Exendin-4 alleviates high glucose-induced rat mesangial cell dysfunction through the AMPK pathway.

BACKGROUND/AIMS: Glucagon-like peptide-1 (GLP-1), which counteracts insulin resistance in humans with type 2 diabetes, has been shown to ameliorate diabetic nephropathy in experimental models. However, the mechanisms through which GLP-1 modulates renal function remained illdefined. The present study investigated the putative mechanisms underlying effects of exendin-4, a GLP-1 analog, on mesangial cell proliferation and fibronectin. METHODS: Rat mesangial cells (MCs) were treated with exendin-4 under high glucose conditions. AMP-activated protein kinase (AMPK) inhibitors (compound C) and agonists (AICAR) were used to analyze the role of this kinase. Cell proliferation was measured using a MTT assay. Fibronectin expression and AMPK-signaling pathway activity were assessed using ELISA and Western blotting, respectively. The production of matrix metalloproteinase (MMP)-2 and tissue inhibitors of metalloproteinases (TIMP)-2 was evaluated using quantitative real-time RT-PCR. RESULTS: Exendin-4 inhibited cell proliferation and fibronectin secretion in high glucose-induced MCs. It also caused phosphorylation of AMPK and subsequently increased the ratio of MMP-2 to TIMP-2, which resulted in the degradation of fibronectin. Exendin-4 reversed extracellular signal-regulated kinase (ERK) phosphorylation and enhanced expression of mammalian target of rapamycin (mTOR) in MCs. Moreover, the activation of the AMPK pathway by exendin-4 was induced by AICAR, which was inhibited by compound C. CONCLUSION: Exendin-4 exerts an inhibitory effect on cell proliferation and fibronectin secretion in rat MCs, partly through AMPK activation. These results may explain some of the beneficial effects of exendin-4 on the kidney.

Retinal thickness and microvascular alterations observed by optical coherence tomography in antineutrophil cytoplasmic antibody-associated vasculitis: a cross-sectional study.

Background: As an autoimmune disease, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) often affects multiple organs, including the ocular system. This study aims to investigate differences in retinal thickness (RT) and retinal superficial vascular density (SVD) between patients with AAV and healthy controls (HCs) using optical coherence tomography angiography (OCTA). Currently, these differences are not clear. Methods: A total of 16 AAV individuals (32 eyes) and 16 HCs (32 eyes) were recruited to this cross-sectional study conducted in the First Affiliated Hospital of Nanchang University from June 2023 to September 2023. The study protocol conformed with the tenets of the Declaration of Helsinki (as revised in 2013). Each image observed by OCTA was divided into 9 regions using the Early Treatment Diabetic Retinopathy Study (ETDRS) subzones as a guide. Results: In the full layer, the RT of AAV patients was found to be significantly reduced in the inner superior (IS, P<0.001), outer superior (OS, P=0.003), inner temporal (IT, P=0.003), and outer temporal (OT, P<0.001) regions; inner RT was significantly lower in the IS (P=0.006), OS (P<0.001), inner nasal (IN, P=0.005), outer nasal (ON, P<0.001), and center (C, P=0.01) regions than that in HCs. Outer RT of AAV patients showed a reduction in the IS (P<0.001), as well as IT (P=0.008), and OT (P<0.001) regions. No statistically significant differences were seen in the different subregions in other different layers (P>0.05). Only the inner inferior (II) and outer inferior (OI) regions of SVD in AAV patients did not differ significantly from controls. All other regions showed a reduction in SVD. The details are as follows: IS (P<0.001), OS (P<0.001), IT (P=0.005), OT (P<0.001), IN (P<0.001), ON (P<0.001), and C (P=0.003). According to receiver operating characteristic (ROC) curve analysis, the full IS region [area under the curve (AUC): 0.8892, 95% confidence interval (CI): 0.8041-0.9742, P<0.001] had the highest diagnostic value for AAV-induced reduction in RT. The IS (AUC: 0.9121, 95% CI: 0.8322-0.9920, P<0.001) region was also the most sensitive to changes in SVD of AAV individuals. In addition, we found that SVD in the IN region (r=-0.4224, 95% CI: -0.6779 to -0.0757, P=0.02) as well as mean visual acuity (r=-0.3922, 95% CI: -0.6579 to -0.0397, P=0.03) of AAV patients were negatively correlated with disease duration. However, we did not find an association between SVD and RT in this study. Conclusions: The findings from OCTA indicated a reduction in RT and SVD among patients with AAV. OCTA allows for the evaluation of AAV-related ocular lesions and holds promise for monitoring of disease progression through regular evaluations.

Retinal microvascular changes in patients with pancreatitis and their clinical significance.

