Berberine alleviates intestinal barrier dysfunction in glucolipid metabolism disorder hamsters by modulating gut microbiota and gut-microbiota-related tryptophan metabolites.

BACKGROUND: Barberry plants can be considered as useful additives and functional compounds in various industries, especially in the food industry. Berberine (BBR), the most important functional compound in the barberry roots, has recently been used to treat obesity, diabetes, and atherosclerosis. Gut microbiota and the intestinal barrier play an important role in the development of glucolipid metabolism disorders (GLMDs). However, the association of gut microbiota metabolism disorder and the intestinal barrier dysfunction effect of BBR in GLMDs remains elusive. RESULTS: The results showed that administration of BBR could increase the number of colonic glands and goblet cell mucus secretion, improve the intestinal barrier function, and reduce the serum glycolipid level in GLMD hamsters. Interestingly, BBR was metabolized into 12 metabolites by gut microbiota, and the main metabolic pathways were oxidation, demethylation, and hydrogenation. In addition, BBR significantly improved the species diversity and uniformity of gut microbiota and promoted the proliferation of beneficial microbiota. Furthermore, the levels of tryptophan metabolites, such as indole, indole-3-acetamide, indole-3-acetaldehyde, indole-3-pyruvic acid, and indole-3-acetic acid were significantly altered by BBR. Both the intestinal tight junction proteins and intestinal immune factors were altered by BBR. CONCLUSION: BBR could alleviate intestinal barrier dysfunction of GLMDs by modulating gut microbiota and gut-microbiota-related tryptophan metabolites, which may be one of the pharmacological mechanisms for the treatment of GLMDs. © 2022 Society of Chemical Industry.

Inonotus obliquus (Chaga) against HFD/STZ-induced glucolipid metabolism disorders and abnormal renal functions by regulating NOS-cGMP-PDE5 signaling pathway.

Our prior investigations have established that Inonotus obliquus (Chaga) possesses hypoglycemic effects. Persistent hyperglycemia is known to precipitate renal function abnormalities. The functionality of the kidneys is intricately linked to the levels of cyclic guanosine-3',5'-monophosphate (cGMP), which are influenced by the activities of nitric oxide synthase (NOS) and phosphodiesterase (PDE). Enhanced cGMP levels can be achieved either through the upregulation of NOS activity or the downregulation of PDE activity. The objective of the current study is to elucidate the effects of Chaga on disorders of glucolipid metabolism and renal abnormalities in rats with type 2 diabetes mellitus (T2DM), while concurrently examining the NOS-cGMP-PDE5 signaling pathway. A model of T2DM was developed in rats using a high-fat diet (HFD) combined with streptozotocin (STZ) administration, followed by treatment with Chaga extracts at doses of 50 and 100 mg·kg-1 for eight weeks. The findings revealed that Chaga not only mitigated metabolic dysfunctions, evidenced by improvements in fasting blood glucose, total cholesterol, triglycerides, and insulin resistance, but also ameliorated renal function markers, including serum creatinine, urine creatinine (UCr), blood urea nitrogen, 24-h urinary protein, and estimated creatinine clearance. Additionally, enhancements in glomerular volume, GBM thickness, podocyte foot process width (FPW), and the mRNA and protein expressions of podocyte markers, such as nephrin and wilms tumor-1, were observed. Chaga was found to elevate cGMP levels in both serum and kidney tissues by increasing mRNA and protein expressions of renal endothelial NOS and neural NOS, while simultaneously reducing the expressions of renal inducible NOS and PDE5. In summary, Chaga counteracts HFD/STZ-induced glucolipid metabolism and renal function disturbances by modulating the NOS-cGMP-PDE5 signaling pathway. This research supports the potential application of Chaga in the clinical prevention and treatment of T2DM and diabetic nephropathy (DN), with cGMP serving as a potential therapeutic target.

Mitigation of gestational diabetes-induced endothelial dysfunction through FGF21-NRF2 pathway activation involving L-Cystine.

Gestational diabetes mellitus (GDM) disrupts glucolipid metabolism, endangering maternal and fetal health. Despite limited research on its pathogenesis and treatments, we conducted a study using serum samples from GDM-diagnosed pregnant women. We performed metabolic sequencing to identify key small molecule metabolites and explored their molecular interactions with FGF21. We also investigated FGF21's impact on GDM using blood samples from affected women. Our analysis revealed a novel finding: elevated levels of L-Cystine in GDM patients. Furthermore, we observed a positive correlation between L-Cystine and FGF21 levels, and found that L-Cystine induces NRF2 expression via FGF21 for a period of 96 h. Under high glucose (HG) conditions, FGF21 upregulates NRF2 and downstream genes NQO1 and EPHX1 via AKT phosphorylation induced by activation of IRS1, enhancing endothelial function. Additionally, we confirmed that levels of FGF21, L-Cystine, and endothelial function at the third trimester were effectively enhanced through appropriate exercise and diet during pregnancy in GDM patients (GDM + ED). These findings suggest FGF21 as a potential therapeutic agent for GDM, particularly in protecting endothelial cells. Moreover, elevated L-Cystine via appropriate exercise and diet might be a potential strategy to enhance FGF21's efficacy.

The association between early pregnancy exposure to green space and maternal glucolipid metabolism disorders: evaluation of the mediating role of serum 25-hydroxyvitamin D.

