4-octyl itaconate inhibits high glucose induced renal tubular epithelial cell fibrosis through TGF-ß-ROS pathway.

Diabetic kidney disease (DKD) is one of the most serious complications of diabetes and has become the leading cause of end-stage kidney disease, causing serious health damage and a huge economic burden. Tubulointerstitial fibrosis play important role in the development of DKD. Itaconate, a macrophage-specific metabolite, has been reported to have anti-oxidant, anti-inflammatory effects. However, it is unknown whether it perform anti-fibrotic effect in renal tubular epithelial cells. In this current study, we observed that in human renal tubular epithelial cells (HK2), high glucose induced an increase in transforming growth factor ß (TGF-ß) production, and upregulated the expressions of fibronectin and collagen I through the TGF-ß receptor as verified by administration of TGF-ß receptor blocker LY2109761. Treatment with 4-octyl itaconate (4-OI), a derivant of itaconic acid, reduced the TGF-ß production induced by high glucose and inhibited the pro-fibrotic effect of TGF-ß in a dose-dependent manner. In addition, we found that 4-OI exerted its anti-fibrotic effect by inhibiting the excessive production of ROS induced by high glucose and TGF-ß. In summary, 4-OI could ameliorate high glucose-induced pro-fibrotic effect in HK2 cell, and blocking the expression of TGF-ß and reducing the excessive ROS production may be involved in its anti-fibrotic effect.

Development of Serum Lactate Level-Based Nomograms for Predicting Diabetic Kidney Disease in Type 2 Diabetes Mellitus Patients.

Purpose: To establish nomograms integrating serum lactate levels and traditional risk factors for predicting diabetic kidney disease (DKD) in type 2 diabetes mellitus (T2DM) patients. Patients and methods: A total of 570 T2DM patients and 100 healthy subjects were enrolled. T2DM patients were categorized into normal and high lactate groups. Univariate and multivariate logistic regression analyses were employed to identify independent predictors for DKD. Then, nomograms for predicting DKD were established, and the model performance was evaluated using the area under the receiver operating characteristic curve (AUC), calibration, and decision curve analysis (DCA). Results: T2DM patients exhibited higher lactate levels compared to those in healthy subjects. Glucose, platelet, uric acid, creatinine, and hypertension were independent factors for DKD in T2DM patients with normal lactate levels, while diabetes duration, creatinine, total cholesterol, and hypertension were indicators in high lactate levels group (P<0.05). The AUC values were 0.834 (95% CI, 0.776 to 0.891) and 0.741 (95% CI, 0.688 to 0.795) for nomograms in both normal lactate and high lactate groups, respectively. The calibration curve demonstrated excellent agreement of fit. Furthermore, the DCA revealed that the threshold probability and highest Net Yield were 17-99% and 0.36, and 24-99% and 0.24 for the models in normal lactate and high lactate groups, respectively. Conclusion: The serum lactate level-based nomogram models, combined with traditional risk factors, offer an effective tool for predicting DKD probability in T2DM patients. This approach holds promise for early risk assessment and tailored intervention strategies.

Effects of SGLT2 inhibitors on cardiac function and health status in chronic heart failure: a systematic review and meta-analysis.