Acute pancreatitis, a common exocrine inflammatory disease affecting the pancreas, is characterized by intense abdominal pain and multiple organ dysfunction. However, the alterations in retinal blood vessels among individuals with acute pancreatitis remain poorly understood. This study employed optical coherence tomography angiography (OCTA) to examine the superficial and deep retinal blood vessels in patients with pancreatitis. Sixteen patients diagnosed with pancreatitis (32 eyes) and 16 healthy controls (32 eyes) were recruited from the First Affiliated Hospital of Nanchang University for participation in the study. Various ophthalmic parameters, such as visual acuity, intraocular pressure, and OCTA image for retina consisting of the superficial retinal layer (SRL) and the deep retinal layer (DRL), were recorded for each eye. The study observed the superficial and deep retinal microvascular ring (MIR), macrovascular ring (MAR), and total microvessels (TMI) were observed. Changes in retinal vascular density in the macula through annular partitioning (C1-C6), hemispheric quadrant partitioning (SR, SL, IL, and IR), and early diabetic retinopathy treatment studies (ETDRS) partitioning methods (R, S, L, and I). Correlation analysis was employed to investigate the relationship between retinal capillary density and clinical indicators. Our study revealed that in the superficial retinal layer, the vascular density of TMI, MIR, MAR, SR, IR, S, C2, C3 regions were significantly decreased in patients group compared with the normal group. For the deep retinal layer, the vascular density of MIR, SR, S, C1, C2 regions also reduced in patient group. The ROC analysis demonstrated that OCTA possesses significant diagnostic performance for pancreatitis. In conclusion, patients with pancreatitis may have retinal microvascular dysfunction, and OCTA can be a valuable tool for detecting alterations in ocular microcirculation in pancreatitis patients in clinical practice.

[Regulation of hepatic lipid metabolism by adiponectin via IRS-2 phosphorylation in OLETF rats].

OBJECTIVE: To explore the effect and mechanism of adiponectin on hepatic lipid metabolism in Otsuka Long Evans Tokushima fatty (OLETF) rats. METHODS: Twenty male OLETF rats and 10 male Long-Evans Tokushima (LETO) rats were sacrificed at 8, 32 or 40-week old to examine the fasting blood glucose, plasma insulin, adiponectin and blood lipid profile. The levels of triglyceride, cholesterol, adiponectin, phosphotyrosine of IRS-2, acetyl-coenzyme A carboxylase and sterol regulatory element-binding protein 1 (SREBP-1) mRNA in liver tissue were determined by chemical enzymatic assay, enzyme-linked immunosorbent assay (ELISA) or Western blot. RESULTS: Higher insulin level, lower insulin sensitivity index and deteriorated lipid metabolism was observed in OLETF rats since 32-week age. ACC (acetyl coenzyme A carboxylase) and SREBP-1 mRNA expression, lowered plasma adiponectin (OLETF vs LETO: 8 weeks age, 2.38 ± 0.23 vs 3.1 ± 0.17, P < 0.05; 32 weeks age, 1.51 ± 0.05 vs 2.84 ± 0.34, P < 0.01; 40 weeks age, 1.24 ± 0.04 vs 2.64 ± 0.49 ng/ml, P < 0.01) and liver tissue (8, 32 or 40 weeks age, 2.24 ± 0.18 vs 2.68 ± 0.13, 2.04 ± 0.19 vs 2.51 ± 0.14, 1.76 ± 0.12 vs 2.47 ± 0.21 µg/g respectively, P < 0.05) as well as elevated triglyceride (TG) (40 weeks age, TG 1.88 ± 0.11 vs 0.51 ± 0.07 mmol/L, P < 0.01) and cholesterol (40 weeks age, total cholesterol 0.94 ± 0.17 vs 0.69 ± 0.14 mmol/L, P < 0.01) and lowered IRS-1 (insulin receptor substrate 1) tyrosine phosphorylation in liver tissue in OLETF rats were observed. The hepatic adiponectin was positively correlated with the level of py-IRS2 and inversely with those of hepatic ACC, SREBP-1 mRNA, triglyceride and cholesterol (r = -0.431, -0.396, -0.353, -0.349, P < 0.05). CONCLUSION: Adiponectin may affect the signaling pathway of hepatic insulin via tyrosine phosphorylation of IRS-2. It is involved in the regulation of hepatic lipid metabolism.

Renoprotective effects of brown adipose tissue activation in diabetic mice.

