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No Incidence of Liver Cancer Was Observed in A Retrospective Studyof Patients with Aristolochic Acid Nephropathy

Chinese Journal of Integrative Medicine 2024年第2期30卷 99-106页

作者： SU Tao FANG Zhi-e GUO Yu-ming WANG Chun-yu WANG Jia-bo JI Dong BAI Zhao-fang YANG Li xiao xiao-he Renal Division Department of MedicinePeking University First HospitalBeijing(100034)China Department of Pharmacy Chongqing Hospital of Traditional Chinese MedicineChongqing(400021)China Department of hepatology Fifth Medical Center of Chinese PLA General HospitalBeijing(100039)China China Military Institute of Chinese Materia Fifth Medical Center of Chinese PLA General HospitalBeijing(100039)China Phase I Clinical Trials Unit Department of Medicine for Infectious DiseasesFifth Medical Center of Chinese PLA General HospitalBeijing(100039)China Department of Pharmacy Affiliated Hospital of Shandong University of Traditional Chinese MedicineJinan(250000)China National Key Laboratory of Kidney Diseases Beijing(100039)China

Objective:To assess the risk of aristolochic acid(AA)-associated cancer in patients with AA nephropathy(AAN).Methods:A retrospective study was conducted on patients diagnosed with AAN at Peking University First Hospital from January 1997 to December ***-term surveillance and follow-up data were analyzed to investigate the influence of different factors on the prevalence of *** primary endpoint was the incidence of liver cancer,and the secondary endpoint was the incidence of urinary cancer during 1 year after taking AA-containing medication to ***:A total of 337 patients diagnosed with AAN were included in this *** the initiation of taking AA to the termination of follow-up,39 patients were diagnosed with *** cases of liver cancer were observed throughout the entire follow-up period,with urinary cancer being the predominant type(34/39,87.17%).Logistic regression analysis showed that age,follow-up period,and diabetes were potential risk factors,however,the dosage of the drug was not significantly associated with urinary ***:No cases of liver cancer were observed at the end of ***,a high prevalence of urinary cancer was observed in AAN *** a direct causality between AA and HCC is challenging.

关键词： aristolochic acid hepatocellular carcinoma urinary cancer drug safety retrospective study

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Inhibition of hepatitis B virus via selective apoptosis modulation by Chinese patent medicine Liuweiwuling Tablet

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World Journal of Gastroenterology 2024年第13期30卷 1911-1925页

作者： Fei-Lin Ge Yan Yang Lan-Lan Si Yuan-Hua Li Meng-Zhen Cao Jun Wang Zhao-Fang Bai Zhi-Gang Ren xiao-he xiao Yan Liu Department of Chinese Medicine State Key Laboratory of Antiviral DrugsThe First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052Henan ProvinceChina The Fifth Medical Center of Chinese PLA General Hospital Beijing 100039China College of Traditional Chinese Medicine Chongqing Medical UniversityChongqing 400010China Beijing Key Laboratory of Emerging Infectious Diseases Peking University Ditan Teaching HospitalBeijing 100015China Department of Infectious Diseases State Key Laboratory of Antiviral Drugsthe First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052Henan ProvinceChina

