目的:探讨补肾壮骨方治疗非创伤性股骨头坏死(non-traumatic osteonecrosis of the femoral head,NONFH)肝肾亏虚证的功效内涵。方法:①网络药理学研究。检索TCMIP v2.0、ETCM2.0、HERB数据库,收集补肾壮骨方的靶标基因,从项目组前期研...目的:探讨补肾壮骨方治疗非创伤性股骨头坏死(non-traumatic osteonecrosis of the femoral head,NONFH)肝肾亏虚证的功效内涵。方法:①网络药理学研究。检索TCMIP v2.0、ETCM2.0、HERB数据库,收集补肾壮骨方的靶标基因,从项目组前期研究中获取NONFH肝肾亏虚证相关差异表达基因,以NONFH肝肾亏虚证典型症状为关键词检索NONFH肝肾亏虚证典型症状相关基因。将上述基因合并,构建补肾壮骨方治疗NONFH肝肾亏虚证蛋白质互作网络,从中筛选关键靶标基因,并对其进行KEGG信号通路富集分析,结合文献对相关信号通路进行药理作用分析。以靶标基因与信号通路、信号通路与药理作用的映射关系为基础,结合文献报道,构建补肾壮骨方治疗NONFH肝肾亏虚证“组方中药-关键靶标-信号通路-功效-药理作用-临床症状”关联网络。②临床研究。选择77例(120髋)NONFH肝肾亏虚证患者,采用口服补肾壮骨方治疗6个月。分别采用股骨头坏死临床疗效评价标准和北京中医药大学X线评价系统进行临床疗效和影像学疗效评价。结果:①网络药理学研究结果。从构建的补肾壮骨方治疗NONFH肝肾亏虚证蛋白质互作网络中共筛选出556个关键靶标基因,这些基因共参与39条与NONFH肝肾亏虚证有关的信号通路,主要涉及纠正骨代谢紊乱、纠正脂代谢紊乱、矫正免疫-炎症失衡、改善血液循环受阻4种药理作用。纠正骨代谢紊乱涉及靶标基因183个,纠正脂代谢紊乱涉及靶标基因176个,矫正免疫-炎症失衡涉及靶标基因171个,改善血液循环受阻涉及靶标基因125个。构建的“组方中药-关键靶标-信号通路-功效-药理作用-临床症状”关联网络直观显示了补肾壮骨方治疗NONFH肝肾亏虚证的功效内涵。②临床研究结果。临床疗效评价结果显示,治疗6个月后患者的髋关节疼痛强度评分、髋关节屈曲功能评分、行走距离评分及临床疗效总分均较治疗前降低[(5.86±1.96)分,(2.26±1.84)分,t=25.672,P=0.000;(5.76±1.62)分,(3.46±1.68)分,t=38.411,P=0.000;(6.31±1.41)分,(0.78±0.74)分,t=46.771,P=0.000;(5.92±1.18)分,(2.32±1.06)分,t=48.263,P=0.000];临床疗效优88髋、良28髋、可2髋、差2髋。影像学疗效评价结果显示,治疗后3年影像学疗效优17髋、良25髋、可67髋、差11髋;股骨头形态稳定109髋、进展11髋,坏死灶改善67髋、稳定34髋、进展19髋,骨关节炎稳定100髋、进展20髋。结论:补肾壮骨方治疗NONFH肝肾亏虚证的机制为纠正骨代谢和脂代谢紊乱、免疫-炎症失衡及血液循环受阻,其中纠正骨代谢紊乱可能是最主要的机制。展开更多
Rheumatoid arthritis(RA),a globally increasing autoimmune disorder,is associated with increased disability rates due to the disruption of iron metabolism.Tripterygium glycoside tablets(TGTs),a Tripterygium wilfordii H...Rheumatoid arthritis(RA),a globally increasing autoimmune disorder,is associated with increased disability rates due to the disruption of iron metabolism.Tripterygium glycoside tablets(TGTs),a Tripterygium wilfordii Hook.f.(TwHF)-based therapy,exhibit satisfactory clinical efficacy for RA treatment.However,drug-induced liver injury(DILI)remains a critical issue that hinders the clinical application of TGTs,and the molecular mechanisms underlying the efficacy and toxicity of TGTs in RA have not been fully elucidated.To address this problem,we integrated clinical multi-omics data associated with the anti-RA efficacy and DILI of TGTs with the chemical and target profiling of TGTs to perform a systematic network analysis.Subsequently,we identified effective and toxic targets following experimental validation in a collagen-induced arthritis(CIA)mouse model.Significantly different transcriptome–protein–metabolite profiles distinguishing patients with favorable TGTs responses from those with poor outcomes were identified.Intriguingly,the clinical efficacy and DILI of TGTs against RA were associated with metabolic