BACKGROUND: Brown adipose tissue (BAT) has been regarded as a potential target organ to combat obesity and related metabolic disorders. However, the effect of BAT activation on the development of diabetic kidney disease (DKD) remains unclear. METHODS: Diabetic mice were induced by streptozotocin (STZ) combined with a high-fat diet. To activate BAT, mice were administered 1 mg/kg per day, i.p., CL316,243, a ß3 -adrenergic receptor agonist, for 4 weeks. Blood glucose, serum lipids, adipokines, 24-hour urinary albumin, 8-hydroxydeoxyguanosine (8-OHdG), and circulating microRNA (miRNA) levels were analyzed, in addition to renal pathology. Histological changes (fibrosis, inflammation) were evaluated in the kidneys, as was the expression of oxidative stress-related genes. Renal signaling pathways (fibroblast growth factor [Fgf]21/ß-klotho/FGF receptor 1c and AMP-activated protein kinase[AMPK]/sirtuin 1 [Sirt1]/peroxisome proliferator-activated receptor-γ coactivator-1α [Pgc1α]) were also evaluated. RESULTS: Compared with untreated STZ-diabetic mice, CL316,243 treatment reduced blood glucose, albeit not significantly (20.58 ± 3.55 vs 23.60 ± 3.90 mM), and significantly decreased triglycerides and low-density lipoprotein cholesterol and increased high-density lipoprotein cholesterol. Simultaneously, BAT activation significantly decreased 24-hour urinary albumin (34.21 ± 6.28 vs 70.46 ± 15.81 µg/24 h; P < 0.05) and 8-OHdG, improved renal fibrosis, inflammation, and oxidative stress, and ameliorated renal morphological abnormalities. In addition to enhancing BAT activity, CL316,243 significantly increased serum adiponectin concentrations and renal Fgf21 sensitivity, and reactivated the renal AMPK/Sirt1/Pgc1α signaling pathway. Furthermore, CL316,243 treatment increased levels of some circulating miRNAs and downregulated expression of their target genes in the kidney. CONCLUSIONS: Activating BAT could improve kidney injury in diabetic mice via metabolic improvements and renal AMPK activation by beneficial adipokines and miRNAs.

[Secondary organic tracers in summer PM2.5 aerosols from Baima Spring Scenic Area, Yaan, Sichuan Province].

Integrated PM2.5 aerosol samples were collected at Baima Spring Scenic Area, a forest site of Yaan, Sichuan Province, during the summer of 2010. Organic speciation including isoprene oxidation products (2-methyltetrols, C5-alkene trols, 2-methylyceric acid), alpha-/beta-pinene oxidation products (norpinic acid, 3-hydroxyglutaric acid, 3-methy-1,2,3-butanetricarboxylic acid), and small molecular carboxylic acid (malic acid, 2-hydroxyglutaric acid) were analyzed. The generation mechanisms of SOA as well as their influencing factors were particularly discussed. Results show that average concentrations of 2-methyltetrols, C5-alkene triols, 2-methyglyceric acid, norpinic acid, 3-hydroxyglutaric acid and 3-methy-1,2,3-butanetricarboxylic acid are 63.3, 45.0, 4.4, 4.1, 5.0, 5.3 ng x m(-3) respectively, of 24-hour lapse samples. SOA compounds are consistent with higher concentrations in the day than during the night only except for norpinic acid. Relatively high level of biogenic SOA at the study area is concerned with many environmental factors, i. e. local abundant vegetations, warm and humid climate, sunken valley topography, the atmospheric pollution state, etc.

[Relationship between intrauterine infection and the gene polymorphism of DC-SIGN/DC-SIGNR in the pregnant women of HBV positive].

OBJECTIVE: To investigate the influence of the individual genotype differences of DC-SIGN and DC-SIGNR on the mother-to-neonate intrauterine infection of HBV. METHODS: The genotypes of the gene DC-SIGN and DC-SIGNR in the pregnant women with HBV positive were detected by PCR and agarose gel electrophoresis. The significant difference of gene diversity of DC-SIGN and DC-SIGNR was analyzed by chi-square test. RESULTS: (1) All of 29 cases in intrauterine infection group were 7/7 DC-SIGN genotype. In the non-intrauterine infection group, 7/5 genotype were observed in 2 of 54 cases, and the other 52 cases were 7/7 genotype. The two groups was no significant difference (P = 0.54). (2) 29 cases of intrauterine infection group was observed 4 genotypes of DC-SIGNR such as 7/7, 7/5, 9/7 and 6/5, the genotype frequencies were 0.3793, 0.3448, 0.2414 and 0.0345 respectively. 54 cases of non-intrauterine infection group was found 6 genotypes such as 7/7, 7/5, 9/5, 9/7, 7/6 and 6/5, genotype frequencies were 0.5186, 0.1481, 0.0926, 0.1852, 0.0370 and 0.0185 respectively. The distribution of 7/5 genotype in the intrauterine infection group (29 cases) and the non-intrauterine infection group (54 cases) was statistically significant (P = 0.038) , and no significant difference was found in other genotypes between the two groups (P > 0.05). CONCLUSION: The gene DC-SIGN showed relatively little variation in the pregnant women infected with HBV. On the countrary, there were multiple genotypes of the gene DC-SIGNR in these women, and the genotype "7/5" of DC-SIGNR might be one of the susceptibility genes associated with intrauterine infection.