions.

关键词： bleomycin idiopathic pulmonary fibrosis lipopolysaccharide liver injury murine model

Epigenetic modification in liver fibrosis:Promising therapeutic direction with significant challenges ahead

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1009-1029页

作者： Runping liu Yajing li Qi Zheng Mingning Ding Huiping Zhou Xiaojiaoyang Li School of Chinese Materia Medica Beijing University of Chinese MedicineBeijing 102400China School of life Sciences Beijing University of Chinese MedicineBeijing 102400China Department of Microbiology and Immunology Virginia Commonwealth UniversityRichmondVA 22460USA

liver fibrosis,characterized by scar tissue formation,can ultimately result in liver failure.It’s a major cause of morbidity and mortality globally,often associated with chronic liver diseases like hepatitis or alcoholic and non-alcoholic fatty liver diseases.However,current treatment options are limited,highlighting the urgent need for the development of new therapies.As a reversible regulatory mechanism,epigenetic modification is implicated in many biological processes,including liver fibrosis.Exploring the epigenetic mechanisms involved in liver fibrosis could provide valuable insights into developing new treatments for chronic liver diseases,although the current evidence is still controversial.This review provides a comprehensive summary of the regulatory mechanisms and critical targets of epigenetic modifications,including DNA methylation,histone modification,and RNA modification,in liver fibrotic diseases.The potential cooperation of different epigenetic modifications in promoting fibrogenesis was also highlighted.Finally,available agonists or inhibitors regulating these epigenetic mechanisms and their potential application in preventing liver fibrosis were discussed.In summary,elucidating specific druggable epigenetic targets and developing more selective and specific candidate medicines may represent a promising approach with bright prospects for the treatment of chronic liver diseases.

关键词： liver fibrosis Epigenetics regulation DNA methylation Histone acetylation Histone methylation mRNA methylation Non-coding RNA Drug development

Integrative lipidomic and transcriptomic study unravels the therapeutic effects of saikosaponins A and D on non-alcoholic fatty liver disease

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Acta Pharmaceutica Sinica B 2021年第11期11卷 3527-3541页

作者： Xiaojiaoyang Li Junde Ge Yajing li Yajie Cai Qi Zheng Nana Huang Yiqing Gu Qi Han Yunqian li Rong Sun Runping liu Beijing University of Chinese Medicine Beijing 100029China The Second Hospital of Shandong University Shandong UniversityJi'nan 250033China Advanced Medical Research Institute Shandong UniversityJi'nan 250012China

Nonalcoholic fatty liver disease(NAFLD)has become one of the most prominent causes of chronic liver diseases and malignancies.However,few therapy has been approved.Radix Bupleuri(RB)is the most frequently used herbal medicine for the treatment of liver diseases.In the current study,we aim to systemically evaluate the therapeutic effects of saikosaponin A(SSa)and saikosaponin D(SSd),the major bioactive monomers in RB,against NAFLD and to investigate the underlying mechanisms.Our results demonstrated that both SSa and SSd improved diet-induced NAFLD.Integrative lipidomic and transcriptomic analysis revealed that SSa and SSd modulated glycerolipid metabolism by regulating related genes,like lipe and lipg.SSd profoundly suppressed the fatty acid biosynthesis by downregulating Fasn and Acaca expression and promoted fatty acid degradation by inducing Acox1 and Cpt1 a expression.Bioinformatic analysis further predicted the implication of master transcription factors,including peroxisome proliferator-activated receptor alpha(PPARα),in the protective effects of SSa and SSd.These results were further confirmed in vitro in mouse primary hepatocytes.In summary,our study uncoded the complicated mechanisms underlying the promising anti-steatosis activities of saikosaponins(SSs),and provided critical evidence inspiring the discovery of innovative therapies based on SSa and SSd for the treatment of NAFLD and related complications.

