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中国毒理学会第七次全国会员代表大会暨中国毒理学会第六次中青年学者科技论坛

作者： Shuhao Su Chunxu Hai Xin Wang Department of Toxicology Shaanxi Key Lab of Free Radical Biology and Medicine School of Public Health Fourth Military Medical University

Polychlorinated biphenyls (PCBs) exposure is closely associated with obesity and diabetes. However, the mechanism of PCBs-induced adiposity and insulin resistance is not clear and the intervention is limited. We have found that oleanolic acid (OA) is a natural triterpenoid,possessing antioxidant and anti-diabetic activity, and hepatocyte nuclear factor 1b (HNF1b) is an important regulator of glucose and lipid metabolism. The present study aimed to investigate the effect of OA on Aroclor 1254-induced adiposity and insulin resistance and explore the possible involvement of HNF1b. We showed that OA significantly attenuated Aroclor 1254-induced insulin resistance and abnormal changes of glucose and lipid parameters. OA inhibited the increase of adipose weight and adipocyte size in Aroclor 1254-treated mice and repressed adipocyte differentiation in vitro. In addition, OA markedly inhibited Aroclor 1254-induced increase of ROS,oxidant products, NOX4 expression, decrease of SOD1, SOD2, GCLC, GCLM and Gpx1expression, and increase of PPARγsignaling. Aroclor 1254 resulted in a decrease of HNF1b expression in adipose of mice and adipocytes, which was inhibited by OA. Upregulation of HNF1b blocked Aroclor 1254-induced oxidative stress, adipocyte differentiation and insulin resistance. Downregulation of HNF1b inhibited OA-induced protective effects against Aroclor1254-associated oxidative stress, adipocyte differentiation and insulin resistance. The antioxidant Vitamin C reduced Aroclor 1254-induced ROS generation in vitro, but had no significant effect on HNF1b expression, oxidative stress and metabolic dysfunction in vivo. OA could inhibit PCBs mixture-induced oxidative injury and glucose/lipid metabolic dysfunction via HNF1b-mediated regulation of redox homeostasis. Our data suggest that HNF1b is a new on/off switch of redox homeostasis and OA-stimulated HNF1b-endogenous antioxidant activity is a potential option for the intervention of PCBs exposure-related adiposity and in

关键词： Polychlorinated biphenyls oleanolic acid Hepatocyte nuclear factor 1b oxidative stress Metabolic dysfunction Vitamin C

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oleanolic acid Inhibits Colorectal Cancer Growth and Angiogenesis through Multiple Cellular Pathways

Oleanolic Acid Inhibits Colorectal Cancer Growth and Angioge...

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第十一次中国中西医结合实验医学学术研讨会

作者：林久茂魏丽慧沈阿灵蔡巧燕詹友知彭军福建中医药大学中西医结合研究院

The development of colorectal cancer(CRC) is strongly correlated with the aberrant activation of multiple intracellular signaling transduction cascades including STAT3,Hedgehog,Akt and MAPK pathways which usually function *** addition,crosstalk between these pathways forms a complicated signaling network that is regulated by compensatory ***,most of the currently used and single-target-based anti-tumor agents might not always be therapeutically effective. Moreover,long-term use of these agents often generates drug *** problems highlight the urgent need for the development of novel anti-cancer chemotherapies. oleanolic acid(OA) is a major active compound present in many medicinal herbs that have long been used for the clinical treatment of *** previous studies have demonstrated an anti-tumor effect for OA,the precise mechanisms of its tumorcidal activity are not well *** the present study,using CRC mouse xenograft model and the human colon carcinoma cell line HT-29,we evaluated the efficacy of OA against tumor growth in vivo and in vitro and investigated the underlying molecular mechanisms. We found that OA inhibits cancer growth without appearant ***,OA significantly suppresses the activation of several CRC-related signaling pathways and alters the expression of critical target *** molecular effects lead to the induction of apoptosis,inhibition of cellular proliferation,and inhibition of tumor angiogenesis. These data demonstrate that OA possesses a broad range of anti-cancer activities due to its ability to affect multiple intracellular targets,suggesting that OA could be a novel multi-potent therapeutic agent for cancer treatment.

