雷公藤多甙联合厄贝沙坦对糖尿病肾病患者尿足细胞排泄影响及机制探讨

目的 观察雷公藤多甙(TwHF)联合厄贝沙坦对糖尿病肾病(DKD)患者尿足细胞的影响,探讨TwHF对DKD患者肾脏保护作用的机制.方法 前瞻性入选45例2型糖尿病肾病患者,分为3组,TwHF治疗组(DT,15例)、厄贝沙坦治疗组(DI,15例)及联合治疗组(DTI,15例).经6周洗脱期后分别给予TwHF(1～2 mg· kg-1·d-1)、厄贝沙坦(150 ～ 300 mg/d)和TwHF联合厄贝沙坦(厄贝沙坦150～300 mg/d加TwHF 1 ～2 mg·kg-1·d-1)干预12周.15例健康志愿者作为正常对照.采用间接免疫荧光法检测单克隆抗体podocalyxin标记的尿足细胞.双抗体夹心酶联免疫吸附法测定尿结缔组织生长因子(CTGF)、骨桥蛋白(OPN)和转化生长因子β1(TGFβ1).结果 2型糖尿病肾病患者尿脱落足细胞较对照组明显增多(P＜0.01),DKD患者尿中脱落的足细胞检出率为86.6％.尿足细胞阳性DKD患者尿CTGF、OPN及TGFβ1表达明显高于阴性尿足细胞者(P ＜0.05或0.01).相关分析表明尿蛋白量与尿足细胞的排泄计数明显相关(r=0.79,P＜0.01);尿足细胞的排泄计数与尿CTGF、OPN及TGFβ1表达水平明显相关(r=0.56、0.41、0.44,P值均＜0.01).应用TwHF、厄贝沙坦及两者联合干预12周后,尿蛋白及尿足细胞排泄较治疗前均明显减少(P值均＜0.01).各治疗组尿CTGF、OPN、TGFβ1表达较治疗前均明显降低(P值均＜0.01),且以联合组变化最明显(P＜0.05).结论 尿脱落足细胞可能是预测DKD进展的有效因子.TwHF对DKD患者尿足细胞有重要的保护作用,其机制可能与抑制CTGF、OPN及TGFβ1表达有关,TwHF联合厄贝沙坦对DKD患者足细胞保护具有协同作用.     

脂代谢紊乱在糖尿病肾脏疾病发病机制中的研究进展

DKD患者常伴血脂紊乱,脂质调控与DKD发生发展密切相关.脂质通过沉积、脂质修饰、促发炎症反应、诱导IR、促进细胞凋亡等多种途径,参与DKD发生发展.本文对脂代谢紊乱在DKD发病机制中的研究进展进行综述,旨在为临床治疗DKD提供依据.     

细胞焦亡在糖尿病肾病发病机制中作用的研究进展

糖尿病肾脏病(DKD)是糖尿病患者最主要的微血管并发症之一,其发病机制主要与代谢紊乱、血流动力学异常、氧化应激等有关,炎性反应贯穿于DKD全过程。细胞焦亡(pyroptosis)是新发现的一种细胞死亡形式,由NOD样受体蛋白3(NLRP3)炎症小体激活,依赖半胱氨酸蛋白水解酶(caspase)-1/4/5/11,通过G...     

Krüppel样转录因子9在糖尿病肾脏病中的研究进展

糖尿病肾脏病(DKD)是糖尿病的重要并发症, 可发展为终末期肾病, 其发生发展与高血糖、氧化应激、炎症等导致的肾脏纤维化相关, 早期诊断及干预可延缓DKD进展, 但目前仍有诸多局限。近年来, 寻找DKD特异性的生物标志物协助早期诊断、探索新的治疗靶点已成为研究热点。Krüppel样转录因子(KLF)家族是一类与真核细胞的转录调控密切相关的转录家族, 参与细胞增殖、分化和凋亡等多个生命过程的调控, 其家族成员KLF9是一种能调控机体多种途径、发挥不同生物学作用的转录因子, 参与多种系统疾病的发生发展。越来越多的研究表明, KLF9可以调节与糖尿病/肥胖诱导的肾脏疾病及其细胞凋亡、炎症、氧化应激等相关的多种途径, 在糖尿病及其并发症中起到关键的调节作用, 但目前KLF9在DKD中的相关研究尚未见系统综述报道。该文重点从机体糖脂代谢紊乱、氧化应激、免疫炎症等病理生理过程为切入点, 系统综述KLF9在DKD中的研究进展, 以提高临床对KLF9与DKD发生发展相关性的认识。     

