Effect of proanthocyanidins on blood lipids: A systematic review and meta-analysis.

Proanthocyanidins (PCs) are natural antioxidant polyphenols and their effect on the regulation of blood lipids is still controversial. This study was conducted to evaluate the effect of PCs on lipid metabolism. We searched PubMed, Embase, Web of Science, Chinese biomedical literature service system, China National Knowledge Internet, and Wanfang Data with no time restriction until March 18, 2022, using various forms of "proanthocyanidins" and "blood lipid" search terms. Randomized controlled trials investigating the relationship between PCs and lipid metabolism were included. The standard system of Cochrane Collaboration was used to assess the quality of studies. We standardized mean differences (SMDs) with 95% confidence interval (CI) using the random-effects model, Cohen approach. Seventeen studies (17 trials, N = 1138) fulfilled the eligibility criteria. PCs significantly reduced triglyceride, and increased recombinant apolipoprotein A1. Subgroup analysis showed a significant reduction in triglycerides in older adults (≥60 years) and total cholesterol for participants who were not overweight or obese (body mass index <24). An intervention duration of greater than 8 weeks reduced triglyceride and low-density lipoprotein cholesterol levels but increased high-density lipoprotein cholesterol. Different doses of PCs could regulate triglycerides, high-density lipoprotein cholesterol and total cholesterol. PCs have beneficial effects on circulating lipids and may represent a new approach for treating or preventing lipid metabolism disorders. However, more high-quality studies are needed to confirm these results.

BDH1-mediated ßOHB metabolism ameliorates diabetic kidney disease by activation of NRF2-mediated antioxidative pathway.

A ketogenic diet (KD) and ß-hydroxybutyrate (ßOHB) have been widely reported as effective therapies for metabolic diseases. ß-Hydroxybutyrate dehydrogenase 1 (BDH1) is the rate-limiting enzyme in ketone metabolism. In this study, we examined the BDH1-mediated ßOHB metabolic pathway in the pathogenesis of diabetic kidney disease (DKD). We found that BDH1 is downregulated in the kidneys in DKD mouse models, patients with diabetes, and high glucose- or palmitic acid-induced human renal tubular epithelial (HK-2) cells. BDH1 overexpression or ßOHB treatment protects HK-2 cells from glucotoxicity and lipotoxicity by inhibiting reactive oxygen species overproduction. Mechanistically, BDH1-mediated ßOHB metabolism activates NRF2 by enhancing the metabolic flux of ßOHB-acetoacetate-succinate-fumarate. Moreover, in vivo studies showed that adeno-associated virus 9-mediated BDH1 renal expression successfully reverses fibrosis, inflammation, and apoptosis in the kidneys of C57 BKS db/db mice. Either ßOHB supplementation or KD feeding could elevate the renal expression of BDH1 and reverse the progression of DKD. Our results revealed a BDH1-mediated molecular mechanism in the pathogenesis of DKD and identified BDH1 as a potential therapeutic target for DKD.

Tumor-induced osteomalacia characterized by "painful knee joint with difficulty in moving": a case report.

BACKGROUND: Tumor-related osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by severe hypophosphatemia and osteomalacia. The diagnosis of TIO can be very difficult because of its nonspecific nature of clinical manifestations. Here we reported a case of young TIO patient with "painful knee joint with difficulty in moving" to improve the clinical diagnosis and treatment levels. CASE PRESENTATION: The patient's clinical features were consistent with TIO. A tumor was successfully located in left tibial by 68Ga-DOTATATE PET/CT, and then was surgically resected. Upon pathologic assessment, the tumor was diagnosed as phosphaturia stromal tumor (PMT) with positive Vim staining. After the surgery, serum phosphate level rapidly recovered and symptoms significantly improved. CONCLUSION: TIO should be considered in patients with chronically hypophosphorus osteomalacia in the setting of no family history. Early removal of the responsible tumors is clinically essential for the treatment, and imaging examination is of great significance for tumor localization.

Higher Dietary Inflammatory Index Scores Increase the Risk of Diabetes Mellitus: A Meta-Analysis and Systematic Review.

