Biology subjects

Ferrero, H.

Publications and source records attributed to Ferrero, H..

4 recordsLinked to original sources

bioRxiv2025

Vitamin D3 ameliorates R-loop-induced replication stress and chromosomal instability in MED12-mutant uterine fibroids

Uterine fibroids (UFs) are the most important benign neoplastic threat to womens health worldwide, with no long-term noninvasive treatment options currently available. Among known UF driver alterations, somatic mutations in Mediator subunit MED12 are by the far the most prevalent, accounting for up to 80% of these clinically significant lesions. Although it is presently unclear how MED12 mutations trigger neoplastic transformation, MED12-mutant UFs are nonetheless characterized by significant chromosomal loss and rearrangement, suggesting genomic instability as a driving force in tumor development. However, the basis by which MED12 mutations drive genomic instability is not known. Herein, we show that R-loop-driven replication stress in MED12-mutant UFs leads to DNA under-replication and mitotic segregation errors that drive chromosomal instability. Notably, we find that vitamin D3 (VD3), a modifiable risk factor in UF development, suppresses pathogenic R-loop accrual and ameliorates replication stress-driven chromosomal instability, contributing to growth inhibition of patient-derived MED12-mutant UF xenografts in vivo. Altogether these findings uncover a molecular basis by which the predominant UF driver converges with a known risk factor at the interface of genomic instability, with significant translational implications for personalized UF prevention and treatment.

molecular biology↗

bioRxiv2025

Increased TGFβ /Activin-Smad2 signaling is associated with pancreatic β-cell dysfunction and glucose intolerance in gestational diabetes mellitus

BackgroundGestational diabetes mellitus (GDM) is the most common metabolic disease during pregnancy and increases the prevalence of type 2 diabetes in both mothers and offspring. GDM management provides a window of opportunity to prevent and lower the global burden of diabetes across life. Molecular mechanisms underlying GDM are poorly defined. In this study, we explore the potential involvement of transforming growth factor beta (TGF-{beta}) signaling in GDM as this pathway has been reported to affect pancreatic {beta}-cell development, proliferation and identity. MethodsWe developed a GDM animal model. Serum circulating levels of TGF{beta} family ligands were measured in mice and human GDM. Pancreatic TGF{beta} signaling was investigated at the level of gene and protein expression. ResultsOur GDM animal model recapitulates the main pathophysiological features of human GDM including glucose intolerance, decreased insulin sensitivity and pancreatic {beta}-cell malfunction. Islets from GDM mice showed impaired insulin secretion and content, altered ion channel activity, and decreased {beta}-cell replication rate. This was accompanied by increased Smad2 signaling activation. Elevated serum activin-A and inhibin levels were found in mice and human GDM, suggesting their role as upstream signaling transducers of pancreatic Smad2 activation. Pharmacological inhibition of TGF{beta}/Activin-Smad2 signaling in mouse pancreatic islets resulted in improved pancreatic {beta}-cell function and regeneration capacity of {beta}-cells. ConclusionsOur data disclose that disruption of pancreatic Smad2 pathway plays a critical role in the pathogenesis of GDM, contributing to abnormal glucose homeostasis and inadequate insulin secretion. Attenuation of this signaling pathway could represent a putative therapeutic target for GDM. HighlightsO_LIHigh fat diet just before and during pregnancy leads to gestational diabetes in mice. C_LIO_LIActivin and inhibin serum levels are increased in human and mice gestational diabetes. C_LIO_LIEnhanced pancreatic Smad2 signaling contributes to inadequate insulin secretion in gestational diabetes. C_LIO_LIInhibition of Smad2 signaling improves pancreatic {beta}-cell function and proliferation. C_LI

physiology↗

bioRxiv2022

EXPLORING THE EFFECTS OF METABOLISM-DISRUPTING CHEMICALS ON PANCREATIC alpha-CELL BIOLOGY: A SCREENING TESTING APPROACH

Humans are constantly exposed to many environmental pollutants, some of which have been largely acknowledged as key factors in the development of metabolic disorders such as diabetes and obesity. These chemicals have been classified as endocrine-disrupting chemicals (EDCs) and, more recently, since they can interfere with metabolic functions, they have been renamed as metabolism-disrupting chemicals (MDCs). MDCs are present in many consumer products, including food packaging, personal care products, plastic bottles and containers, and detergents. The scientific literature has ever-increasingly focused on insulin-releasing pancreatic {beta}-cells as one of the main targets for MDCs. Evidence highlights that these substances may disrupt glucose homeostasis, altering pancreatic {beta}-cell physiology. However, their potential impact on glucagon-secreting pancreatic -cells remains poorly known despite the essential role that this cellular type plays in controlling glucose metabolism. In the present study, we have selected seven paradigmatic EDCs representing major toxic classes, including bisphenols, phthalates, perfluorinated compounds, metals, and pesticides. By using an in vitro cell-based model, the pancreatic -cell line TC1-9, we have explored the effects of these compounds on pancreatic -cell viability, gene expression, and secretion. Our results indicated that most of the selected chemicals studied caused functional alterations in pancreatic -cells. Moreover, we revealed, for the first time, their direct effects on key molecular aspects of pancreatic -cell biology.

pharmacology and toxicology↗

bioRxiv2022

SCREENING OF RELEVANT METABOLISM-DISRUPTING CHEMICALS ON PANCREATIC β-CELLS: EVALUATION OF MURINE AND HUMAN IN VITRO MODELS

Endocrine-disrupting chemicals (EDCs) are chemical substances that can interfere with the normal function of the endocrine system. EDCs are ubiquitous and can be found in a variety of consumer products such as food packaging materials, personal care and household products, plastic additives, and flame retardants. Over the last decade, the impact of EDCs on human health has been widely acknowledged as they have been associated with different endocrine diseases. Among them, a subset called metabolism-disrupting chemicals (MDCs) are able to promote metabolic changes that can lead to the development of metabolic disorders such as diabetes, obesity, hepatic steatosis, and metabolic syndrome, among others. Despite this, today, there are still no definitive and standardized in vitro tools to support the metabolic risk assessment of existing and emerging MDCs for regulatory purposes. Here, we evaluated two different pancreatic cell-based in vitro systems, the murine pancreatic {beta}-cell line MIN6 as well as the human pancreatic {beta}-cell line EndoC- {beta}H1. Both were challenged with a range of relevant concentrations of seven well-known EDCs (bisphenol-A (BPA), bisphenol-S (BPS), bisphenol-F (BPF), perfluorooctanesulfonic acid (PFOS), di(2-ethylhexyl) phthalate (DEHP), cadmium chloride (CdCl2) and dichlorodiphenyldichloroethylene (DDE)). The screening revealed that most of the tested chemicals have detectable deleterious effects on glucose-stimulated insulin release, insulin content, electrical activity, gene expression, and/or viability. Our data provide new molecular information on the direct effects of the selected chemicals on key aspects of pancreatic {beta}-cell function such as the stimulus-secretion coupling and ion channel activity. In addition, we found that, in general, the sensitivity and responses were comparable to those from other in vivo studies reported in the literature. Overall, our results suggest that both systems can serve as effective tools for rapid screening of potential MDC effects on pancreatic {beta}-cell physiology as well for deciphering and better understanding the molecular mechanisms that underlie their action.

pharmacology and toxicology↗