PURPOSE: Numerous clinical studies have explored sodium-glucose cotransporter 2 inhibitor (SGLT2i) in patients with chronic heart failure (CHF), with or without type 2 diabetes mellitus (T2DM), and SGLT2i were proved to significantly reduce CHF hospitalization, cardiovascular death, cardiovascular mortality, all-cause mortality and myocardial infarction in patients with or without T2DM. However, only a limited few have investigated the effects of SGLT-2i on HF disease-specific health status and cardiac function. This meta-analysis aims to assess the effects of SGLT2i on disease-specific health status and cardiac function in CHF patients. METHODS: A comprehensive search was conducted of trials by searching in PubMed, EMBASE, CENTRAL, Scopus, and Web of Science, and two Chinese databases (CNKI and Wanfang), Clinical Trials ( http://www. CLINICALTRIALS: gov ) were also searched. RESULTS: A total of 18 randomized controlled trials (RCTs) involving 23,953 participants were included in the meta-analysis. The effects of SGLT2 inhibitors were compared with control or placebo groups in CHF with or without T2DM. The SGLT2 inhibitors group exhibited a significant reduction in pro b-type natriuretic peptide (NT-proBNP) levels by 136.03 pg/ml (95% confidence interval [CI]: -253.36, - 18.70; P = 0.02). Additionally, a greater proportion of patients in the SGLT2 inhibitors group showed a ≥ 20% decrease in NT-proBNP (RR = 1.45, 95% CI [0.92, 2.29], p = 0.072). However, no statistically significant difference was observed for the effects on B-type natriuretic peptide (BNP). The use of SGLT-2 inhibitors led to a noteworthy improvement in LVEF by 2.79% (95% CI [0.18, 5.39];P = 0.036). In terms of health status, as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ) and 6-minute walk distance, SGLT2 inhibitors led to a significant improvement in KCCQ clinical summary (KCCQ-CS) score (WMD = 1.7, 95% CI [1.67, 1.73], P < 0.00001), KCCQ overall summary (KCCQ-OS) score (WMD = 1.73, 95% CI [0.94, 2.52], P < 0.00001), and KCCQ total symptom (KCCQ-TS) score (WMD = 2.88, 95% CI [1.7, 4.06], P < 0.00001). Furthermore, the occurrence of KCCQ-CS and KCCQ-OS score increases ≥ 5 points had relative risks (RR) of 1.25 (95% CI [1.11, 1.42], P < 0.00001) and 1.15 (95% CI [1.09, 1.22], P < 0.00001), respectively. Overall, SGLT2 inhibitors increased the 6-minute walk distance by 23.98 m (95% CI [8.34, 39.62]; P = 0.003) compared to control/placebo from baseline. CONCLUSIONS: The SGLT2 inhibitors treatment offers an effective strategy for improving NT-proBNP levels, Kansas City Cardiomyopathy Questionnaire scores and 6-minute walk distance in CHF with or without T2DM. These findings indicate that SGLT2i improve cardiac function and health status in CHF with or without T2DM, and provide valuable guidance for clinicians making treatment decisions for patients with CHF.

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.

High glucose-induced endothelial STING activation inhibits diabetic wound healing through impairment of angiogenesis.

Chronic hyperglycemia-induced impairment of angiogenesis is important in diabetic foot ulcer (DFU). Additionally, the stimulator of interferon gene (STING), which is a key protein in innate immunity, mediates palmitic acid-induced lipotoxicity in metabolic diseases through oxidative stress-induced STING activation. However, the role of STING in DFU is unknown. In this study, we established a DFU mouse model with streptozotocin (STZ) injection and found that the expression of STING was significantly increased in the vascular endothelial cells of wound tissues from diabetic patients and in the STZ-induced diabetic mouse model. We further established high glucose (HG)-induced endothelial dysfunction with rat vascular endothelial cells and found that the expression of STING was also increased by high-glucose treatment. Moreover, the STING inhibitor, C176, promoted diabetic wound healing, whereas the STING activator, DMXAA, inhibited diabetic wound healing. Consistently, STING inhibition reversed the HG-induced reduction of CD31 and vascular endothelial growth factor (VEGF), inhibited apoptosis, and promoted migration of endothelial cells. Notably, DMXAA treatment alone was sufficient to induce endothelial cell dysfunction as a high-glucose treatment. Mechanistically, STING mediated HG-induced vascular endothelial cell dysfunction by activating the interferon regulatory factor 3/nuclear factor kappa B pathway. In conclusion, our study reveals an endothelial STING activation-mediated molecular mechanism in the pathogenesis of DFU and identifies STING as a novel potential therapeutic target for DFU.

