Biology subjects

Medina, D.

Publications and source records attributed to Medina, D..

7 recordsLinked to original sources

bioRxiv2025

Late-Onset Preeclampsia is characterised by Accelerated Placental Aging

Late-onset preeclampsia (LOPE) is a major pregnancy complication characterised by hypertension and placental dysfunction, resolving only upon delivery. Here, we show that LOPE placentae undergo accelerated molecular aging, marked by telomere attrition, DNA damage and trophoblast senescence. Using primary placental tissue and trophoblast organoids, we demonstrate oxidative stress as a driver of telomere shortening and angiogenic imbalance. Inflammation did not alter placental aging trajectories. Antioxidant treatment (superoxide dismutase) preserved telomere length, reduced DNA damage and restored angiogenic balance, highlighting oxidative stress as a modifiable determinant of placental aging. We identify reduced expression of telomeric repeat-containing RNAs (TERRAs) as a molecular hallmark of LOPE, and show that antisense oligonucleotide-mediated TERRA depletion exacerbates telomere erosion and senescence. Together, these findings delineate oxidative stress and TERRA loss as mechanisms driving placental decline, establish trophoblast organoids as a tractable model of placental aging, and reveal potential therapeutic avenues for mitigating preeclampsia-associated placental dysfunction.

developmental biology↗

bioRxiv2023

Senolytic Intervention Improves Cognition, Metabolism, and Adiposity in Female APPNL-F/NL-F Mice.

Senescent cells accumulate throughout the body and brain contributing to unhealthy aging and Alzheimers disease (AD). The APPNL-F/NL-F amyloidogenic AD mouse model exhibits increased markers of senescent cells and the senescence-associated secretory phenotype (SASP) in visceral white adipose tissue before plaque accumulation and cognitive decline. We hypothesized that senolytic intervention would alleviate cellular senescence thereby improving spatial memory in APPNL-F/NL-F mice. Thus, four month old male and female APPNL-F/NL-F mice were treated monthly with vehicle, 5 mg/kg Dasatinib + 50 mg/kg Quercetin, or 100 mg/kg Fisetin. Blood glucose levels, energy metabolism, spatial memory, amyloid burden, and senescent cell markers were assayed. Dasatinib + Quercetin treatment in female APPNL-F/NL-F mice increased oxygen consumption and energy expenditure resulting in decreased body mass. White adipose tissue mass was decreased along with senescence markers, SASP, blood glucose, and plasma insulin and triglycerides. Hippocampal senescence markers and SASP were reduced along with soluble and insoluble amyloid-{beta} (A{beta})42 and senescence associated-{beta}-gal activity leading to improved spatial memory. Fisetin had negligible effects on these measures in female APPNL-F/NL-F mice while neither senolytic intervention altered these parameters in the male mice. Considering women have a greater risk of dementia, identifying senotherapeutics appropriate for sex and disease stage is necessary for personalized medicine.

neuroscience↗

bioRxiv2022

Coinfection with chytrid genotypes drives divergent infection dynamics reflecting broad epidemiological patterns

By altering the abundance, diversity, and distribution of species -- and their pathogens -- globalization may inadvertently select for more virulent pathogens. In Brazils Atlantic Forest, a hotspot of amphibian biodiversity, the pet trade has facilitated the co-occurrence of previously isolated enzootic and panzootic lineages of the pathogenic amphibian-chytrid ( Bd) and generated new virulent recombinant genotypes ( hybrid). Epidemiological data indicate that amphibian declines are most severe in hybrid zones, suggesting that coinfections are causing more severe infections or selecting for higher virulence. We investigated how coinfections involving these genotypes shaped virulence and transmission. Overall, coinfection favored the more virulent and competitively superior panzootic genotype, despite dampening its virulence and transmission. However, for the least virulent and least competitive genotype, coinfection increased both pathogen virulence and transmission. Thus, by integrating experimental and epidemiological data, our results provide mechanistic insight into how globalization can select for, and propel, the emergence of introduced hypervirulent lineages, such as the globally distributed panzootic lineage of Bd.

ecology↗

bioRxiv2021

Sexual dimorphic responses of C57BL/6 mice to Fisetin or Dasatinib and Quercetin cocktail oral treatment

Senolytic treatment in aged mice clears senescent cell burden leading to functional improvements. However, less is known regarding the effects of these compounds when administered prior to significant senescent cell accumulation. From 4-13 months of age, C57BL/6 male and female mice received monthly oral dosing of either 100 mg/kg Fisetin or a 5 mg/kg Dasatinib (D) plus 50 mg/kg Quercetin (Q) cocktail. During treatment, several aspects of healthy aging were assayed including glucose metabolism using an insulin and glucose tolerance test, cognitive performance using Morris water maze and novel object recognition, and energy metabolism using indirect calorimetry. Afterwards, mice were euthanized for plasma and tissue specific markers of senescence-associated secretory phenotype (SASP) and white adipose tissue accumulation (WAT). Sexually dimorphic treatment effects were observed. Fisetin treated male mice had reduced SASP, enhanced glucose and energy metabolism, improved cognitive performance, and increased mRNA expression of adiponectin receptor 1 and glucose transporter 4. D+Q treatment had minimal effects in male C57BL/6 mice, but was detrimental to females causing increased SASP expression along with accumulation of WAT depots. Reduced energy metabolism and cognitive performance were also noted. Fisetin treatment had no effect in female C57BL/6 mice potentially due to a slower rate of biological aging. In summary, the senolytic treatment in young adulthood, has beneficial, negligible, or detrimental effects in C57BL/6 mice dependent upon sex and treatment. These observations should serve as a note of caution in this rapidly evolving and expanding field of investigation. Graphical AbstractMale and female C57BL/6 mice were treated with once monthly oral doses of either Dasatinib (D) + Quercetin (Q) or Fisetin from 4-13 months of age. Females treated with D+Q had increased adiposity and SASP markers (red spheres) along with decreased metabolism (blue flame) and cognitive performance. Males treated with Fisetin had reduced SASP markers (blue spheres) as well as improved metabolism (red flame) and cognition. No effects were observed in females treated with Fisetin or males treated with D+Q. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/467509v2_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@1d7f450org.highwire.dtl.DTLVardef@e8b32forg.highwire.dtl.DTLVardef@14be597org.highwire.dtl.DTLVardef@1ce31af_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2019

