Coreopsis tinctoria improves energy metabolism in obese hyperglycemic mice.

Coreopsis tinctoria (CT) improves energy metabolism. However, the role of CT in alleviating obesity-induced hyperglycemia by targeting the liver remains unknown. Therefore, this article aims to explore the mechanism by which CT improves energy metabolism and resists hyperglycemia. The water and ethanol extracts of CT were administered to high-fat diet-induced (HFD) obese C57BL/6J mice at a dose of 4 g/kg.bw (low-dose water extract, WL; low-dose ethanol extract, EL) or 10 g/kg.bw (high-dose water extract, WH; high-dose ethanol extract, EH). Mice that consumed a maintenance diet (LFD) were included as blank controls. Network pharmacology, liquid chromatography-mass spectrometry (LC-MS), L02 cell cultivation, and liver transcriptomics were used to examine the mechanism and functional components of CT against obesity-induced hyperglycemia. The results indicated that WL significantly (p < 0.05) alleviated glucose intolerance and insulin resistance in obesity-induced hyperglycemia. Kaempferol is the main active compound of CT, which demonstrated significant (p < 0.05) anti-hyperglycemic effects in obese mice and L02 cells. Finally, kaempferol significantly (p < 0.05; fold change >1.2) shifted the genes involved in carbon metabolism, glycolysis/gluconeogenesis, and the mitogen-activated protein kinase (MAPK) pathways toward the trend of LFD, indicating that it exerts an anti-hyperglycemic effect through these molecular mechanisms. Overall, oral intake of CT lowers blood glucose and improves insulin sensitivity in mice with obesity-induced hyperglycemia. Kaempferol is the primary functional component of CT.

Diallyl trisulfide ameliorates bone loss and alters specific gut microbiota and serum metabolites in natural aging mice.

Aging is a major cause of bone loss and osteoporosis. Diallyl trisulfide (DATS), one of the main organic sulfides in garlic oil, has been shown to alleviate arthritis in mice. However, further research is still needed to determine how DATS affects bone formation and bone loss in aging mice. Here, we established a mouse model of natural aging for dietary DATS intervention. DATS treatment improved the bone microstructure, including the disorganized arrangement of bone trabeculae and promoted collagen synthesis, as confirmed by micro-CT and histological analyses. The abundance of beneficial bacteria for bone formation, such as Clostridiaceae and Erysipelotrichaceae, and the microbial diversity and community richness were all altered by DATS, according to 16S rRNA sequencing data. 14 potential biomarkers and 9 important metabolic pathways were examined using serum metabolomics analysis. Additionally, there has been a significant reduction in sphingosine, which is directly associated with bone metabolism. The level of sphingosine and relative abundance of Clostridium were found to be negatively correlated by correlation analysis, indicating that bacteria may regulate bone reconstruction via influencing metabolites. Furthermore, Runx2 and ß-catenin gene expression levels increased in bones, which may be related to the ameliorative mechanism of DATS. Our results suggested that DATS may prevent age-related bone loss by upregulating osteogenic gene expression through altering gut microbes and serum metabolism.

Toxicity and Impact of Silica Nanoparticles on the Configuration of Gut Microbiota in Immunodeficient Mice.