Effects of ginseng consumption on the biomarkers of oxidative stress: A systematic review and meta-analysis.

Oxidative stress (OS) is a key factor involved in the initiation and development of chronic diseases. Despite its widespread acceptance as an antioxidant, the effects of ginseng on OS in human clinical trials have not been comprehensively analyzed. Therefore, this study aimed to synthesize the results of previous randomized clinical trials (RCTs) examining the impact of ginseng consumption on OS indicators. PubMed, Web of Science, Scopus, and Cochrane databases were searched for articles on the effects of ginseng consumption on oxidative stress markers up to March 20, 2023. Standardized mean difference (SMD) and 95% confidence intervals (CIs) were used to assess effect sizes. Twelve RCTs with 15 effect sizes revealed that the effects of ginseng lowered serum malondialdehyde (MDA) levels (SMD = 0.45, 95% CI: -0.87, -0.08; p = 0.03) and significantly increased the serum total antioxidant capacity (TAC) (SMD = 0.23, 95% CI: 0.01, 0.45; p = 0.04), oxidative dismutase (SOD) (SMD = 0.39, 95% CI: 0.21, 0.57; p < 0.0001), glutathione (GSH) (SMD = 0.36; 95% CI: 0.11, 0.61; p = 0.005), and glutathione reductase (GR) (SMD = 0.56; 95% CI: 0.31, 0.81; p < 0.0001) levels compared to the effects of placebo. However, the effects on serum glutathione peroxidase (GPx) and catalase (CAT) were not significant. Moreover, subgroup analysis based on intervention duration showed that ginseng consumption increased GPx (SMD = 0.91, 95% CI: 0.05, 1.78; p = 0.039) and CAT (SMD = 0.74, 95% CI: 0.27, 1.21; p = 0.002) levels after more than 4 weeks of intervention. According to the results of this meta-analysis, ginseng supplementation dramatically reduced MDA levels and increased TAC, SOD, GSH, and GR levels. Our results open up a new line of defense against oxidative stress-induced diseases.

Effect of Omega-3 Polyunsaturated Fatty Acids on Cardiovascular Outcomes in Patients with Diabetes: A Meta-analysis of Randomized Controlled Trials.

The current guidelines recommend that people consume 2 or more servings of fat-rich fish per week to obtain enough omega-3 (ω-3) polyunsaturated fatty acids to prevent cardiovascular events. However, the cardiovascular benefits of ω-3 polyunsaturated fatty acids in patients with diabetes are unclear, and related large-scale trials have produced conflicting results. We aimed to perform a meta-analysis of all randomized controlled trials that attempted to assess the effects of ω-3 fatty acid supplementation on cardiovascular outcomes in patients with diabetes. In PubMed, EMBASE, and the Cochrane Library, we searched for data from all randomized controlled trials on ω-3 fatty acids and cardiovascular outcomes in patients with diabetes published before July 2022. Eight eligible studies involving 57,754 participants were ultimately included. Meta-analysis showed that ω-3 fatty acid supplementation reduces cardiovascular disease (CVD) risk in patients with diabetes (rate ration [RR] = 0.93; 95% confidence interval [CI]: 0.90, 0.97; P = 0.0009). Among them, eicosapentaenoic acid (EPA), but not EPA plus docosahexaenoic acid (DHA), significantly reduced the risk of CVD in patients with diabetes (EPA [RR = 0.81; 95% CI: 0.73, 0.90; P=0.0001]). This meta-analysis suggests that ω-3 fatty acid supplementation is an effective strategy to prevent CVD in patients with diabetes, but further well-designed, large-scale randomized controlled trials are necessary to evaluate the safety of ω-3 fatty acid supplementation, and its effect on atrial fibrillation. This study was registered with PROSPERO as CRD42022346302.

