Ramulus Mori (Sangzhi) Alkaloids Alleviate High-Fat Diet-Induced Obesity and Nonalcoholic Fatty Liver Disease in Mice

Chen, Yanmin; Lian, Chunfang; Sun, Qian-Wen; Wang, Tingting; Liu, Yuan-Yuan; Ye, Jun; Gao, Lili; Yang, Yanfang; Liu, Shuainan; Shen, Zhufang; Liu, Yuling

doi:10.3390/antiox11050905

Cited by 18 publications

(14 citation statements)

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“…Our previous research found that SZ-A inhibited body weight gain in HFD mice in a dose-dependent manner and that a dose of 400 mg/kg had the most notable effect on body weight inhibition [ 11 ]. In this study, six-week-old C57BL/6J mice were fed an HFD for 14 weeks, and then administered SZ-A (i.g.)…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies have reported that SZ-A could restore diabetic β-cells, improve insulin resistance, and modulate the gut microbiota and intestinal barrier integrity in KKAy mice with signs of obesity and diabetes [ 9 , 10 ]. Additionally, it has been reported that SZ-A could alleviate non-alcoholic fatty liver disease (NAFLD) in high-fat diet (HFD)-induced obese mice [ 11 ]. It was also demonstrated that SZ-A could inhibit body weight gain in HFD mice in a dose-dependent manner, with SZ-A at a dose of 400 mg/kg having the most significant effect.…”

Section: Introductionmentioning

confidence: 99%

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Ramulus Mori (Sangzhi) Alkaloids Ameliorate Obesity-Linked Adipose Tissue Metabolism and Inflammation in Mice

et al. 2022

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Obesity has become a global epidemic disease as it is closely associated with a chronic low-grade inflammatory state that results in metabolic dysfunction. Ramulus Mori (Sangzhi) alkaloids (SZ-A) derived from Morus alba L. were licensed to treat type 2 diabetes (T2DM) in 2020. In this study, we explored the effect of SZ-A on adipose tissue metabolism and inflammation using an obesity model induced by a high-fat diet (HFD). C57BL/6J mice were fed high fat for 14 weeks and followed by SZ-A 400 mg/kg treatment via gavage for another six weeks, during which they were still given the high-fat diet. The results showed that SZ-A notably reduced body weight and serum levels of lipid metabolism-related factors, such as triglycerides (TG) and total cholesterol (TC); and inflammation-related factors, namely tumor necrosis factor alpha (TNFα), interleukin 6 (IL6), fibrinogen activator inhibitor-1 (PAI-1), angiopoietin-2 (Ang-2), and leptin (LEP), in the HFD-induced mice. SZ-A increased the protein and mRNA expression of lipid metabolism-related factors, including phosphorylated acetyl coenzyme A carboxylase (p-ACC), phosphorylated hormone-sensitive triglyceride lipase (p-HSL), adipose triglyceride lipase (ATGL), and peroxisome proliferator-activated receptor-alpha (PPARα), in adipose tissue. Immunohistochemistry results demonstrated that SZ-A significantly reduced the infiltration of pro-inflammatory M1-type macrophages in epididymal fat. The data also suggested that SZ-A down-regulates the transcriptional levels of inflammatory factors Il6, Tnfα, monocyte chemoattractant protein-1 (Mcp1), and F4/80, and up-regulates interleukin 4 (Il4), interleukin 10 (Il10), and interleukin 13 (Il13) in adipose tissue. Overall, the results indicate that SZ-A exhibits potential in regulating lipid metabolism and ameliorating obesity-linked adipose inflammation.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ramulus Mori (Sangzhi) Alkaloids Ameliorate Obesity-Linked Adipose Tissue Metabolism and Inflammation in Mice

et al. 2022

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“…Among these three major alkaloid components, DNJ has the highest proportion, accounting for more than 50% of the total alkaloid, and the sum of the three main components accounts for more than 80% of the total alkaloid. Besides its good hypoglycemic effect, previous studies have confirmed that SZ-A has multiple pharmacological effects, including alleviating high-fat diet-induced obesity and nonalcoholic fatty liver disease and ameliorating obesity-linked adipose tissue metabolism and inflammation, indicating the potential of SZ-A to regulate obesity and metabolic syndrome (Chen et al, 2022;Sun et al, 2022). Accumulated evidence confirmed that gut microbiota and their metabolic profiles played an important role in the occurrence and development of obesity and metabolic syndrome.…”

Section: Introductionmentioning

confidence: 87%

“…The current clinical hypoglycemic dose is 5 mg/kg, which was converted to 60 mg/kg for mice. To explore the potential of SZ-A in reducing body weight, we previously investigated the weight loss effect of 100 and 200 mg/kg SZ-A treatment for 8 weeks in HFD-feeding KKAy mice and 400 mg/kg SZ-A treatment for 6 weeks in HFD-feeding C57BL/6J mice (Liu et al, 2021;Chen et al, 2022;Sun et al, 2022).…”

Section: Sz-a Effectively Regulates the Body Weight Of Obese Mice Ind...mentioning

confidence: 99%

Ramulus mori (Sangzhi) alkaloids regulates gut microbiota disorder and its metabolism profiles in obese mice induced by a high-fat diet

Liu

et al. 2023

Front. Pharmacol.

