CHEMICAL TPANSFORMATION OF TRIPTOLIDE

Triptolide(1) gave 2-9 under various conditions specified in the text.

Triptolide protects against 1-methyl-4-phenyl pyridinium-induced dopaminergic neurotoxicity in rats:Implication for immunosuppressive therapy in Parkinson’s disease

Objective Neuroinflammation with microglial activation has been implicated to have a strong association with the progressive dopaminergic neuronal loss in Parkinson＇s disease （PD）. The present study was undertaken to evaluate the activation profile of microglia in 1-methyl-4-phenyl pyridinium （MPP^＋）-induced hemiparkinsonian rats. Triptolide, a potent immunosuppressant and microglia inhibitor, was then examined for its efficacy in protecting dopaminergic neurons from injury and ameliorating behavioral disabilities induced by MPP^＋. Methods The rat model of PD was established by intranigral microinjection of MPP^＋. At baseline and on day 1, 3, 7, 14, 21 following MPP^＋ injection, the degree of microglial activation was examined by detecting the immunodensity of OX-42 （microglia marker） in the substantia nigra （SN）. The number of viable dopaminergic neurons was determined by measuring tyrosine hydroxylase （TH） positive neurons in the SN. Behavioral performances were evaluated by counting the number of rotations induced by apomorphine, calculating scores of forelimb akinesia and vibrissae-elicited forelimb placing asymmetry. Results Intranigral injection of MPP^＋ resulted in robust activa- tion of microglia, progressive depletion of dopaminergic neurons, and ongoing aggravation of behavioral disabilities in rats. Triptolide significantly inhibited microglial activation, partially prevented dopaminergic cells from death and improved behavioral performances. Conclusion These data demonstrated for the first time a neuroprotective effect of triptolide on dopaminergic neurons in MPP^＋ induced hemiparkinsonian rats. The protective effect of triptolide may, at least partially, be related to the inhibition of MPP^＋-induced microglial activation. Our results lend strong support to the use of immunosuppressive agents in the management of PD.

16-Hydroxytriptolide" An Active Compound from Tripterygium wilfordii

From the dried roots and leaves of Tripterygium wilfordii^(1.2),a new diter- penoid triepoxide,16-hydroxytriptolide was isolated,and its structure and stereochemistry elucidated as 16-(S)-hydroxy-triptolide on the basis of spectral data(IR, MS, UV,~1HNMR,^(13)CNMR,2d-NMR,Selective Long-range DEPT)and x-ray crystallographic analysis.This compound showed definite antiinflammatory action,strong immunosuppressive and antifertile activities.In addition,a known compound,triptolide was also isolated and all the spectral signals of^1 HNMR and ^(13)CNMR were assigned.

西北农林科技大学生命科学学院研究团队发现小分子药物triptolide诱导细胞自噬的新机制

2015年12月29日,Oncotarget杂志（IF=6.359）在线发表西北农林科技大学生命科学学院雷鸣教授课题组的最新研究成果“Triptolide induces protective autophagy through activation of the CaMKKβ-AMPK signaling pathway in prostate cancer cells”（DOI：10.18632/oncotarget.6783）。

地西他滨治疗老年骨髓增生异常综合征的疗效以及与TP53基因突变的相关性

目的探讨不同剂量地西他滨治疗老年骨髓增生异常综合征(MDS)的疗效及不良反应,以及TP 53突变对疗效的影响。方法选取本院2020年4月至2022年5月收治的MDS病人共52例,所有病人按照入院先后及适应证分为A组(地西他滨20 mg/d×5 d)28例、B组(地西他滨10 mg/d×10 d)24例,比较2组6周期治疗结束后的临床疗效、不良反应以及地西他滨疗效与TP 53基因突变之间的相关性。结果A组总有效率为39.3%,B组总有效率为37.5%,2组总有效率差异无统计学意义。2组3~4级中性粒细胞减少、3~4级血小板减少、3~4级贫血发生率差异无统计学意义;2组感染、肝脏受损、发热、胃肠道反应发生率差异无统计学意义。TP 53突变型组治疗总有效率为83.3%,TP 53野生型组有效率为12.9%,2组差异有统计学意义(P<0.01)。结论地西他滨20 mg/d×5 d和地西他滨10 mg/d×10 d治疗方案的总有效率相当,不良反应发生率相当,但TP 53突变型病人对地西他滨的反应率明显高于野生型。

