PMID- 37806092 OWN - NLM STAT- MEDLINE DCOM- 20231115 LR - 20231115 IS - 1950-6007 (Electronic) IS - 0753-3322 (Linking) VI - 168 DP - 2023 Dec TI - Inhibition of MD2 by natural product-drived JM-9 attenuates renal inflammation and diabetic nephropathy in mice. PG - 115660 LID - S0753-3322(23)01458-0 [pii] LID - 10.1016/j.biopha.2023.115660 [doi] AB - Diabetic kidney disease (DKD) is one of the severe complications of diabetes mellitus-related microvascular lesions, which remains the leading cause of end-stage kidney disease. The genesis and development of DKD is closely related to inflammation. Myeloid differentiation 2 (MD2) mediates hyperlyciemia-induced renal inflammation and DKD development and is considered as a potential therapeutic target of DKD. Here, we identified a new small-molecule MD2 inhibitor, JM-9. In vitro, JM-9 suppressed high glucose (HG) and palmitic acid (PA)-induced inflammation in MPMs, accompanied by inhibition of MD2 activation and the downstream TLR4/MyD88-MAPKs/NFkappaB pro-inflammatory signaling pathway. Macrophage-derived factors increased the fibrotic and inflammatory responses in renal tubular epithelial cells, which were inhibited by treating macrophages with JM-9. Then, we investigated the therapeutic effects against DKD in streptozotocin-induced type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) mouse models. Treatment with JM-9 prevented renal inflammation, fibrosis, and dysfunction by targeting MD2 in both T1DM and T2DM models. Our results show that JM-9, a new small-molecule MD2 inhibitor, protects against DKD by targeting MD2 and inhibiting MD2-mediated inflammation. In summary, JM-9 is a potential therapeutic agent for DKD. CI - Copyright (c) 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved. FAU - Wang, Minxiu AU - Wang M AD - Department of Pharmacy and Institute of Inflammation, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. FAU - Zhang, Qianhui AU - Zhang Q AD - Department of Pharmacy and Institute of Inflammation, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. FAU - Lou, Shuaijie AU - Lou S AD - Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. FAU - Jin, Leiming AU - Jin L AD - Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang 311399, China. FAU - Wu, Gaojun AU - Wu G AD - Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. FAU - Wu, Wenqi AU - Wu W AD - Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. FAU - Tang, Qidong AU - Tang Q AD - Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. FAU - Wang, Yi AU - Wang Y AD - Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. FAU - Long, Xiaohong AU - Long X AD - Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. FAU - Huang, Ping AU - Huang P AD - Department of Pharmacy and Institute of Inflammation, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, China. FAU - Luo, Wu AU - Luo W AD - Department of Pharmacy and Institute of Inflammation, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, China; Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. FAU - Liang, Guang AU - Liang G AD - Department of Pharmacy and Institute of Inflammation, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang 311399, China. Electronic address: wzmcliangguang@163.com. LA - eng PT - Journal Article DEP - 20231007 PL - France TA - Biomed Pharmacother JT - Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie JID - 8213295 SB - IM MH - Mice MH - Animals MH - *Diabetic Nephropathies/drug therapy/metabolism MH - *Diabetes Mellitus, Type 1/complications/drug therapy MH - *Diabetes Mellitus, Type 2 MH - *Nephritis MH - Inflammation/drug therapy OTO - NOTNLM OT - Diabetic kidney disease OT - Inflammation OT - JM-9 OT - Macrophage OT - Myeloid differentiation 2 COIS- Declaration of Competing Interest The authors declare that they have no conflict of interest. EDAT- 2023/10/09 00:41 MHDA- 2023/11/15 06:42 CRDT- 2023/10/08 18:12 PHST- 2023/07/26 00:00 [received] PHST- 2023/10/02 00:00 [revised] PHST- 2023/10/04 00:00 [accepted] PHST- 2023/11/15 06:42 [medline] PHST- 2023/10/09 00:41 [pubmed] PHST- 2023/10/08 18:12 [entrez] AID - S0753-3322(23)01458-0 [pii] AID - 10.1016/j.biopha.2023.115660 [doi] PST - ppublish SO - Biomed Pharmacother. 2023 Dec;168:115660. doi: 10.1016/j.biopha.2023.115660. Epub 2023 Oct 7.