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Protection of podocytes is one of the important means to delay the progression of diabetic nephropathy (DN), and glucagon-like peptide-1 (GLP-1) has been shown to have a protective effect on the kidney in DN models, but whether it has a protective effect on podocytes and the potential mechanisms of action remain largely unknown. In the present study, we established a type 2 diabetes mellitus (T2DM) mouse model by high-fat diet feeding combined with streptozotocin (STZ) induction and administered the intervention for 14 weeks. We found that liraglutide significantly ameliorated podocyte injury in DN mice. Mechanistically, we detected glucagon-like peptide-1 receptor (GLP-1R) protein expression levels in kidney tissues by immunohistochemical staining, immunofluorescence staining, and western blotting and found that podocytes could express GLP-1R and liraglutide treatment could restore GLP-1R expression in the kidney tissues of DN mice. Furthermore, we found that NLRP3-induced inflammation and pyroptosis were positively correlated with podocyte injury in DN mice, and liraglutide inhibited the expression of NLRP3-induced inflammation and pyroptosis-related proteins. Our results suggest that liraglutide protects DN mouse podocytes by regulating GLP-1R in renal tissues and by regulating NLRP3-induced inflammation and pyroptosis.
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Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, Hunan, China
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Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, Hunan, China
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Objective
Ghrelin regulates body weight, food intake, and blood glucose. It also regulates insulin secretion from pancreatic islet cells. LEAP2 is a newly discovered endogenous ligand of the growth hormone secretagogue’s receptor (GHSR). It not only antagonizes the stimulation of GHSR by ghrelin but also inhibits the constitutive activation of GHSR as an inverse agonist. Type 2 diabetes (T2D) patients have endocrine disorders with metabolic imbalance. Plasma levels of ghrelin and LEAP2 may be changed in obese and T2D patients. However, there is no report yet on circulating LEAP2 levels or ghrelin/LEAP2 ratio in T2D patients. In this study, fasting serum ghrelin and LEAP2 levels in healthy adults and T2D patients were assessed to clarify the association of two hormones with different clinical anthropometric and metabolic parameters.
Design
A total of 16 females and 40 males, ages 23–68 years old normal (n = 27), and T2D patients (n = 29) were enrolled as a cross-sectional cohort.
Results
Serum levels of ghrelin were lower but serum levels of LEAP2 were higher in T2D patients. Ghrelin levels were positively correlated with fasting serum insulin levels and HOMA-IR in healthy adults. LEAP2 levels were positively correlated with age and hemoglobin A1c (HbA1c) in all tested samples. Ghrelin/LEAP2 ratio was negatively correlated with age, fasting blood glucose, and HbA1c.
Conclusions
This study demonstrated a decrease in serum ghrelin levels and an increase in serum LEAP2 levels in T2D patients. LEAP2 levels were positively correlated with HbA1c, suggesting that LEAP2 was associated with T2D development. The ghrelin/LEAP2 ratio was closely associated with glycemic control in T2D patients showing a negative correlation with glucose and HbA1c.
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Objective
To explore the relationship between estradiol (E2) and thyroid function during the second trimester of pregnancy and the effect of E2 on sodium iodide transporter (NIS) expression in cultured thyroid cells.
Materials and methods
We analyzed relationships between E2 and thyroid function in 196 pregnant women during the second trimester. Multiple linear regression analysis was performed between E2 and thyroid function. The human thyroid Nthy-ori3-1 cells were cultured in different E2 concentrations, and the mRNA levels of NIS, estrogen receptor (ER)-α, and ER-β were measured by quantitative real-time PCR. Their protein levels were assessed by western blot.
Results
E2 was positively correlated with thyroid-stimulating hormone (TSH) and negatively correlated with free thyroxine (FT4) (P < 0.05). When we corrected for age, BMI, alanine aminotransferase, and serum creatinine, E2 was still negatively correlated with FT4 (P < 0.5) during the second trimester. In Nthy-ori3-1 cells treated with 10 nM E2, NIS and ER-β mRNA levels were significantly reduced, while ER-α mRNA level was not altered (P > 0.5). Moreover, 10 nM E2 significantly decreased protein levels of ER-β, phosphorylated versions of protein kinase A (p-PKA), phosphorylated versions of cAMP response element-binding protein (p-CREB), and NIS, while treatment with the ER-β inhibitor restored the expression of p-PKA, p-CREB, and NIS (P < 0.05).
Conclusion
High concentration of E2 has a negative correlation with FT4. High concentration of E2 can inhibit the NIS expression through the ER-β-mediated pathway, which may cause thyroid hormone fluctuations during pregnancy.
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A new subcategory, grade 3 neuroendocrine tumors, is incorporated into the grading system of pancreatic neuroendocrine neoplasms in the 2017 WHO classification in order to differentiate grade 3 neuroendocrine tumors from neuroendocrine carcinomas. The 2019 WHO classification extends the concept of grade 3 neuroendocrine tumors to gastrointestinal high-grade neuroendocrine neoplasms. However, there is still limited study focusing on the gastric grade 3 neuroendocrine tumors and gastric neuroendocrine carcinomas. We retrospectively enrolled 151 gastric high-grade neuroendocrine neoplasms patients, who underwent radical resection from January 2007 to December 2015. Clinicopathologic and prognostic features were studied. The Surveillance, Epidemiology, and End Results (SEER) database was used to verify the prognostic determinants found in the Zhongshan cohort. Neuroendocrine carcinomas showed a higher Ki67 index and higher mitotic count than grade 3 neuroendocrine tumors. We identified 109 (72.2%) patients with neuroendocrine carcinomas, 12 (7.9%) patients with grade 3 neuroendocrine tumors, and 30 (19.9%) patients with mixed neuroendocrine-non-neuroendocrine neoplasms. Although neuroendocrine carcinomas demonstrated higher Ki67 index (P = 0.004) and mitoses (P = 0.001) than grade 3 neuroendocrine tumors, their prognosis after radical resection did not demonstrate significant differences (P = 0.709). Tumor size, perineural invasion, and TNM stage were independent prognostic factors of gastric high-grade neuroendocrine neoplasms.