Clinical characteristics and treatment compounds of obesity-related kidney injury.

Disorders in energy homeostasis can lead to various metabolic diseases, particularly obesity. The obesity epidemic has led to an increased incidence of obesity-related nephropathy (ORN), a distinct entity characterized by proteinuria, glomerulomegaly, progressive glomerulosclerosis, and renal function decline. Obesity and its associated renal damage are common in clinical practice, and their incidence is increasing and attracting great attention. There is a great need to identify safe and effective therapeutic modalities, and therapeutics using chemical compounds and natural products are receiving increasing attention. However, the summary is lacking about the specific effects and mechanisms of action of compounds in the treatment of ORN. In this review, we summarize the important clinical features and compound treatment strategies for obesity and obesity-induced kidney injury. We also summarize the pathologic and clinical features of ORN as well as its pathogenesis and potential therapeutics targeting renal inflammation, oxidative stress, insulin resistance, fibrosis, kidney lipid accumulation, and dysregulated autophagy. In addition, detailed information on natural and synthetic compounds used for the treatment of obesity-related kidney disease is summarized. The synthesis of detailed information aims to contribute to a deeper understanding of the clinical treatment modalities for obesity-related kidney diseases, fostering the anticipation of novel insights in this domain.

Semaglutide alters gut microbiota and improves NAFLD in db/db mice.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease associated with type 2 diabetes mellitus (T2D). NAFLD can progress to nonalcoholic steatohepatitis (NASH), cirrhosis, and even cancer, all of which have a very poor prognosis. Semaglutide, a novel glucagon-like peptide-1 (GLP-1) receptor agonist, has been recognized as a specific drug for the treatment of diabetes. In this study, we used a gene mutation mouse model (db/db mice) to investigate the potential liver-improving effects of semaglutide. The results showed that semaglutide improved lipid levels and glucose metabolism in db/db mice. HE staining and oil red staining showed alleviation of liver damage and reduction of hepatic lipid deposition after injection of semaglutide. In addition, semaglutide also improved the integrity of gut barrier and altered gut microbiota, especially Alloprevotella, Alistpes, Ligilactobacillus and Lactobacillus. In summary, our findings validate that semaglutide induces modifications in the composition of the gut microbiota and ameliorates NAFLD, positioning it as a promising therapeutic candidate for addressing hepatic steatosis and associated inflammation.

Astilbin protects from sepsis-induced cardiac injury through the NRF2/HO-1 and TLR4/NF-κB pathway.

Cardiac dysfunction and arrhythmia are severe complications of sepsis-induced cardiomyopathy and are associated with an increased risk of morbidity and mortality. Currently, the precise mechanism for sepsis-induced myocardial damage remains unclear. Astilbin, a flavonoid, is reported to have anti-inflammatory, antioxidative, and antiapoptotic properties. However, the effects of astilbin on sepsis-induced cardiomyopathy have not been studied so far. This study aims to investigate the effect of astilbin in sepsis-induced myocardial injury and elucidate the underlying mechanism. In vivo and in vitro sepsis models were created using lipopolysaccharide (LPS) as an inducer in H9C2 cardiomyocytes and C57BL/6 mice, respectively. Our results demonstrated that astilbin reduced myocardial injury and improved cardiac function. Moreover, astilbin prolonged the QT and corrected QT intervals, attenuated myocardial electrical remodeling, and promoted gap junction protein (Cx43) and ion channels expression, thereby reducing the susceptibility of ventricular fibrillation. In addition, astilbin alleviated LPS-induced inflammation, oxidative stress, and apoptosis. Astilbin suppressed the toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway in vivo and in vitro models. Astilbin remarkedly upregulated the nuclear factor erythroid 2-related factor 2 (NRF2) and heme oxygenase 1 (HO-1) expression. The in vitro treatment with an NRF2 inhibitor reversed the inhibition of the TLR4/NF-κB pathway and antioxidant properties of astilbin. Astilbin attenuated LPS-induced myocardial injury, cardiac dysfunction, susceptibility to VF, inflammation, oxidative stress, and apoptosis by activating the NRF2/HO-1 pathway and inhibiting TLR4/ NF-κB pathway. These results suggest that astilbin could be an effective and promising therapeutics target for the treatment of sepsis-induced cardiomyopathy.

Muscone attenuates susceptibility to ventricular arrhythmia by inhibiting NLRP3 inflammasome activation in rats after myocardial infarction.

