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bavachin induces apoptosis in colorectal cancer cells through Gadd45a via the MAPK signaling pathway

Chinese Journal of Natural Medicines 2023年第1期21卷 36-46页

作者： WANG Mengru TIAN Baopeng SHEN Jie XU Shilin LIU Cong GUAN Ling GUO Min DOU Jie College of Life Science and Technology China Pharmaceutical UniversityNanjing 211198China

bavachin is a dihydroflavonoid compound isolated from Psoralea corylifolia,and exhibits anti-bacterial,anti-inflammatory,anti-tumor and lipid-lowering activities.Recent attention has gradually drawn on bavachin-induced apoptosis in many human cancer cell lines.However,the anti-cancer effects and related mechanisms in colorectal cancer remain unknown.Here,we investigated the effects of bavachin on colorectal cancer in vivo and in vitro.The results showed that bavachin inhibited the proliferation of human colorectal cancer cells and induce apoptosis.These changes were mediated by activating the MAPK signaling pathway,which significantly up-regulated the expression of Gadd45a.Furthermore,Gadd45a silencing obviously attenuated bavachin-mediated cell apoptosis.Inhibition of the MAPK signaling pathway by JNK/ERK/p38 inhibitors also weakened the up-regulation of Gadd45a by bavachin.The anticancer effect of bavachin was also validated using a mouse xenograft model of human colorectal cancer.In conclusion,these findings suggest that bavachin induces the apoptosis of colorectal cancer cells through activating the MAPK signaling pathway.

关键词： bavachin Apoptosis Colorectal cancer Gadd45a MAPK

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A Scd1-mediated metabolic alteration participates in liver responses to low-dose bavachin

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药物分析学报:英文版 2023年第7期13卷 806-816页

作者： Pan Shen Zhi-Jie Bai Lei Zhou Ning-Ning Wang Zhe-Xin Ni De-Zhi Sun Cong-Shu Huang Yang-Yi Hu Cheng-Rong Xiao Wei Zhou Bo-Li Zhang Yue Gao Department of Pharmaceutical Sciences Beijing Institute of Radiation MedicineBeijing100850China State Key Laboratory of Component-based Chinese Medicine Tianjin University of Traditional Chinese MedicineTianjin301617China

Hepatotoxicity induced by bioactive constituents in traditional Chinese medicines or herbs,such as bavachin(BV)in Fructus Psoraleae,has a prolonged latency to overt drug-induced liver injury in the clinic.Several studies have described BV-induced liver damage and underlying toxicity mechanisms,but little attention has been paid to the deciphering of organisms or cellular responses to BV at no-observed-adverse-effect level,and the underlying molecular mechanisms and specific indicators are also lacking during the asymptomatic phase,making it much harder for early recognition of hepatotoxicity.Here,we treated mice with BV for 7 days and did not detect any abnormalities in biochemical tests,but found subtle steatosis in BV-treated hepatocytes.We then profiled the gene expression of hepatocytes and non-parenchymal cells at single-cell resolution and discovered three types of hepatocyte subsets in the BV-treated liver.Among these,the hepa3 subtype suffered from a vast alteration in lipid metabolism,which was characterized by enhanced expression of apolipoproteins,carboxylesterases,and stearoyl-CoA desaturase 1(Scd1).In particular,increased Scd1 promoted monounsaturated fatty acids(MUFAs)synthesis and was considered to be related to BV-induced steatosis and polyunsaturated fatty acids(PUFAs)generation,which participates in the initiation of ferroptosis.Additionally,we demonstrated that multiple intrinsic transcription factors,including Srebf1 and Hnf4a,and extrinsic signals from niche cells may regulate the above-mentioned molecular events in BV-treated hepatocytes.Collectively,our study deciphered the features of hepatocytes in response to BV insult,decoded the underlying molecular mechanisms,and suggested that Scd1 could be a hub molecule for the prediction of hepatotoxicity at an early stage.