雷公藤甲素治疗db／db糖尿病小鼠的疗效观察

目的:利用db/db小鼠验证雷公藤甲素对糖尿病肾脏损伤的治疗作用,探讨雷公藤甲素防治糖尿病肾病的机制. 方法:9周龄的db/db和db/m小鼠分为五组:(1)db/m正常对照组;(2)dh/dh糖尿病对照组;(3)缬沙坦治疗纽;(4)雷公藤甲素低剂最治疗组;(5)雷公藤甲素高剂繁治疗组.于4周、8周及12周测定各组24h尿白蛋白、血生化和体重.光镜观察肾小球病变,电镜观察足突改变,并作定量分析.免疫病理观察足细胞裂孔膜蛋白nephrin,足细胞损伤标志物desmin,炎症反应标志物单核细胞趋化蛋白1(MCP-1),氧化应激标志物4羟壬烯醛(4-HNE)的表达. 结果:db/db小鼠经雷公藤甲素治疗后蛋白尿下降,肾小球肥大和足细胞损伤减轻,肾组织炎症和氧化应激状态改善,同时高血脂和肥胖减轻.该作用随治疗时间延长,效果更加明显,且高剂量疗效优于低剂量.雷公藤甲素降低蛋白尿、改善肾小球肥大的作用与缬沙坦相似,但降低肾组织炎症和氧化应激的作用雷公藤甲素比缬沙坦更强. 结论:雷公藤甲索能明显降低dh/db小鼠尿蛋白的排泄,减轻肾组织炎症反应,改善肾脏组织病变,对糖尿病肾脏损伤具有显著且更全面的治疗作用.     

肿瘤坏死因子-α与糖尿病肾病

肿瘤坏死因子（TNF）-α是重要的炎症因子,近来越来越多的证据显示其在糖尿病肾病（DKD）的发生发展中起重要作用。实验与临床研究均已经证实,TNF-α在DKD中通过多种机制产生。肾脏损伤,而且其活性调节的潜在益处已作为目前临床治疗的一个策略。     

肠道菌群失衡与肠道屏障损伤在糖尿病肾脏疾病中的研究进展

肠道菌群失衡可以破坏肠道屏障功能,致病菌及其有害代谢产物穿过肠黏膜屏障移位至血液,造成慢性炎症,加重肾脏损伤。肠道微生态的恢复有望成为糖尿病肾脏疾病(DKD)治疗的新靶点。大量的研究证实,DKD中存在肠道菌群失衡与肠道屏障损伤,但其具体致病机制尚未阐明。本文以“微生物-肠-肾轴”为切入点进行叙述,对DKD中存在的肠道菌群失衡、肠道屏障损伤及恢复肠道微生态的措施进行综述,有望为DKD的预防和治疗提供新的思路。     

脂肪因子镍纹样蛋白在糖尿病肾脏病中作用的研究进展

糖尿病肾脏病(DKD)是指糖尿病引起的慢性肾脏病, 是2型糖尿病的常见慢性并发症, 也是终末期肾病(ERSD)的主要原因。早期对DKD进行干预, 可减轻及延缓肾脏病变的进展。但目前临床在DKD的诊治方面仍存在诸多局限。因此, 对于DKD的早期诊断及干预的研究成为了糖尿病领域的热点问题。镍纹样蛋白(Metrnl)是一种新型脂肪因子, 其具有纠正脂代谢紊乱、降低炎症应答、改善胰岛素抵抗等生理作用, 在代谢性疾病中发挥着重要作用。Metrnl在DKD中的作用也逐渐被发现, 该文就Metrnl在DKD中的潜在作用进行综述, 以期为临床诊治提供更多思路。     

