Molecular and Cellular Endocrinology最新文献

Angiotensin II (Ang II) is a protein hormone capable of physiologically regulating blood pressure through diverse mechanisms. Ang II is mainly produced by the liver at homeostatic levels. However, excessive production of Ang II is closely associated with a series of pathological events in the body. The endothelial dysfunction is one of these pathological events that can drive vascular anomalies. The excessive exposure of endothelial cells (ECs) to Ang II may induce endothelial dysfunction via diverse mechanisms. One of these mechanisms is Ang II-mediated mitochondrial oxidative stress. In this mini-review, we aimed to discuss the molecular mechanisms of Ang II-mediated endothelial dysfunction through mitochondrial oxidative stress and the protective role of nitric oxide in ECs. Deciphering these mechanisms may disclose novel therapeutic strategies to prevent endothelial dysfunction and associated diseases induced by elevated leves of Ang II in the blood.

Ovarian cancer (OC) adjusts energy metabolism in favor of its progression and dissemination. Because melatonin (Mel) has antitumor actions, we investigated its impact on energy metabolism and kinase signaling in OC cells (SKOV-3 and CAISMOV-24). Cells were divided into control and Mel-treated groups, in the presence or absence of the antagonist luzindole. There was a decrease in the levels of HIF-1α, G6PDH, GAPDH, PDH, and CS after Mel treatment even in the presence of luzindole in both OC cells. Mel treatment also reduced the activity of OC-related enzymes including PFK-1, G6PDH, LDH, CS, and GS whereas PDH activity was increased. Lactate and glutamine levels dropped after Mel treatment. Mel further promoted a reduction in the concentrations of CREB, JNK, NF-kB, p-38, ERK1/2, AKT, P70S6K, and STAT in both cell lines. Mel reverses Warburg-type metabolism and possibly reduces glutaminolysis, thereby attenuating various oncogenic molecules associated with OC progression and invasion.

Context

Adrenarche is a normal developmental event in mid-childhood characterized by increasing adrenal androgen secretion. The role of the classic androgen pathway has been well described in adrenarche, but the role of newer active androgens and additional androgen pathways is less clear.

Objective

To study the contribution of novel androgens and related steroid biosynthesis pathways to the development of adrenarche, and to identify additional steroid biomarkers of adrenarche.

Design

A longitudinal study of children aged 6–8 years at baseline, followed up at ages 8–10 and 14–16 years. A total of 34 children (20 girls) with clinical and/or biochemical signs of adrenarche (cases) and 24 children (11 girls) without these signs (controls) at age 8–10 years were included. Serum steroid profiling was performed by liquid chromatography high-resolution mass spectrometry.

Main outcome measures

Thirty-two steroids compartmentalized in progestagens, gluco- and mineralocorticoid pathways, and four androgen related pathways, including the classic, backdoor, 11-oxy, and 11-oxy backdoor pathways.

Results

The classic and 11-oxy androgen pathways were more active, and serum concentrations of main androgens in the classic (dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione and androsterone) and 11-oxy (11β-hydroxyandrostenedione, 11β-hydroxytestosterone, 11-ketoandrostenedione, and 11-ketotestosterone) pathways were higher in cases at ages 6–8 and 8–10 years. Pregnenolone concentrations at adrenarchal age (8–10 years) and cortisol concentrations at adolescence (14–16 years) were higher in cases. 11β-hydroxyandrosterone and 11-ketoandrosterone tended to be higher in cases with clinical signs compared to cases who had only biochemical evidence of adrenarche, albeit they were detected at low levels. In biomarker analyses, calculated steroid ratios with cortisol, cortisone, or 11-deoxycortisone as dividers were better classifiers for adrenarche than single steroids. Among these ratios, androstenedione/cortisone was the best.

Conclusions

The classic and 11-oxy androgen pathways are active in adrenarche. Children with earlier timing of adrenarche have higher serum cortisol levels at late pubertal age, suggesting that early adrenarche might have long-term effects on adrenal steroidogenesis by increasing the activity of the glucocorticoid pathway. Future studies should employ comprehensive steroid profiling to define novel classifiers and biomarkers for adrenarche and premature adrenarche.

The aim of the present research was to explore the mechanisms underlying the role of dopamine in the regulation of insulin secretion in beta cells. The effect of dopamine on insulin secretion was investigated on INS 832/13 cell line upon glucose and other secretagogues stimulation. Results show that dopamine significantly inhibits insulin secretion stimulated by both glucose and other secretagogues, while it has no effect on the basal secretion. This effect requires the presence of dopamine during incubation with the various secretagogues. Both electron microscopy and immunohistochemistry indicate that in beta cells the D₂ dopamine receptor is localized within the insulin granules. Blocking dopamine entry into the insulin granules by inhibiting the VMAT2 transporter with tetrabenazine causes a significant increase in ROS production. Our results confirm that dopamine plays an important role in the regulation of insulin secretion by pancreatic beta cells through a regulated and precise compartmentalization mechanisms.

Research question

Granulosa cells (GCs) dysfunction plays a crucial role in the pathogenesis of polycystic ovary syndrome (PCOS). It is reported that YTH domain-containing family protein 2 (YTHDF2) is upregulated in mural GCs of PCOS patients. What effect does the differential expression of YTHDF2 have in PCOS patients?