The relationship between dietary inflammatory index (DII) scores and the risk of diabetes mellitus (DM) is unclear; therefore, a systematic review and meta-analysis of the current published literature was conducted. Relevant studies published online (PubMed, Embase, and Web of Science) until February 1, 2021 were identified for review. The initial search yielded 13 reports, and after perusing their titles, abstracts, and full texts, 5 studies were deemed appropriate for inclusion in the systematic review and meta-analysis. Individuals with higher DII scores (representing a more proinflammatory diet) had a higher risk of DM (pooled odds ratio 1.32, 95% confidence interval 1.01-1.72, I2 58.6%, p < 0.05). Although the current meta-analysis indicated a trend toward a positive association between DII and DM, further evidence-especially from larger prospective studies in different countries-is needed to clarify this association.

Butyrate ameliorates alcoholic fatty liver disease via reducing endotoxemia and inhibiting liver gasdermin D-mediated pyroptosis.

BACKGROUND: Alcoholic fatty liver disease (AFLD) is characterized by hepatic steatosis and carries an elevated risk of cirrhosis and hepatocellular carcinoma. However, the mechanism of AFLD has not been elucidated thoroughly, and there are still no efficient therapies in clinic. Notably, butyrate, one kind of short-chain fatty acids produced by gut microbiota, has been shown to improve methionine-choline-deficient diet-induced non-alcoholic steatohepatitis. And our previous study found that butyrate ameliorated endotoxemia in db/db mice. In this study, we aimed to explore the role of butyrate in the development of AFLD. METHODS: C57BL/6 mice were treated with saline (normal control), alcohol with or without butyrate by gavage for 6 months. AFLD was evaluated by the levels of serum alcohol, aspartate aminotransferase (AST), alanine transaminase (ALT), triglyceride (TG) and intrahepatic TG. And the histology and inflammation in liver and colon were analyzed using hematoxylin-eosin (H&E) staining, immunohistochemistry and western blot. In addition, gut microbiota composition was analyzed using the V3-V4 regions of the bacterial 16S ribosomal RNA gene by sequence. Furthermore, we performed in vitro experiment to verify the role of butyrate in hepatocyte by western blot and transmission electron microscopy. RESULTS: We found that butyrate ameliorated alcohol-induced hepatic steatosis and inflammation. Furthermore, chronic alcohol feeding induced dysbiosis and dysfunction of the gut microbiota, disrupted the intestinal barrier, and increased serum endotoxin levels. Meanwhile, butyrate improved the intestinal barrier disruption and endotoxemia induced by alcohol, but did not significantly alleviate the microbiome dysfunction. Mechanistically, butyrate ameliorated AFLD by inhibiting gasdermin D (GSDMD)-mediated pyroptosis. CONCLUSIONS: In summary, we found butyrate ameliorated alcoholic fatty liver by down-regulating GSDMD-mediated pyroptosis. We speculate that butyrate improves AFLD mainly by maintaining intestinal barrier function and alleviating gut leakage. These findings suggest that butyrate may have the potential to serve as a novel treatment for AFLD.

Kuwanon G protects HT22 cells from advanced glycation end product-induced damage.

The incidence of diabetic encephalopathy is increasing as the population ages. Evidence suggests that formation and accumulation of advanced glycation end products (AGEs) plays a pivotal role in disease progression, but limited research has been carried out in this area. A previous study demonstrated that Kuwanon G (KWG) had significant anti-oxidative stress and anti-inflammatory properties. As AGEs are oxidative products and inflammation is involved in their generation it is hypothesized that KWG may have effects against AGE-induced neuronal damage. In the present study, mouse hippocampal neuronal cell line HT22 was used. KWG was shown to significantly inhibit AGE-induced cell apoptosis in comparison with a control treatment, as determined by both MTT and flow cytometry. Compared with the AGEs group, expression of pro-apoptotic protein Bax was reduced and expression of anti-apoptotic protein Bcl-2 was increased in the AGEs + KWG group. Both intracellular and extracellular levels of acetylcholine and choline acetyltransferase were significantly elevated after KWG administration in comparison with controls whilethe level of acetylcholinesterase decreased. These changes in protein expression were accompanied by increased levels of superoxide dismutase and glutathione peroxidase synthesis and reduced production of malondialdehyde and reactive oxygen species. Intracellular signaling pathway protein levels were determined by western blot and immunocytochemistry. KWG administration was found to prevent AGE-induced changes to the phosphorylation levels of Akt, IκB-α, glycogen synthase kinase 3 (GSK3)-α and ß, p38 MAPK and NF-κB p65 suggesting a potential neuroprotective effect of KWG against AGE-induced damage was via the PI3K/Akt/GSK3αß signaling pathway. The findings of the present study suggest that KWG may be a potential treatment for diabetic encephalopathy.

