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cryptotanshinone induces apoptosis of activated hepatic stellate cells via modulating endoplasmic reticulum stress

World Journal of Gastroenterology 2023年第17期29卷 2616-2627页

作者： Xiao-Xue Hou Yu-Wen Li Jia-Li Song Wen Zhang Rui Liu Hui Yuan Tian-Tong Feng Zheng-Yi Jiang Wen-Ting Li Chuan-Long Zhu Department of Infectious Disease The First Affiliated Hospital of Nanjing Medical UniversityNanjing 210009Jiangsu ProvinceChina Department of Pediatrics The First Affiliated Hospital of Nanjing Medical UniversityNanjing 210009Jiangsu ProvinceChina Department of Infectious and Tropical Diseases The Second Affiliated Hospital of Hainan Medical UniversityHaikou 570000Hainan ProvinceChina

BACKGROUND cryptotanshinone(CPT)has wide biological functions,including anti-oxidative,antifibrosis,and anti-inflammatory ***,the effect of CPT on hepatic fibrosis is *** To investigate the effects of CPT treatment on hepatic fibrosis and its underlying mechanism of *** Hepatic stellate cells(HSCs)and normal hepatocytes were treated with different concentrations of CPT and *** CCK-8 assay was used to determine cell *** cytometry was used to measure apoptosis and cell cycle *** transcription polymerase chain reaction(RT-PCR)and Western blot analyses were used to measure mRNA levels and protein expression of endoplasmic reticulum stress(ERS)signaling pathway related molecules,*** tetrachloride(CCL4)was used to induce in vivo hepatic fibrosis in *** were treated with CPT and salubrinal,and blood and liver samples were collected for histopathological *** We found that CPT treatment significantly reduced fibrogenesis by modulating the synthesis and degradation of the extracellular matrix in *** inhibited cell proliferation and induced cell cycle arrest at the G2/M phase in cultured ***,we found that CPT promoted apoptosis of activated HSCs by upregulating expression of ERS markers(CHOP and GRP78)and activating ERS pathway molecules(PERK,IRE1α,and ATF4),which were inhibited by *** of ERS by salubrinal partially eliminated the therapeutic effect of CPT in our CCL4-induced hepatic fibrosis mouse *** CPT can promote apoptosis of HSCs and alleviate hepatic fibrosis through modulating the ERS pathway,which represents a promising strategy for treating hepatic fibrosis.

关键词： Hepatic fibrosis Endoplasmic reticulum stress cryptotanshinone Hepatic stellate cells Apoptosis

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cryptotanshinone ameliorates cladribine-induced cognitive impairment in rats

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Asian Pacific Journal of Tropical Biomedicine 2023年第7期13卷 296-305页

作者： Khadga Raj Aran G.D.Gupta Shamsher Singh Neuroscience Division Department of PharmacologyISF College of Pharmacy(An Autonomous College)MogaPunjabIndia-142001 I.K.Gujral Punjab Technical University JalandharIndia Department of Pharmaceutics ISF College of PharmacyMogaPunjabIndia-142001

Objective:To evaluate the neuroprotective effect of cryptotanshinone against cladribine-induced cognitive impairment in ***:Rats were administered with cladribine(1 mg/kg,p.o.)and cryptotanshinone(10 and 20 mg/kg,i.p.)for four *** tests such as Morris water maze and elevated plus maze were conducted to check memory impairment caused by *** day 29,all rats were sacrificed,and the brains were separated for estimation of neuroinflammatory factors,biochemical parameters,neurotransmitters,Aβ(1-42),blood-brain barrier permeability,nuclear factor erythroid 2-related factor 2(Nrf2),and brain-derived neurotrophic factor(BDNF).Results:Treatment with cryptotanshinone dose-dependently enhanced spatial memory,improved the levels of neurotransmitter and antioxidant enzymes,and suppressed proinflammatory cytokine *** also decreased Aβ(1-42)accumulation and increased the levels of Nrf2 and BDNF in the ***,the histopathological results showed that cryptotanshinone reduced cladribine-induced neuronal death in the ***:cryptotanshinone exhibits a promising neuroprotective effect against cladribine-induced cognitive impairment in preclinical studies,and may be a potential phytochemical for the treatment and management of cognitive impairment.

