PMID- 33383371 OWN - NLM STAT- MEDLINE DCOM- 20210723 LR - 20240229 IS - 1950-6007 (Electronic) IS - 0753-3322 (Linking) VI - 135 DP - 2021 Mar TI - Babao Dan improves neurocognitive function by inhibiting inflammation in clinical minimal hepatic encephalopathy. PG - 111084 LID - S0753-3322(20)31277-4 [pii] LID - 10.1016/j.biopha.2020.111084 [doi] AB - BACKGROUND AND PURPOSE: Inflammation has been considered a precipitating event that contributes to neurocognitive dysfunction in minimal hepatic encephalopathy (MHE). Inhibition TLR-4 related inflammation can effectively improve neurocognitive dysfunction of MHE. Our previous study showed that Babao Dan (BBD) effectively inhibited inflammation and ameliorated neurocognitive function in rats with acute hepatic encephalopathy (HE) and chronic HE. The mechanism may lie in the regulation of TLR4 signaling pathway. Therefore, this study aimed to evaluate the role of BBD in the treatment of MHE patients with cirrhosis and to elucidate the underlying mechanism by which BBD regulated TLR4 pathway to alleviate inflammation. METHODS: A randomized controlled trial (n = 62) was conducted to evaluate the clinical efficacy between BBD plus lactulose (n = 31) and lactulose alone (n = 31) in MHE patients by testing neurocognitive function (NCT-A and DST), blood ammonia, liver function (ALT, AST and TBIL) and blood inflammation (IL-1beta, IL-6 and TNF-alpha). Afterward, we detected NO, inflammatory cytokines (IL-1beta, IL-6 and TNF-alpha) and the phosphorylation of P65, JNK, ERK as well as P38 in LPS-activated rat primary bone marrow-derived macrophages (BMDMs), peritoneal macrophages (PMs), and mouse primary BMDMs/PMs/microglia/astrocytes, to investigate the underlying mechanism of BBD inhibiting inflammation through TLR4 pathway. Also, the survival rate of mice, liver function (ALT, AST), blood inflammation (IL-1beta, IL-6 and TNF-alpha), inflammatory cytokines (IL-1beta, IL-6 and TNF-alpha) and histopathological changes in the liver, brain and lung were measured to assess the anti-inflammatory effect of BBD on neurocognitive function in endotoxin shock/endotoxemia mice. RESULTS: BBD combined with lactulose significantly ameliorated neurocognitive function by decreasing NCT-A (p＜0.001) and increasing DST (p＜0.001); inhibited systemic inflammation by decreasing IL-1beta (p＜0.001), IL-6(p＜0.001) and TNF-alpha (p＜0.001); reduced ammonia level (p = 0.005), and improved liver function by decreasing ALT(p = 0.043), AST(p = 0.003) and TBIL (p = 0.026) in MHE patients. Furthermore, BBD inhibited gene and protein expression of IL-1beta, IL-6 and TNF-alpha as well as NO in rat primary BMDMs/PMs, and mouse primary BMDMs/PMs/microglia/astrocytes in a dose-dependent manner. BBD inhibited the activation of mouse primary BMDMs/PMs/microglia/astrocytes by regulating TLR4 pathway involving the phosphorylation of P65, JNK, ERK and P38. Also, BBD reduced the mortality of mice with endotoxin shock/endotoxemia; serum levels of ALT, AST, IL-1beta, IL-6 and TNF-alpha; gene expression of IL-1beta, IL-6 and TNF-alpha in the liver, brain and lung, and tissue damage in the liver and lung. CONCLUSION: Our study provided for the first time clinical and experimental evidence supporting the use of BBD in MHE, and revealed that BBD could play a crucial role in targeting and regulating TLR4 inflammatory pathway to improve neurocognitive function in MHE patients. CI - Copyright (c) 2020 The Author(s). Published by Elsevier Masson SAS.. All rights reserved. FAU - Lu, Bingjie AU - Lu B AD - Shuguang Hospital, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: bingjie_lu@outlook.com. FAU - Wu, Chao AU - Wu C AD - Shuguang Hospital, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: wuchaotcm@163.com. FAU - Azami, Nisma Lena Bahaji AU - Azami NLB AD - Shuguang Hospital, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: nl.azami@outlook.com. FAU - Xie, Dong AU - Xie D AD - Shuguang