This study was conducted to investigate the effects of a high-fat diet (HFD) and high-fat and high-cholesterol diet (HFHCD) on glucose and lipid metabolism and on the intestinal microbiota of the host animal. A total of 30 four-week-old female C57BL/6 mice were randomly divided into three groups (n = 10) and fed with a normal diet (ND), HFD, or HFHCD for 12 weeks, respectively. The HFD significantly increased body weight and visceral adipose accumulation and partly lowered oral glucose tolerance compared with the ND and HFHCD. The HFHCD increased liver weight, liver fat infiltration, liver triglycerides, and liver total cholesterol compared with the ND and HFD. Moreover, it increased serum high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and total cholesterol compared with the ND and HFD and upregulated alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase significantly. The HFHCD also significantly decreased the α-diversity of the fecal bacteria of the mice, to a greater extent than the HFD. The composition of fecal bacteria among the three groups was apparently different. Compared with the HFHCD-fed mice, the HFD-fed mice had more Oscillospira, Odoribacter, Bacteroides, and [Prevotella], but less [Ruminococcus] and Akkermansia. Cecal short-chain fatty acids were significantly decreased after the mice were fed the HFD or HFHCD for 12 weeks. Our findings indicate that an HFD and HFHCD can alter the glucose and lipid metabolism of the host animal differentially; modifications of intestinal microbiota and their metabolites may be an important underlying mechanism.

Metabolic syndrome and obesity have become serious threats to public health worldwide. This study was conducted to evaluate the anti‐adipogenesis and metabolism‐regulating effects of heat‐inactivated Streptococcus thermophilus MN‐ZLW‐002 (MN‐ZLW‐002), which can be used as a yogurt starter. In vitro study suggested that MN‐ZLW‐002 stimulated the RAW264.7 macrophages to produce significant amounts of interleukin (IL)‐6, IL‐10 and tumour necrosis factor (TNF)‐α and induced intense phosphorylation of P38, p44/42 MAPK and nuclear factor κB. MN‐ZLW‐002‐stimulated RAW264.7‐conditioned medium (CM) notably suppressed the differentiation and adipogenesis of 3T3‐L1 pre‐adipocytes. The 12‐week in vivo study suggested that orally administered MN‐ZLW‐002 significantly reduced the weight gain of mice caused by the high‐fat diet (HFD) at weeks 3–8; decreased fasting blood glucose levels at week 4 and week 8; decreased serum total triglyceride level at week 12. MN‐ZLW‐002 also reduced serum IL‐1β and chemokine ligand 3 levels in the HFD‐fed mice. These findings suggest that heat‐inactivated MN‐ZLW‐002 can suppress adipocytes differentiation and lipid accumulation by regulating the immune response, possibly via the release of cytokines, particularly TNF‐α; MN‐ZLW‐002 can improve metabolism‐related indicators in the early stage of HFD intervention and regulate the related pro‐inflammatory immune response.