High Glucose-Induced Kidney Injury via Activation of Necroptosis in Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is a major microvascular complication of diabetes mellitus (DM) and is closely associated to programmed cell death. However, the complex mechanisms of necroptosis, an alternative cell death pathway, in DKD pathogenesis are yet to be elucidated. This study indicates that necroptosis is involved in DKD induced by high glucose (HG) both in vivo and in vitro. HG intervention led to the activation of RIPK1/RIPK3/MLKL signaling, resulting in renal tissue necroptosis and proinflammatory activation in streptozotocin/high-fat diet- (STZ/HFD-) induced diabetic mice and HG-induced normal rat kidney tubular cells (NRK-52E). We further found that in HG-induced NRK-52E cell, necroptosis might, at least partly, depend on the levels of reactive oxygen species (ROS). Meanwhile, ROS participated in necroptosis via a positive feedback loop involving the RIPK1/RIPK3 pathway. In addition, blocking RIPK1/RIPK3/MLKL signaling by necrostatin-1 (Nec-1), a key inhibitor of RIPK1 in the necroptosis pathway, or antioxidant N-acetylcysteine (NAC), an inhibitor of ROS generation, could effectively protect the kidney against HG-induced damage, decrease the release of proinflammatory cytokines, and rescue renal function in STZ/HFD-induced diabetic mice. Inhibition of RIPK1 effectively decreased the activation of RIPK1-kinase-/NF-κB-dependent inflammation. Collectively, we demonstrated that high glucose induced DKD via renal tubular epithelium necroptosis, and Nec-1 or NAC treatment downregulated the RIPK1/RIPK3/MLKL pathway and finally reduced necroptosis, oxidative stress, and inflammation. Thus, RIPK1 may be a therapeutic target for DKD.

The Association Between Serum Magnesium Levels and Gestational Diabetes Mellitus: a Systematic Review and Meta-Analysis.

Observational studies suggest that the potential role of magnesium remains controversial in gestational diabetes mellitus (GDM). This meta-analysis aims to consolidate the available information from observational studies that have focused on the relationship between magnesium levels and GDM. A systematic and comprehensive literature search was conducted in PubMed, Embase, Web of Science, CNKI, and Wanfang databases. Data were extracted independently by two investigators. Standardized mean differences (SMD) and 95% confidence intervals (CIs) were used to summarize the circulating magnesium levels (CI). This meta-analysis included a total of 17 studies involving 2858 participants including 1404 GDM cases and 1454 healthy controls, which showed that magnesium levels were significantly lower in GDM compared to healthy controls (SMD: - 0.35; 95% CI: - 0.62, - 0.07, P = 0.013). Likewise, the same phenomenon was observed in the third trimester (SMD = - 1.07; 95% CI: - 1.84 to - 0.29, P = 0.007). Other subgroup analyses revealed that this trend of decreasing magnesium concentration was only observed in Europeans (SMD = - 0.64; 95% CI: - 0.90, - 0.38, P < 0.0001). This meta-analysis revealed that serum magnesium levels were lower in patients with GDM than in healthy pregnant women, and this discrepancy was most pronounced in European populations and during the third trimester. Nevertheless, current evidence suggests that circulating magnesium deficiency is associated with gestational diabetes; the challenge for the future is to further elucidate the possible benefits of preventing gestational diabetes through magnesium supplementation.

Angiotensin Receptor Blocker is Associated with a Lower Fracture Risk: An Updated Systematic Review and Meta-Analysis.