关键词： Alzheimer's disease Cladribine cryptotanshinone Neurotransmitters Neuroprotective Proinflammatory cytokines Cognitive deficit

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cryptotanshinone inhibits cytotoxin-associated gene A-associated development of gastric cancer and mucosal erosions

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World Journal of Gastrointestinal Oncology 2021年第7期13卷 693-705页

作者： Zhang-Ming Chen Jie Hu Yuan-Min Xu Wei He Lei Meng Ting Huang Song-Cheng Ying Zhe Jiang A-Man Xu Department of General Surgery Fourth Affiliated Hospital of Anhui Medical UniversityHefei 230001Anhui ProvinceChina Department of General Surgery First Affiliated Hospital of Anhui Medical UniversityHefei 230022Anhui ProvinceChina Department of Surgery East District of First Affiliated Hospital of Anhui Medical University(Feidong People's Hospital)Hefei 230001Anhui ProvinceChina Department of Immunology School of Basic Medical SciencesAnhui Medical UniversityHefei 230032Anhui ProvinceChina

BACKGROUND Approximately 90%of new cases of noncardiac gastric cancer(GC)are related to Helicobacter pylori(***),and cytotoxin-associated gene A(CagA)is one of the main pathogenic *** studies have shown that the pharmacological effects of cryptotanshinone(CTS)can be used to treat a variety of ***,the effects of CTS on ***,especially CagA+strain-induced gastric mucosal lesions,on the development of GC is *** To assess the role of CTS in CagA-induced proliferation and metastasis of GC cells,and determine if CagA+*** strains causes pathological changes in the gastric mucosa of *** The effects of CTS on the proliferation of GC cells were assessed using the Cell Counting Kit-8(CCK-8)assay,and the abnormal growth,migration and invasion caused by CagA were detected by CCK-8 and transwell *** transfection with pSR-HA-CagA and treatment with CTS,proliferation and metastasis were evaluated by CCK-8 and transwell assays,respectively,and the expression of Src homology 2(SH2)domain–containing phosphatase 2(SHP2)and phosphorylated SHP2(p-SHP2)was detected using western blotting in AGS *** enzymelinked immunosorbent assay was used to determine the immunoglobulin G(IgG)level against CagA in patient *** were divided into four groups and administered *** strains(CagA+or CagA-)and CTS(or PBS)intragastrically,and establishment of the chronic infection model was verified using polymerase chain reaction and sequencing of isolated *** and eosin staining was used to assess mucosal erosion in the stomach and toxicity to the liver and *** CTS inhibited the growth of GC cells in dose-and time-dependent *** of CagA promoted the growth,migration,and invasion of GC ***,we demonstrated that CTS significantly inhibited the CagAinduced abnormal proliferation,migration,and invasion of GC ***,the expression of p-SHP2 protein in tumor tissue was relate

关键词： Cytotoxin associated gene A SHP2 cryptotanshinone Helicobacter pylori Chronic infection model

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cryptotanshinone switches target from estrogen receptor α to breast cancer resistance protein(BCRP/ABCG2) to reverse multidrug resistance in breast cancer

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中国药理学与毒理学杂志 2019年第10期 885-886页

作者： NI Wen-ting FAN Hui YU Su-yun CHEN Wen-xing LU Yin Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica School of Pharmacy Nanjing University of Chinese Medicine

OBJECTIVE Targeting individual molecule is not only difficult to cure multigenic cancers, but also prone to inducing resistance. The so-cal ed multidrug resistance(MDR) in breast cancer is highly associated with estrogen receptor α induction and the overexpression of breast cancer resistance protein(BCRP) ***, one of the strategies to overcome MDR is to inhibit the expression of the transporter by small molecule inhibitors. METHODS Western blotting and RT-PCR were used respectively for quantification of protein expression and m RNA, non-reducing gradientgel electrophoresis and fluorescence resonance energy transfer(FRET) microscopy imaging for determination of BCRP dimer. RESULTS cryptotanshinone(CPT) a natural anti-cancer compound,was found to bind BCRP and inhibit its membrane dimerization to attenuate its transport function. And this process is dependent on estrogen receptor α(ERα) in breast cancer. Furthermore, the resistant breast cancer cells with high BCRP expression are also sensitive to CPT followed with the inhibition of membrane dimer of BCRP although they are ERα-negative, suggesting that BCRP expression is essential to CPT reversing the ***, the combination of CPT and chemotherapy drugs could obviously enhance the chemotherapeutic effect in vitro. CONCLUSION Totally, we thought that CPT is a novel natural BCRP inhibitor via blocking the formation of BCRP membrane dimer. At the presence of ERα, it functions via ERα regulation, but directly propels BCRP at the absence of ER in resistant cells. CPT can target multi molecules and switch the target from ERα to BCRP in ERα-negative breast cancer, contributing to decrease the occurrence of resistance and reverse multidrug resistance in breast cancer.