Green space and 25-hydroxyvitamin D (25(OH)D) can affect maternal and infant health, but limited studies have examined their effects on disorders of maternal glucolipid metabolism. We aimed to explore the interaction between green space, maternal serum 25(OH)D, and disorders of glucolipid metabolism in early pregnancy. A total of 2551 pregnant women were recruited from the Maanshan Maternal and Child Health Hospital birth cohort in China between 2020 and 2022. We calculated average residential greenness during early pregnancy using 250 m normalized difference vegetation index (NDVI) from satellites. Serum biomarkers (25(OH)D, total cholesterol (TC), triglycerides (TG), high-density lipoprotein-cholesterol(HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1(ApoA1), and apolipoprotein B(ApoB)) were measured. Associations between the factors were analyzed using multiple linear regression, mediation analysis, and stratified analysis. After adjusting for potential confounders, green space exposure associated with decreased TG (- 7.8%; 95% confidence interval (CI): - 12.8, - 2.9), TC (- 7.0%; 95% CI: - 11.4, - 2.7), and LDL-C (- 8.4%; 95% CI: - 12.9, - 3.9), ApoB (- 2.0%; 95% CI: - 3.0, - 1.0) and increased HDL-C (2.7%; 95% CI: 1.5, 3.8) and ApoA1 (5.1%; 95% CI: 3.9, 6.3) for each IQR increase in NDVI. A comparable link was found between maternal serum 25(OH)D and indicators of glucolipid metabolism (P < 0.05). In addition, mediation analysis showed that the association between green space exposure and maternal glucolipid metabolic index was mediated by serum 25(OH)D at 6.37%. In stratified analyses, a considerable association between 25(OH)D and glucolipid metabolic index (except TG) was observed only at higher green space exposures. This study confirms that high levels of green space exposure in early pregnancy and vitamin D are associated with a reduced risk of glucolipid metabolism disorders and suggests that green space may favor glucolipid metabolism by increasing vitamin D levels, particularly at high NDVI values.

Associations Between Serum TNF-α, IL-6, hs-CRP and GLMD in Obese Children and Adolescents: A Cross-Sectional Study.

Purpose: To explore the relationships between serum tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP) levels and glucolipid metabolism disorders (GLMD) in obese children and adolescents. Patients and Methods: In this cross-sectional study, 105 obese children and adolescents were selected for the detection of TNF-α, IL-6, hs-CRP, and glycolipid metabolism indicators. All participants were divided into elevated TNF-α group (≥8.1 pg/mL; n=49) and normal TNF-α group (<8.1 pg/mL; n=56), elevated IL-6 group (≥5.9 pg/mL; n=13) and normal IL-6 group (<5.9 pg/mL; n=92), elevated hs-CRP group (≥3.0 mg/L; n=44) and normal hs-CRP group (<3.0 mg/L; n=61), respectively. Results: Low-density lipoprotein cholesterol (LDL-C) in the elevated TNF-α group was higher than that in the normal TNF-α group (P=0.010). TNF-α was positively correlated with LDL-C (P=0.005). Fasting insulin (FINS) and homeostasis model assessment of insulin resistance (HOMA-IR) in the elevated IL-6 group were higher than those in the normal IL-6 group (all for P <0.05), while high-density lipoprotein cholesterol (HDL-C) in the elevated IL-6 group was lower than that in the normal IL-6 group (P<0.001). IL-6 was positively correlated with FINS, 2-hour postprandial insulin, HOMA-IR and triglyceride (all for P <0.01), while was negatively correlated with HDL-C (P=0.006). Moreover, hs-CRP was positively correlated with FINS and HOMA-IR (all for P <0.05). Conclusion: There may be correlations between serum TNF-α, IL-6, hs-CRP levels and GLMD in obese children and adolescents. Attention should be paid to monitoring serum inflammatory factors and preventing their elevation in obese children and adolescents, thus reducing the occurrence of GLMD.

Hypoglycemic and hypolipidemic dual activities of extracts and flavonoids from Desmodium caudatum and an efficient synthesis of the most potent 8-prenylquercetin.

Since glucolipid metabolism disorders is often the mono-target therapy fails in managing blood glucose and lipid levels and the other complications, it is urgent and necessary to seek for the new potential drugs or functional food acting on multi-targets. The hypoglycemic and hypolipidemic dual activities of the root, stems and leaves of Desmodium caudatum, which is used for traditional Chinese medicine, was evaluated. Twelve extracts with different extraction conditions were prepared and extract 9 was find to exhibit potential inhibitory activities of fructose-1, 6-bisphosphatase (FBPase), α-glucosidase, and pancrelipase, as well as promote cellular glucose consumption and reduce cellular content of lipid. Five flavonoids were isolated and identified from extract 9, among which 8-prenylquercetin exhibited potent α-glucosidase (IC50 = 4.38 µM) and FBPase (IC50 = 3.62 µM) dual inhibitory activity, which were 75-fold higher than acarbose (IC50 = 330.10 µM) and comparable with AMP (IC50 = 2.92 µM). In addition, 8-prenylquercetin was able to promote glucose consumption and reduce lipid content. Besides, an efficient synthesis of the most potent 8-prenylquercetin was developed from inexpensive and commercially available rutin in 21% overall yield by 6 steps, which lay the foundation of preparation sufficient amount for follow-up study.