Background: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are widely used in the treatment of hypertension. Hypertension is often accompanied by osteoporosis. However, the relationship between ACEI/ARB and fractures remains controversial. The purpose of this meta-analysis was to update the potential relationship between ACEI/ARB and fractures. Methods: This meta-analysis was identified through PubMed, EMBASE, Cochrane Library, and Web of Science. Related studies about ACEI/ARB with the risk of fracture were published from inception to June 2022. Results: Nine qualified prospective designed studies, involving 3,649,785 subjects, were included in this analysis. Overall, the RRs of ACEI compared with the nonusers were 0.98 (95% CI: 0.88, 1.10; P < 0.001) for composite fractures and 0.96 (95% CI: 0.87, 1.05; P=0.048) for hip fractures; the RRs of ARB compared to the nonusers were 0.82 (95% CI: 0.73, 0.91; P < 0.001) for composite fractures and 0.85 (95% CI: 0.74, 0.97; P=0.028) for hip fractures. Furthermore, in the subgroup analysis, male may benefit from ARB (RR = 0.65, 95% CI: 0.49, 0.89, P=0.028), and the European may also benefit from ARB (RR = 0.86, 95% CI: 0.80, 0.93, P=0.015). Conclusions: ACEI usage will not decrease the risk of osteoporosis fracture. On the contrary, ARB usage can decrease the risk of total fracture and hip fracture, especially for males and Europeans. Compared with ACEI, for patients at higher risk of fracture in cardiovascular diseases such as hypertension, the protective effect of ARB should be considered.

Intermittent hypoxia-induced METTL3 downregulation facilitates MGLL-mediated lipolysis of adipocytes in OSAS.

Intermittent hypoxia (IH) is the core pathological feature of obstructive sleep apnea syndrome (OSAS), and insulin resistance (IR) is the most common metabolic complication of OSAS. Studies have shown that the levels of free fatty acids (FFAs), which are mainly released from adipocytes by lipolysis, are elevated in OSAS and play an important role in the development of IR. However, whether and how IH regulates adipocyte lipolysis in OSAS is not clear. Here, we revealed that the apnea hypopnea index was positively correlated with the serum levels of FFAs and FFA release from adipocytes in OSAS. In addition, IH facilitated lipolysis and FFA release from adipocytes by downregulating the level of METTL3. METTL3 downregulation impaired N6-methyladenosine (m6A) levels in MGLL mRNA and reduced MGLL expression, thereby promoting lipolysis. In addition, we identified YTHDF2 as the m6A reader that interacts with MGLL mRNA, accelerating its degradation. Furthermore, our data showed reduced levels of METTL3 and elevated levels of MGLL in the adipose tissues of OSAS patients and indicated an effect of METTL3 on lowering FFA levels and improving IR in rats with chronic IH. In conclusion, our study provides new insights into the development and treatment of IR in OSAS.

Association Between Circulating Regulator of Calcineurin 2 Concentrations With Overweight and Obesity.

Background: Regulator of calcineurin 2 (RCAN2) has been reported to promote food intake and weight gain in animal studies. However, its effect on body weight in humans is unclear. Objective: This study aimed to investigate the relationship between serum RCAN2 concentrations and participants with overweight/obesity. Methods: A cross-sectional study was performed in 872 Chinese adults, including 348 participants with normal weight (NW), 397 participants with overweight (OW), and 127 participants with obesity (OB). All participants were divided into NW, OW and OB groups according to their body mass index (BMI). Serum RCAN2 concentrations were determined by enzyme-linked immunosorbent assay. Results: Serum RCAN2 concentrations gradually increased with the increase of BMI (p < 0.001). The percentages of OW/OB gradually increased in tandem with increasing tertiles of RCAN2 (p < 0.001). Additionally, serum RCAN2 concentrations were significantly correlated with a series of anthropometric and metabolic parameters, predominantly including body weight, BMI, SBP, DBP, total cholesterol, triglycerides, HDL-C, LDL-C (all p < 0.05). Furthermore, logistic regression analysis showed that the risk of OW/OB was significantly increased with the increase of serum RCAN2 concentrations. Receiver operation characteristic (ROC) curve analysis revealed that serum RCAN2, especially serum RCAN2/(AST/ALT) ratio, might serve as a candidate biomarker for obesity. Conclusion: Serum RCAN2 concentrations were increased in subjects with OW/OB. The increased serum RCAN2 concentrations were associated with the increased risks of OW/OB.