关键词： Saikosaponin Nonalcoholic fatty liver disease lipidome Transcriptome lipid metabolism

Chuanxiong Rhizoma extracts prevent liver fibrosis via targeting CTCF-c-MYC-H19 pathway

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Chinese Herbal Medicines 2024年第1期16卷 82-93页

作者： Yajing li Fanghong li Mingning Ding Zhi Ma Shuo li Jiaorong Qu Xiaojiaoyang Li School of life Sciences Beijing University of Chinese MedicineBeijing 100029China School of Chinese Materia Medica Beijing University of Chinese MedicineBeijing 100029China

Objective:Hepatic fibrosis has been widely considered as a conjoint consequence of almost all chronic liver diseases.Chuanxiong Rhizoma(Chuanxiong in Chinese,CX)is a traditional Chinese herbal product to prevent cerebrovascular,gynecologic and hepatic diseases.Our previous study found that CX extracts significantly reduced collagen contraction force of hepatic stellate cells(HSCs).Here,this study aimed to compare the protection of different CX extracts on bile duct ligation(BDL)-induced liver fibrosis and investigate plausible underlying mechanisms.Methods:The active compounds of CX extracts were identified by high performance liquid chromatography(HPLC).Network pharmacology was used to determine potential targets of CX against hepatic fibrosis.Bile duct hyperplasia and liver fibrosis were evaluated by serologic testing and histopathological evaluation.The expression of targets of interest was determined by quantitative real-time PCR(qPCR)and Western blot.Results:Different CX extracts were identified by tetramethylpyrazine,ferulic acid and senkyunolide A.Based on the network pharmacological analysis,42 overlap targets were obtained via merging the candidates targets of CX and liver fibrosis.Different aqueous,alkaloid and phthalide extracts of CX(CX_(AE),CX_(AL) and CXP_(HL))significantly inhibited diffuse severe bile duct hyperplasia and thus suppressed hepatic fibrosis by decreasing CCCTC binding factor(CTCF)-c-MYC-long non-coding RNA H19(H19)pathway in the BDL-induced mouse model.Meanwhile,CX extracts,especially CX_(AL) and CX_(PHL) also suppressed CTCF-c-MYC-H19 pathway and inhibited ductular reaction in cholangiocytes stimulated with taurocholate acid(TCA),lithocholic acid(LCA)and transforming growth factor beta(TGF-β),as illustrated by decreased bile duct proliferation markers.Conclusion:Our data supported that different CX extracts,especially CX_(AL) and CX_(PHL) significantly alleviated hepatic fibrosis and bile duct hyperplasia via inhibiting CTCF-c-MYC-H19 pathway,providing novel insights into the anti-f

关键词： Chuanxiong Rhizoma cholangiocytes ductular reaction ligusticum chuanxiong Hort. liver fibrosis lncRNA H19

Cassiae Semen improves non-alcoholic fatty liver disease through autophagy-related pathway

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Chinese Herbal Medicines 2023年第3期15卷 421-429页

作者： Mingning Ding Fei Zhou Yijie li Chuanyang liu Yiqing Gu Jianzhi Wu Guifang Fan Yajing li Xiaojiaoyang Li School of life Sciences Beijing University of Chinese MedicineBeijing 100029China School of Chinese Materia Medica Beijing University of Chinese MedicineBeijing 100029China School of Traditional Chinese Medicine Beijing University of Chinese MedicineBeijing 100029China