Neuro-genetic plasticity of Caenorhabditis elegans behavioral thermal tolerance

BackgroundAnimal responses to thermal stimuli involve intricate contributions of genetics, neurobiology and physiology, with temperature variation providing a pervasive environmental factor for natural selection. Thermal behavior thus exemplifies a dynamic trait that requires non-trivial phenotypic summaries to appropriately capture the trait in response to a changing environment. To characterize the deterministic and plastic components of thermal responses, we developed a novel micro-droplet assay of nematode behavior that permits information-dense summaries of dynamic behavioral phenotypes as reaction norms in response to increasing temperature (thermal tolerance curves, TTC).\n\nResultsWe found that C. elegans TTCs shift predictably with rearing conditions and developmental stage, with significant differences between distinct wildtype genetic backgrounds. Moreover, after screening TTCs for 58 C. elegans genetic mutant strains, we determined that genes affecting thermosensation, including cmk-1 and tax-4, potentially play important roles in the behavioral control of locomotion at high temperature, implicating neural decision-making in TTC shape rather than just generalized physiological limits. However, expression of the transient receptor potential ion channel TRPA-1 in the nervous system is not sufficient to rescue rearing-dependent plasticity in TTCs conferred by normal expression of this gene, indicating instead a role for intestinal signaling involving TRPA-1 in the adaptive plasticity of thermal performance.\n\nConclusionsThese results implicate nervous system and non-nervous system contributions to behavior, in addition to basic cellular physiology, as key mediators of evolutionary responses to selection from temperature variation in nature.

genetics↗

bioRxiv2019

Synthetic lethality screening reveals FDA-approved drugs that overcome ATP7B-mediated tolerance of tumor cells to cisplatin

Tumor resistance to chemotherapy represents an important challenge in modern oncology. Although platinum (Pt)-based drugs have demonstrated excellent therapeutic potential, their effectiveness in a wide range of tumors is limited by the development of resistance mechanisms. One of these mechanisms includes increased cisplatin sequestration/efflux by the copper-transporting ATPase, ATP7B. However, targeting ATP7B to reduce Pt tolerance in tumors could represent a serious risk because suppression of ATP7B might compromise copper homeostasis, as happens in Wilson disease.\n\nTo circumvent ATP7B-mediated Pt tolerance we employed a high-throughput screen (HTS) of an FDA/EMA-approved drug library to detect safe therapeutic molecules that promote cisplatin toxicity in the resistant ovarian carcinoma cell line IGROV-CP20. Using a synthetic lethality approach we identified and validated three hits (Tranilast, Telmisartan and Amphotericin B) that could reduce cisplatin resistance. All three drugs induced Pt-mediated DNA damage and inhibited either expression or trafficking of ATP7B in a tumor-specific manner. Global transcriptome analyses showed that Tranilast and Amphotericin B affect expression of genes operating in several pathways that confer tolerance to cisplatin. In the case of Tranilast, these included key molecular players operating in the distribution of platinum to different intracellular compartments. In particular, Tranilast was found to suppress ATOX1 and, as a consequence, ATOX1-mediated trafficking of ATP7B in response to cisplatin.\n\nConsidering the well-known safety profiles of Tranilast, Telmisartan and Amphotericin B, these drugs emerge as potential candidates that might be used for the rapid development of new therapeutic strategies to overcome resistance of tumors to Pt-based chemotherapy.

cancer biology↗

bioRxiv2017

gene2drug: a Computational Tool for Pathway-based Rational Drug Repositioning

MotivationDrug repositioning has been proposed as an effective shortcut to drug discovery. The availability of large collections of transcriptional responses to drugs enables computational approaches to drug repositioning directly based on measured molecular effects.\n\nResultsWe introduce a novel computational methodology for rational drug repositioning, which exploits the transcriptional responses following treatment with small molecule. Specifically, given a therapeutic target gene, a prioritisation of potential effective drugs is obtained by assessing their impact on the transcription of genes in the pathway(s) including the target. We performed in silico validation and comparison with a state-of-art technique based on similar principles. We next performed experimental validation in two different real-case drug repositioning scenarios: (i) upregulation of the glutamate-pyruvate transaminase, which has been shown to induce reduction of oxalate levels in a mouse model of primary hyperoxaluria, and (ii) activation of the transcription factor TFEB, a master regulator of lysosomal biogenesis and autophagy, whose modulation may be beneficial in neurodegenerative disorders.\n\nAvailabilityfree at http://gene2drug.tigem.it\n\nContactdibernardo@tigem.it

bioinformatics↗