PMID- 36481528 OWN - NLM STAT- MEDLINE DCOM- 20230105 LR - 20230111 IS - 1878-1705 (Electronic) IS - 1567-5769 (Linking) VI - 114 DP - 2023 Jan TI - Arctigenin mitigates insulin resistance by modulating the IRS2/GLUT4 pathway via TLR4 in type 2 diabetes mellitus mice. PG - 109529 LID - S1567-5769(22)01014-1 [pii] LID - 10.1016/j.intimp.2022.109529 [doi] AB - Arctigenin (AR), extracted from Arctium lappa L. (Burdock), is a folk herbal medicine used to treat diabetes. However, its mechanism of action has remained elusive. In this study, type 2 diabetes mellitus (T2DM) mice received AR orally for 10 weeks to evaluate its therapeutic effect based on changes in glucose and lipid metabolism, histological examination of target tissues, and liver immunohistochemistry. Furthermore, HepG2 insulin-resistant cells were established to verify the mechanism of AR against diabetes. The results showed that AR treatment reduced blood glucose and lipid levels, reversing liver as well as pancreas tissue damage in T2DM mice. AR reduced the levels of pro-inflammatory cytokines in the serum of T2DM mice, as well as those in insulin-resistant HepG2 cell supernatants, while increasing interleukin-10 (IL-10) levels. The levels of p-p65, phospho-c-Jun N-terminal kinase (p-JNK), induced nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) were reduced in the liver tissue of T2DM mice, accompanied by an upregulation of glucose transporter 4 (GLUT4) and insulin receptor substrate 2 (IRS-2). In vitro studies further showed that AR downregulated toll-like receptor 4-mediated inflammation, while upregulating insulin pathway-related proteins and ultimately improving glucose uptake in insulin-resistant HepG2 cells. In conclusion, AR protected mice from insulin resistance, and its therapeutic effect was likely associated with inhibition of toll-like receptor 4 inflammatory signaling to reactivate IRS-2/GLUT4. CI - Copyright (c) 2022 Elsevier B.V. All rights reserved. FAU - Zhou, Yuyan AU - Zhou Y AD - School of Pharmacy, Drug Research & Development Center, Wannan Medical College, Wuhu, Anhui 241002, China; Anesthesia Laboratory and Training Center of Wannan Medical College, China; Anhui Provincial Engineering Research Center for Polysaccharide Drugs, Anhui Provincial Engineering Laboratory for Screening and Re-evaluation of Active Compounds of Herbal Medicines in Southern Anhui, Anhui Province Key Laboratory of Active Biological Macromolecules, Wuhu 241002, China. FAU - Liu, Lina AU - Liu L AD - Department of Thyroid and Breast Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, China. FAU - Xiang, Ruoxuan AU - Xiang R AD - School of Pharmacy, Drug Research & Development Center, Wannan Medical College, Wuhu, Anhui 241002, China. FAU - Bu, Xiaoyang AU - Bu X AD - School of Pharmacy, Drug Research & Development Center, Wannan Medical College, Wuhu, Anhui 241002, China; Anhui Provincial Engineering Research Center for Polysaccharide Drugs, Anhui Provincial Engineering Laboratory for Screening and Re-evaluation of Active Compounds of Herbal Medicines in Southern Anhui, Anhui Province Key Laboratory of Active Biological Macromolecules, Wuhu 241002, China. FAU - Qin, Guozheng AU - Qin G AD - School of Pharmacy, Drug Research & Development Center, Wannan Medical College, Wuhu, Anhui 241002, China; Anhui Provincial Engineering Research Center for Polysaccharide Drugs, Anhui Provincial Engineering Laboratory for Screening and Re-evaluation of Active Compounds of Herbal Medicines in Southern Anhui, Anhui Province Key Laboratory of Active Biological Macromolecules, Wuhu 241002, China. FAU - Dai, Jiajia AU - Dai J AD - Anhui Provincial Engineering Research Center for Polysaccharide Drugs, Anhui Provincial Engineering Laboratory for Screening and Re-evaluation of Active Compounds of Herbal Medicines in Southern Anhui, Anhui Province Key Laboratory of Active Biological Macromolecules, Wuhu 241002, China; School of Public Health, Wannan Medical College, Wuhu 241002, China. FAU - Zhao, Zhigang AU - Zhao Z AD - School of Pharmacy, Drug Research & Development Center, Wannan Medical College, Wuhu, Anhui 241002, China; Anhui Provincial Engineering Research Center for Polysaccharide Drugs, Anhui Provincial Engineering Laboratory for Screening and Re-evaluation of Active Compounds of Herbal Medicines in Southern Anhui, Anhui Province Key Laboratory of Active Biological Macromolecules, Wuhu 241002, China. FAU - Fang, Xue AU - Fang X AD - School of Pharmacy, Drug Research & Development Center, Wannan Medical College, Wuhu, Anhui 241002, China. FAU - Yang, Shuo AU - Yang S AD - School of Pharmacy, Drug Research & Development Center, Wannan Medical College, Wuhu, Anhui 241002, China. FAU - Han, Jun AU - Han J AD - School of Pharmacy, Drug Research & Development Center, Wannan Medical College, Wuhu, Anhui 241002, China; Anhui Provincial Engineering Research Center for Polysaccharide Drugs, Anhui Provincial Engineering Laboratory for Screening and Re-evaluation of Active Compounds of Herbal Medicines in Southern Anhui, Anhui Province Key Laboratory of Active Biological Macromolecules, Wuhu 241002, China. Electronic address: hanjun@wnmc.edu.cn. FAU - Wang, Guodong AU - Wang G AD - School of Pharmacy, Drug Research & Development Center, Wannan Medical College, Wuhu, Anhui 241002, China; Anhui Provincial Engineering Research Center for Polysaccharide Drugs, Anhui Provincial Engineering Laboratory for Screening and Re-evaluation of Active Compounds of Herbal Medicines in Southern Anhui, Anhui Province Key Laboratory of Active Biological Macromolecules, Wuhu 241002, China. Electronic address: wangguodong@wnmc.edu.cn. LA - eng PT - Journal Article DEP - 20221206 PL - Netherlands TA - Int Immunopharmacol JT - International immunopharmacology JID - 100965259 RN - U76MR9VS6M (arctigenin) RN - 0 (Toll-Like Receptor 4) RN - 0 (Insulin Receptor Substrate Proteins) RN - 0 (Insulin) RN - 0 (Tlr4 protein, mouse) RN - 0 (Irs2 protein, mouse) SB - IM MH - Mice MH - Animals MH - *Insulin Resistance MH - *Diabetes Mellitus, Type 2/metabolism MH - Toll-Like Receptor 4/metabolism MH - Insulin Receptor Substrate Proteins/metabolism MH - Insulin OTO - NOTNLM OT - Arctigenin OT - Insulin receptor substrate 2 OT - Insulin resistance OT - Toll-like receptor 4 OT - Type 2 diabetes mellitus COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2022/12/09 06:00 MHDA- 2023/01/06 06:00 CRDT- 2022/12/08 23:39 PHST- 2022/08/23 00:00 [received] PHST- 2022/11/28 00:00 [revised] PHST- 2022/11/28 00:00 [accepted] PHST- 2022/12/09 06:00 [pubmed] PHST- 2023/01/06 06:00 [medline] PHST- 2022/12/08 23:39 [entrez] AID - S1567-5769(22)01014-1 [pii] AID - 10.1016/j.intimp.2022.109529 [doi] PST - ppublish SO - Int Immunopharmacol. 2023 Jan;114:109529. doi: 10.1016/j.intimp.2022.109529. Epub 2022 Dec 6.