Elevated Serum Regulator of Calcineurin 2 is Associated With an Increased Risk of Non-Alcoholic Fatty Liver Disease.

Background: The promoting effect of the regulator of calcineurin 2 (RCAN2) in hepatic steatosis has been observed in animal studies. However, the association of RCAN2 with non-alcoholic fatty liver disease (NAFLD) in humans remains unclear. This study aimed to evaluate the expression of RCAN2 in the liver of mice with hepatic steatosis and in the serum of NAFLD patients and to explore the relationship between serum RCAN2 levels and NAFLD. Methods: The mRNA and protein expression of RCAN2 were detected by quantitative real-time PCR (qRT-PCR) and Western blot. NAFLD was diagnosed by abdominal ultrasonography. Circulating RCAN2 levels were measured by ELISA kits. The relationship between serum RCAN2 levels and NAFLD was assessed. Results: qRT-PCR and Western blot analysis showed that compared with the corresponding controls, the mRNA and protein expression of RCAN2 were significantly increased in the liver tissues of db/db and mice on a high-fat diet. Serum RCAN2 levels were markedly elevated in NAFLD patients compared with non-NAFLD subjects. Binary logistic regression analysis showed that serum RCAN2 levels were significantly associated with NAFLD. Receiver operation characteristic (ROC) curve analysis showed that serum RCAN2 might act as a predictive biomarker for NAFLD [area under the curve (AUC) = 0.663, 95% CI = 0.623-0.702], and the serum RCAN2/(AST/ALT) ratio displayed improved predictive accuracy (AUC = 0.816, 95% CI = 0.785-0.846). Conclusion: Elevated serum RCAN2 levels were associated with an increased risk of NAFLD. Serum RCAN2, especially the serum RCAN2/(AST/ALT) ratio, might be a candidate diagnostic marker for NAFLD.

Bdh1 overexpression ameliorates hepatic injury by activation of Nrf2 in a MAFLD mouse model.

In 2020, a group of experts officially suggested metabolic dysfunction associated with fatty liver disease "MAFLD" as a more appropriate overarching term than NAFLD, indicating the key role of metabolism in fatty liver disease. Bdh1, as the rate-limiting enzyme of ketone metabolism, acts as an important metabolic regulator in liver. However, the role of Bdh1 in MAFLD is unclear. In this study, we used the transgenic db/db mice as a MAFLD mouse model and observed the downregulated expression of Bdh1 in fatty liver. In addition, expression of Bdh1 was also reduced by palmitic acid (PA) treatment in LO2 cells. Bdh1 knockdown led to ROS overproduction and ROS-induced inflammation and apoptosis in LO2 cells, while Bdh1 overexpression protected LO2 cells from lipotoxicity by inhibiting ROS overproduction. Mechanistically, Bdh1-mediated ßOHB metabolism inhibits ROS overproduction by activation of Nrf2 through enhancement of metabolic flux composed of ßOHB-AcAc-succinate-fumarate. Notably, adeno-associated virus (AAV)-mediated Bdh1 overexpression successfully reversed the hepatic function indexes, fibrosis, inflammation, and apoptosis in fatty livers from db/db mice. In conclusion, our study revealed a Bdh1-mediated molecular mechanism in pathogenesis of metabolic dysfunction related liver disease and identified Bdh1 as a novel potential therapeutic target for MAFLD.

Chronic Ethanol Consumption Induces Osteopenia via Activation of Osteoblast Necroptosis.