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The imbalance of gut microbiota has been confirmed to have a close pathological and physiological correlation with obesity and metabolic syndrome. Ramulus Mori (Sangzhi) Alkaloids (SZ-A) derived from twigs of mulberry was approved by the National Medical Products Administration of China in 2020 for the treatment of type 2 diabetes mellitus. In addition to its hypoglycemic effect, previous studies have confirmed that SZ-A also alleviates high-fat diet-induced obesity and non-alcoholic fatty liver disease and ameliorates obesity-linked adipose tissue metabolism and inflammation, indicating the potential of SZ-A to regulate obesity and metabolic syndrome. However, whether SZ-A can improve obesity and metabolic syndrome by regulating gut microbiota and its metabolism profiles remains unclear. The purpose of this study was to assess the effect of SZ-A on gut microbiota in obese mice and to explore the association among changes in gut microbiota, obesity, and lipid metabolism. The results showed that oral administration of SZ-A could significantly reduce body weight, fat mass, and the level of total cholesterol and low-density lipoprotein in serum in obese mice induced by a high-fat diet. Interestingly, SZ-A also regulated gut microbiota and changed the fecal metabolite composition of obese mice. Compared with the high-fat diet group, the ratio of Firmicutes to Bacteroides changed at the phylum level and the abundance of Bifidobacterium and Akkermansia muciniphila significantly increased at the genus level in the SZ-A group. The gut microbiota of the SZ-A group was reshaped and the relative abundance of microbial genes in bile acid metabolism and fatty acid metabolism were altered, which was consistent with the metabolomics results. Additionally, SZ-A greatly enriched the number of goblet cells and reduced inflammatory colon injury and pro-inflammatory macrophage infiltration induced by a high-fat diet in obese mice. In conclusion, SZ-A can alleviate obesity and metabolic syndrome by improving the gut microbiota and its metabolism profiles of obese mice induced by a high-fat diet.

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“…The liver has been proven to be one of the main target organs of hypoglycemic drugs. For example, Ramulus Mori (Sangzhi) alkaloids directly reduce FBG levels in obese mice by regulating liver and adipose tissue ( 11 ). Metformin (MET) is a classic clinical hypoglycemic drug that exerts a hypoglycemic effect in the liver by activating AMPK and regulating the inflammatory response in liver cells ( 12 ).…”

Section: Introductionmentioning

confidence: 99%

Simiao Wan and its ingredients alleviate type 2 diabetes mellitus via IRS1/AKT2/FOXO1/GLUT2 signaling

Xia

Xu²,

et al. 2023

Front. Nutr.

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BackgroundType 2 diabetes mellitus (T2DM) is a metabolic disease. Simiao Wan (SMW) is a commonly used clinical drug for hyperuricemia treatment. SMW has been confirmed to improve insulin resistance and is expected to be a novel hypoglycemic agent. However, the hypoglycemic bioactive ingredients and mechanisms of action of SMW are unclear.ObjectiveTo explore the hypoglycemic effects and reveal the mechanisms of SMW and bioactive ingredients (SMW-BI).Study design and methodsThe hypoglycemic effects of SMW and SMW-BI were verified in a mouse model of T2DM induced by streptozotocin (STZ) and a high-fat and high-sugar diet (HFSD). Network pharmacology was used to predict the mechanisms of SMW and SMW-BI. Histological analysis and real-time quantitative polymerase chain reaction (RT-qPCR) verified network pharmacology results. RT-qPCR results were further verified by immunofluorescence (IFC) and molecular docking. The correlation between proteins and biochemical indicators was analyzed by Spearman’s correlation.ResultsChlorogenic acid, phellodendrine, magnoflorine, jateorhizine, palmatine, berberine, and atractydin were identified as SMW-BI. After 8 weeks of treatment, SMW and SMW-BI decreased the levels of fasting blood glucose (FBG), total cholesterol (TC), triacylglycerols (TG) and low-density lipoprotein cholesterol (LDL-C), increased the level of high-density lipoprotein cholesterol (HDL-C), alleviated weight loss, and increased serum insulin levels in T2DM mice. In addition, SMW and SMW-BI improved hepatocyte morphology in T2DM mice, decreased the number of adipocytes, and increased liver glycogen. Network pharmacological analysis indicated that SMW and SMW-BI may exert hypoglycemic by regulating insulin receptor substrate 1 (IRS1)/RAC-beta serine/threonine-protein kinase (AKT2)/forkhead box protein O1 (FOXO1)/glucose transporter type 2 (GLUT2) signaling. Moreover, correlation analysis showed that SMW and SMW-BI were associated with activation of IRS1, AKT2, and GLUT2, and inhibiting FOXO1. RT-qPCR revealed that SMW and SMW-BI could increase levels of IRS1, AKT2, and GLUT2 in the livers of T2DM mice and lower the level of FOXO1. Furthermore, immunofluorescence analysis showed that FOXO1 expression in the livers of T2DM mice decreased after oral administration of SMW and SMW-BI. Furthermore, molecular docking showed that SMW-BI could bind directly to IRS1 and AKT2.ConclusionSMW and SMW-BI are potential hypoglycemic drugs that alleviate T2DM by regulating IRS1/AKT2/FOXO1 signaling. Our study provides a research idea for screening the bioactive ingredients in traditional Chinese medicine (TCM).

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Ramulus Mori (Sangzhi) Alkaloids Alleviate High-Fat Diet-Induced Obesity and Nonalcoholic Fatty Liver Disease in Mice

Cited by 18 publications

References 42 publications

Ramulus Mori (Sangzhi) Alkaloids Ameliorate Obesity-Linked Adipose Tissue Metabolism and Inflammation in Mice

Ramulus Mori (Sangzhi) Alkaloids Ameliorate Obesity-Linked Adipose Tissue Metabolism and Inflammation in Mice

Ramulus mori (Sangzhi) alkaloids regulates gut microbiota disorder and its metabolism profiles in obese mice induced by a high-fat diet

Simiao Wan and its ingredients alleviate type 2 diabetes mellitus via IRS1/AKT2/FOXO1/GLUT2 signaling

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