Search

Metformin, an antidiabetic drug, has recently been repositioned in the treatment of several nondiabetic disorders, including reproductive disorders such as polycystic ovarian syndrome, where it improves endometrial functions. In vitro studies employing supratherapeutic concentrations (5-20 mmol/L) of metformin have reported antiproliferative effects on endometrial epithelial and stromal cells. However, animal and human studies have revealed that therapeutic serum concentrations of metformin range between 20 and 70 [micro]mol/L. In the present study, the effect of therapeutic concentrations of metformin was studied on endometrial epithelial cells (EECs). Therapeutic concentrations of metformin induced proliferation in Ishikawa and HEC-1A cells. The proliferation of EECs was found to be mammalian target of rapamycin (mTOR) dependent. Interestingly, therapeutic metformin concentrations were not able to activate the classical AMP-activated protein kinase (AMPK) signaling. On the contrary, supratherapeutic metformin concentration (10 mmol/L) inhibited mTOR and activated AMPK signaling. Microarray analysis of metformin-treated HEC-1A cells revealed dose-dependent differential effects on biological pathways associated with translation, ribosomal RNA processing, mitochondrial translation, and cell proliferation. Therapeutic concentrations of metformin upregulated mitochondrial number as demonstrated by increased MitoTracker[TM] Red staining and enhanced succinate dehydrogenase expression; however, higher concentration (10 mmol/L) abrogated the same. Our results suggest that therapeutic concentrations of metformin augment mitochondrial strength and induce mTOR-dependent endometrial cell proliferation. Key words: metformin, endometrium, proliferation, microarray, mitochondria, Introduction Metformin, primarily an antidiabetic drug, has been repositioned for various other nondiabetic purposes in recent years. Metformin, which was discovered initially to treat type 2 diabetes, has been shown [...]

Pulmonary arterial hypertension (PAH) is characterized by abnormal outgrowth of pulmonary artery smooth muscle cells (PASMCs) of the media. Abundant expression of endothelin-1 (ET-1) and activated p38 mitogen-activated protein kinase (p38MAPK) has been observed in PAH patients. p38MAPK has been implicated in cell proliferation. An unspecified disturbance in bone morphogenetic protein (BMP) signaling may be involved in the development of PAH. Type I receptors (BMPR1A and BMPR1B) and type II receptor (BMPR2) transduce signals via two distinct pathways, i.e., canonical and non-canonical pathways, activating Smad1/5/8 and p38MAPK, respectively. BMPR1B expression was previously reported to be enhanced in the PASMCs of patients with idiopathic PAH. BMP15 binds specifically to BMPR1B. We assessed the effects of ET-1 on BMP receptor expression and cell proliferation. BMP2 increased BMPR1B expression in human PASMCs after pretreatment with ET-1 in vitro. Although BMP2 alone did not affect PASMC proliferation, BMP2 treatment after ET-1 pretreatment significantly accelerated PASMC proliferation. PH-797804, a selective p38MAPK inhibitor, abrogated this proliferation. Similarly, after ET-1 pretreatment, BMP15 significantly accelerated the proliferation of PASMCs, whereas stimulation with BMP15 alone did not. In conclusion, in PASMCs, ET-1 exposure under pathological conditions alters BMP signaling to activate p38MAPK, resulting in cell proliferation. Key words: BMPR1B, BMP15, endothelin, p38MAPK, pulmonary artery smooth muscle cells L'hypertension arterielle pulmonaire (HAP) se caracterise par l'excroissance anormale de cellules musculaires lisses de la media de l'artere pulmonaire (CMLAP). On a observe une expression de l'endotheline 1 (ET-1) et de la MAPKp38 (pour << p38 mitogen-activated protein kinase >>) abondante chez les patients atteints d'HAP. La MAPKp38 a ete mise en cause dans la proliferation cellulaire. Des perturbations non specifiees de la voie de signalisation de la BMP (pour << bone morphogenetic protein >>) pourraient jouer un role dans l'apparition de l'HAP. Les recepteurs de type I (BMPR1A et BMPR1B) et de type II (BMPR2) permettent la transduction du signal par l'intermediaire de deux voies de signalisation distinctes : canonique et non canonique, activant la Smad1/5/8 et la MAPKp38, respectivement. On a rapporte precedemment que l'expression des BMPR1B est amplifiee dans les CMLAP de patients atteints d'HAP idiopathique. La BMP15 se lie au BMPR1B de maniere specifique. Nous avons evalue l'effet de l'ET-1 sur l'expression des recepteurs du BMP et la proliferation des cellules. Avec l'administration prealable d'ET-1 in vitro, le BMP2 entrainait une augmentation de l'expression des BMPR1B dans les CMLAP humaines. Meme si le BMP2 seul n'a pas affecte la proliferation des CMLAP, l'administration d'ET-1 prealablement a celle du BMP2 entrainait une acceleration marquee de la proliferation des CMLAP. Le PH-797804, un inhibiteur selectif de la MAPKp38, permettait d'abolir cette proliferation. De maniere analogue, l'administration d'ET-1 prealablement a celle du BMP15 entrainait une acceleration marquee de la proliferation des CMLAP, mais pas la stimulation a l'aide de BMP15 seul. En conclusion, dans les CMLAP, l'exposition a l'ET-1 en situation pathologique entraine des perturbations dans la voie de signalisation de BMP pour activer la MAPKp38, ce qui entraine une proliferation cellulaire. [Traduit par la Redaction] Mots-cles : BMPR1B, BMP15; endotheline, MAPKp38, cellules musculaires lisses d'artere pulmonaire, Introduction Pulmonary arterial hypertension (PAH) is a progressive disease that presents as persistently elevated pulmonary vascular resistance and increased pulmonary arterial pressure (Frazier and Burke 2012). Only limited treatments for [...]