Nanoparticles (NPs), having exceptional physicochemical and electrical characteristics with lower toxicity, have evolved as dynamic drug delivery carriers in living organisms. Potentially, the intragastric gavage of silica nanoparticles (SiNPs) affects gut microbiota profiles in immunodeficient mice. In this study, the impact of SiNPs of variable size and dosage was investigated in cyclophosphamide (Cy)-induced immunodeficient mice, specifically on their immune functions and gut microbiota, through physicochemical and metagenomic analysis. SiNPs of different sizes and doses were gavaged to Cy-induced immunodeficient mice for 12 days at an interval of 24 h to investigate their effects on immunological functions and the gut microbiome of mice. Our results showed that SiNPs had no significant toxicological effects on the cellular and hematological activities of immunodeficient mice. Furthermore, after the administration of different levels of SiNPs, no immune dysfunction was found in the immunosuppressed mice groups. However, gut-microbial studies and comparisons of characteristic bacterial diversity and compositions demonstrated that SiNPs significantly affect the abundance of different bacterial communities. LEfSe analysis revealed that SiNPs significantly increased the abundance of Lactobacillus, Sphingomonas, Sutterella, Akkermansia, and Prevotella, and potentially reduced Ruminococcus and Allobaculum. Thus, SiNPs significantly regulate and modify the configuration of the gut microbiota in immunodeficient mice. These dynamic variations in the intestinal bacterial community, abundance, and diversity provide new insight into the regulation and administration of silica-based NPs. This would be helpful for the further demonstration of the mechanism of action and prediction of the potential effects of SiNPs.

Sulforaphane Ameliorates Nonalcoholic Fatty Liver Disease Induced by High-Fat and High-Fructose Diet via LPS/TLR4 in the Gut-Liver Axis.

The gut-liver axis has emerged as a key player in the progression of non-alcoholic fatty liver disease (NAFLD). Sulforaphane (SFN) is a bioactive compound found in cruciferous vegetables; however, it has not been reported whether SFN improves NAFLD via the gut-liver axis. C57BL/6 mice were fed a high-fat and high-fructose (HFHFr) diet, with or without SFN gavage at doses of 15 and 30 mg·kg-1 body weight for 12 weeks. The results showed that SFN reduced weight gain, hepatic inflammation, and steatosis in HFHFr mice. SFN altered the composition of gut microbes. Moreover, SFN enhanced the intestinal tight junction protein ZO-1, reduced serum LPS, and inhibited LPS/TLR4 and ERS pathways to reduce intestinal inflammation. As a result, SFN protected the intestinal integrity and declined the gut-derived LPS translocations to the liver in HFHFr diet-induced mice. SFN decreased the liver LPS levels and inhibited the LPS/TLR4 pathway activations, thus inhibiting the pro-inflammatory cytokines. Notably, Spearman correlation analysis showed that the protective effect of SFN on intestinal barrier integrity and its anti-inflammatory effect on the liver was associated with improved intestinal dysbiosis. Above all, dietary intervention with SFN attenuates NAFLD through the gut-liver axis.

Mitochondrial pyruvate carrier 1 regulates fatty acid synthase lactylation and mediates treatment of nonalcoholic fatty liver disease.

BACKGROUND AND AIMS: NAFLD has become a major metabolic disease worldwide. A few studies have reported the potential relationship between mitochondrial pyruvate carrier 1 (MPC1) and inflammation, fibrosis, and insulin sensitivity in obese or NASH mouse models. However, the impact of MPC1 on NAFLD-related liver lipid metabolism and its role in the NAFLD progression require further investigation. APPROACH AND RESULTS: MPC1 expression was measured in liver tissues from normal controls and patients with NAFLD. We characterized the metabolic phenotypes and expression of genes involved in hepatic lipid accumulation in MPC1 systemic heterozygous knockout (MPC1 +/- ) mice. Hepatic protein lactylation was detected using Tandem Mass Tags proteomics and verified by the overexpression of lactylation mutants in cells. Finally, the effect of MPC1 inhibition on liver inflammation was examined in mice and AML-12 cells. Here, we found that MPC1 expression was positively correlated to liver lipid deposition in patients with NAFLD. MPC1 +/- mice fed with high-fat diet had reduced hepatic lipid accumulation but no change in the expression of lipid synthesis-related genes. MPC1 knockout affected the lactylation of several proteins, especially fatty acid synthase, through the regulation of lactate levels in hepatocytes. Lactylation at the K673 site of fatty acid synthase inhibited fatty acid synthase activity, which mediated the downregulation of liver lipid accumulation by MPC1. Moreover, although MPC1 knockout caused lactate accumulation, inflammation level was controlled because of mitochondrial protection and macrophage polarization. CONCLUSIONS: In NAFLD, MPC1 levels are positively correlated with hepatic lipid deposition; the enhanced lactylation at fatty acid synthase K673 site may be a downstream mechanism.