Design

Mural GCs and cumulus GCs from 15 patients with PCOS and 15 ovulatory controls and 4 cases of pathological sections in each group were collected. Real-time PCR, Western Blot, immunohistochemistry, and immunofluorescence experiments were conducted to detect gene and protein expression. RNA immunoprecipitation assay was performed to evaluate the binding relationship between YTHDF2 and MSS51. Mitochondrial morphology, cellular ATP and ROS levels and glycolysis-related gene expression were detected after YTHDF2 overexpression or MSS51 inhibition.

Results

In the present study, we found that YTHDF2 was upregulated in GCs of PCOS patients while MSS51 was downregulated. YTHDF2 protein can bind to MSS51 mRNA and affect MSS51 expression. The reduction of MSS51 expression or the increase in YTHDF2 expression can lead to mitochondrial damage, reduced ATP levels, increased ROS levels and reduced expression of LDHA, PFKP and PKM.

Conclusions

YTHDF2 may regulate the expression of MSS51, affecting the structure and function of mitochondria in GCs and interfering with cellular glycolysis, which may disturb the normal biological processes of GCs and follicle development in PCOS patients.

Endometriosis is an estrogen-dependent and progesterone-resistant gynecological inflammatory disease of reproductive-age women. Progesterone resistance, loss of progesterone receptor -B (PR-B) in the stromal cells of the endometrium, is one of the hallmarks of endometriosis and a major contributing factor for infertility in endometriosis patients. Loss of PR-B in the stromal cells of the endometriotic lesions poses resistance to the success of progesterone-based therapy. The working hypothesis is that PR-B is hypermethylated and epigenetically silenced, and inhibition of AKT and ERK1/2 pathways will decrease the hypermethylation, reverse the epigenetic silencing, and restore the expression of PR-B via DNA methylation and histone modification mechanisms in the endometriotic lesions. The objectives are to (i) determine the effects of dual inhibition of AKT and ERK1/2 pathways on the expression of PR-B and DNA methylation and histone modification protein machinery in the endometriotic lesions and (ii) identify the underlying epigenetic mechanisms of PR-B restoration in the endometriotic lesions. The results indicate that dual inhibition of AKT and ERK1/2 pathways decreases the hypermethylation, reverses the epigenetic silencing, and restores the expression of PR-B via DNA methylation and H3K9 and H3K27 methylation mechanisms in the endometriotic lesions or endometriotic stromal cells of human origin. These results support the novel concept that restored expression of PR-B in the endometriotic lesions and endometrium may improve the clinical outcome of progesterone therapy in endometriosis patients.

Adipose tissue macrophages (ATMs) are key players in the development of obesity and associated metabolic inflammation, which contributes to systemic metabolic dysfunction, and understanding the interaction between macrophages and adipocytes is crucial for developing novel macrophage-based strategies against obesity. Here, we found that Legumain (Lgmn), a well-known lysosomal cysteine protease, is expressed mainly in the ATMs of obese mice. To further define the potential role of Lgmn-expressing macrophages in the generation of an aberrant metabolic state, Lgmn^F/F; LysM^Cre mice, which do not express Lgmn in macrophages, were maintained on a high-fat diet (HFD), and metabolic parameters were assessed. Macrophage-specific Lgmn deficiency protects mice against HFD-induced obesity, diminishes the quantity of proinflammatory macrophages in obese adipose tissues, and alleviates hepatic steatosis and insulin resistance. By analysing the transcriptome and proteome of murine visceral white adipose tissue (vWAT) after HFD feeding, we determined that macrophage Lgmn deficiency causes changes in lipid metabolism and the inflammatory response. Furthermore, the reciprocity of macrophage-derived Lgmn with integrin α5β1 in adipocytes was tested via colocalization analyses. It is further demonstrated in macrophage and adipocyte coculture system that macrophage derived Lgmn bound to integrin α5β1 in adipocytes, therefore attenuating PKA activation, downregulating lipolysis-related proteins and eventually exacerbating obesity development. Overall, our study identified Lgmn as a previously unrecognized regulator involved in the interaction between ATMs and adipocytes contributing to diet-induced obesity and suggested that Lgmn is a potential target for treating metabolic disorders.

Understanding the effects of psychosocial stress on serum cholesterol may offer valuable insights into the relationship between psychological disorders and endocrine diseases. However, these effects and their underlying mechanisms have not been elucidated yet. Here we show that serum corticosterone, total cholesterol and low-density lipoprotein cholesterol (LDL-C) are elevated in a mouse model of psychosocial stress. Furthermore, alterations occur in AdipoR2-mediated AMPK and PPARα signaling pathways in liver, accompanied by a decrease in LDL-C clearance and an increase in cholesterol synthesis. These changes are further verified in wild-type and AdipoR2 overexpression HepG2 cells incubated with cortisol and AdipoR agonist, and are finally confirmed by treating wild-type and hepatic-specific AdipoR2 overexpression mice with corticosterone. We conclude that increased glucocorticoid mediates the effects of psychosocial stress to elevate serum cholesterol by inhibiting AdipoR2-mediated AMPK and PPARα signaling to decrease LDL-C clearance and increase cholesterol synthesis in liver.