肾小球血管内皮细胞糖萼与糖尿病肾脏病的研究进展

与其他糖尿病并发症相比, 糖尿病肾脏病(DKD)的患病率在过去的30年里并无显著下降。聚焦纤维化或出现蛋白尿后的治疗无法逆转DKD, 识别其始动机制对DKD的治疗更有意义。糖尿病背景下的肾小球血管内皮细胞糖萼(GEG)的损害是引起滤过屏障受损的初始和关键步骤, 可作为预防或延缓DKD进展的重要靶点。目前认为, 内皮细胞糖萼(EG)的调节主要由促进糖萼合成和降解机制之间的平衡决定。糖尿病引起的EG的变化可能部分反映了高血糖直接抑制EG成分的更新;蛋白水解酶如基质金属蛋白酶9、透明质酸酶1或乙酰肝素酶在糖尿病患者中的表达增加, 并且在这种病理环境下可以参与GEG的降解;促血管生成分子(包括炎症介质和血管内皮生长因子)表达上升, 会导致肾小球内皮细胞活化和渗透性增加, 对GEG的调节亦发挥重要作用。目前, DKD的防控形势依然严峻, 未来DKD的治疗应提前至糖尿病诊断之初, 而非出现蛋白尿后的"强弩之末"。     

AMPK与糖尿病肾脏疾病

糖尿病肾脏疾病(DKD)的发病机制十分复杂,其发生、发展是在遗传背景基础上多因素综合作用的结果,目前认为高血糖是引起DKD进展的主要原因,炎性反应和氧化应激加速了DKD的病理过程.腺苷酸活化蛋白激酶(AMPK)是“细胞能量调节器”,在调节糖、脂代谢方面起重要作用.AMPK作为一个重要的信号通路,通过参与细胞蛋白质合成、机体炎性反应和氧化应激等过程,在延缓DKD的发生、发展中发挥了重要作用.     

The Chinese anti-inflammatory and immunosuppressive herbal remedy Tripterygium wilfordii Hook F

Various preparations of Tripterygium wilfordii Hook F (TwHF) have been used in the treatment of a number of autoimmune and inflammatory diseases since the 1960s. Accumulated data from the clinical trials suggest efficacy of this treatment in a number of rheumatic diseases, including rheumatoid arthritis and systemic lupus erythematosus. Studies on the relationship of the chemical components of TwHF and its immunosuppressive and anti-inflammatory effects suggest that diterpenoid compounds with epoxide groups account for the therapeutic effects of this herbal remedy. This herbal remedy is therefore a unique and powerful alternative therapy for autoimmune and inflammatory diseases.     

Tripterygium wilfordii Hook F. in the treatment of synovitis,acne, pustulosis,hyperostosis, and osteitis syndrome: a clinical trial

Clinical Rheumatology - This study aimed to investigate the efficacy and safety of Tripterygium wilfordii Hook F. (TwHF) in the treatment of osteoarticular lesions in synovitis, acne, pustulosis,...     

The Chinese herb Tripterygium wilfordii Hook F for the treatment of systemic sclerosis-associated interstitial lung disease: data from a Chinese EUSTAR Center

Clinical Rheumatology - To assess the efficacy and safety of the Chinese herb Tripterygium wilfordii Hook F (TwHF) for the treatment of systemic sclerosis-associated interstitial lung disease...     

Suppression of renal disease and arthritis, and prolongation of survival in MRL-lpr mice treated with an extract of Tripterygium wilfordii Hook f.

OBJECTIVE. Treatment of MRL-lpr/lpr mice with Tripterygium wilfordii Hook f (TWHf) to evaluate its effects on mortality, renal disease, and arthritis. METHODS. Mice were fed water (group A, control), TWHf (group B), or first water and then TWHf (group C) from age 7 weeks until age 21 weeks. RESULTS. Arthritis and glomerulonephritis were decreased in groups B and C mice, and survival was increased in group B mice. CONCLUSION. TWHf decreases the mortality rate, and severity of glomerulonephritis and arthritis in MRL-lpr/lpr mice.     

Inhibition of type II collagen induced arthritis in mice by an immunosuppressive extract of Tripterygium wilfordii Hook f.

The effects of Tripterygium wilfordii Hook f (TWHf), a Chinese herbal remedy, on type II collagen induced arthritis (CIA) in DBA/1LacJ mice were determined. Mice were divided into 4 groups receiving oral treatment for 63 days: Group A, sham feedings; Group B, TWHf (78 mg/day); Group C, TWHf (140 mg/day); Group D, TWHf (140 mg/day) starting 21 days after collagen immunization. Arthritis incidence was reduced and day of onset delayed in Groups B and C compared with A. Arthritic joint counts, arthritic severity scores, and anticollagen antibody titers were decreased in Groups B, C, and D compared with A. Histopathology revealed destructive arthritis only in Group A. Our results indicate that TWHf is a potent immunosuppressive inhibitor of CIA, even when treatment is begun 3 weeks after immunization.     