关键词： oleanolic acid colorectal cancer signaling pathway apoptosis and proliferation angiogenesis

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Differential Effects of Ursolic acid and oleanolic acid on Mitochondrial ATP Generation in H9c2 Cardiomyocytes and Lipopolysaccharide-Induced Cell Proliferation in Mouse Splenocytes: Yang versus Yin

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Chinese Medicine 2021年第3期12卷 37-46页

作者： Hoi Yan Leung Kai Chit Cheung Kam Ming Ko Division of Life Science Hong Kong University of Science & Technology Hong Kong China

In the present study, two cell-based systems for assessing Yang and Yin activities were for the first time used to investigate the effect of ursolic acid (UA) and oleanolic acid (OA). The results indicated that while UA was only active in the Yang assay, OA produced activity in the Yin assay. The Yang/Yin activity of UA/OA may be attributed to their distinct molecular structures, which confer their differential ability to interact with mitochondrial membrane or cellular membrane lipids, with resultant membrane fluidization and potentiation of biological responses.

关键词： Yang Yin Ursolic acid oleanolic acid Mitochondrial ATP Generation Splenocytes

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Proliferation-Inhibiting and Apoptosis-lnducing Effects of Ursolic acid and oleanolic acid on Multi-Drug Resistance Cancer Cells in Vitro

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Chinese Journal of Integrative Medicine 2011年第8期17卷 607-611页

作者：单建贞宣嫣艳阮姝琴孙梅 Department of Oncology the Second Affiliated HospitalSchool of MedicineZhejiang University Cancer Institute School of MedicineZhejiang University Department of Traditional Chinese Medicine the Second Affiliated HospitalSchool of MedicineZhejiang University

Objective：To investigate the proliferation-inhibiting and apoptosis-inducing effects of ursolic acid（UA） and oleanolic acid（OA） on multi-drug resistance（MDR） cancer cells in ***：UA and OA in different concentrations（0-100μmol/L） were added separately to cultures of different cancer cell lines, including the human colon cancer cell lines SW480 and SW620,human acute myelocytic leukemia cancer cell lines HL60 and HL60/ADR,human chronic myelogenous leukemia cell lines K562 and K562/ADR,and the human breast cancer cell lines MCF-7 and MCF-7/*** of UA and OA on cell proliferation were detected by 3-（4,5-dimethyl-2-thiazole）-2-5-biphenly-tetrazole bromide（MTT） method and effects on cell apoptosis were tested by flow cytometry（FCM） and Western blot at 24,48,and 72 h after ***：Both UA and OA showed significant inhibition on parent and MDR cell lines in a time- and concentration-dependent manner;the drug-resistant multiple of them on K562 and K562/ADR as well as on HL60 and HL60/ADR was 1;the effects of UA were better than those of OA in inhibiting cell growth of solid colonic cancer and breast *** SW480 cells were treated by UA at the concentrations of 0-40μmol/L for 48 h,FCM showed that annexin V （AV） positive cells and hypodiploid peak ratio increased along with the increase in the drug＇s concentrations; and Western blot found that expressions of Bcl-2,Bcl-xL and survivin decreased in a concentration-dependent ***：Both UA and OA have antitumor effects on cancer cells with MDR,and the optimal effect is shown by UA on colonic cancer ***,UA shows cell apoptosis-inducing effect on SW480,possibly by way of down-regulating the expressions of apoptosis antagonistic proteins,Bcl-2,Bcl-xL,and survivin.

