Biology subjects

Athar, F.

Publications and source records attributed to Athar, F..

7 recordsLinked to original sources

bioRxiv2026

A Biphasic Effect of Alcohol on Endothelial Plasticity Through Regulation of Endothelial-to-Mesenchymal Transition

BackgroundAlcohol consumption influences cardiovascular disease, but whether it does so by affecting endothelial plasticity is unknown. We tested whether alcohol regulates endothelial-to-mesenchymal transition (EndMT) to influence arterial pathology. MethodsHCAEC and HUVEC were exposed to inflammatory cytokines (TGF{beta} {+/-} IL1{beta}) or hypoxia in the presence of ethanol (0-100 mM). EndMT was assessed by changes in cell marker expression, SNAIL levels, and migration assays. In vivo, carotid ligation was performed in mice gavaged with/without either daily moderate ethanol (2-drink equivalent/d) or episodic binge exposure (7-drink equivalent, 2 days/week) and myo-endothelial cell population assessed. ResultsCytokines and hypoxia induced EndMT in vitro, characterized by loss of endothelial markers, increased mesenchymal markers, elevated SNAIL, and enhanced migratory capacity. Low-to-moderate dose ethanol (5-25 mM) attenuated these changes, preserving endothelial phenotype, whereas high dose ethanol (50-100 mM) either had no effect or exacerbated EndMT. The inhibitory effect of moderate ethanol on cytokine- and hypoxia-induced changes in SMA and Cdh5 expression was abrogated by {gamma}-secretase inhibition, consistent with involvement of Notch signaling. Carotid ligation induced neointimal formation and accumulation of myo-endothelial cells indicative of EndMT. Daily moderate ethanol significantly attenuated neointimal hyperplasia and diminished the myo-endothelial cell population, whereas in contrast, episodic binge ethanol exposure increased pathologic remodeling and myo-endothelial cell abundance. ConclusionsAlcohol modulates endothelial trans-differentiation in a biphasic manner. Low-to-moderate alcohol exposure suppresses EndMT and limits pathological remodeling, whereas binge-level exposure promotes these processes. These findings identify regulation of endothelial plasticity as a potential novel mechanism linking alcohol consumption patterns to vascular disease risk. NEW AND NOTEWORTHYWe identify a previously unrecognized biphasic effect of alcohol on endothelial phenotypic plasticity. Low-to-moderate dose alcohol suppresses endothelial-to-mesenchymal transition (EndMT), whereas high-level (binge) exposure promotes this pro-atherogenic process. Given the central role of EndMT in vascular remodelling and atherosclerosis, these findings provide a mechanistic framework linking alcohol consumption patterns and cardiovascular disease risk - potentially explaining both the protective effect at low/moderate levels, and the detrimental impact of heavy alcohol use. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/718463v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1febae2org.highwire.dtl.DTLVardef@9f5ff1org.highwire.dtl.DTLVardef@153ea69org.highwire.dtl.DTLVardef@42b1ed_HPS_FORMAT_FIGEXP M_FIG C_FIG Injurious stimuli can trigger endothelial cells (EC) to undergo endothelial-to-mesenchymal transition (EndMT) that contributes to arterial remodeling and disease. EndMT is regulated in a biphasic manner by alcohol with low-to-moderate levels (1-3 drink equivalent) suppressing EndMT and attenuating vascular remodeling, whereas higher level/binge exposure (7 drink equivalent) promotes these processes. Graphic created using Biorender.

cell biology↗

bioRxiv2026

Mutation of eat-2 in C. elegans is not a reliable model for dietary restriction studies