homeostasis between iron and bone and between iron and lipids,respectively.Particularly,the signal transducer and activator of transcription 3(STAT3)–hepcidin(HAMP)/lipocalin 2(LCN2)–tartrate-resis tant acid phosphatase type 5(ACP5)and STAT3–HAMP–acyl-CoA synthetase long-chain family member 4(ACSL4)–lysophosphatidylcholine acyltransferase 3(LPCAT3)axes were identified as key drivers of the efficacy and toxicity of TGTs.TGTs play dual roles in ameliorating CIA-induced pathology and in inducing hepatic dysfunction,disruption of lipid metabolism,and hepatic lipid peroxidation.Notably,TGTs effectively reversed“iron–bone”disruptions in the inflamed joint tissues of CIA mice by inhibiting the STAT3–HAMP/LCN2–ACP5 axis,subsequently leading to“iron–lipid”disturbances in the liver tissues via modulation of the STAT3–HAMP–ACSL4–LPCAT3 axis.Additional bidirectional validation experiments were conducted using MH7A and AML12 cells to confirm the bidirectional regulatory effects of TGTs on key targets.Collectively,our data highlight the association between iron-mediated metabolic homeostasis and the clinical efficacy and toxicity of TGT in RA therapy,offering guidance for the rational clinical use of TwHF-based therapy with dual therapeutic and toxic potential.展开更多
文摘目的:探讨补肾壮骨方治疗非创伤性股骨头坏死(non-traumatic osteonecrosis of the femoral head,NONFH)肝肾亏虚证的功效内涵。方法:①网络药理学研究。检索TCMIP v2.0、ETCM2.0、HERB数据库,收集补肾壮骨方的靶标基因,从项目组前期研究中获取NONFH肝肾亏虚证相关差异表达基因,以NONFH肝肾亏虚证典型症状为关键词检索NONFH肝肾亏虚证典型症状相关基因。将上述基因合并,构建补肾壮骨方治疗NONFH肝肾亏虚证蛋白质互作网络,从中筛选关键靶标基因,并对其进行KEGG信号通路富集分析,结合文献对相关信号通路进行药理作用分析。以靶标基因与信号通路、信号通路与药理作用的映射关系为基础,结合文献报道,构建补肾壮骨方治疗NONFH肝肾亏虚证“组方中药-关键靶标-信号通路-功效-药理作用-临床症状”关联网络。②临床研究。选择77例(120髋)NONFH肝肾亏虚证患者,采用口服补肾壮骨方治疗6个月。分别采用股骨头坏死临床疗效评价标准和北京中医药大学X线评价系统进行临床疗效和影像学疗效评价。结果:①网络药理学研究结果。从构建的补肾壮骨方治疗NONFH肝肾亏虚证蛋白质互作网络中共筛选出556个关键靶标基因,这些基因共参与39条与NONFH肝肾亏虚证有关的信号通路,主要涉及纠正骨代谢紊乱、纠正脂代谢紊乱、矫正免疫-炎症失衡、改善血液循环受阻4种药理作用。纠正骨代谢紊乱涉及靶标基因183个,纠正脂代谢紊乱涉及靶标基因176个,矫正免疫-炎症失衡涉及靶标基因171个,改善血液循环受阻涉及靶标基因125个。构建的“组方中药-关键靶标-信号通路-功效-药理作用-临床症状”关联网络直观显示了补肾壮骨方治疗NONFH肝肾亏虚证的功效内涵。②临床研究结果。临床疗效评价结果显示,治疗6个月后患者的髋关节疼痛强度评分、髋关节屈曲功能评分、行走距离评分及临床疗效总分均较治疗前降低[(5.86±1.96)分,(2.26±1.84)分,t=25.672,P=0.000;(5.76±1.62)分,(3.46±1.68)分,t=38.411,P=0.000;(6.31±1.41)分,(0.78±0.74)分,t=46.771,P=0.000;(5.92±1.18)分,(2.32±1.06)分,t=48.263,P=0.000];临床疗效优88髋、良28髋、可2髋、差2髋。影像学疗效评价结果显示,治疗后3年影像学疗效优17髋、良25髋、可67髋、差11髋;股骨头形态稳定109髋、进展11髋,坏死灶改善67髋、稳定34髋、进展19髋,骨关节炎稳定100髋、进展20髋。结论:补肾壮骨方治疗NONFH肝肾亏虚证的机制为纠正骨代谢和脂代谢紊乱、免疫-炎症失衡及血液循环受阻,其中纠正骨代谢紊乱可能是最主要的机制。