Hospital, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: xdieong@163.com. FAU - Zhao, Changqing AU - Zhao C AD - Shuguang Hospital, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: 1343518024@qq.com. FAU - Xu, Wan AU - Xu W AD - Shuguang Hospital, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: wanxufocus@163.com. FAU - Hui, Dengcheng AU - Hui D AD - Shuguang Hospital, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: dchui1874@163.com. FAU - Chen, Xi AU - Chen X AD - Shanghai Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, 200082, China. Electronic address: dinachen166@126.com. FAU - Sun, Runfei AU - Sun R AD - Shuguang Hospital, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: jiaowosrf@163.com. FAU - Song, Jingru AU - Song J AD - Shuguang Hospital, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: songjr22@163.com. FAU - An, Yongtong AU - An Y AD - Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd., Shanghai, 201203, China. Electronic address: anyt@sphchina.com. FAU - Li, Kun AU - Li K AD - The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: lik@sphchina.com. FAU - Wang, Huijun AU - Wang H AD - The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: huijun.wang@outlook.com. FAU - Ye, Guan AU - Ye G AD - Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd., Shanghai, 201203, China. Electronic address: yeg@sphchina.com. FAU - Sun, Mingyu AU - Sun M AD - Shuguang Hospital, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: mysun248@hotmail.com. LA - eng PT - Journal Article PT - Randomized Controlled Trial DEP - 20201228 PL - France TA - Biomed Pharmacother JT - Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie JID - 8213295 RN - 0 (Anti-Inflammatory Agents) RN - 0 (babao dan) RN - 0 (Cytokines) RN - 0 (Drugs, Chinese Herbal) RN - 0 (Inflammation Mediators) RN - 0 (Tlr4 protein, mouse) RN - 0 (Toll-Like Receptor 4) SB - IM MH - Aged MH - Animals MH - Female MH - Humans MH - Male MH - Middle Aged MH - Pregnancy MH - *Anti-Inflammatory Agents/adverse effects/therapeutic use MH - Astrocytes/drug effects/metabolism MH - *Brain/drug effects/metabolism/physiopathology MH - Cells, Cultured MH - China MH - *Cognition/drug effects MH - *Cytokines/metabolism MH - Disease Models, Animal MH - *Drugs, Chinese Herbal/adverse effects/therapeutic use MH - Endotoxemia/drug therapy/metabolism MH - *Hepatic Encephalopathy/drug therapy/metabolism/physiopathology/psychology MH - *Inflammation Mediators/metabolism MH - Macrophages/drug effects/metabolism MH - Mice, Inbred C57BL MH - Microglia/drug effects/metabolism MH - Time Factors MH - Toll-Like Receptor 4/metabolism MH - Treatment Outcome MH - Mice OTO - NOTNLM OT - Acrylamide (PubChem CID: 6579) OT - Ammonium persulfate (PubChem CID: 62648) OT - BBD OT - Carbon tetrachloride (PubChem CID: 5943) OT - Dimethyl sulfoxide (DMSO) (PubChem CID: 679) OT - Disodium hydrogen phosphate (PubChem CID:24203) OT - Ethanol (PubChem CID: 702) chloroform (PubChem CID: 6212) OT - Formaldehyde (PubChem CID: 712) OT - Glycine (PubChem CID: 750) OT - MHE OT - Methanol (PubChem CID: 887) OT - Neurocognitive function OT - Neuroinflammation OT - Potassium chloride (PubChem CID: 4873) OT - Potassium dihydrogen phosphate (PubChem CID: 516951) OT - Sodium chloride (PubChem CID: 5234) OT - Sodium dihydrogen phosphate (PubChem CID:23672064) OT - Sodium dodecyl sulfate (PubChem CID: 3423265) OT - Systemic inflammation OT - TLR4 pathway OT - Thioacetamide (PubChem CID: 2723949) OT - Tris (PubChem CID: 6503) OT - Xylene (PubChem CID: 6850715) EDAT- 2021/01/01 06:00 MHDA- 2021/07/23 06:00 CRDT- 2020/12/31 20:13 PHST- 2020/09/03 00:00 [received] PHST- 2020/11/22 00:00 [revised] PHST- 2020/11/28 00:00 [accepted] PHST- 2021/01/01 06:00 [pubmed] PHST- 2021/07/23 06:00 [medline] PHST- 2020/12/31 20:13 [entrez] AID - S0753-3322(20)31277-4 [pii] AID - 10.1016/j.biopha.2020.111084 [doi] PST - ppublish SO - Biomed Pharmacother. 2021 Mar;135:111084. doi: 10.1016/j.biopha.2020.111084. Epub 2020 Dec 28.