BACKGROUND Liuweiwuling Tablet(LWWL)is a Chinese patent medicine approved for the treatment of chronic inflammation caused by hepatitis B virus(HBV)*** studies have indicated an anti-HBV effect of LWWL,specifically in terms of antigen inhibition,but the underlying mechanism remains *** To investigate the potential mechanism of action of LWWL against *** In vitro experiments utilized three HBV-replicating and three non-HBV-replicating cell *** in vivo experiment involved a hydrodynamic injectionmediated mouse model with HBV *** and metabolomics were used to investigate the underlying mechanisms of action of *** In hepG2.1403F cells,LWWL(0.8 mg/mL)exhibited inhibitory effects on HBV DNA,hepatitis B surface antigen and pregenomic RNA(pgRNA)at rates of 51.36%,24.74%and 50.74%,*** inhibition rates of LWWL(0.8mg/mL)on pgRNA/covalently closed circular DNA in hepG2.1403F,hepG2.2.15 and hepG2.A64 cells were 47.78%,39.51%and 46.74%,*** of transcriptomics and metabolomics showed that the anti-HBV effect of LWWL was primarily linked to pathways related to apoptosis(PI3K-AKT,CASP8-CASP3 and P53 pathways).Apoptosis flow analysis revealed that the apoptosis rate in the LWWL-treated group was significantly higher than in the control group(CG)among HBV-replicating cell lines,including hepG2.2.15(2.92%±1.01%vs 6.68%±2.04%,PhepG2.A64(4.89%±1.28%vs 8.52%±0.50%,PhepG2.1403F(3.76%±1.40%vs 7.57%±1.35%,Phere were no significant differences in apoptosis rates between the non-HBV-replicating hepG2 cells(5.04%±0.74%vs 5.51%±1.57%,P>0.05),L02 cells(5.49%±0.80%vs 5.48%±1.01%,P>0.05)and LX2 cells(6.29%±1.54%vs 6.29%±0.88%,P>0.05).TUNEL staining revealed a significantly higher apoptosis rate in the LWWL-treated group than in the CG in the HBVreplicating mouse model,while no noticeable difference in apoptosis rates between the two groups

关键词： hepatitis B virus Chinese patent medicine Antiviral activity Antiviral mechanism Selective apoptosis

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Compatibility with Fructus Ligustri Lucidi Effectively Mitigates Idiosyncratic Liver Injury of Epimedii Folium by Modulating NOD-like Receptor Family Pyrin Domain Containing 3 Inflammasome Activation

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World Journal of Traditional Chinese Medicine 2024年第2期10卷 159-170页

作者： xiao-Mei Zhao Zhi-Xin Wu Yan Wang Ying-Jie Xu Ye Xiu Xu Dong Jun-Jie Li Gui-Ji Lv Si-Hao Wang Yu-Rong Li Zhao-Fang Bai xiao-he xiao Department of Pharmacy Chengdu University of Traditional Chinese MedicineChengdu China Department of hepatology The Fifth Medical Center of PLA General HospitalBeijingChina Department of Military Patient Management The Fifth Medical Center of PLA General HospitalBeijingChina Department of hepatology China Military Institute of Chinese Materia The Fifth Medical Center of PLA General HospitalBeijingChina Departmentof hepatology National Key Laboratory of Kidney DiseasesBeijingChina

Background: Idiosyncratic drug-induced liver injury(IDILI) is a serious side effect of drugs, Epimedii Folium(EF) is unequivocally implicated in idiosyncratic liver injury onset, potentially due to its ability to perturb the NOD-like receptor family pyrin domain containing 3(NLRP3) inflammasome. Fructus Ligustri Lucidi(FLL), a frequently used medicinal combination with EF, has not yet been investigated for its ability to ameliorate EF-associated hepatotoxicity. Aims and Objectives: Study on the mechanism of compatibility of FLL to alleviate liver injury caused by EF. Materials and Methods: Western blot was used to determine the expression of related proteins, ELISA was used to detect the secretion of related inflammatory factors IL-1β, IL-18, IL-6 and TNF-α, liver injury indexes were detected and liver pathological tissue staining was used to evaluate the liver injury. Results: Our results demonstrated that EF exerted a particular augmenting effect on the stimulation of the NLRP3 inflammasome mediated by nigericin or ATP, whereas FLL suppressed the NLRP3 inflammasome stimulation. Furthermore, an equal EF to FLL ratio significantly reduced the stimulatory effects of EF. Moreover, EF has the potential to induce hepatic injury and augment pro-inflammatory cytokine synthesis in rats subjected to LPS. However, when combined with FLL, the detrimental effects of EF were mitigated. Conclusions: FLL possesses the capacity to attenuate EF-associated hepatotoxicity by suppressing EF-triggered NLRP3 inflammasome activation. Thus, FLL holds promise for improving the clinical safety profile of EF, shedding light on the potential of compatibility and detoxification theories in traditional Chinese medicine.

