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OBJECTIVE: Polycystic ovarian syndrome (PCOS) is a complex heterogeneous disorder characterized by hyperandrogenism, irregular menses, and subfertility and often accompanied by other related comorbid disorders such as insulin resistance, obesity, and type 2 diabetes. Several genetic risk factors predispose to PCOS, but most are still unknown. Up to 30% of women with PCOS may have hyperaldosteronism. Blood pressure and the ratio of blood levels of aldosterone to renin are higher in women with PCOS compared to healthy controls, even if still in the normal range; and the aldosterone antagonist spironolactone has been used as therapy for PCOS, mainly due to its antiandrogenic activity. Thus, we aimed to investigate the potential pathogenetic role of the mineralocorticoid receptor gene (NR3C2) as the encoded NR3C2 product binds aldosterone and plays a role in folliculogenesis, fat metabolism, and insulin resistance. SUBJECTS AND METHODS: Within 212 Italian families with T2D and phenotyped for PCOS, we analyzed 91 single nucleotide polymorphisms in the NR3C2 gene. We tested the NR3C2 variants for linkage and linkage disequilibrium to the PCOS phenotype by using parametric analysis. RESULTS: We found 18 novel risk variants significantly linked to and/or associated with the risk of PCOS. CONCLUSIONS: We are the first to report NR3C2 as a risk gene in PCOS. However, our findings need to be replicated in other ethnic groups in order to reach more solid conclusions. [ABSTRACT FROM AUTHOR]

Introduction: The mineralocorticoid receptor gene (NR3C2) appears to modulate stress and cognitive performance in patients with major depressive disorder (MDD). In addition, abnormalities in NR3C2 are associated in rodents with type 2 diabetes (T2D) and in humans with features of metabolic syndrome. Of note, NR3C2 antagonists are approved treatments in heart failure and chronic kidney disease with T2D. The NR3C2 gene is therefore a candidate gene for studying T2D-MDD comorbidity. To our knowledge, no study has so far reported risk variants in the NR3C2 gene with either MDD and/or T2D. Materials and methods: In 212 multigenerational Italian families with enriched family history of T2D and with MDD, we analyzed 86 single nucleotide polymorphisms (SNPs) within the NR3C2 gene for parametric linkage to and/or linkage disequilibrium (LD) with T2D and MDD. Results: We identified a total of 7 independent SNPs significantly linked to/in LD with MDD only, 20 SNPs significantly linked to/in LD with T2D only, and 9 SNP significantly linked to/in LD with both T2D and MDD. The SNPs were statistically significant across different models. Two sets of LD blocks were MDD-specific, and one set was T2D-specific. In silico analysis of the risk variants predicted 3 variants with potential functional effects. Conclusions: This is the first study to report NR3C2 as a novel risk gene in T2D and MDD comorbidity. However, our results need to be replicated in other ethnicities.

Background: The molecular heterogeneity of clear cell renal cell carcinoma (ccRCC) leads to a high mortality of the disease, which seriously threatens the life of patients. Therefore, this study explored the functional significance and mechanism of microRNA-155-5p and nuclear receptor subfamily 3 group C member 2 (NR3C2) in the regulation of ccRCC. Methods: Expression levels of microRNA-155-5p and NR3C2 mRNA in ccRCC cells were analyzed by qRT-PCR, and the protein expression of NR3C2 in human ccRCC cells was measured by Western blot. Biological functions were determined through a series of in vitro experiments. The interaction between microRNA-155-5p and NR3C2 was tested by luciferase reporter gene assay. In addition, the effect of overexpressed or silenced microRNA-155-5p on cell phenotypes was evaluated in ccRCC cells. Results: Experimental data suggested that overexpression or silencing of microRNA-155-5p in ccRCC could boost or suppress cancer cell proliferation and other malignant behaviors. Rescue experiments revealed that microRNA-155-5p facilitated the proliferation, migration, and invasion and suppressed the apoptosis of ccRCC by directly inhibiting the expression of NR3C2. Conclusions: This is the first study to generate new insights into the role of microRNA-155-5p/NR3C2 interaction in promoting the process of ccRCC, and it is possible to bring a turning point for the treatment of ccRCC. [ABSTRACT FROM AUTHOR]

[Display omitted] • LCN2 is correlated with ER stress and is highly expressed in MCAO mice and OGD cells. • Knockdown of LCN2 alleviates ER stress, cell apoptosis, and inflammation in MCAO mice. • Knockdown of LCN2 alleviates ER stress and cell apoptosis in OGD-treated HT22 cells. • NR3C2 activates LCN2 transcription. • LCN2 upregulation restores ER stress and cell apoptosis reduced by NR3C2 knockdown. Endoplasmic reticulum (ER) stress can lead to cell death and worsen tissue damage during ischemic events. Nuclear receptor subfamily 3 group C member 2 (NR3C2) and lipocalin 2 (LCN2) are known to be associated with ER stress. In this study, we obtained a potential interaction between NR3C2 and LCN2 through bioinformatics. The primary objective was to investigate their roles and interactions in the context of ER stress in ischemic cerebral infarction (ICI). A mouse model of ICI was generated by middle cerebral artery occlusion, resulting in elevated levels of NR3C2 and LCN2 in brain tissues. NR3C2 bound to the LCN2 promoter, thereby activating its transcription. Either knockdown of LCN2 or NR3C2 led to an improvement in neurologic deficits in mice, along with a reduction in infract size, tissue damage, ER stress, inflammation, and cell apoptosis in their brain tissues. Similar results were reproduced in HT22 cells, where LCN2 or NR3C2 knockdown alleviated oxygen-glucose deprivation-induced ER stress, inflammation, and cell apoptosis while improving cell viability. However, the protective effects of NR3C2 knockdown were counteracted when LCN2 was overexpressed, both in vitro and in vivo. Overall, this study demonstrates that NR3C2 activates LCN2 transcription, ultimately promoting ER stress and cell apoptosis in the context of ICI. [ABSTRACT FROM AUTHOR]