Ghrelin exerts key effects on islet hormone secretion to regulate blood glucose levels. Here, we sought to determine whether ghrelin's effects on islets extend to the alteration of islet size and [beta] cell mass. We demonstrate that reducing ghrelin - by ghrelin gene knockout (GKO), conditional ghrelin cell ablation, or high-fat diet (HFD) feeding - was associated with increased mean islet size (up to 62%), percentage of large islets (up to 854%), and [beta] cell cross-sectional area (up to 51%). In GKO mice, these effects were more apparent in 10- to 12-week-old mice than in 4-week-old mice. Higher [beta] cell numbers from decreased [beta] cell apoptosis drove the increase in [beta] cell cross-sectional area. Conditional ghrelin cell ablation in adult mice increased the [beta] cell number per islet by 40% within 4 weeks. A negative correlation between islet size and plasma ghrelin in HFD-fed plus chow-fed WT mice, together with even larger islet sizes in HFD-fed GKO mice than in HFD-fed WT mice, suggests that reduced ghrelin was not solely responsible for diet-induced obesity-associated islet enlargement. Single-cell transcriptomics revealed changes in gene expression in several GKO islet cell types, including upregulation of Manf, Dnajc3, and Gnas expression in [beta] cells, which supports decreased [beta] cell apoptosis and/or increased [beta] cell proliferation. These effects of ghrelin reduction on islet morphology might prove useful when designing new therapies for diabetes., Introduction Ghrelin is secreted primarily by gastric ghrelin cells (1). It is mainly via binding to CNS and pituitary growth hormone secretagogue receptors (GHSRs) that ghrelin's actions to increase GH [...]

* Context.--A number of fibro-osseous and osteocartilaginous lesions, especially common in the small bones of the hand and feet, pose a diagnostic challenge and have historically been thought to be reactive lesions. However, modern molecular techniques when supplementing clinical, radiographic, and histologic evaluation suggest they may, in fact, be neoplasms. Objective.--To review the clinical presentation and histopathologic, molecular, and radiologic features of selective bone lesions, focusing most specifically on subungual exostosis, florid reactive periostitis, and bizarre periosteal osteochondromatous proliferation. Data Sources.--Literature review and personal experience are the sources of this review. Conclusions.--Some lesions previously thought to be reactive are locally aggressive and demonstrate reproducible molecular abnormalities, and thus may be neoplasms. Although most common in the bones of the fingers and toes, these lesions also occur in long and other bones. The clinical presentations, radiologic appearances, and histopathologic features often overlap, making the diagnosis challenging, and these lesions may require molecular evaluation to maximize accurate prognostication., Subungual exostosis (SE), florid reactive periostitis (FRP), and bizarre parosteal osteochondromatous proliferation (BPOP) are benign lesions that commonly arise from the small trabecular bones of the hands and feet in [...]