PMID- 37359004 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20230701 IS - 2296-858X (Print) IS - 2296-858X (Electronic) IS - 2296-858X (Linking) VI - 10 DP - 2023 TI - New anti-diabetic drug Morus alba L. (Sangzhi) alkaloids (SZ-A) improves diabetic nephropathy through ameliorating inflammation and fibrosis in diabetic rats. PG - 1164242 LID - 10.3389/fmed.2023.1164242 [doi] LID - 1164242 AB - BACKGROUND: Morus alba L. (Sangzhi) alkaloid (SZ-A) is a new antidiabetic drug approved by the China National Medical Products Administration in 2020. Diabetic nephropathy (DN) is a common diabetic complication and an important cause of morbidity and mortality in patients with diabetes. The effects of SZ-A on DN remain unknown. PURPOSE: This study evaluated the effects of SZ-A on DN in Zucker diabetic fatty (ZDF) rats and explored the underlying mechanisms based on nitrosative stress, inflammation, and fibrosis. METHODS: Diabetic ZDF rats were orally administered 100 and 200 mg/kg of SZ-A once daily for 9 weeks. The glucose metabolism and kidney function were assayed. The pathological injury and fibrosis of the kidneys were separately evaluated using hematoxylin and eosin staining and Masson's staining. The oxidative and nitrosative stress and inflammation were assayed by determining the levels of related indices in the blood and kidneys and quantifying the related gene and protein expression. The expression of transforming growth factor beta1 (TGFbeta1) gene and protein were assayed by quantitative real-time PCR and immunohistochemistry, respectively. The renal transcriptomics was analyzed using RNA sequencing. RESULTS: Repeated treatment with SZ-A significantly improved glucose metabolism, dose-dependently decreased the levels of blood urea nitrogen, urinary albumin, and beta2-microglobulin, and evidently relieved the renal injury in diabetic ZDF rats. As for the mechanisms, SZ-A remarkably ameliorated systemic nitrosative stress through lowering the levels of blood inducible nitric oxide synthase and nitric oxide, and significantly relieved systemic and renal inflammation by reducing the levels of blood interleukin-1beta and monocyte chemoattractant protein-1 (MCP-1) and decreasing the levels of renal C-reactive protein content and expression of tumor necrosis factor-alpha in the kidneys. SZ-A also improved renal fibrosis by lowering the expression of TGFbeta1 in the kidneys. Additionally, SZ-A significantly lowered the expression of stimulator of chondrogenesis 1 in the kidneys. CONCLUSION: Repeated treatments with SZ-A significantly ameliorates DN by regulating systemic nitrosative stress, renal inflammation, and renal fibrosis partially through inhibition of the cytokine-NO and TGF-beta1 signaling in ZDF rats, providing evidence for the additional application of SZ-A in clinical use for the treatment of DN. CI - Copyright (c) 2023 Li, Liu, Ji, Fu, Cao, Huan, Lei, Gao, Chen, Feng, Zhang, Li, Liu, Liu and Shen. FAU - Li, Caina AU - Li C AD - Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. FAU - Liu, Quan AU - Liu Q AD - Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. FAU - Ji, Wenming AU - Ji W AD - Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. FAU - Fu, Yaxin AU - Fu Y AD - Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. FAU - Cao, Hui AU - Cao H AD - Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. FAU - Huan, Yi AU - Huan Y AD - Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. FAU - Lei, Lei AU - Lei L AD - Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. FAU - Gao, Xuefeng AU - Gao X AD - Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. FAU - Chen, Leilei AU - Chen L AD - Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. FAU - Feng, Cunyu AU - Feng C AD - Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. FAU - Zhang, Lin AU - Zhang L AD - Department of Endocrinology, Department of Medical Records, Beijing Tongren Hospital, Capital Medical University, Beijing, China. FAU - Li, Pingping AU - Li P AD - Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. FAU - Liu, Yuling AU - Liu Y AD - Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. FAU - Liu, Shuainan AU - Liu S AD - Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. FAU - Shen, Zhufang AU - Shen Z AD - Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. LA - eng PT - Journal Article DEP - 20230609 PL - Switzerland TA - Front Med (Lausanne) JT - Frontiers in medicine JID - 101648047 PMC - PMC10289017 OTO - NOTNLM OT - Morus alba L. (Sangzhi) alkaloids OT - diabetic nephropathy OT - inflammation OT - nitrosative stress OT - oxidative stress OT - renal fibrosis COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor QL declared a shared parent affiliation with the author LZ at the time of review. EDAT- 2023/06/26 19:07 MHDA- 2023/06/26 19:08 PMCR- 2023/06/09 CRDT- 2023/06/26 12:16 PHST- 2023/02/12 00:00 [received] PHST- 2023/05/11 00:00 [accepted] PHST- 2023/06/26 19:08 [medline] PHST- 2023/06/26 19:07 [pubmed] PHST- 2023/06/26 12:16 [entrez] PHST- 2023/06/09 00:00 [pmc-release] AID - 10.3389/fmed.2023.1164242 [doi] PST - epublish SO - Front Med (Lausanne). 2023 Jun 9;10:1164242. doi: 10.3389/fmed.2023.1164242. eCollection 2023.