关键词： cryptotanshinone breast cancer resistance protein estrogen receptor α multidrug resistance

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Preparation and characterisation of solid dispersions of tanshinone ⅡA, cryptotanshinone and total tanshinones

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Asian Journal of Pharmaceutical Sciences 2017年第1期12卷 85-97页

作者： Xifeng Zhai Chunguang Li George Binh Lenon Charlie C.L.Xue Weize Li Traditional&Complementary Medicine Program School of Health SciencesRMIT UniversityBundooraVictoriaAustralia School of Pharmaceutical Sciences Xi’an Medical UniversityXi’anChina Center for Complementary Medicine Research National Institute of Complementary MedicineUniversity of Western SydneyCampbelltown CampusPenrithNew SouthWalesAustralia

Total tanshinones are lipophilic active constituents extracted from Salvia miltiorrhiza *** ⅡA and cryptotanshinone are the major components in total ***, the bioavailability of both compounds is low due to poor water solubility. To enhance the solubility and dissolution rate of tanshinone ⅡA, cryptotanshinone and total tanshinones,three common used hydrophilic carriers including PEG 6000, poloxamer 188 and PVP K30 were used to prepare the solid dispersions at different ratios, respectively. The solid dispersions were characterised by scanning electron microscopy(SEM), differential scanning calorimetry(DSC) and Fourier transform infrared spectroscopy(FTIR). The results of powder X-ray diffraction confirmed the microcrystal state of total tanshinones in solid dispersions and no chemical interaction between total tanshinones and carriers was observed in FTIR spectra. The solubility and dissolution rate of tanshinone ⅡA and cryptotanshinone were significantly increased in all solid dispersions. Regarding tanshinone ⅡA, the solubility and dissolution rate of in solid dispersions prepared with poloxamer 188 were significantly higher than that with PEG 6000 and PVP K30. The higher solubility and dissolution rate of cryptotanshinone were obtained in solid dispersion of PVP K30 than that of PEG 6000 solid dispersions but no significant difference from poloxamer 188 solid dispersions. The results indicate that the superior carrier for preparation of tanshinone ⅡA and total tanshinones solid dispersions is poloxamer 188, and that for cryptotanshinone is PVP K30.

关键词： cryptotanshinone Tanshinone ⅡA Total tanshinones Solid dispersion Dissolution rate

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Development of cryptotanshinone-loaded pellets for angina chronotherapy:In vitro/in vivo prediction and evaluation

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Asian Journal of Pharmaceutical Sciences 2018年第4期13卷 310-316页

作者： Zhenghua Li Shuangshuang Zhang Hongxiang Yan Jianping Liu Department of Pharmaceutics China Pharmaceutical University

The clinical manifestations of variant angina is unevenly distributed during the 24 h, thusthe in vivo performance of drugs should be tailored according to the angina circadianrhythm. cryptotanshinone(CTN) is one of the representative bioactive lipid-soluble com-ponents of Danshen which has been commonly used for cardiovascular diseases such asangina pectoris. The aim of this study was to develop a novel CTN sustained-released pel-lets(CTN-SRPs) to precisely synchronize the CTN plasma concentrations with predictedoccurrence of angina pectoris for angina chronotherapy. A deconvolution-based methodwas applied to develop and optimize the CTN-SRPs. The plasma concentration-time curveof CTN immediate-released formulation after oral administration in rats was used as theweight function. The predicted plasma concentration-time curve of CTN-SRPs simulatedaccording to the incidence of variant angina during 24 h was used as the response func-tion. Then the desired drug release profile of CTN-SRPs was calculated based on deconvo-lution using weight function and response function, and subsequently used for guiding theformulation optimization. CTN-SRPs were prepared with the combinations of PVP, polox-amer 127 and EC as matrix using fluidized bed technology. An orthogonal design was em-ployed to obtain the optimal formulation with its release profile similar with the desiredone. Pharmacokinetic studies validated that the actual plasma concentration-time curve ofthese optimized CTN-SRPs was similar with the predicted one. In addition, the percent er-rors(%PE) of CTN plasma concentrations in 8–12 h were less than 10%. In conclusion, thisdeconvolution-based method could be applied to adjust the in vivo performance of drugs forangina chronotherapy.