关键词： Epimedii Folium Fructus Ligustri Lucidi idiosyncratic drug-induced liver injury NOD-like receptor family pyrin domain containing 3 inflammasome traditional Chinese medicine

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Traffic anomaly detection algorithm for CAN bus using similarity analysis Chao Wang,Xueqiao Xu∗,Ke xiao,Yunhua he,Guangcan Yang School of Information Science and Technology,Traffic anomaly detection algorithm for CAN bus using similarity analysis

High-Confidence Computing

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High-Confidence Computing 2024年第3期4卷 64-74页

作者： Chao Wang Xueqiao Xu Ke xiao Yunhua he Guangcan Yang School of Information Science and Technology North China University of TechnologyBeijing 100144North China University of TechnologyBeijing 100144

Recently,vehicles have experienced a rise in networking and informatization,leading to increased security *** the most widely used automotive bus network,the Controller Area Network(CAN)bus is vulnerable to attacks,as security was not considered in its original *** paper proposes SIDuBzip2,a traffic anomaly detection method for the CAN bus based on the bzip2 compression *** proposed method utilizes the pseudo-periodic characteristics of CAN bus traffic,constructing time series of CAN IDs and calculating the similarity between adjacent time series to identify abnormal *** method consists of three parts:the conversion of CAN ID values to characters,the calculation of similarity based on bzip2 compression,and the optimal solution of model *** experimental results demonstrate that the proposed SIDuBzip2 method effectively detects various attacks,including Denial of Service,replay,basic injection,mixed injection,and suppression *** addition,existing CAN bus traffic anomaly detection methods are compared with the proposed method in terms of performance and delay,demonstrating the feasibility of the proposed method.

关键词： Automotive safety CAN bus Anomaly detection

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基于HLA-B*35∶01的何首乌致免疫特异质肝损伤易感成分预测

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中国新药杂志 2024年第4期33卷 351-359页

作者：吴承钊高云娟牛明王伽伯母光頔赵旭肖小河成都中医药大学药学院成都611137 中国人民解放军总医院第五医学中心全军中医药研究所北京100039 中国人民解放军总医院第五医学中心血液病医学部北京100071 首都医科大学中医药学院北京100069 中国人民解放军总医院第五医学中心肝病医学部北京100039

目的:何首乌致肝损伤与HLA-B*35∶01等位基因密切相关,本研究借助机器学习和分子对接技术初步探索何首乌中潜在的HLA-B*35∶01易感成分。方法:通过检索文献和相关数据库,收集不良反应(ADR)与人类的主要组织相容性复合体(HLA)等位基因具... 详细信息

目的:何首乌致肝损伤与HLA-B*35∶01等位基因密切相关,本研究借助机器学习和分子对接技术初步探索何首乌中潜在的HLA-B*35∶01易感成分。方法:通过检索文献和相关数据库,收集不良反应(ADR)与人类的主要组织相容性复合体(HLA)等位基因具有相关性的药物作为阳性数据集,未发现相关性的作为阴性数据集,利用PaDEL-Descriptor软件计算分子描述符,采用朴素贝叶斯(Na6ve Bayes)构建二分类模型。利用模型预测何首乌中与HLA相关的ADR风险成分,并结合分子对接技术进一步分析其与HLA-B*35∶01蛋白晶体的结合能力以及结合模式。结果:使用Na6ve Bayes算法构建的二分类模型平均准确率(ACC)为0.750,利用模型从何首乌41种成分中识别出了28种可能引起与HLA相关的ADR成分。分子对接结果显示何首乌中10种成分与HLA-B*35∶01均具有较好的结合能力。多肽对接结果分析,反式二苯乙烯苷、大黄素-1-O-β-D-葡萄糖苷、大黄素甲醚-8-O-β-D-葡萄糖苷3种成分能够使非HLA-B*35∶01呈递肽P1(LPEPLPQGQLTAY)和P2(EECDSELEIKRY)的亲和性提高,并且与P1和P2间具有优势相互作用。结论:研究基于化学描述符构建分类预测模型,并结合分子对接技术预测何首乌中潜在的3种HLA-B*35∶01易感成分,辅助何首乌特异质肝损伤(IDILI)成分研究。