Fibrosis and abnormal expression of connexin 43 (Cx43) in the ventricle play vital roles in ventricular arrhythmias (VAs) after myocardial infarction (MI). Muscone, an active monomer of heart-protecting musk pill, has various biological activities, but its effect on susceptibility to VAs in rats with MI has not been determined. In the present study, we investigated the effects of muscone on ventricular inflammation, fibrosis, Cx43 expression, and the occurrence of VAs after MI. An MI model was established by ligating the proximal left anterior descending coronary artery. Then, the MI model rats were administered muscone (2 mg/kg/day) or vehicle (saline)via intragastric injection for 14 days. Cardiac function was evaluated by echocardiography, and an in vivo electrophysiological study was performed on Day 14. Cardiac inflammation, fibrosis, and Cx43 expression were determined by histochemical analysis and western blot analysis. Our results indicated that muscone treatment significantly improved cardiac function and inhibited ventricular inflammation, fibrosis, and nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing 3 (NLRP3) inflammasome activation. Electrocardiogrphy and electrophysiology studies showed that muscone shortened the QRS interval, QT interval, QTc interval, and action potential duration; prolonged the effective refractory period; and reduced susceptibility to VAs in rats after MI. Furthermore, Cx43 expression in the BZ was increased by muscone treatment, and this change was coupled by inhibition of the NLRP3/IL-1ß/p38 MAPK pathway. Taken together, our results demonstrated that muscone reduces susceptibility to VA, mainly by decreasing ventricular inflammation and fibrosis, and attenuates abnormal Cx43 expression by inhibiting NLRP3 inflammasome activation after myocardial infarction in rats.

Short-term fasting reshapes fat tissue.

Intermittent fasting, which can effectively reduce obesity and improve the related metabolic syndrome has become an exciting research area in recent years. Adipose tissue is pivotal in regulating the metabolism and determining the occurrence of obesity. In the current study, we aimed to investigate the effects of acute fasting (AF) on fat tissue. Mice were subjected to AF for 36 h, receiving normal chow (low-fat diet [LFD]) or a high-fat diet (HFD), with free ad libitum access to drinking water, and those fed on free-diet counterparts without fasting serveding as controls. We found that AF obviously reshaped the morphology of fat tissue (WAT) and promoted the beiging of white adipose tissue in both LFD- and HFD-fed mice. AF principally improved the lipid metabolism, and increased the M2- polarization of macrophages in WAT white fat tissue of HFD-fed mice. Interestingly, we found that AF dramatically upregulated Sirt5 expression levels and fat tissue succinylation, suggesting that AF-induced beneficial effects on fat might occur via the regulation of Sirt5 levels and altered succinylation in fatty tissues. Our study clearly showed the remodeling function of adipose tissue during AF; in terms of mechanism, the regulation of succinylation levels by AF might provide new insights into the mechanism(s) underlying the improvement in fat metabolism by energy restriction.

Pigment epithelium-derived factor inhibits high glucose-induced JAK/STAT signalling pathway activation in human glomerular mesangial cells.

OBJECTIVE: To further elucidate the mechanism of the anti-fibrogenic role of pigment epithelium-derived factor (PEDF) on diabetic nephropathy. METHODS: Human glomerular mesangial cells (HMCs) were treated with 30 mmol/l D-glucose for different time intervals (6, 12, 24, and 48 hrs). To examine the beneficial effect of PEDF, we incubated the HMCs with high glucose (30 mmol/L) in the presence of different concentrations of PEDF (10, 40, and 100 nmol/l) for 24 hrs. The study took place in the Laboratory of Endocrinology, Renmin Hospital of Wuhan University, Wuhan, China between July 2012 and December 2012. Transforming growth factor-beta1 (TGF-beta1) and fibronectin (FN) mRNA was measured by reverse transcription-polymerase chain reaction (RT-PCR). The protein synthesis of TGF-beta1 and FN in the culture medium of HMC was detected by enzyme-linked immunosorbent assay. The phosphorylation levels of Janus kinase2 (JAK2) and signal transducers and activators of transcription1 (STAT1) were measured using western blotting. RESULTS: The exposure of HMCs to 30 mmol/L glucose caused the activation of JAK2 and STAT1. It upregulated TGF-beta1 expression and increased protein synthesis of FN. These high glucose-induced changes were suppressed by PEDF. CONCLUSION: The PEDF can decrease the expression of TGF-beta1 and FN, possibly by inhibiting the phosphorylation of JAK/STAT, which may offer a promising strategy in the treatment of diabetic nephropathy.

Pigment epithelium-derived factor inhibits high glucose induced oxidative stress and fibrosis of cultured human glomerular mesangial cells.

OBJECTIVE: To evaluate whether pigment epithelium-derived factor (PEDF) could prevent human mesangial cells (HMCs) from elevated glucose-induced oxidative stress and fibrosis. METHODS: The study took place in the Endocrinology Laboratory of Renmin Hospital of Wuhan University, Wuhan, China from December 2009 to June 2010. The HMCs were treated with different concentrations of dextroglucose (5.6, 15, and 30 mmol/l), and 5.6 mmol/l D-glucose+24.4 mmol/l D-mannitol (osmotic control) for 24 and 48 hours. To examine the beneficial effect of PEDF, HMCs were also incubated with high glucose (30 mmol/L) in the presence of different concentrations of PEDF (5, 10, 40, 100, and 160 nmol/l) for 48 hours. RESULTS: The PEDF significantly inhibited the overexpression of transforming growth factor-beta 1, and extracellular matrix proteins (fibronectin and collagen IV) induced by the elevated glucose in HMCs. The PEDF also impeded high glucose-induced reactive oxygen species generation in HMCs. CONCLUSION: These results suggest that PEDF by virtue of its anti-oxidative and anti-fibrogenic properties may have a therapeutic potential in diabetic nephropathy.