Sodium Butyrate Improves Liver Glycogen Metabolism in Type 2 Diabetes Mellitus.

Liver plays a central role in modulating blood glucose level. Our most recent findings suggested that supplementation with microbiota metabolite sodium butyrate (NaB) could ameliorate progression of type 2 diabetes mellitus (T2DM) and decrease blood HbA1c in db/db mice. To further investigate the role of butyrate in homeostasis of blood glucose and glycogen metabolism, we carried out the present study. In db/db mice, we found significant hypertrophy and steatosis in hepatic lobules accompanied by reduced glycogen storage, and expression of GPR43 was significantly decreased by 59.38 ± 3.33%; NaB administration significantly increased NaB receptor G-protein coupled receptor 43 (GPR43) level and increased glycogen storage in both mice and HepG2 cells. Glucose transporter 2 (GLUT2) and sodium-glucose cotransporter 1 (SGLT1) on cell membrane were upregulated by NaB. The activation of intracellular signaling Protein kinase B (PKB), also known as AKT, was inhibited while glycogen synthase kinase 3 (GSK3) was activated by NaB in both in vivo and in vitro studies. The present study demonstrated that microbiota metabolite NaB possessed beneficial effects on preserving blood glucose homeostasis by promoting glycogen metabolism in liver cells, and the GPR43-AKT-GSK3 signaling pathway should contribute to this effect.

Sodium butyrate supplementation ameliorates diabetic inflammation in db/db mice.

Endotoxemia has been recognized to be closely accompanied with type 2 diabetes mellitus (T2DM) and is responsible for many diabetic complications. Recent study suggests the potential role of butyrate, a short-chain fatty acid (SCFA) from microbiota metabolite, on T2DM. Gut-leak is a key event in diabetic-endotoxemia. To investigate if butyrate could ameliorate diabetic-endotoxemia, both in vivo and in vitro experiments were carried out in the present study. The effect of butyrate supplementation on blood HbA1c and inflammatory cytokines were determined in db/db mice; gut barrier integrity and expression of tight junction proteins were investigated both in vivo and in vitro Oral butyrate administration significantly decreased blood HbA1c, inflammatory cytokines and LPS in db/db mice; inflammatory cell infiltration was reduced, and gut integrity and intercellular adhesion molecules were increased as detected by HE staining, immunohistochemistry and Western blot. By gut microbiota assay, ratio of Firmicutes:Bacteroidetes for gut microbiota was reduced by butyrate. In Caco-2 cells, butyrate significantly promoted cell proliferation, decreased inflammatory cytokines' secretion, enhanced cell anti-oxidative stress ability and preserved the epithelial monocellular integrity, which was damaged by LPS. The present findings demonstrated that butyrate supplementation could ameliorate diabetic-endotoxemia in db/db mice via restoring composition of gut microbiota and preserving gut epithelial barrier integrity.

ATP2B1 Gene Silencing Increases NO Production Under Basal Conditions Through the Ca2+/calmodulin/eNOS Signaling Pathway in Endothelial Cells.

Emerging epidemiological and experimental evidence has shown that the ATP2B1 gene is associated with blood pressure control. Impaired eNOS activity and NO production may be among the mechanisms involved. However, little is known about how PMCA1, which is encoded by the ATP2B1 gene, regulates the activity of eNOS and NO production. In the present study, we investigated the role of the ATP2B1 gene in regulating eNOS activity and NO production under basal conditions in HUVECs and explored the mechanisms involved. Silencing ATP2B1 gene expression resulted in higher NO production and eNOS activity under basal conditions in HUVECs. Additionally, ATP2B1 gene silencing resulted in enhanced intracellular calcium concentrations compared to that in the negative siRNA-transfected HUVECs. The enhanced eNOS activity mediated by ATP2B1 gene silencing was Ca2+/calmodulin dependent, as verified by the administration of the calcium chelator BAPTA-AM or the calmodulin-specific antagonist W7. Taken together, silencing ATP2B1 gene expression results in higher NO production and eNOS activity under basal conditions in HUVECs. Furthermore, the enhanced eNOS activity induced by ATP2B1 gene silencing may be mediated via higher levels of intracellular Ca2+, and the effect was confirmed to be dependent on the eNOS-calmodulin interaction.