关键词： Chronotherapy Deconvolution Angina pectoris cryptotanshinone In vitro/in vivo performance Control release

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cryptotanshinone increases the sensitivity of liver cancer to sorafenib by inhibiting the STAT3/Snail/ epithelial mesenchymal transition pathway

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Frigid Zone Medicine 2022年第2期2卷 119-128页

作者： Zhiyu Li Kegong Chen Chao Cui Yinghui Wang Dequan Wu Department of Liver Surgery The Second Affiliated Hospital of Harbin Medical UniversityHarbin 150081China Department of General Surgery The Fourth Affiliated Hospital of Harbin Medical UniversityHarbin 150001China Department of Cardiothoracic Surgery The Second Affiliated Hospital of Harbin Medical UniversityHarbin 150081China Department of Gastrointestinal Surgery The First Affiliated Hospital of Gannan Medical UniversityGanzhou 341099China Department of Physical Examination Center The Second Affiliated Hospital of Harbin Medical UniversityHarbin 150081China

Objective:Sorafenib resistance has been a major factor limiting its clinical use as a targeted drug in liver *** present study aimed to investigate whether cryptotanshinone can enhance the sensitivity of liver cancer and reduce the resistance to ***:Sorafenib-resistant cells were established based on HepG2 and Huh7 cell *** the anti-tumor effect of sorafenib combined with cryptotanshinone on the sorafenib-resistant cells was verified by MTT,colony formation,transwell assays and tumor growth xenograft ***,the effects of the combined treatment on the expression of phosphorylated(p)-STAT3,as well as epithelial mesenchymal transition(EMT)and apoptosis related proteins of cells were evaluated by western blot ***:It was identified that cryptotanshinone inhibited the viability of both HepG2 and Huh7 cells in a dose-and time-dependent manner,and decreased p-STAT3 expression rather than total STAT3 expression at a concentration of 40μmol/*** the sorafenib-resistant cells,sorafenib in combination with cryptotanshinone markedly inhibited cell viability,invasion and migration compared with sorafenib *** contrast,increased p-STAT3 level by colivelin led to the inhibition of the synergistic effect of cryptotanshinone and sorafenib not only on cell viability,but also on EMT and apoptosis,suggesting that cryptotanshinone and sorafenib may act by downregulating STAT3 ***,the inhibition of carcinogenicity effect was also verified in xenografted tumor ***:The present results indicated that cryptotanshinone could synergize with sorafenib to inhibit the proliferative,invasive,and migratory abilities of sorafenib-resistant cells by downregulating STAT3 signaling.

关键词： cryptotanshinone sorafenib sorafenib-resistance STAT3 signaling liver cancer

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Effects of cryptotanshinone on immune functions in rats with adjuvant arthritis

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Chinese Medical Journal 2009年第24期122卷 3039-3042页

作者： ZHENG Fu-lin CHANG Yan JIA Xiao-yi WEI Wei Department of Pharmacology Medical College Anhui University of Science and Technology Huainan Anhui 232001 China Institute of Clinical Pharmacology Anhui Medical University Hefei Anhui 230032 China

Background cryptotanshinone （CT） was originally isolated from the dried roots of Salvia militorrhiza, an herb that is used extensively in Asian medicine and the extracts of this herb have been used in the treatment of several pathologies, including cardiovascular diseases, hematological abnormalities, hepatitis, and hyperlipidemia, but no studies had been carried on the treatment for rheumatic diseases with it. This study aimed to investigate the effects of cryptotanshinone on immune functions in rats with adjuvant arthritis （AA）. Methods Complete Freund＇s adjuvant was used to induce AA in rats. Thymus and spleen was aseptically taken from normal rats and the AA rats. Then a thymus lymphoid cell suspension, splenic lymphoid cell suspension and peritoneal macrophage cell suspension were prepared. After adding CT （0.1 ug/ml, 1.0 ug/ml, 10 ug/ml, 100 ug/ml, 1000 ug/ml） into the suspension, T and B lymphocytes proliferation was determined by 3-（4,5-2 dimethylthiazal-2yl）2,5- diphenyltetrazoliumbromide （MTT） assay. And the activities of interleukin-1 （IL-1） and IL-2 were measured by the mouse lymphocytes proliferation assay. Results Thymic T and splenic B lymphocyte proliferation of the AA rat was significantly lower, and could be stored through using CT in vitro. CT （100ug/ml and 1000ug/ml） increased T or B lymphocytes proliferation in vitro （P 〈0.01）. In AA rats, the levels of IL-1 released by abdominal PMφ significantly increased whereas the level of IL-2 released by T cells decreased in vitro. CT （1000 pg/ml） decreased the production of IL-1 and promoted production of IL-2 in vitro （P 〈0.05）. Conclusions CT can ameliorate the abnormal immunological functions in AA rats.