Objective:Cassiae Semen(CS,Juemingzi in Chinese)has been used for thousands of years in ancient Chinese history for relieving constipation,improving liver function as well as preventing myopia.Here we aimed to elucidate the anti-steatosis effect and underlying mechanism of CS against non-alcoholic fatty liver disease(NAFLD).Methods:High-performance liquid chromatography(HPLC)was used to identify the major components of CS water extract.Mice were fed with a high-fat and sugar-water(HFSW)diet to induce hepatic steatosis and then treated with CS.The anti-NAFLD effect was determined by measuring serum biomarkers and histopathology staining.Additionally,the effects of CS on cell viability and lipid metabolism in oleic acid and palmitic acid(OAPA)-treated HepG2 cells were measured.The expression of essential genes and proteins involved in lipid metabolism and autophagy signalings were measured to uncover the underlying mechanism.Results:Five compounds,including aurantio-obtusin,rubrofusarin gentiobioside,cassiaside C,emodin and rhein were simultaneously identified in CS extract.CS not only improved the diet-induced hepatic steatosis in vivo,as indicated by decreased number and size of lipid droplets,hepatic and serum triglycerides(TG)levels,but also markedly attenuated the OAPA-induced lipid accumulation in hepatocytes.These lipid-lowering effects induced by CS were largely dependent on the inhibition of fatty acid synthase(FASN)and the activation of autophagy-related signaling,including AMP-activated protein kinase(AMPK),light chain 3-II(LC3-II)/LC3-1 and autophagy-related gene5(ATG5).Conclusion:Our study suggested that CS effectively protected liver steatosis via decreasing FASN-related fatty acid synthesis and activating AMPK-mediated autophagy,which might become a promising therapeutic strategy for relieving NAFLD.

关键词： autophagy AMPK Cassia obtusifolia L. Cassia tora L. Cassiae Semenfatty acid synthesis non-alcoholic fatty acid disease

Chuanxiong Rhizoma extracts prevent cholestatic liver injury by targeting H3K9ac-mediated and cholangiocyte-derived secretory protein PAI-1 and FN

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Chinese Journal of Natural Medicines 2023年第9期21卷 694-709页

作者： li Yajing MA Zhi DING Mingning JIA Kexin XU Bing ZHOU Fei LUO Ranyi XUE Xiaoyong WU Ruiyu GAO Feng li xiaojiaoyang School of life Sciences Beijing University of Chinese MedicineBeijing 100029China School of Chinese Materia Medica Beijing University of Chinese MedicineBeijing 100029China

Chuanxiong Rhizoma(CX,the dried rhizome of ligusticum wallichii Franch.),a well-known traditional Chinese medicine,is clinically used for treating cardiovascular,cerebrovascular and hepatobiliary diseases.Cholestatic liver damage is one of the chronic liver diseases with limited effective therapeutic strategies.Currently,little is known about the mechanism links between CX-induced anti-cholestatic action and intercellular communication between cholangiocytes and hepatic stellate cells(HSCs).The study aimed to evaluate the hepatoprotective activity of different CX extracts including the aqueous,alkaloid,phenolic acid and phthalide extracts of CX(CX_(AE),CX_(AL),CX_(PA)and CX_(PHL))and investigate the intercellular communication-related mechanisms by which the most effective extracts work on cholestatic liver injury.The active compounds of different CX extracts were identified by UPLC-MS/MS.A cholestatic liver injury mouse model induced by bile duct ligation(BDL),and transforming growth factor-β(TGF-β)-treated human intrahepatic biliary epithelial cholangiocytes(HIBECs)and HSC cell line(LX-2 cells)were used for in vivo and in vitro studies.Histological and other biological techniques were also applied.The results indicated that CX_(AE),CX_(AL)and CX_(PHL)significantly reduced ductular reaction(DR)and improved liver fibrosis in the BDL mice.Meanwhile,both CX_(AE)and CX_(PHL)suppressed DR in injured HIBECs and reduced collagen contraction force and the expression of fibrosis biomarkers in LX-2 cells treated with TGF-β.CX_(PHL)suppressed the transcription and transfer of plasminogen activator inhibitor-1(PAI-1)and fibronectin(FN)from the‘DR-like’cholangiocytes to activated HSCs.Mechanistically,the inhibition of PAI-1 and FN by CX_(PHL)was attributed to the untight combination of the acetyltransferase KAT2A and SMAD3,followdd by the suppression of histone 3 lysine 9 acetylation(H3K9ac)-mediated transcription in cholangiocytes.In conclusion,CX_(PHL)exerts stronger anti-cholestatic activity in vivo and in vitro than othe

关键词： Chuanxiong Rhizoma Cholestatic liver injury Ductular reaction Cholangiocytes Hepatic stellate cell