ATP2B1 gene Silencing Increases Insulin Sensitivity through Facilitating Akt Activation via the Ca2+/calmodulin Signaling Pathway and Ca2+-associated eNOS Activation in Endothelial Cells.

Endothelial cell insulin resistance may be partially responsible for the higher risk of atherosclerosis and cardiovascular disease in populations with insulin resistance and type 2 diabetes mellitus (T2DM). A genome-wide association study revealed a significant association between the ATPase plasma membrane Ca2+ transporting 1 (ATP2B1) gene and T2DM in two community-based cohorts from the Korea Association Resource Project. However, little is known about the implication of the ATP2B1 gene on T2DM. In the present study, we investigated the role of the ATP2B1 gene in endothelial cell insulin sensitivity. ATP2B1 gene silencing resulted in enhanced intracellular calcium concentrations and increased insulin-induced Akt activation compared to that in the negative siRNA-transfected HUVECs (Human Umbilical Vein Endothelial Cells). The elevated insulin sensitivity mediated by ATP2B1 gene silencing was Ca2+/calmodulin-dependent, as verified by administration of the calcium chelator BAPTA-AM or the calmodulin-specific antagonist W7. Moreover, higher levels of phosphorylation of eNOS (Ser1177) were observed in ATP2B1-silenced HUVECs. In addition to BAPTA-AM and W7, L-NAME, an eNOS antagonist, abolished insulin-induced Akt phosphorylation at Ser473 in both si-Neg and si-ATP2B1-transfected endothelial cells. These results indicate that the enhanced insulin sensitivity in ATP2B1-silenced endothelial cells is alternatively dependent on an increase in intracellular Ca2+ and the subsequent activation of the Ca2+/calmodulin/eNOS/Akt signaling pathway. In summary, ATP2B1 gene silencing increased insulin sensitivity in endothelial cells by directly modulating the Ca2+/calmodulin signaling pathway and via the Ca2+/calmodulin/eNOS/Akt signaling pathway alternatively.

Decreased plasma neuregulin 4 concentration is associated with increased high-sensitivity C-reactive protein in newly diagnosed type 2 diabetes mellitus patients: a cross-sectional study.

AIMS: Inflammation has been reported to be involved in the pathogenesis of atherosclerosis. This principal objective of this study was to investigate if the secretion of neuregulin 4 (Nrg4), a soluble protein associated with metabolic syndrome and subclinical cardiovascular disease, is correlated with the inflammation marker high-sensitivity C-reactive protein (hs-CRP) in patients with newly diagnosed type 2 diabetes mellitus (nT2DM). METHODS: A study group of 311 nT2DM patients was divided into three subgroups based on hs-CRP tertiles. Multiple linear regression was conducted to explore the association between plasma Nrg4 and hs-CRP levels. RESULTS: The nT2DM patients with the highest hs-CRP levels (>2.46 mg/L) exhibited higher atherogenic coefficients and atherogenic index of plasma (AIP) levels, but lower levels of plasma Nrg4, as compared to those with the lowest hs-CRP levels (<0.63 mg/L). Plasma Nrg4 levels were inversely associated with white blood cell count, hs-CRP, and AIP and positively associated with high-density lipoprotein cholesterol (HDL-C), before and after adjustment for age, gender, body mass index (BMI), and body fat percentage (P < 0.01 or P < 0.05). hs-CRP was the factor most strongly associated with plasma Nrg4 levels. CONCLUSIONS: These results indicate that lower plasma Nrg4 levels may be associated with elevated hs-CRP in nT2DM patients. It generates the hypothesis that decreased levels of Nrg4 may trigger the development of atherosclerosis through its proinflammatory effects. These findings need to be confirmed by further prospective studies.