奥希替尼联合培美曲塞/铂类对表皮生长因子受体合并TP53基因突变的非小细胞肺癌疗效及预后分析

目的探究奥希替尼联合培美曲塞/铂类对EGFR合并TP53突变的非小细胞肺癌(NSCLC)疗效及预后分析。方法选取中国人民解放军联勤保障部队第904医院在2016年1月至2022年6月间诊治的80例表皮生长因子受体合并TP53基因突变的NSCLC患者纳入本次研究,随机数字法分为对照组(40例)和研究组(40例)。对照组行奥希替尼治疗,研究组行奥希替尼联合培美曲塞/铂类化疗治疗。对两组临床疗效、血清指标水平、用药安全性以及预后进行对比分析。结果研究组总缓解率(ORR)和疾病控制率(DCR)均优于对照组(P<0.05)。治疗后,两组细胞角蛋白19片段(CYFRA21-1)、癌胚抗原(CEA)水平均低于治疗前(P<0.05),研究组低于对照组(P<0.05)。治疗后,两组白细胞介素4(IL-4)、血管内皮生长因子(VEGF)、细胞间黏附分子-1(ICAM-1)水平均低于治疗前(P<0.05),研究组低于对照组(P<0.05)。两组不良反应差异无统计学意义(P>0.05)。研究组随访1年后的生存率明显高于对照组(P<0.05)。治疗后,两组生存质量测定表(EORTC QLQ-C30)评分高于治疗前(P<0.05),研究组高于对照组(P<0.05)。结论奥希替尼联合培美曲塞/铂类化疗方案用于EGFR合并TP53基因突变的NSCLC的临床治疗,可有效发挥抗肿瘤效果,下调炎症水平,提升疗效,改善患者预后,且用药具有较高安全性,不会明显增加不良反应。

贝伐珠单抗联合TP化疗方案治疗晚期NSCLC的疗效

目的观察贝伐珠单抗联合TP化疗方案治疗晚期非小细胞肺癌(NSCLC)的临床疗效。方法回顾性选取2020年1月-2022年12月滨州市中心医院收治的晚期NSCLC患者60例,依据用药方法不同分为TP化疗组(n=30)、联合化疗组(n=30)。TP化疗组患者采用TP化疗方案治疗,联合化疗组患者在TP化疗组基础上给予贝伐珠单抗注射液治疗,2组均以3周为1个周期,共治疗4个周期。比较2组近期疗效,化疗前后肿瘤标志物(癌胚抗原、糖类抗原125、细胞角蛋白19片段抗原21-1、神经元特异性烯醇化酶)、血管生成促进因子[碱性成纤维细胞生长因子(bFGF)、血管内皮生长因子(VEGF)]、免疫指标(CD3^(+)、CD4^(+)、CD8^(+)、CD4^(+)/CD8^(+))、视觉模拟评分法(VAS)评分、生活质量评定量表(QOL)评分,不良反应,中位生存期,无进展生存期。结果联合化疗组疾病控制率为96.67%,高于TP化疗组的73.33%(χ^(2)=4.706,P=0.030)。化疗4个周期后,2组癌胚抗原、糖类抗原125、细胞角蛋白19片段抗原21-1、神经元特异性烯醇化酶、bFGF、VEGF水平低于化疗前,且联合化疗组低于TP化疗组(P<0.05或P<0.01);2组CD3^(+)、CD4^(+)、CD4^(+)/CD8^(+)高于化疗前,CD8^(+)低于化疗前,且联合化疗组高/低于TP化疗组(P<0.01);2组VAS评分低于化疗前,QOL评分高于化疗前,且联合化疗组低/高于TP化疗组(P<0.01)。TP化疗组与联合化疗组不良反应发生率比较,差异无统计学意义(P>0.05)。联合化疗组中位生存期、无进展生存期长于TP化疗组(P<0.01)。结论贝伐珠单抗与TP化疗方案联合应用于晚期NSCLC的治疗,效果显著,能有效降低患者的肿瘤标志物水平,提高免疫功能,抑制肿瘤进展,并提升生活质量,可延长患者的生存期,且不会增加不良反应。