Triptolide induces caspase-dependent cell death mediated via the mitochondrial pathway in leukemic cells

Triptolide, a diterpenoid isolated from the Chinese herb Tripterygium wilfordii Hook.f, has shown antitumor activities in a broad range of solid tumors. Here, we examined its effects on leukemic cells and found that, at 100 nM or less, it potently induced apoptosis in various leukemic cell lines and primary acute myeloid leukemia (AML) blasts. We then attempted to identify its mechanisms of action. Triptolide induced caspase-dependent cell death accompanied by a significant decrease in XIAP levels. Forced XIAP overexpression attenuated triptolide-induced cell death. Triptolide also decreased Mcl-1 but not Bcl-2 and Bcl-X(L) levels. Bcl-2 overexpression suppressed triptolide-induced apoptosis. Further, triptolide induced loss of the mitochondrial membrane potential and cytochrome C release. Caspase-9 knock-out cells were resistant, while caspase-8-deficient cells were sensitive to triptolide, suggesting criticality of the mitochondrial but not the death receptor pathway for triptolide-induced apoptosis. Triptolide also enhanced cell death induced by other anticancer agents. Collectively, our results demonstrate that triptolide decreases XIAP and potently induces caspase-dependent apoptosis in leukemic cells mediated through the mitochondrial pathway at low nanomolar concentrations. The potent antileukemic activity of triptolide in vitro warrants further investigation of this compound for the treatment of leukemias and other malignancies.     

Effect of an extract of the Chinese herbal remedy Tripterygium wilfordii Hook F on human immune responsiveness

Tripterygium wilfordii Hook F (TWH) is a vine-like plant that grows in a wide area of south China. An alcohol extract of this plant known as T2 has been suggested to be effective in the treatment of rheumatoid arthritis (RA). To examine the mechanism by which this herbal remedy might be effective in RA, the capacity of T2 to alter human immune responsiveness in vitro was investigated. Human peripheral blood mononuclear cells were obtained from normal adults and separated into purified populations of monocytes, T cells, and B cells. T2 at 0.1-1 micrograms/ml inhibited antigen- and mitogen-stimulated proliferation of T cells and B cells, interleukin-2 (IL-2) production by T cells, and immunoglobulin production by B cells. T2 did not affect IL-2 receptor expression by T cells, IL-1 production by monocytes, or the capacity of monocytes to present antigen. Inhibition could not be accounted for by nonspecific toxicity. These results support the conclusion that T2 exerts a powerful suppressive effect on human immune responses. This action might account for its therapeutic effectiveness in RA.     

A phase I study of ethyl acetate extract of the chinese antirheumatic herb Tripterygium wilfordii hook F in rheumatoid arthritis.

OBJECTIVE: To explore the efficacy and safety of ethyl acetate (EA) extracts of the Chinese herbal remedy Tripterygium wilfordii Hook F (TWHF) for treatment of patients with a variety of inflammatory and autoimmune diseases including rheumatoid arthritis (RA). METHODS: The roots of TWHF were extracted sequentially by ethyl alcohol and ethyl acetate and the content of the extract documented. An open label, dose escalation Phase I study was performed in 1993 in 13 patients with established RA. Clinical manifestations and laboratory findings were examined before and every 4 weeks after starting treatment with the EA extract. RESULTS: Three patients withdrew from the trial during the first 16 weeks of the dose escalation. These patients received a maximum dosage of 180 mg/day. There were no adverse effects or disease improvement observed in these patients. Nine of the remaining 10 patients tolerated the EA extract up to a dosage of 570 mg/day. There were no withdrawals related to adverse events in the trial except for one patient who developed diastolic hypertension at a dose of 180 mg/day of EA extract. Six of 10 patients treated with 180 mg/day of EA extract showed disease improvement. Eight of the 9 patients who received EA extract at doses > 360 mg/day experienced improvement in both clinical manifestations and laboratory findings. One patient met American College of Rheumatology criteria for remission. CONCLUSION: The EA extract of TWHF at dosages up to 570 mg/day appeared to be safe, and doses > 360 mg/day were associated with clinical benefit in patients with RA.