This study aimed to evaluate the possible anti-obesity effects of orlistat and ezetimibe and determine the mechanism by which they alter the composition of gut microbiota and short-chain fatty acids (SCFAs) in mice with a high-fat diet (HFD)-induced obesity. Eighty male, specific pathogen-free C57BL/6J mice aged 3 weeks were divided into four groups (n = 20). The NCD group was fed with a normal diet, and the HFD, HFD+ORL, and HFD+EZE groups were fed with HFD for 20 weeks. From the 13th week onward, the HFD+ORL and HFD+EZE groups were administered with orlistat and ezetimibe, respectively. The glucose and lipid metabolism of the tested mice were evaluated by analyzing blood biochemical indicators during the intervention. Furthermore, the changes in the structure of the fecal microbiota and the fecal SCFA content were analyzed by 16S rRNA sequencing and gas chromatography-mass spectrometry, respectively. HFD induced the obesity phenotype in mice. Compared to the HFD group, the body weight, visceral fat-to-body weight ratio, serum total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C), and oral glucose tolerance test (OGTT) of the HFD+ORL group significantly decreased, whereas fecal butyric acid levels significantly increased. Ezetimibe intervention significantly reduced the OGTT, serum TC, and HDL-C levels only. The α-diversity of the gut microbiota significantly decreased after intervention with orlistat and ezetimibe. Orlistat altered the relative abundance of some bacteria in the fecal microbiota. The populations of Firmicutes, Alistipes, and Desulfovibrio decreased, whereas those of Verrucomicrobia and Akkermansia significantly increased. Ezetimibe caused changes only in some low-abundance bacteria, as manifested by a decrease in Proteobacteria and Desulfovibrio, and an increase in Bacteroides. The administration of orlistat and ezetimibe can characteristically influence the body weight and serum lipid metabolism, and glucolipid levels in diet-induced obese mice and is accompanied by significant changes in the gut microbiota and SCFAs. These results suggest that the two drugs might exert their own specific anti-obesity effects by modulating the gut microbiota in a different manner. The enhanced health-promoting effect of orlistat might result from its stronger ability to alter the gut microbiota and SCFAs, at least partly.

Human dihydroorotate dehydrogenase (DHODH) is a viable target for the development of therapeutics to treat cancer and immunological diseases, such as rheumatoid arthritis (RA), psoriasis and multiple sclerosis (MS). Herein, a series of acrylamide-based novel DHODH inhibitors as potential RA treatment agents were designed and synthesized. 2-Acrylamidobenzoic acid analog 11 was identified as the lead compound for structure−activity relationship (SAR) studies. The replacement of the phenyl group with naphthyl moieties improved inhibitory activity significantly to double-digit nanomolar range. Further structure optimization revealed that an acrylamide with small hydrophobic groups (Me, Cl or Br) at the 2-position was preferred. Moreover, adding a fluoro atom at the 5-position of the benzoic acid enhanced the potency. The optimization efforts led to potent compounds 42 and 53 ‒ 55 with IC 50 values of 41, 44, 32, and 42 nmol/L, respectively. The most potent compound 54 also displayed favorable pharmacokinetic (PK) profiles and encouraging in vivo anti-arthritic effects in a dose-dependent manner.

It is well documented that obesity and metabolic syndrome have a deep association with the intestinal immune system of the host animal. Recent studies indicate that some selected probiotics can modulate the immune responses of the host animal, thereby altering its lipid metabolism. However, the underlying mechanisms are still not fully understood. This study was conducted to investigate the possibility of probiotics to activate macrophages in the hosts, thus alter the differentiation of pre-adipocytes. In this study, Streptococcus thermophilus MN-ZLW-002 (MN-ZLW-002) was co-cultured with RAW264.7 macrophages, with Lactobacillus rhamnosus GG (LGG) as a control. The conditioned medium (CM) of the co-culture was collected and then added to 3T3-L1 pre-adipocytes. Viable and heat-killed (80 °C, 30 min) MN-ZLW-002 stimulated RAW264.7 cells to produce significant amounts of interleukin (IL)-6 and tumor necrosis factor (TNF)-α and induced intense phosphorylation of P38, p44/42 MAPK (ERK) and nuclear factor κB (NF-κB). Cytokine production reduced dramatically when heat-killed MN-ZLW-002 was treated with Ribonuclease. Viable and heat-killed LGG induced less cytokine production and little signaling protein activation. Viable and heat-killed MN-ZLW-002-stimulated RAW264.7-CM notably suppressed pre-adipocytes differentiation. However, viable LGG-stimulated RAW264.7-CM had a weaker effect and heat-killed LGG-stimulated RAW264.7-CM had no effect. These findings suggest that viable and heat-killed (80 °C, 30 min) MN-ZLW-002 may alter its lipid metabolism by regulating its immune response, possibly via the release of cytokine, particularly TNF-α. The RNA of heat-killed MN-ZLW-002 may be a key component Biological and Pharmaceutical Bulletin Advance Publicationin its immune activation effect.