贵阳市MSM人群中HIV、TP、HSV-2感染的实验结果分析

目的分析贵阳市男男性行为者(MSM)人群中HIV、TP及HSV-2感染的实验检测结果,为该人群的艾滋病防控工作提供参考依据。方法通过同伴推动抽样法招募MSM人员为调查对象,对其血液样本进行HIV、TP及HSV-2检测,并分析实验检测结果。结果577例研究对象中,共发现HIV抗体阳性者、TP特异性抗体阳性者及HSV-2抗体阳性者116例(20.1%)、107例(18.5%)、74例(12.8%);HIV^(+)TP、HIV^(+)HSV-2、TP^(+)HSV-2以及HIV^(+)TP^(+)HSV-2合并感染者24例(4.2%)、8例(1.4%)、11例(1.9%)、20例(3.5%)。实验检测结果分析表明,新发现HIV感染者的WB试验各个反应带型频率不一,带型组合多样化;CD4^(+)T淋巴细胞绝对值计数最小为10个/μL,最大为914个/μL,平均值为(316.2±160.6)个/μL。病毒载量最高值>7 log_(10)/mL,最低值为1.5 log_(10)/mL,平均值为(4.3±0.9)log_(10)/mL。结论贵阳市MSM人群HIV、TP及HSV-2的感染率较高,合并感染情况较为严重,防治形势严峻,应加强本地区MSM人群的HIV、TP及HSV-2防治工作;同时应结合检测结果制定相关的治疗及防治措施,提高感染者的健康水平。

信迪利单抗联合TP化疗方案治疗对晚期非小细胞肺癌患者肿瘤标志物和免疫平衡的影响

目的:探讨信迪利单抗联合紫杉醇+顺铂(Taxol+Platinum,TP)化疗方案治疗晚期非小细胞肺癌(non small cell lung cancer,NSCLC)患者的效果及对肿瘤标志物、免疫平衡的影响。方法:选择2022年1月—2023年9月寿光市人民医院接收的88例晚期NSCLC患者,根据随机数字表法分为对照组(TP化疗)、观察组(TP化疗联合信迪利单抗),各44例。比较两组疾病缓解效率、肿瘤标志物、免疫指标、不良反应发生情况。结果:观察组疾病总缓解率为84.09%,高于对照组的59.09%,差异有统计学意义(P<0.05)。治疗前,两组糖类抗原125(carbohydrate antigen 125,CA125)、糖类抗原153(carbohydrate antigen 153,CA153)、癌胚抗原(carcinoembryonic antigen,CEA)、CD3^(+)、CD4^(+)、CD8^(+)比较,差异均无统计学意义(P>0.05);治疗后,观察组CA125、CA153、CEA、CD8^(+)均低于对照组,而CD3^(+)、CD4^(+)均高于对照组,差异均有统计学意义(P<0.05)。两组不良反应总发生率比较,差异无统计学意义(P>0.05)。结论:TP化疗联合信迪利单抗治疗晚期NSCLC的缓解效果显著,能够进一步下调肿瘤标志物表达,调节免疫平衡,安全性高。

老年胃癌患者癌组织KLF17、TP53蛋白表达及临床意义

目的观察老年胃癌患者组织Krüppel样因子17(KLF17)、TP53蛋白表达及分析其临床意义。方法选取2021年9月—2023年5月哈尔滨医科大学附属第四医院消化内科接诊的108例老年胃癌病例,采用免疫组织化学法测定患者的癌组织、癌旁组织KLF17、TP53蛋白表达,并分析其与胃癌患者临床病理参数、预后的相关性。结果癌组织KLF17、TP53蛋白表达阳性率分别为37.04%、12.96%,均低于癌旁组织66.67%、44.44%(均P<0.05);癌组织中KLF17蛋白表达水平与肿瘤直径、TNM分期、淋巴结转移、脉管侵犯呈负相关,TP53蛋白表达与肿瘤直径、TNM分期呈负相关(P<0.05);癌组织KLF17、TP53蛋白阳性表达者无进展生存时间(PFS)、总生存时间(OS)均长于阴性表达者(均P<0.05)。结论老年胃癌患者癌组织KLF17蛋白、TP53蛋白阳性表达比例可能低,且二者均与其临床病理可能呈独立负相关,并影响患者预后,有一定临床检测意义。