关键词： bavachin Hepatotoxicity Scd1 Lipid metabolism Single-cell RNA-Seq

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bavachin enhances NLRP3 inflammasome activation induced by ATP or nigericin and causes idiosyncratic hepatotoxicity

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Frontiers of Medicine 2021年第4期15卷 594-607页

作者： Nan Qin Guang Xu Yan Wang Xiaoyan Zhan Yuan Gao Zhilei Wang Shubin Fu Wei Shi Xiaorong Hou Chunyu Wang Ruisheng Li Yan Liu Jiabo Wang Haiping Zhao Xiaohe Xiao Zhaofang Bai China Military Institute of Chinese Materia the Fifth Medical CentreChinese PLA General HospitalBeijing 100039China Department of Pharmacy Nantong Hospital of Traditional Chinese MedicineNantong 226300China School of Pharmacy Henan University of Chinese MedicineZhengzhou 450046China School of Traditional Chinese Medicine Capital Medical UniversityBeijing 100069China Research Center for Clinical and Translational Medicine the Fifth Medical CentreChinese PLA General HospitalBeijing 100039China School of Traditional Chinese Medicine Jiangxi University of Traditional Chinese MedicineNanchang 330004China Integrative Medical Centre the Fifth Medical CentreChinese PLA General HospitalBeijing 100039China

Psoraleae Fructus(PF)is a well-known traditional herbal medicine in China,and it is widely used for osteoporosis,vitiligo,and other diseases in clinical settings.However,liver injury caused by PF and its preparations has been frequently reported in recent years.Our previous studies have demonstrated that PF could cause idiosyncratic drug-induced liver injury(IDILI),but the mechanism underlying its hepatotoxicity remains unclear.This paper reports that bavachin isolated from PF enhances the specific stimuli-induced activation of the NLRP3 inflammasome and leads to hepatotoxicity.bavachin boosts the secretion of IL-ip and caspase-1 caused by ATP or nigericin but not those induced by poly(I:C),monosodium urate crystal,or intracellular lipopolysaccharide.bavachin does not affect AIM2 or NLRC4 inflammasome activation.Mechanistically,bavachin specifically increases the production of nigericin-induced mitochondrial reactive oxygen species among the most important upstream events in the activation of the NLRP3 inflammasome.bavachin increases the levels of aspartate transaminase and alanine aminotransferase in serum and hepatocyte injury accompanied by the secretion of IL-ip via a mouse model of lipopolysaccharide-mediated susceptibility to IDILI.These results suggest that bavachin specifically enhances the ATP-or nigericin-induced activation of the NLRP3 inflammasome.bavachin also potentially contributes to PF-induced idiosyncratic hepatotoxicity.Moreover,bavachin and PF should be evaded among patients with diseases linked to the ATP-or nigericin-mediated activation of the NLRP3 inflammasome,which may be a dangerous factor for liver injury.

关键词： Psoraleae Fructus bavachin idiosyncratic drug-induced liver injury caspase-1 IL-lp NLRP3 inflammasome

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bavachin改善高脂饮食诱导的非酒精性脂肪肝的作用及机制研究

Bavachin改善高脂饮食诱导的非酒精性脂肪肝的作用及机制研究

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作者：林丽安徽医科大学

学位级别：硕士

bavachin是一类从补骨脂果实中提取的黄酮类化合物，在亚洲各国被用作一种传统中草药。有研究证实bavachin参与调节3T3-L1细胞的胰岛素敏感性，可抑制机体炎症和癌症等疾病发生和发展，与肿瘤和代谢性疾病密切相关。但bavachin是否参与... 详细信息