关键词： ursolic acid oleanolic acid multi-drug resistance cancer cell proliferation inhibition apoptosis

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Use of Experimental Design in the Optimization of Extraction of oleanolic acid and Ursolic acid in Fructus crataegi

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Tsinghua Science and Technology 2001年第2期6卷 164-167页

作者：罗国安 Department of Chemistry Tsinghua University Beijing 100084 China

Extraction of active constituents is the key to economic exploitation of herbal drugs in which appropriate use of experimental design can be employed. This paper used even-plan design to assess parameters for optimum extraction of ursolic acid and oleanolic acid in Fructus crataegi. In this approach, three factors, namely solvent concentration, extraction time and solvent volume, were evaluated according to even-plan design, in which several factors are usually simultaneously varied. As a result the number of experiments as well as time, was reduced as compared with the univariate approach and other designs. It was demonstrated that with even-plan design, useful information on extraction parameters can be obtained for the extraction of herbal drugs and could therefore be successfully applied to screen extraction conditions for herbal drugs.

关键词： Fructus crataegi experimental design even-plan design ursolic acid oleanolic acid

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Preparation and characterization of oleanolic acid-loaded solid lipid nanoparticles for oral administration

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Journal of Chinese Pharmaceutical Sciences 2011年第3期20卷 259-265页

作者：孙慧张现化王硕涂盈峰赵荣生谢英北京大学医学部药学院药剂学系北京100191 北京大学第三附属医院药剂科北京100191 瑞士巴塞尔大学药学院

oleanolic acid-loaded solid lipid nanoparticles（OA-SLNs）were prepared by using an improved emulsion-solvent evaporation *** size,zeta potential,encapsulation efficiency,and loading efficiency of OA-SLNs were（104.5±11.7）nm, （-25.5±1.8）mV,（94.2±3.9）%,and（4.71±0.15）%,*** morphology was illustrated by TEM as sphere stuffed *** XRD and DSC spectra confirmed that the OA molecules were dispersed uniformly into SLN *** results of in vitro release test suggested that OA was released slowly at a rate of 4.88%per hour from SLN preparation,which was consistent with the Zero-order Released *** addition,OA-SLNs were stable in artificial gastric juice and artificial intestinal ***,our results provided new data for the potential application of OA-SLNs in oral administration.

关键词： oleanolic acid Solid lipid nanoparticles Preparation Characterization

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The oleanolic acid Derivative ZQL-3d Exerts Anticancer Effects via miR-221-3p/ASPP2 and Modulates Trastuzumab Resistance in Breast Cancer

The Oleanolic Acid Derivative ZQL-3d Exerts Anticancer Effec...

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2021年中国肿瘤标志物学术大会暨第十五届肿瘤标志物青年科学家论坛

作者： Yiwen Ma Shisheng Wang Xiaorui Li Jun Yang Tao Sun Department of Breast Medicine Cancer Hospital of China Medical University College of Pharmaceutical Science and Technology Dalian University of Technology Key Laboratory of Liaoning Breast Cancer Research

Background: With the application of targeted drugs, survival and prognosis of HER2-positive breast cancer patients have improved significantly, but single-target small-molecule kinase inhibitors have developed resistance during clinical application due to mutations in residues at the target protein binding site. Therefore, the development of novel multi-target inhibitors that can overcome tumor resistance is an urgent problem in the current antitumor drug research. In recent years, oleanolic acid(OA) and its derivatives have attracted much attention because of their anti-tumor, anti-inflammatory,antiviral, anti-infective, immunomodulatory and other biological activities. In this study, we investigated the role of a novel OA derivative ZQL-3 d in breast cancer and its relationship with trastuzumab resistance and its molecular ***: The anticancer effect of ZQL-3 d was detected by CCK8, cell cloning assay, flow cytometry,transwell, and scratch assay, and the expression levels of cell function-related pathway indicators were detected by qPCR and Western blotting and other molecular biology techniques. The micro RNA indicator miR-221-3 p and downstream target ASPP2 related to drug resistance in HER2-positive breast cancer were predicted and screened by bioinformatics, and the correlation was verified by dual luciferase reporter gene assay. To investigate the overcoming effect of ZQL-3 d on trastuzumab resistance in JIMT-1 and the changes of related pathway indicators when transfected with overexpression and silencing of miR-221-3 p and ASPP2, ***: ZQL-3 d was able to exert anticancer effects in breast cancer cells of different molecular fractions,especially in JIMT-1, where ZQL-3 d combined with trastuzumab showed significantly superior antitumor effects than trastuzumab *** miR-221-3 p level was down-regulated after incubation of ZQL-3 d in JIMT-1. JIMT-1 resistance to trastuzumab was alleviated after constructing a silent miR-221-3