Targets and molecular mechanisms of triptolide in cancer therapy

Triptolide（TPL/TL） is a natural drug with novel anticancer effects. Preclinical studies indicated that TPL inhibits cell proliferation, induces cell apoptosis, inhibits tumor metastasis and enhances the effect of other therapeutic methods in various cancer cell lines. Multiple molecules and signaling pathways, such as caspases, heat-shock proteins, NF-κB, and deoxyribonucleic acid（DNA） repair-associated factors, are associated with the anti-cancer effect. TPL also improves chemoradiosensitivity in cancer therapy. Phase I trials indicate the potential clinical value of TPL use. However, further trials with larger sample sizes are needed to confirm these results.

Effect of Triptolide on Reproductive Endocrinology and Dihydrotestosterone Receptors in Rats

Triptolide was given orally to adult male Sprague-Dawley rat sat a dosage of 75 μg/kg for 35 days.After 28 days of treatment,the result of mating tests showed that all the drug treated rats were infertile.At the end of drug treatment,the density of caudal spermatozoa and the weight of cpididymis were reduced significantly.All the spermatozoa were immobile.There was no detectable damage of spermatogenesis and epididymal epithelia in triptolide treated rats under microscopical examination.However,modcrate and severe damage of spermatozoa were seen in the corpus and caudal epididymis.The content of cytosolic and nuclear dihydrotestosterone (DHT) receptors in the caput and caudal epididymides was increased but insignificantly as compared with that of the controls.However, the content of DHT receptor in the cytosal of the ventral prostate was elevated very,significantly (P< 0.01).This result suggests that one of the sitcs of action of triptolide might be the epididymis.

奥妥珠单抗联合化疗治疗多线化疗后进展且塞利尼索无效的TP53突变Burkitt淋巴瘤

Burkitt淋巴瘤是一种高度侵袭性的非霍奇金B细胞淋巴瘤(B-NHL),其特征为IGH/MYC基因易位及MYC蛋白高表达。多线化疗后进展且在使用小分子核输出蛋白1(XPO1)抑制剂塞利尼索后仍无效的TP53突变Burkitt淋巴瘤是目前的治疗难点,可选择的治疗方案十分有限,目前仍无有效治疗手段,且预后极差。本文报道伴TP53突变Burkitt淋巴瘤多线化疗后进展且塞利尼索治疗无效的患者2例。患者均接受奥妥珠单抗(G)联合二线方案治疗(1例G-DA-EPOCH方案、1例Ibru+GB方案),目前疗效评估均达到完全缓解(CR),主要不良反应为输液相关反应,经对症支持治疗后明显缓解。以奥妥珠单抗为代表的新药治疗可为目前多线化疗后进展且塞利尼索无效的TP53突变Burkitt淋巴瘤患者的治疗提供参考。

TPS联合“PBL+CBL”双轨教学在肿瘤放疗住培中的应用

目的 探讨放射治疗计划系统(Treatment Planning System,TPS)联合“问题教学法(problembased learning,PBL)+病例教学法(case-based learning,CBL)”双轨教学在肿瘤放射治疗(放疗)住院医师规范化培训(“住培”)中教学成果。方法 选取2020.9至2022.12在陕西省人民医院放疗科接受放疗“住培”的32名住院医师为研究对象,按随机数字表法分成试验组、对照组,每组16名。其中试验组接受TPS联合“PBL+CBL”双轨教学的教学模式,对照组接受传统教学模式。教学结束后对全部住院医师举行住院医师规范化培训考核及教学满意度问卷调查。结果 试验组住院医师的专业理论知识成绩(88.63±4.319)、临床实践能力成绩(4.19±5.256)及经典病例分析成绩(88.44±4.761)明显优于对照组住院医师(分别为:82.44±8.238、79.88±4.924、80.06±3.907),差异具有统计学意义(P<0.05)。试验组住院医师对教学的满意度明显高于对照组,具有统计学意义(P<0.05)。结论 采用TPS联合“PBL+CBL”双轨教学的教学模式进行肿瘤放疗住院医师规范化培训,有效提高肿瘤放疗住院医师的临床技能操作能力等,切实提高了“住培”教学质量。