基金supported by the Scientific and Technological Innovation Project of the China Academy of Chinese Medical Sciences(CI2021A03807 and CI2021A01501)the National Natural Science Foundation of China(82330124)+2 种基金the Beijing Municipal Natural Science Foundation(7212186)the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(ZYYCXTD-C-202002)the Key Laboratory of Beijing for Identification and Safety Evaluation of Chinese Medicine,Institute of Chinese Materia Medica,China Academy of Chinese Medical Sciences.
文摘Rheumatoid arthritis(RA),a globally increasing autoimmune disorder,is associated with increased disability rates due to the disruption of iron metabolism.Tripterygium glycoside tablets(TGTs),a Tripterygium wilfordii Hook.f.(TwHF)-based therapy,exhibit satisfactory clinical efficacy for RA treatment.However,drug-induced liver injury(DILI)remains a critical issue that hinders the clinical application of TGTs,and the molecular mechanisms underlying the efficacy and toxicity of TGTs in RA have not been fully elucidated.To address this problem,we integrated clinical multi-omics data associated with the anti-RA efficacy and DILI of TGTs with the chemical and target profiling of TGTs to perform a systematic network analysis.Subsequently,we identified effective and toxic targets following experimental validation in a collagen-induced arthritis(CIA)mouse model.Significantly different transcriptome–protein–metabolite profiles distinguishing patients with favorable TGTs responses from those with poor outcomes were identified.Intriguingly,the clinical efficacy and DILI of TGTs against RA were associated with metabolic homeostasis between iron and bone and between iron and lipids,respectively.Particularly,the signal transducer and activator of transcription 3(STAT3)–hepcidin(HAMP)/lipocalin 2(LCN2)–tartrate-resis tant acid phosphatase type 5(ACP5)and STAT3–HAMP–acyl-CoA synthetase long-chain family member 4(ACSL4)–lysophosphatidylcholine acyltransferase 3(LPCAT3)axes were identified as key drivers of the efficacy and toxicity of TGTs.TGTs play dual roles in ameliorating CIA-induced pathology and in inducing hepatic dysfunction,disruption of lipid metabolism,and hepatic lipid peroxidation.Notably,TGTs effectively reversed“iron–bone”disruptions in the inflamed joint tissues of CIA mice by inhibiting the STAT3–HAMP/LCN2–ACP5 axis,subsequently leading to“iron–lipid”disturbances in the liver tissues via modulation of the STAT3–HAMP–ACSL4–LPCAT3 axis.Additional bidirectional validation experiments were conducted using MH7A and AML12 cells to confirm the bidirectional regulatory effects of TGTs on key targets.Collectively,our data highlight the association between iron-mediated metabolic homeostasis and the clinical efficacy and toxicity of TGT in RA therapy,offering guidance for the rational clinical use of TwHF-based therapy with dual therapeutic and toxic potential.