关键词： cryptotanshinone adjuvant arthritis immunopharmacological effect," rat

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Effects and mechanisms of cryptotanshinone on rats with adjuvant arthritis

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Chinese Medical Journal 2011年第24期124卷 4293-4298页

作者： ZHENG Fu-lin CHANG Yan JIA Xiao-yi HUANG Min WEI Wei Department of Phar-macology Medical College Anhui Universityof Science and Technology Huainan Anhui 232001 China Institute of Clinical Pharmacology Anhui Medical UniversityHefei Anhui 230032 China School of Pharmaceutical Sciences Sun Yat-sen UniversityGuangzhou Guangdong 510006 China

Background cryptotanshinone （CT） is the major active constituent of Salvia miltiorrhiza Bunge. The present study was carried out to investigate the effects of CT on rats with adjuvant arthritis （AA）. Methods AA was induced by the metatarsal footpad injection with complete Freund＇s adjuvant in male Sprague-Dawley rats. The secondary inflammatory reaction was evaluated by hind paw swelling and the polyarthritis index. Activity of interleukin-1 （IL-1） was detected by the concanavalin A-induced thymocytes proliferation assay. The lymphocytes proliferation and IL-2 production were assayed by 3-（4,5-2dimethylthiazal-2yl）2,5-diphenyltetrazoliumbromide （MTT） and activated mouse splenocytes proliferation, respectively. Results Intragastric administration of CT （50 and 100 mg/kg） significantly decreased secondary inflammatory reactions and increased the spleen and thymus index. There was a marked immunologic and inflammatory response in the AA model, which was accompanied by the decrease of thymocyte proliferation and IL-2 production as well as the increase of IL-1 production. CT apparently enhanced thymocyte proliferation and decreased IL-1 production in AA rats. Conclusion These results indicate that CT may exert its anti-inflammatory and immunoregulatory effects through inhibiting lymphocyte proliferation and production of pro-inflammatory mediators.

关键词： cryptotanshinone adjuvant arthritis lymphocyte proliferation cytokine

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The forecast of anticancer targets of cryptotanshinone based on reverse pharmacophore-based screening technology

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Chinese Journal of Natural Medicines 2014年第6期12卷 443-448页

作者： YUAN Dong-Ping LONG Jun LU Yin LIN Jie TONG Li College of Pharmacy Nanjing University of Chinese Medicine Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica Nanjing University of Chinese Medicine School of Life Science Yunnan University Traditional Chinese and Tibetan Medicine Research Centre Medical College of Qinghai Univercity

Anticancer targets of cryptotanshinone were evaluated and rapidly forecasted with PharmMapper, a reverse pharmacophore-based screening platform, as well as drug target databases, including PDTD, DrugBank and TTD. The pathway analyses for the collection of anticancer targets screened were carried out based on the KEGG pathway database, followed by the forecast of potential pharmacological activities and pathways of the effects of cryptotanshinone, and verification of some of the targets screened using whole cell tests. The results showed that a total of eight targets with anticancer potential were screened, including MAP2K1, RARα, RXRα, PDK1, CHK1, AR, Ang-1 R, and Kif11. These targets are mainly related to four aspects of the cancer growth: the cell cycle, angiogenesis, apoptosis, and androgen receptor. The cell tests showed that cryptotanshinone can inhibit the viability of human hepatoma cells SMMC-7721, which is related to the reduction of expression of MAP2K1 mRNA. This method provides a strong clue for the study of the anticancer effects and mechanisms of action of cryptotanshinone in the future.

关键词： cryptotanshinone Pharmacophore Reverse screening technology Anticancer Human hepatoma cells Forecast of target

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