关键词：特异质型肝损伤人类白细胞抗原何首乌预测方法

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免疫应激介导的朝藿定B协同补骨脂甲素导致特异质肝损伤的拟靶向代谢组学研究

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中国中药杂志 2024年第2期49卷 443-452页

作者：林蒙蒙李蓥滢曹波徐静肖小河李国辉李春雨国家癌症中心国家肿瘤临床医学研究中心中国医学科学院北京协和医学院肿瘤医院北京100021 解放军总医院第五医学中心北京100039

补骨脂和淫羊藿是临床常用药对,既往研究显示两药可能引起特异质肝损伤,然而其物质基础以及发生机制尚不清楚。该研究基于肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)介导的免疫应激小鼠模型,以补骨脂及淫羊藿中2个主要化学成分... 详细信息

补骨脂和淫羊藿是临床常用药对,既往研究显示两药可能引起特异质肝损伤,然而其物质基础以及发生机制尚不清楚。该研究基于肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)介导的免疫应激小鼠模型,以补骨脂及淫羊藿中2个主要化学成分补骨脂甲素和朝藿定B为研究对象,通过检测细胞上清液中乳酸脱氢酶(lactate dehydrogenase,LDH)释放量和小鼠血浆中丙氨酸氨基转氨酶(alanine aminotransferase,ALT)、天冬氨酸氨基转氨酶(aspartate transaminase,AST)含量,苏木精-伊红(hematoxylin-eosin,he)染色观察肝脏病理学变化情况,分别在细胞及动物水平评估补骨脂甲素联合朝藿定B引起肝损伤的程度。借助拟靶向代谢组学技术和多元统计分析方法,考察给药前后小鼠血浆中内源性代谢物的影响,筛选差异代谢标志物,并进行京都基因与基因组百科全书(Kyoto Encyclopedia of Genes and Genomes,KEGG)富集通路分析。结果表明,在细胞水平,使用TNF-α刺激2 h后,相较于正常组及单独给药组,补骨脂甲素可以使hepG2细胞中LDH释放量显著增加;补骨脂甲素联合朝藿定B后,LDH释放量在原来基础上进一步显著增加。在动物水平,对于正常小鼠,单独或联合补骨脂甲素均不引起肝损伤;对于免疫应激模型小鼠,单独给药补骨脂甲素或者朝藿定B均可引起肝损伤,补骨脂甲素或者朝霍定B联合给药时肝损伤进一步增强,表现为小鼠血浆中ALT、AST含量显著升高,并伴随肝脏组织大量炎性免疫细胞浸润。基于拟靶向代谢组学技术,筛选得到7个共有差异代谢物,根据受试者操作特性(receiver operating characteristic,ROC)曲线分析结果,其中曲线下面积(area under curve,AUC)大于0.9的包括D-氨基葡萄糖6-磷酸、N1-甲基-2-吡咯-5-甲酰胺、17β-硝基-5a-雄甾烷、葛花苷元-7-O-葡萄糖醛酸苷、N-(1-脱氧-1-果糖基)缬氨酸。因此,这5个差异代谢物可能是潜在的生物标志物。此外,烟酸盐和烟酰胺代谢及亚油酸代谢通路可能是补骨脂甲素联合朝藿定B诱导特异质肝损伤的关键代谢通路。综上,在TNF-α介导免疫应激的条件下,朝藿定B联合补骨脂甲素导致机体代谢扰动可能是二者协同导致特异质性药物性肝损伤(idiosyncratic drug-induced liver injury,IDILI)的重要机制。

关键词：中成药补骨脂甲素朝藿定B 特异质肝损伤肿瘤坏死因子-α 拟靶向代谢组学

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药学学报 2024年第3期59卷 621-632页

作者：李蓥滢林蒙蒙曹波李莹徐静肖小河李国辉李春雨国家癌症中心/国家肿瘤临床医学研究中心/中国医学科学院北京协和医学院肿瘤医院北京100021 解放军总医院第五医学中心北京100039