Chronic high-dose alcohol consumption impairs bone remodeling, reduces bone mass, and increases the risk of osteoporosis and bone fracture. However, the mechanisms underlying alcohol-induced osteoporosis are yet to be elucidated. In this study, we showed that excess intake of ethyl alcohol (EtOH) resulted in osteopenia and osteoblast necroptosis in mice that led to necrotic lesions and reduced osteogenic differentiation in bone marrow mesenchymal stem cells (BMMSCs). We found that EtOH treatment led to the activation of the RIPK1/RIPK3/MLKL signaling, resulting in increased osteoblast necroptosis and decreased osteogenic differentiation and bone formation both in vivo and in vitro. We further discovered that excessive EtOH treatment-induced osteoblast necroptosis might partly depend on reactive oxygen species (ROS) generation; concomitantly, ROS contributed to necroptosis of osteoblasts through a positive feedback loop involving RIPK1/RIPK3. In addition, blocking of the RIPK1/RIPK3/MLKL signaling by necrostatin-1 (Nec-1), a key inhibitor of RIPK1 kinase in the necroptosis pathway, or antioxidant N-acetylcysteine (NAC), an inhibitor of ROS, could decrease the activation of osteoblast necroptosis and ameliorate alcohol-induced osteopenia both in vivo and in vitro. Collectively, we demonstrated that chronic high-dose alcohol consumption induced osteopenia via osteoblast necroptosis and revealed that RIPK1 kinase may be a therapeutic target for alcohol-induced osteopenia.

Low serum Maresin-1 levels are associated with non-alcoholic fatty liver disease: a cross-sectional study.

BACKGROUND: Maresin-1 (MaR1) is an anti-inflammatory pro-resolving mediator and is considered a potential regulator of metabolic diseases. Non-alcoholic fatty liver disease (NAFLD) is a very common metabolic liver disease. However, little information is available on the relationship between MaR1 and NAFLD in humans. Therefore, the study explored the association between serum MaR1 levels and NAFLD. METHODS: A cross-sectional study was conducted in 240 Chinese people, including 116 non-NAFLD subjects and 124 NAFLD patients. Serum MaR1 levels were determined by enzyme-linked immunosorbent assay (ELISA). The association between MaR1 and NAFLD was assessed. RESULTS: Circulating MaR1 levels in NAFLD patients were markedly lower than those in non-NAFLD subjects (63.63 [59.87-73.93] vs 73.11 [65.12-84.50] pg/mL, P = 0.000). The percentages of patients with NAFLD gradually decreased with the increase of MaR1 quartiles (P < 0.001). Furthermore, serum MaR1 levels were positively associated with aspartate aminotransferase/alanine aminotransferase (AST/ALT), albumin, the albumin-globulin-ratio, and high-density lipoprotein cholesterol (HDL-C) (all P < 0.05) and negatively associated with body mass index (BMI), waist circumference, hip circumference, the waist-to-hip ratio, ALT, gamma-glutamyl transpeptidase (GGT), uric acid, triglyceride (TG), and fasting blood glucose (FBG) (all P < 0.05) after adjusting for sex and age. Binary logistic regression analysis revealed that serum MaR1 levels were significantly associated with NAFLD. CONCLUSIONS: Circulating MaR1 levels were decreased in patients with NAFLD, and a negative correlation was identified between NAFLD and serum MaR1 concentrations. Decreased MaR1 might be involved in the development of NAFLD.

G-quadruplex DNA: a novel target for drug design.

G-quadruplex (G4) DNA is a type of quadruple helix structure formed by a continuous guanine-rich DNA sequence. Emerging evidence in recent years authenticated that G4 DNA structures exist both in cell-free and cellular systems, and function in different diseases, especially in various cancers, aging, neurological diseases, and have been considered novel promising targets for drug design. In this review, we summarize the detection method and the structure of G4, highlighting some non-canonical G4 DNA structures, such as G4 with a bulge, a vacancy, or a hairpin. Subsequently, the functions of G4 DNA in physiological processes are discussed, especially their regulation of DNA replication, transcription of disease-related genes (c-MYC, BCL-2, KRAS, c-KIT et al.), telomere maintenance, and epigenetic regulation. Typical G4 ligands that target promoters and telomeres for drug design are also reviewed, including ellipticine derivatives, quinoxaline analogs, telomestatin analogs, berberine derivatives, and CX-5461, which is currently in advanced phase I/II clinical trials for patients with hematologic cancer and BRCA1/2-deficient tumors. Furthermore, since the long-term stable existence of G4 DNA structures could result in genomic instability, we summarized the G4 unfolding mechanisms emerged recently by multiple G4-specific DNA helicases, such as Pif1, RecQ family helicases, FANCJ, and DHX36. This review aims to present a general overview of the field of G-quadruplex DNA that has progressed in recent years and provides potential strategies for drug design and disease treatment.