Diallyl Trisulfide Prevents Adipogenesis and Lipogenesis by Regulating the Transcriptional Activation Function of KLF15 on PPARγ to Ameliorate Obesity.

SCOPE: Diallyl trisulfide (DATS) is a bioactive compound in garlic. The anti-obesity effect of garlic oil has been reported, but the role and mechanism of DATS in preventing obesity remain to be explored. METHODS AND RESULTS: Studies with high-fat-diet-induced obese mice and 3T3-L1 adipocytes are performed. The results show that DATS significantly reduces lipid accumulation and repairs disordered metabolism in vivo by restraining adipogenesis and lipogenesis, and promoting lipolysis and fatty acid oxidation in white adipose tissue. In cells, DATS plays different roles at different stages of adipocyte differentiation. Notably, DATS reduces lipid accumulation mainly by inhibiting adipogenesis and lipogenesis at the late stage. KLF15 is knocked down in 3T3-L1 cells, which eliminate the inhibitory effect of DATS on adipogenesis and lipogenesis. The dual-luciferase reporter and ChIP assays indicate that DATS can inhibit the transcriptional activation function of KLF15 on PPARγ by inhibiting the binding of KLF15 to PPARγ promoter. The function comparison of structural analogs and the intervention of dithiothreitol show that disulfide bond is crucial for DATS to work. CONCLUSION: DATS prevents obesity by regulating the transcriptional activation function of KLF15 on PPARγ.

Gynostemma pentaphyllum and Gypenoside-IV Ameliorate Metabolic Disorder and Gut Microbiota in Diet-Induced-Obese Mice.

Gynostemma pentaphyllum (G. pentaphyllum) is a perennial liana herb of the Cucurbitaceae family which has both nutraceutical and pharmacological functions. The objective of the current study was to investigate the preventative effects of G. pentaphyllum and Gypenoside-IV (GP-IV, a saponin monomer in G. pentaphyllum) on metabolic symptoms in high fat diet induced obese (DIO) mice with gut microbiota dysbiosis. G. pentaphyllum water extract (GPWE, 150 mg/kg•d- 1) and GP-IV (50 mg/kg•d- 1) were orally administered to DIO mice by gavage for 10 weeks. The results showed that both GPWE and GP-IV prevented obesity development by decreasing body weight gain, reducing fat mass/body weight ratio and inhibiting adipocyte hypertrophy. GPWE and GP-IV also improved lipid profile and glucose tolerance effectively. Moreover, GPWE and GP-IV treatments partly restored gut microbiota in DIO mice. Typically, GPWE and GP-IV reduced Firmicutes to Bacteroidetes ratio, increased the abundance of certain health-promoting bacteria and reduced the abundance of microbiota that were associated with metabolic disorders. We conclude that GPWE and GP-IV can ameliorate metabolic symptoms possibly via modulating gut microbiota in DIO mice.

Pleurotus Ostreatus Ameliorates Obesity by Modulating the Gut Microbiota in Obese Mice Induced by High-Fat Diet.

Pleurotus ostreatus (PO), a common edible mushroom, contains rich nutritional components with medicinal properties. To explore the effect of PO on ameliorating obesity and modulating the gut microbiota, we administered the mice with a low-fat diet or high-fat diet containing different dosages of PO (mass fraction: 0%, 2.5%, 5% and 10%). The body weight, adipose tissue weight, GTT, ITT, blood lipids, serum biomarkers of liver/kidney function, the gut microbiota and function were measured and analyzed after 6 weeks of PO treatment. The results showed PO prevented obesity, maintained glucose homeostasis and beneficially modulated gut microbiota. PO modified the composition and functions of gut microbiota in obese mice and make them similar to those in lean mice, which contributed to weight loss. PO significantly increased the relative abundance of Oscillospira, Lactobacillus group and Bifidobacterium, while decreased the relative abundance of Bacteroides and Roseburia. The prediction of gut microbiota function showed PO upregulated lipid metabolism, carbohydrate metabolism, bile acid biosynthesis, while it downregulated adipocytokine signaling pathway and steroid hormone biosynthesis. Correlation analysis further suggested the potential relationship among obesity, gut microbiota and the function of gut microbiota. In conclusion, all the results indicated that PO ameliorated obesity at least partly by modulating the gut microbiota.