bavachin是一类从补骨脂果实中提取的黄酮类化合物，在亚洲各国被用作一种传统中草药。有研究证实bavachin参与调节3T3-L1细胞的胰岛素敏感性，可抑制机体炎症和癌症等疾病发生和发展，与肿瘤和代谢性疾病密切相关。但bavachin是否参与肝脏糖脂代谢调节尚无报道。为此，本课题主要研究bavachin在体内外对肝脏糖脂代谢的调节作用。主要通过分离和培养小鼠肝脏原代细胞以及构建非酒精性脂肪肝病模型小鼠，在细胞和动物水平分别给予bavachin处理，以q-PCR和westernblot为主要研究手段，探究了bavachin在细胞和动物水平对于胰岛素敏感性以及在肝脏脂代谢过程中的调节作用。本研究发现，在小鼠肝脏原代细胞中，bavachin处理组可以显著增加胰岛素刺激引起的AKT的磷酸化水平;此外，bavachin处理可以显著降低脂肪酸诱导的细胞TG合成，表现出抑制脂肪合成相关基因的表达。并且在高糖高胰岛素诱导的肝细胞脂肪变性模型中，用bavachin处理后，脂肪合成相关蛋白表达降低，油红染色可见细胞中脂滴较对照组体积变小以及数量减少;在小鼠和人的正常肝细胞系中，bavachin处理组均和上述结果一致。在动物水平，我们证实bavachin可以显著改善由于高脂饮食诱导引起的小鼠脂肪肝症状。IPGTT和IPITT实验结果证实，bavachin改善了高脂饮食诱导的葡萄糖耐受和胰岛素抵抗。上述结果表明bavachin有望成为治疗代谢性疾病，如肥胖、2型糖尿病和非酒精性脂肪肝病的一种新型药物。

关键词：非酒精性脂肪肝病脂肪合成甘油三脂胰岛素敏感性 bavachin

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基于HOTTIP调控骨肉瘤细胞铁死亡机制探讨补骨脂二氢黄酮的抗肿瘤效果

基于HOTTIP调控骨肉瘤细胞铁死亡机制探讨补骨脂二氢黄酮的抗肿瘤...

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作者：丁寿常广州中医药大学

学位级别：硕士

目的:基于长链非编码RNA HOTTIP调控骨肉瘤细胞铁死亡的分子机制,探讨补骨脂二氢黄酮bavachin的抗肿瘤效果。方法:通过查阅文献,发现HOTTIP在骨肉瘤组织中比癌旁组织表达要更高。再对课题组原有HOTTIP KO小鼠骨髓进行转录组测序,分析铁... 详细信息