Dietary restriction (DR) extends lifespan in many animal species. In C. elegans, Eat mutants with pharyngeal defects that impair feeding exhibit reduced growth rate and fertility and are typically long-lived, suggesting a DR effect. We report that Eat mutant longevity is largely or wholly a consequence of suppression of feeding activity-dependent infection of the pharynx by their E. coli food source. eat-2 mutants, widely used as a DR model, were among only 2/8 Eat mutants tested whose longevity were to any degree independent of bacterial infection. Moreover, among Eat mutants, phenotypic indicators of reduced nutrition correlated with one another, yet not with longevity. These findings document how, if infection is excluded, Eat mutants experience reduced nutrition, but in most cases not longevity, i.e. life-extending DR effects are not typical of Eat mutants. Thus, eat-2 longevity is partially due to infection resistance rather than DR, and residual, pharyngeal infection-independent longevity (contributing [~]40% of the total increase in lifespan) could reflect DR, or alternatively some other consequence of their nicotinic acetylcholine receptor defect.

physiology↗

bioRxiv2026

Altered metabolic health during pregnancy in mice with lean polycystic ovary syndrome-like traits from high prenatal AMH

Polycystic ovary syndrome (PCOS) is a heterogenous reproductive disorder that is often associated with metabolic dysfunction, as well as comorbidities such as pregnancy complications. Although metabolic traits like hyperinsulinemia (i.e., elevated insulin without hypoglycemia) likely exacerbate the reproductive and metabolic features of PCOS, the precise impacts of specific metabolic traits on PCOS pathogenesis, symptom severity, and comorbidity incidence are not known. The aim of our study was to investigate the relationships between insulin levels, PCOS-like traits, and pregnancy complications by limiting endogenous insulin production in a mouse model of PCOS. Using Ins1-null mice with modulated Ins2 gene dosage (Ins1-/-:Ins2+/- versus Ins1-/-:Ins2+/+ littermates), we longitudinally assessed metabolic and reproductive phenotypes in PCOS-like mice generated via prenatal anti-Mullerian hormone (PAMH) exposure. We observed mild reproductive characteristics of PCOS in PAMH mice of both genotypes, including increased anogenital distances, delayed puberty, and disrupted estrous cycling, but did not detect robust PAMH-induced metabolic changes across six months. In the absence of PAMH-aggravated metabolic dysfunction or hyperinsulinemia--even in mice fed a high-fat, high-sucrose diet--reducing Ins2 gene dosage did not notably change most measured traits. However, high-fat, high-sucrose-fed PAMH pregnant dams exhibited a diminished pregnancy-induced insulinogenic response and a trend for reduced {beta}-cell mass compared to control mice, together with superior blood glucose homeostasis despite the physiological challenges of pregnancy. Therefore, while Ins1-null PAMH mice did not manifest pronounced PCOS-like metabolic features, prenatal AMH exposure can cause shifts in metabolic homeostasis during pregnancy.

physiology↗

bioRxiv2025

Lowering insulin mitigates female reproductive aging and diet-induced ovarian dysfunction

Hyperinsulinemia has consequences beyond metabolic dysfunction, including reproductive system effects. We found that hyperinsulinemia at age 46-47 was predictive of earlier menopause in the Study of Womens Health Across the Nation. To test causality between insulin levels and reproductive aging, we longitudinally evaluated chow- or high-fat, high-sucrose (HFHS)-fed Ins1-null female mice with full or partial Ins2 insulin gene expression. Ins1-/-;Ins2+/-mice had lower HFHS-induced hyperinsulinemia and less weight gain than their full-Ins2 littermates, despite comparable HFHS-induced glucose intolerance up to 9 months. By 15 months, Ins1-/-;Ins2+/+ ovaries showed multinucleated giant cell accumulation with HFHS, while Ins1-/-;Ins2+/- mice were protected against this response and maintained a higher reserve of follicles. Moreover, aged Ins1-/-;Ins2+/- mice were 9-fold more likely to conceive on HFHS than hyperinsulinemic Ins1-/-;Ins2+/+ mice. Elevated insulin is therefore a critical mechanistic link between metabolic dysfunction and reproductive aging, and curtailing insulin levels protects against subfertility and HFHS-induced ovarian decline.

physiology↗

bioRxiv2025

Glucose enrichment accelerates C. elegans reproductive aging via non-autonomous DAF-2/insulin-like receptor signaling in somatic tissues

