PMID- 37499844 OWN - NLM STAT- MEDLINE DCOM- 20230918 LR - 20230918 IS - 1872-7573 (Electronic) IS - 0378-8741 (Linking) VI - 318 IP - Pt A DP - 2024 Jan 10 TI - Total flavonoids of Hippophae rhamnoides L. improves type 2 diabetes symptoms in rats through down-regulating of the DAG/PRKCA/MAPK10/p65/TNF-alpha signalling pathway. PG - 116962 LID - S0378-8741(23)00830-9 [pii] LID - 10.1016/j.jep.2023.116962 [doi] AB - ETHNOPHARMACOLOGICAL RELEVANCE: Dry mature fruits of Hippophae rhamnoides L. (HRL), Elaeagnaceae, have traditional functions of invigorating spleen and improving spleen insufficiency. Traditional Chinese medicine (TCM) clinics have been proved that HRL is in favor of diabetes treatment. Modern pharmacological studies demonstrated that total flavones of Hippophae rhamnoides (TFH) are the main substance for HRL to develop anti-inflammation and anti-diabetes functions. However, chemical features, active ingredients and anti-diabetes pharmacological mechanism of HRL still remain unclear. AIM OF THE STUDY: Key targets and metabolites in anti-type-II diabetes mellitus (T2DM) of TFH have been explored based on AGE-RAGE signaling pathway in diabetic complications. The anti-T2DM mechanism of TFH has been elaborated from comprehensive perspectives, including target prediction, metabolites, potential metabolic pathways, and so on. MATERIALS AND METHODS: In this study, a qualitative test of chemical composition of HRL was carried out based on ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). The anti-T2DM targets and pathways of HRL were predicted through network pharmacological approach. The T2DM rat model was induced by high-fat and high-glucose diet combined with streptozotocin (STZ). The T2DM model was evaluated through fasting blood glucose level, body weight, serum biochemical indicators, insulin levels and homeostatic model assessment of insulin resistance. The key metabolic pathways were screened through the correlation between metabolites and key targets. Finally, the quantitative analysis of key targets and metabolites was verified through experiments. RESULTS: After TFH intervention, the fasting blood-glucose level of T2DM rats induced by high-fat and high-glucose diet combined with streptozotocin (STZ) was downregulated significantly, while body weight, serum liquid level, insulin levels and homeostatic model assessment of insulin resistance (HOMA-IR) were improved. According to ELISA, Western blotting (WB) and reverse transcriptase polymerase chain reaction (RT-PCR), TFH significantly downregulates expression levels of diglyceride (DAG)-activated protein kinase C (PRKCA), mitogen activated protein kinase 10 (MAPK10), human nuclear factor kappaB subunit p65 (NF-kappaB p65) and tumor necrosis factor-alpha (TNF-alpha) in pancreas of STZ-induced rats. CONCLUSIONS: TFH downregulates expressions of PRKCA, MAPK10 and p65 TNF-alpha as well as level of the key metabolite DA in the DAG/PRKCA/MAPK10/TNF-alpha/p65 pathways, improves lipid metabolism disorder, inhibits inflammatory response and thereby relieves symptoms of T2DM. CI - Copyright (c) 2023 Elsevier B.V. All rights reserved. FAU - Yang, Xingjing AU - Yang X AD - Shaanxi University of Chinese Medicine Shaanxi Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, 712083, Xianyang, PR China. FAU - Liu, Yanru AU - Liu Y AD - Shaanxi University of Chinese Medicine Shaanxi Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, 712083, Xianyang, PR China. Electronic address: yanzi_2203@aliyun.com. FAU - Tang, Zhishu AU - Tang Z AD - Shaanxi University of Chinese Medicine Shaanxi Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, 712083, Xianyang, PR China; China Academy of Chinese Medical Sciences, 100700, Beijing, PR China. Electronic address: tzs6565@163.com. FAU - Song, Zhongxing AU - Song Z AD - Shaanxi University of Chinese Medicine Shaanxi Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, 712083, Xianyang, PR China. FAU - Liu, Changle AU - Liu C AD - Shaanxi University of Chinese Medicine Shaanxi Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, 712083, Xianyang, PR China. FAU - Wang, Changli AU - Wang C AD - Inner Mongolia Haitian Pharmaceutical Limited Company, 028000, Tongliao, PR China. LA - eng PT - Journal Article DEP - 20230725 PL - Ireland TA - J Ethnopharmacol JT - Journal of ethnopharmacology JID - 7903310 RN - 0 (Flavonoids) RN - 0 (Tumor Necrosis Factor-alpha) RN - EC 2.7.1.- (Mitogen-Activated Protein Kinase 10) RN - 5W494URQ81 (Streptozocin) RN - IY9XDZ35W2 (Glucose) RN - 0 (Insulins) RN - EC 2.7.11.13 (PRKCA protein, human) RN - EC 2.7.11.13 (Protein Kinase C-alpha) SB - IM MH - Humans MH - Rats MH - Animals MH - *Diabetes Mellitus, Type 2/metabolism MH - Flavonoids/pharmacology MH - Tumor Necrosis Factor-alpha MH - *Hippophae/chemistry MH - Mitogen-Activated Protein Kinase 10/metabolism MH - *Insulin Resistance MH - Streptozocin MH - Signal Transduction MH - Glucose/metabolism MH - Body Weight MH - *Insulins/therapeutic use MH - Protein Kinase C-alpha/metabolism OTO - NOTNLM OT - Hippophae rhamnoides L. OT - PRKCA OT - Total flavones of Hippophae rhamnoides 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- 2023/07/28 01:08 MHDA- 2023/09/18 12:43 CRDT- 2023/07/27 19:15 PHST- 2023/04/06 00:00 [received] PHST- 2023/06/30 00:00 [revised] PHST- 2023/07/23 00:00 [accepted] PHST- 2023/09/18 12:43 [medline] PHST- 2023/07/28 01:08 [pubmed] PHST- 2023/07/27 19:15 [entrez] AID - S0378-8741(23)00830-9 [pii] AID - 10.1016/j.jep.2023.116962 [doi] PST - ppublish SO - J Ethnopharmacol. 2024 Jan 10;318(Pt A):116962. doi: 10.1016/j.jep.2023.116962. Epub 2023 Jul 25.