Venezuelan Institute for Scientific Research

Ovarian aging is a major determinant of female reproductive longevity, characterized by declining oocyte quality and reduced ovarian reserve. With more women delaying childbearing, age-related infertility has become an urgent biomedical concern. Mitochondrial dysfunction plays a central role in this process, leading to oxidative damage and metabolic disturbances that impair oocyte competence. These alterations are linked to poorer outcomes in assisted reproductive technology (ART), particularly for women over 35, who face significantly reduced success rates. This review examines the key mechanisms of ovarian aging, including oxidative stress, DNA damage, telomere shortening, and mitochondrial dysfunction, all contributing to diminished oocyte quality and quantity. Special focus is given to sirtuins, especially SIRT1 and SIRT3, as critical regulators of redox balance in oocytes and granulosa cells. The review also addresses the impact of age-related changes on chromosomal cohesion and ovarian fibrosis. Importantly, mitochondrial insufficiency is increasingly recognized as a factor in broader age-related diseases, such as metabolic disorders and cancer, suggesting shared molecular pathways between reproductive aging and systemic health. Recent advances highlight the potential of targeted nutrient supplementation to modulate redox homeostasis, enhance sirtuin activity, and preserve mitochondrial function-strategies that may benefit both ovarian health and overall aging. This intersection of reproductive biology and mitochondrial medicine is driving interest in pharmacologic interventions to improve oocyte quality and mitigate age-related comorbidities.

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disease of connective tissue caused by mutations in the ACVR1 gene, producing the formation of heterotopic bone in soft tissues.The hallmark sign of the disease is the congenital malformations of the great toes in the affected individuals.Heterotopic ossification is triggered by mild phys. trauma, leading to progressive disability.Its incidence is approx. 1 patient per 1.4 million people worldwide, without gender, ethnic, or geog. localization predisposition.To date, around 25 different mutations have been described, but the substitution of adenine by guanine at nucleotide c.617 replacing an arginine by histidine at residue 206 (p.R206H) accounts for 97 % of cases with classical FOP.Identification of the pathol. alterations in ACVR1 has significant diagnostic and therapeutic implications in the clin. management of FOP.Through mol. anal. of the ACVR1 gene in four unrelated Venezuelan patients, the study aimed to confirm the diagnosis, determine whether in-phase haplotypes differentiated between a de novo event or a common remote gene origin in the country, and aid in the nosog. of this rare disease.The findings supported a de novo recurring phenomena by demonstrating that all the patients had the p.R206H mutation but did not share an in-phase haplotype.

Chagas disease remains a major public health challenge, and there is a need for new therapeutic agents. N-heterocyclic carbene (NHC) complexes, particularly those linked to silver or gold, have shown significant anticancer, antimicrobial, and antiparasitic activities. This study aimed to evaluate the efficacy of four NHC compounds (QMT3, QMT4, QMT7, and QMT8) against Trypanosoma cruzi, the causative agent of Chagas disease. In vitro assays revealed that QMT3 and QMT8 exhibited the strongest antiparasitic effects, with QMT3 showing the highest potency and stability over time (IC₅₀ = 10.3 µg/mL at 24 h). Both compounds induced rapid, irreversible cell death in epimastigotes, primarily through late apoptotic-like and necrotic pathways, as evidenced by Annexin V/PI labeling. Additionally, treatment with QMT3 and QMT8 led to significant increases in intracellular reactive oxygen species (ROS), particularly superoxide (SO). Notably, both compounds displayed high specificity for the parasite with low cytotoxicity towards mammalian cells, although QMT8 was less toxic to host cells than QMT3 at short exposure times. Molecular modeling studies revealed that QMT3, and QMT8 bind to the active site of TryR, a crucial player in maintaining redox homeostasis in trypanosomatids, potentially competing with its natural ligand and disrupting its enzymatic function. These findings suggest that QMT3 and QMT8, silver- and gold-based NHC complexes, act through redox system disruption and TryR inhibition, positioning them as promising candidates for the development of new treatments for Chagas disease.