关键词： oleanolic acid HER2 Breast cancer Micro RNA Drug resistance

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Glycosylated diazeniumdiolates-based oleanolic acid derivatives:Synthesis and biological evaluation as anti-HCC agents

Glycosylated diazeniumdiolates-based oleanolic acid derivati...

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2011年全国药物化学学术会议——药物的源头创新

作者： Junjie Fu,Zhangjian Huang,Yihua Zhang~* Center of Drug Discovery,China Pharmaceutical University,Nanjing 210009,China.

＜正＞Diazeniumdiolates are a class of important nitric oxide（NO） donors.O2-glycosylated diazeniumdiolates exhibit significantly improved stability as compared to their parent diazeniumdiolate ***,they could be reco... 详细信息

关键词： diazeniumdiolates nitric oxide oleanolic acid anti-HCC apoptosis

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Synthesis and Activity of Mannich Base Derivatives of oleanolic acid

Synthesis and Activity of Mannich Base Derivatives of Oleano...

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2011年全国药物化学学术会议——药物的源头创新

作者：王世盛宋志成宋其玲赵伟杰 School of Pharmaceutical Science and Technology Dalian University of Technology

＜正＞oleanolic acid（OA,1） is a naturally occurring triterpenoid,widely distributed in food and medicinal *** and its synthetic derivatives exhibit anti-HIV,antitumor, anti-inflammatory,hepatoprotective and hypoglyc... 详细信息

关键词： oleanolic acid structural modification Mannich reaction a-glucosidase

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The dual induction of apoptosis and autophagy by SZC013, a synthetic oleanolic acid derivative, in gastric cancer cells

The dual induction of apoptosis and autophagy by SZC013, a s...

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2021年中国肿瘤标志物学术大会暨第十五届肿瘤标志物青年科学家论坛

作者： Yiwen Ma Shisheng Wang Xiaorui Li Jun Yang Tao Sun Cancer Hospital of China Medical University Key Laboratory of Liaoning Breast Cancer Research

Background: oleanolic acid(OA) has a variety of pharmacological effects, such as liver protection, antiinflammatory, anti-oxidation and anti-tumor. However, its relatively weak activity and low bioavailability limit its clinical application. In this study, we synthesized a new OA derivative-SZC013,and the anti-tumor effect in breast cancer cells and the mechanism of action are ***: The MTT method was used to determine the survival rate of breast cancer cells treated with different concentrations of OA and SZCO13. PI staining flow cytometry was used to determine the effect of SZC013 on the cell cycle. Changes in cell morphology and ultrastructure after SZC013 treatment were observed with an inverted phase-contrast microscope and a transmission electron microscope. Western blot was used to determine the changes in the expression of apoptosisrelated proteins and autophagy-related proteins after SZC013 ***: The MTT experiment proved that SCZ013 can inhibit the proliferation of breast cancer cells, and its growth inhibitory effect is stronger than that of OA. PI staining flow cytometry proved that SZC013 induced MCF-7 cell cycle arrest in G2/M phase. Inverted phase contrast microscope and transmission electron microscope proved that apoptosis and autophagy were found in MCF-7 cells treated with SZC013. Western blot results suggested that SZC014 may induce MCF-7 cell apoptosis through the mitochondrial pathway. In addition, the up-regulation of Beclin 1 and ATG 5 induced by SZC013 may be related to the autophagy of MCF-7 ***: SZC013, as a new OA derivative, shows stronger anti-breast cancer activity than OA, and this anti-tumor effect may be related to apoptosis and autophagy.

关键词： oleanolic acid Breast cancer apoptosis autophagy

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