Role of Reactive Oxygen Species in Triptolide-induced Apoptosis of Renal Tubular Cells and Renal Injury in Rats

This study investigated the role of reactive oxygen species（ROS） in the pathogenesis of triptolide-induced renal injury in vivo.Rats were randomly divided into 4 groups（n=5 in each）：triptolide group in which the rats were intraperitoneally injected with triptolide solution at a dose of 1 mg/kg of body weight on day 8;control group in which the rats received a single intraperitoneal injection of 0.9% physiological saline on day 8;vitamin C group in which the rats were pretreated with vitamin C by gavage at a dose of 250 mg/kg of body weight per day for 7 days before the same treatment as the control group on day 8;triptolide＋vitamin C group in which the rats were first subjected to an oral administration of vitamin C at a dose of 250 mg/kg of body weight per day for 7 days,and then to the same treatment as the triptolide group on day 8.All the rats were sacrificed on day 10.Blood samples were collected for detection of plasma creatinine（Pcr） and plasma urea nitrogen（PUN） concentrations.Both kidneys were removed.The histological changes were measured by haematoxylin-eosin（HE） staining.The production of ROS was determined by detecting the fluorescent intensity of the oxida-tion-sensitive probe rhodamine 123 in renal tissue.Renal malondialdehyde（MDA） content was meas-ured to evaluate lipid peroxidation level in renal tissue.TUNEL staining was performed to assess apop-tosis of renal tubular cells.Renal expression of apoptosis-related proteins Bcl-2,Bax,Bid,Bad,Fas and FasL,as well as corresponding encoding genes were assessed by Western Blotting and real-time PCR.The results showed that triptolide treatment promoted the generation of a great amount of ROS,up-regulated the expression of Bax,Bid,Bad,Fas and FasL at both protein and mRNA levels,as well as the ratio of Bax to Bcl-2,and caused the apoptosis of renal tubular cells and renal injury.However,pretreatment with an antioxidant,vitamin C,significantly reduced the generation of ROS and effectively inhibited the triptolide-induced apoptosis of renal tubular cells and renal injury.It was concluded that ROS plays a critical role in triptolide-induced apoptosis of renal tubular cells and renal injury.The protective administration of vitamin C may help alleviate triptolide-induced renal injury and nephrotoxicity.

Triptolide prolonged allogeneic islet graft survival in chemically induced and spontaneously diabetic mice without impairment of islet function

BACKGROUND: Triptolide (TPT) is a diterpenoid triepoxide extracted from the Chinese herb Tripterygium wilfordii Hook. F. It exhibits potent immunosuppressive and anti-inflammatory properties. This study was undertaken to investigate its effects on prolongation of islet allograft survival in rodents. Additionally, we investigated whether TPT would be toxic to islet function in vivo. METHODS: We transplanted BALB/c islets to either chemically induced diabetic C57BL/6 mice or spontaneously diabetic non-obese diabetic (NOD) mice. TPT was injected within 2 weeks or continuously, until rejection, in the two combinations. Then, we evaluated the toxicity of TPT on islet function by daily injection to naive BALB/c or diabetic BALB/c that was cured by syngeneic islet transplantation under the kidney capsule. Mice injected with cyclosporine A (CsA) or vehicle served as controls. Intraperitoneal glucose tolerance tests (IPGTTs) performed at 4 and 8 weeks in the naive BALB/c group, and at 2, 4, 6, and 8 weeks in the syngeneic transplanted group. RESULTS: The medium survival time of islets allograft from TPT treated C57BL/6 and NOD recipients were 28.5 days (range 24-30 days, n=10) and 33.0 days (range 15-47 days, n=6), respectively, and they were significantly different from those of the vehicle treated controls, which were 14.0 days (range 13-16 days, n=6) and 5.0 days (range 4-10 days, n=6), respectively (all P<0.0001). The IPGTT demonstrated that there was no difference between the TPT treated and vehicle treated groups, either in the normal or syngeneic transplanted islet BALB/c mice. However, CsA injection impaired islet function in both normal and syngeneic transplanted mice as early as 4 weeks. CONCLUSION: TPT prolonged islets allograft survival in a chemically induced diabetic or an autoimmune diabetic murine model without impairment of islet function. (Hepatobiliary Pancreat Dis Int 2010; 9: 312-318)