特异质药物性肝损伤(IDILI)一直是药物研究的难点和热点。囿于中药成分的复杂,中药相关IDILI物质基础的阐明已成为目前研究的瓶颈问题。本研究以淫羊藿和补骨脂为例,通过建立体外评价模型,拟为初步筛选中药相关IDILI成分提供一种高通量... 详细信息

特异质药物性肝损伤(IDILI)一直是药物研究的难点和热点。囿于中药成分的复杂,中药相关IDILI物质基础的阐明已成为目前研究的瓶颈问题。本研究以淫羊藿和补骨脂为例,通过建立体外评价模型,拟为初步筛选中药相关IDILI成分提供一种高通量的评价方法。本研究首先建立TNF-α介导的hepG2细胞易感模型,以淫羊藿和补骨脂所含指标成分为研究对象,以细胞上清液中乳酸脱氢酶(LDH)释放量为检测指标,构建浓度−毒性响应曲线,并结合协同毒性指数确定两种中药中所含成分的协同毒性作用及强弱关系。LDH测定结果表明,补骨脂甲素、补骨脂酚、补骨脂定、补骨脂乙素、异补骨脂二氢黄酮、新补骨脂异黄酮、淫羊藿次苷I和淫羊藿次苷II对正常细胞和易感状态下的细胞均具有毒性作用,即这些成分既是直接肝损伤成分,又是特异质肝损伤成分;其中补骨脂甲素和新补骨脂异黄酮对正常细胞无毒性作用,但是在易感状态下有明显的细胞毒性作用,即二者为潜在特异质肝损伤易感成分。随后,本研究以补骨脂甲素为代表筛选免疫促进肝损伤成分。结果显示,淫羊藿中10种成分与补骨脂中3种成分属于直接免疫促进肝损伤成分;而特异质免疫促进肝损伤成分在淫羊藿中有10种,补骨脂中有4种;其中新补骨脂异黄酮、补骨脂定和异补骨脂二氢黄酮属于潜在的特异质免疫促进肝损伤易感成分。协同毒性指数结果显示,13种特异质免疫促进肝损伤成分(除脱水淫羊藿素外)与补骨脂甲素联用具有协同增毒作用;3种特异质免疫促进肝损伤易感成分与补骨脂甲素联用具有协同增毒作用,其中与新补骨脂异黄酮联用协同毒性指数最大,而与补骨脂定联用协同毒性指数最小。综上,该方法可成功筛选淫羊藿和补骨脂中肝损伤成分及免疫促进肝损伤成分,并可以区分肝损伤成分类型、各成分的毒性强弱程度和协同作用关系,符合IDILI的特点,以期为中药相关IDILI物质基础研究提供一种有效模型工具。

关键词：淫羊藿补骨脂特异质药物性肝损伤肝损伤成分免疫促进肝损伤成分

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基于NLRP3炎症小体探讨白芍总苷胶囊改善急性肺损伤的作用机制

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中国中药杂志 2024年第10期49卷 2754-2765页

作者：许颖杰王贤玲牟文清文金财王炎修叶董旭李俊杰湛小燕肖小河柏兆方大理大学药学院云南大理671000 中国人民解放军总医院第五医学中心肝病医学部北京100039 道地药材品质保障与资源持续利用全国重点实验室北京100700