Detrimental effects of chronic high-sugar overconsumption can extend from molecular and cellular responses to systemic changes. Reproductive systems are particularly sensitive to diet and energetic state, yet the long-term reproductive consequences of overnutrition are poorly defined. Here, we used Caenorhabditis elegans to study the impacts of glucose excess on reproductive aging. Glucose supplementation shortens C. elegans lifespan, and we found that it also hastens age-related reproductive decline, evidenced by a greater deterioration in oocyte quality and lower fertility with age. We next evaluated insulin-like signaling contributions, as this glucose-responsive pathway is well known to regulate both somatic aging and reproductive aging. Intriguingly, while 20 mM glucose enrichment still shortens the lifespan of daf-2(e1370) mutants, we found that it had no detrimental impact on their reproductive aging phenotypes. Using auxin-induced tissue-selective degradation, we discovered that DAF-2/insulin-like receptor signaling in C. elegans intestine and body wall musculature is required for glucose enrichment to exert damaging impacts on the reproductive system. However, suppressing insulin-like signaling in either of these tissues is sufficient to protect C. elegans against glucose-induced reproductive aging. These findings suggest that insulin-like signalling in metabolically active somatic tissues may represent a key link between overnutrition and reproductive aging.

physiology↗

bioRxiv2024

D1 is a novel enhancer blocker protein that functions via multiple AT-rich simple sequence repeats

Simple sequence repeats (SSRs) are tandem repetitions of 1-6 bp DNA motifs at least 12 bp long. Certain length-enriched SSRs function as enhancers/silencers, enhancer blockers and barriers in a mammalian cell line. However, whether SSRs have similar cis-regulatory functions in vivo and their underlying mechanisms are unknown. To address this, we looked for SSR-binding proteins and investigated if SSRs function as enhancer blockers in vivo. We developed a novel Drosophila assay to assess enhancer blocker activity in vivo and to circumvent the low throughput and position effects seen in traditional enhancer blocker assays. Our assay uses endogenous vestigial gene enhancers, which, when blocked, result in easily scorable wing phenotypes increasing throughput. The attP-attB-based recombination system to integrate test fragments at specific site avoids positional effects. Furthermore, using EMSAs and DNA pull-downs followed by LC-MS/MS, we show that SSRs bind to proteins in a sequence-specific manner and identify 33 unique SSR-binding proteins. One of these proteins, D1, was enriched in several SSRs, viz., AAT14, AAAT10, AAAAT8, AATAT9, AAAG13 and AAAAG11. Using our novel vestigial in vivo enhancer blocker assay, we show for the first time that AT-rich SSRs function as enhancer blockers in a D1-dependent manner in Drosophila.

molecular biology↗

bioRxiv2024

Limited Cell-Autonomous Anticancer Mechanisms in Long-Lived Bats

Bats are remarkably long-lived for their size with many species living more than 20-40 years, suggesting that they possess efficient anti-aging and anti-cancer defenses. Here we investigated requirements for malignant transformation in primary bat fibroblasts in four bat species - little brown bat (Myotis lucifugus), big brown bat (Eptesicus fuscus), cave nectar bat (Eonycteris spelaea) and Jamaican fruit bat (Artibeus jamaicensis) - spanning the bat evolutionary tree and including the longest-lived genera. We show that bat fibroblasts do not undergo replicative senescence and express active telomerase. Bat cells displayed attenuated stress induced premature senescence with a dampened secretory phenotype. Unexpectedly, we discovered that bat cells could be readily transformed by only two oncogenic perturbations or "hits": inactivation of either p53 or pRb and activation of oncogenic RASV12. This was surprising because other long-lived mammalian species require up to five hits for malignant transformation. Additionally, bat fibroblasts exhibited increased p53 and MDM2 transcript levels, and elevated p53-dependent apoptosis. The little brown bat showed a genomic duplication of the p53 gene. We hypothesize that bats evolved enhanced p53 activity through gene duplications and transcriptional upregulation as an additional anti-cancer strategy, similar to elephants. In summary, active telomerase and the small number of oncogenic hits sufficient to malignantly transform bat cells suggest that in vivo bats rely heavily on non-cell autonomous mechanisms of tumor suppression.

cell biology↗