Metformin and Fibrosis: A Review of Existing Evidence and Mechanisms.

Fibrosis is a physiological response to organ injury and is characterized by the excessive deposition of connective tissue components in an organ, which results in the disruption of physiological architecture and organ remodeling, ultimately leading to organ failure and death. Fibrosis in the lung, kidney, and liver accounts for a substantial proportion of the global burden of disability and mortality. To date, there are no effective therapeutic strategies for controlling fibrosis. A class of metabolically targeted chemicals, such as adenosine monophosphate-activated protein kinase (AMPK) activators and peroxisome proliferator-activated receptor (PPAR) agonists, shows strong potential in fighting fibrosis. Metformin, which is a potent AMPK activator and is the only recommended first-line drug for the treatment of type 2 diabetes, has emerged as a promising method of fibrosis reduction or reversion. In this review, we first summarize the key experimental and clinical studies that have specifically investigated the effects of metformin on organ fibrosis. Then, we discuss the mechanisms involved in mediating the antifibrotic effects of metformin in depth.

Gut Microbiota-Derived Trimethylamine N-Oxide and Kidney Function: A Systematic Review and Meta-Analysis.

Elevated circulating trimethylamine N-oxide (TMAO) concentrations have been observed in patients with chronic kidney disease (CKD). We aimed to systematically estimate and quantify the association between TMAO concentrations and kidney function. The PubMed, EMBASE, Cochrane Library, Scopus, and Web of Science databases were systematically searched from 1995 to 1 June, 2020, for clinical studies on circulating TMAO concentrations and kidney function indicators. We used R software to conduct meta-analyses of the extracted data. A cumulative meta-analysis was applied to test whether health status affected the pooled effect value. Meta-regression and subgroup analyses were performed to identify possible sources of heterogeneity. Ultimately, we included a total of 32 eligible clinical studies involving 42,062 participants. In meta-analyses of continuous-outcome variables, advanced CKD was associated with a 67.9 µmol/L (95% CI: 52.7, 83.2; P < 0.01) increase in TMAO concentration, and subjects with high concentrations of TMAO had a 12.9 mL/(min·1.73 m2) (95% CI: -16.6, -9.14; P < 0.01) decrease in glomerular filtration rate (GFR). In meta-analyses of the correlations, TMAO was strongly inversely correlated with GFR [Fisher's z-transformed correlation coefficient (ZCOR): -0.45; 95% CI: -0.58, -0.32; P < 0.01] and positively associated with the urine albumin-to-creatinine ratio (UACR; ZCOR: 0.26; 95% CI: 0.08, 0.43; P < 0.01), serum creatinine (sCr; ZCOR: 0.43; 95% CI: 0.28, 0.58; P < 0.01), urine albumin excretion rate (UAER; ZCOR: 0.06; 95% CI: 0.04, 0.09; P < 0.01), blood urea (ZCOR: 0.50; 95% CI: 0.29, 0.72; P < 0.01), blood uric acid (ZCOR: 0.32; 95% CI: 0.25, 0.38; P < 0.01), and serum cystatin C (CysC; ZCOR: 0.47, 95% CI: 0.44, 0.51; P < 0.01). This is the first systematic review and meta-analysis to reveal a negative association between circulating TMAO concentrations and kidney function.