目的:基于长链非编码RNA HOTTIP调控骨肉瘤细胞铁死亡的分子机制,探讨补骨脂二氢黄酮bavachin的抗肿瘤效果。方法:通过查阅文献,发现HOTTIP在骨肉瘤组织中比癌旁组织表达要更高。再对课题组原有HOTTIP KO小鼠骨髓进行转录组测序,分析铁死亡相关通路的激活情况。进一步在细胞层面验证HOTTIP调控铁死亡的机制,以人骨肉瘤细胞MG63、U20S为研究对象,首先用铁死亡经典诱导剂Erastin、RSL3诱导肿瘤细胞,观察其是否会发生铁死亡,并通过细胞克隆实验检测诱导剂Erastin对细胞增殖能力的影响,细胞活性实验和克隆形成实验都采用铁死亡抑制剂Ferrostatin-1(简称Fer-1)作为回补对照,浓度为2μM,诱导剂Erastin、RSL3浓度分别为10 μM、1μ M;接下来通过Erastin诱导剂诱导骨肉瘤细胞,qPCR实验检测HOTTIP的表达情况。根据qPCR结果接下来分别构建HOTTIP 过表达敲低 U20S-shHOTTIP/shNC、MG63-pHOTTIP/pVector 细胞株,进一步检测细胞活性实验、检测细胞总铁离子、MDA、ROS、GSH等铁死亡相关信号的变化水平,同时检测诱导剂诱导后铁死亡相关蛋白COX2、xCT、GPX4的表达情况。裸鼠原位成瘤实验,在南方医科大学动物中心购买3周龄的雌性裸鼠20只,随机分四组,N=5,饲养7天待裸鼠适应环境后,经由右侧胫骨间隙向股骨骨髓腔注射生长状态良好的U20S-shHOTTIP/shNC细胞株,1.5*106个/只、100μL体积,各10只。待造模9-11天后视肿瘤大小开始给药,腹腔注射铁死亡体内诱导剂Imidazole ketone Erastin(简称IKE,是一类Erastin的衍生物),给药量20mg/kg,注射体积0.lml/10g,以给药第一天为DayO测量肿瘤体积(V=(L*W2)/2),每隔一天给药一次并测量肿瘤体积,监测肿瘤生长率(Tumor growth rate)=Day/Day0*100%,给药后14天处死取材。测量肿瘤重量,取肿瘤组织切片后,免疫组化检测Ki67、GPX4的表达。通过查阅文献,从抗氧化、抗肿瘤的角度出发,找到了祖国传统中医学中临床实践常见的补骨脂二氢黄酮、薯蓣皂苷、二氢姜黄素、没食子酸、人参皂苷Rb3、黄芩苷、甘草苷、虎杖苷等中药单体,参照文献选择相应浓度分别诱导骨肉瘤细胞24h,qPCR实验检测HOTTIP表达水平。再对筛选出的中药进行CCK8实验检测药物的IC50浓度,并以此浓度作为工作浓度进行后续实验。检测药物加药后细胞的增殖水平、总铁、MDA、ROS、GSH 以及 GPX4 的变化情况。再用过表达 HOTTIP 的 MG63-pHOTTIP/pVector进行加药处理,检测过表达HOTTIP后肿瘤细胞在同等加药条件下细胞的增殖水平、总铁、MDA、ROS、GSH以及GPX4的变化情况。综上,先通过体外体内实验研究HOTTIP调控骨肉瘤细胞铁死亡的分子机制,进一步查找到传统中药中能抑制HOTTIP表达进而发挥促进肿瘤细胞铁死亡的中药单体,通过对过表达HOTTIP的MG63-pHOTTIP/pVector进行加药处理,从而探明补骨脂二氢黄酮是否是通过抑制HOTTIP表达促进肿瘤细胞铁死亡从而发挥抗肿瘤作用的。结果:(1)转录组学分析结果提示与WT小鼠相比,KO HOTTIP小鼠多条铁死亡相关通路被异常激活,提示HOTTIP可能与铁死亡相关。(2)细胞活性实验提示Erastin、RSL3诱导后细胞的活性明显降低,但加入抑制剂Fer-1后能缓解这种抑制作用,加入凋亡抑制剂Z-VAD-F-MK、坏死抑制剂Necrosulf-onamide没有缓解;克隆形成实验证明Erastin诱导后肿瘤增殖能力明显减弱,但加入抑制剂Fer-1后能缓解这种作用。细胞活性实验和克隆形成实验都表明骨肉瘤细胞会发生铁死亡。(3)对骨肉瘤细胞系MG63、U20S进行Erastin诱导处理,发现经Erastin诱导后HOTTIP水平都明显降低,且MG63降低水平较U20S更高。因此,对MG63细胞系过表达HOTTIP,U20S细胞系敲低HOTTIP处理。(4)通过对构建的HOTTIP敲低U20S-shHOTTIP/shNC细胞株进行诱导剂处理,检测细胞活性水平、总铁、MDA、ROS、GSH以及铁死亡相关蛋白COX2、xCT、GPX4表达水平。细胞活性实验提示在同等水平的铁死亡诱导剂Erastin、RSL3诱导下,shHOTTIP细胞株与shNC细胞株都发生了铁死亡,并且相比于未敲低的shNC组,敲低的shHOTTIP组细胞存活率明显更低,铁死亡抑制剂Fer-1回补的效果也更弱一些,说明敲低HOTTIP抑制了骨肉瘤细胞的增殖。在检测细胞Total Fe、MDA、ROS水平的实验中发现,在同

关键词：骨肉瘤铁死亡 HOTTIP bavachin 脂质过氧化损伤

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