基于NOD样受体热蛋白结构域相关蛋白3(NOD-like receptor thermal protein domain associated protein 3,NLRP3)炎症小体信号通路探讨白芍总苷胶囊(total glucosides of White Paeony Capsules,TGP)对急性肺损伤(acute lung injury,ALI)模型小鼠的改善作用及分子机制。在小鼠原代骨髓巨噬细胞(bone marrow-derived macrophages,BMDMs)上建立NLRP3炎症小体活化模型,通过蛋白免疫印迹(Western blot,WB)、免疫荧光染色、酶联免疫吸附实验(enzyme-linked immunosorbent assay,ELISA)和流式细胞术探究其分子机制。将C57BL/6J小鼠随机分为空白组、TGP组、模型组(LPS组)、LPS+TGP低剂量组、LPS+TGP高剂量组、LPS+MCC950组、LPS+MCC950+TGP组,每组8只,建立小鼠ALI模型。最后,收集肺泡灌洗液(bronchoalveolar lavage fluid,BALF)以及肺组织。测定各组小鼠肺指数及肺重湿干比,通过苏木精-伊红(he)染色技术分析肺部组织的病理学变化,使用流式细胞术检测各组BALF中中性粒细胞数量,采用ELISA法测定BALF中白细胞介素(interleukin,IL)-1β、IL-6、肿瘤坏死因子(tumor necrosis factor,TNF)-α含量,实时荧光定量PCR(quantitative real-time,RT-qPCR)法测定肺组织中IL-1β、IL-18、IL-6、TNF-α的基因表达。结果表明TGP通过抑制上游线粒体活性氧(mitochondrial reactive oxygen species,mtROS)的产生以及随后的凋亡相关斑点(apoptosis-associated speck,ASC)的寡聚化,显著阻断了NLRP3炎症小体的激活。此外,在小鼠ALI模型中,与空白组相比,模型组肺组织出现肺泡结构破裂,肺泡间隔增厚,肺指数及肺重湿干比明显增高,中性粒细胞数量显著增加,炎性因子水平明显升高;与模型组相比,TGP和MCC950各组的肺组织病理形态明显改善,肺指数和肺重湿干比明显减低,中性粒细胞数量显著减少,炎性因子水平显著下调;值得注意的是,与MCC950组相比,MCC950+TGP组效果无明显差异。综上,该研究揭示了白芍总苷胶囊可能是通过抑制NLRP3炎症小体的激活从而改善小鼠ALI,也提供了一种安全有效的防治ALI/ARDS的候选药物。

关键词：白芍总苷胶囊 NLRP3炎症小体线粒体活性氧 ASC寡聚化脂多糖诱导的急性肺损伤

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Excessive Intake of Gardenia Pigments Requires Vigilance against Accumulation Risk

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Chinese Journal of Integrative Medicine 2022年第6期28卷 545-546页

作者： he Ting-ting xiao xiao-he WANG Jia-bo Senior Department of hepatology the Fifth Medical Center of Chinese PLA General HospitalBeijing100039China School of Traditional Chinese Medicine Capital Medical UniversityBeijing100069China

Gardenia pigments are widely used as additives in food and consequently people suffer from daily overexposure to these pigments,especially in case they consume dietary supplements that use derivatives of Gardenia *** have observed a very unusual adverse reaction clinically,due to herbal and dietary supplement consumption,characterized by bluegreen pigmentation around the eyes(i.e.a distinctive"gardenia blue"facial appearance).

关键词： unusual consequently herbal

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Integrative medicine in the era of cancer immunotherapy: Challenges and opportunities

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Journal of Integrative Medicine 2021年第4期19卷 291-294页

作者： Ning Zhang xiao-he xiao Department of Liver Disease the Fifth Medical Center of Chinese People's Liberation Army General HospitalBeijing 100039China

Cancer immunotherapy has led to a new era of cancer treatment strategies, and transforming healthcare for cancer patients. Meanwhile, reports of immune-related adverse events have been increasing, greatly hindering the use of cancer immunotherapy. Traditional Chinese medicine(TCM), which has been widely used in Asian countries for thousands of years, is known to play a complementary role in the treatment of cancer. Taken in combined with conventional modern therapies, such as resection, ablation and radiotherapy, TCM exerts its main anti-cancer effects in two ways: health-strengthening(Fu-Zheng) and pathogen-eliminating(Qu-Xie). Theoretically, pathogen-eliminating TCM can promote the release of tumor-related antigens and should be able to increase the effect of immunotherapy, while healthstrengthening TCM may have immune-enhancing mechanisms that overlap with immunotherapy. In the era of cancer immunotherapy, it is important to balance the use of TCM and immunotherapy, with the goal of enhancing immune efficacy and antagonizing immune toxicity. In this article, we discuss this issue by considering the mechanism of tumor immunotherapy, alongside the theoretical basis of TCM treatment of tumors, with the aim of bringing new insights to future research in this field.

关键词： Cancer Immunotherapy Traditional Chinese medicine Risk prevention Treatment pattern

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