Coreopsis tinctoria and Its Flavonoids Ameliorate Hyperglycemia in Obese Mice Induced by High-Fat Diet.

With the prevalence of obesity all over the world, human health has been seriously affected. In particular, the number of diabetic and cardiovascular diseases has increased dramatically. The herb Coreopsis tinctoria (C. tinctoria) shows diverse biological and pharmacological activities, which are mainly attributed to its flavonoids. However, the specific functional substances that play an active role in C. tinctoria remain unclear, and its mechanism has not been deeply explored. In this study, we established a diet-induced obesity (DIO) mice model and treated mice with C. tinctoria or kaempferol for 8 weeks. The results showed that both C. tinctoria and kaempferol lowered body weight, reduced fasting blood glucose, and improved glucose tolerance and insulin resistance to alleviate obesity in DIO mice. The level of hemoglobin A1c also decreased significantly after treatment with C. tinctoria and kaempferol. Moreover, the administration of C. tinctoria and kaempferol also restored gut microbiota imbalance and significantly increased Desulfovibrio and Butyricimonas levels, which have been reported to improve glucose metabolism and intestinal health. In general, our study shows that C. tinctoria is a potential hypoglycemic substance for obesity and may reduce blood glucose by regulating gut microbiota, and that kaempferol is one of the effective substances of C. tinctoria.

Aptamer-Functionalized Binary-Drug Delivery System for Synergetic Obesity Therapy.

The targeted delivery of phytochemicals that promote energy expenditure for obesity therapy remains a challenge. This study assembled a functionalized adipo-8 aptamer loaded with allicin using isothermal rolling-circle techniques to form a synergistic adipocyte-targeted binary-drug delivery system for treating obesity. The functionalized adipo-8 aptamer efficiently protected allicin from adsorption, showing significant potential to encapsulate, transport, and release molecular cargos into white adipose tissue. Introducing the negatively charged allicin, a phytochemical able to induce adipose tissue browning, reduced the diameters of DNA-nanoflower from 770 to 380 nm and increased cellular uptake efficiency up to 118.7%. The intracellular distribution observed via confocal microscopy confirmed the successful receptor recognition mediated by aptamers in the DNA-nanoflower-allicin (NFA) framework as well as its excellent stability to escape from lysosomes. In vivo results demonstrated that subcutaneous administration of NFA effectively promoted adipocyte browning and systematic energy expenditure with minimal side effects. Furthermore, the G-quadruplex in the mitochondrial uncoupling protein-1 promoter was found to be an interactive allicin target for regulating thermogenesis to combat obesity.

Correlation between bacterial community succession and propionic acid during gray sufu fermentation.

In order to explore the correlation between the production of propionic acid (PA) and the succession of bacterial community during the fermentation of gray sufu, high-throughput sequencing and HPLC (High Performance Liquid Chromatography) were used to monitor the changes of bacterial community and metabolite content. The abundance and metabolite concentration of Propionibacterium increased rapidly in the early stage of fermentation. In the middle stage, the abundance of Lactobacillus began to increase, while the pH decreased rapidly. In the late stage, the concentration of PA began to decrease, but it remained at a high level at the end of fermentation. Correlation analysis showed that Lactobacillus and Bacillus had a strong negative correlation with PA and its precursor. The results showed that Fusobacterium, Providencia, Lactobacillus and Bacillus could be the key factors to reduce the PA content. This study provides a new idea for the quality control of traditional fermented food.