Clinical Observation on Effect of Triptolide Tablet in Treating Patients with Psoriasis Vulgaris

Objective: To investigate the effects of triptolide tablet in the treatment of patients with psoriasis vulgaris. Methods: By an open clinical study of 103 patients with psoriasis vulgaris. Psoriasis area severity index (PASI) was measured and recorded before and after treatment for efficacy evaluation. Results: Of the 103 patients, markedly effective was got in 41 (39.7%), improved in 37 (35.8%) and ineffective in 25 (24.5%), the total effective rate being 75.7%, and the adverse reaction was shown only in few patients with decreased WBC during the treatment period. Conclusion: Triptolide tablet is effective for the treatment of psoriasis vulgaris during the one-year follow-up.

Triptolide抑制角膜免疫反应及TGF-β诱导角膜基质细胞胶原收缩实验研究

雷公藤内酯醇（Triptolide,TP）是中药雷公藤的一种成分,已证实具有多种药理作用如抗炎、免疫调节等[1]。感染性角膜炎是世界范围内,尤其是发展中国家的主要致盲性眼病之一。TNF-α作为Thl细胞分泌产生的炎性细胞因子之一,与IL-2、IFN-1等共同介导细胞免疫[2,3],这些炎性因子及趋化因子可诱导炎性细胞对组织的浸润功能。

Apoptosis of human pancreatic cancer cells induced by Triptolide

AIM: To investigate apoptosis in human pancreatic cancer cells induced by Triptolide (TL), and the relationship between this apoptosis and expression of caspase-3' bcl-2 and bax. METHODS: Human pancreatic cancer cell line SW1990 was cultured in DMEM media for this study. MTT assay was used to determine the cell growth inhibitory rate in vitro. Flow cytometry and TUNEL assay were used to detect the apoptosis of human pancreatic cancer cells before and after TL treatment. RT-PCR was used to detect the expression of apoptosis-associated gene caspase-3' bcl-2 and bax. RESULTS: TL inhibited the growth of human pancreatic cancer cells in a dose-and time-dependent manner. TL induced human pancreatic cancer cells to undergo apoptosis with typically apoptotic characteristics. TUNEL assay showed that after the treatment of human pancreatic cancer cells with 40 ng/mL TL for 12 h and 24 h, the apoptotic rates of human pancreatic cancer cells increased significantly. RT-PCR demonstrated that caspase-3 and bax were significantly up-regulated in SW1990 cells treated with TL while bcl-2 mRNA was not. CONCLUSION: TL is able to induce the apoptosis in human pancreatic cancer cells. This apoptosis may be mediated by up-regulating the expression of apoptosis- associated caspase-3 and bax gene.

Triptolide Inhibits Cell Growth and Induces G0-G1 Arrest by Regulating P21wap1/cip1 and P27 kip1 in Human Multiple Myeloma RPMI-8226 Cells

Objective： To investigate the effects of triptolide（TPL） on cell growth, cell cycle and the expressions of p21wapl/cipl and p27kipl. Methods： MTT assay was used to determine the cell viability after triptolide treatment in human multiple myeloma RPMI-8226 cells. The effect on cell cycle distribution was determined by flow cytometry. Semi-quantitative reverse transcription-PCR was used to examine the mRNA expressions of p21wapl/cipl and p27kipl. The protein expressions of p21 wapl/cipl and p27kipl were determined by Western blot. Results： Triptolide of varying concentrations induced cell viability inhibition in dose- and time-related fashion and caused Go- G1 phase arrest of cell cycle progression in RPMI-8226 cells. These effects accompanied with up-modulation of the expressions of p21 wapl/cipl and p27kipl. Conclusion： These results suggest that triptolide inhibit cell proliferation and cell cycle progression via up-regulating p21wapl/cipl and p27kipl and triptolide may exert its anti-cancer activity through this pathway.