👤 Diksha Dalal

Genetic variation and lived experiences shape how our hearts respond to chronic stress and development of heart failure, manifested as compromised pumping function and abnormal hemodynamics. The hallmark of heart failure etiology is excessive stress signals followed by maladaptive structural, electrical, and functional changes to the heart muscle, also known as cardiac remodeling. The specific genetic mechanisms which underly such phenomenon, however, are still unclear, due in part to difficulties in accounting for environmental effects in human population studies. To overcome this challenge, we used the Collaborative Cross (CC) mouse population to investigate heritable susceptibility to cardiovascular stress by chronic β-adrenergic receptor stimulation with the β-agonist isoproterenol, which targets the common signaling gateway to heart failure, regardless of the particular upstream stressor. Across 8 founder and 63 CC lines, we measured non-failing and failing heart characteristics represented by cardiac structure and function, organ weights, and cell morphology. Genome-wide QTL mapping detected 49 genome-wide significant loci, collapsing to 20 unique intervals (nine significant for multiple traits and eleven trait-specific), averaging 12.83 Mb in size. To identify high-confidence candidate genes from these loci, we augmented our trait mapping with coding variants drawn from sequencing data, tractability in our in vitro rat cardiomyocyte model, and previously reported protein functions and mouse or human phenotypes. This approach recovered both known regulators, such as Hey2, and new candidates. Functional tests in in vitro models highlight three candidate genes that modulate hypertrophic growth: Abcb10, Mrps5 and Lmod3. Abcb10 knockdown increased cell size at baseline and further with isoproterenol, consistent with loss of a mitochondrial stress-buffering role. Mrps5 knockdown blunted stress-induced hypertrophy, possibly related to its previously known involvement in oxidative stress regulation. Lmod3 knockdown also attenuated hypertrophy, potentially via actin-assembly control under adrenergic stress. Together, these results reveal heritable pathways of β-adrenergic remodeling in mice and provide an interpretable, translational, and stepwise framework to prioritize candidate genes within broad loci for mechanistic studies of heart failure. Show less

Flavonoids are an important class of natural products, particularly, belong to a class of plant secondary metabolites having a polyphenolic structure. They are widely found in fruits, vegetables, and certain beverages. Hispidulin and diosmin are naturally occurring flavonoids recognized for their potential health benefits, such as antioxidant, anti-inflammatory, and neuroprotective properties. Hispidulin is present in several plants, including Arnica montana, Salvia officinalis (sage), and Eupatorium arnottianum. Diosmin is mainly extracted from citrus fruits like lemons and oranges and can also be synthesized from hesperidin, another flavonoid found in citrus fruits. Neurodegenerative diseases are characterized by complex signaling pathways that contribute to neuronal deterioration. The JAK/STAT pathway is involved in inflammatory responses, while the NF-κB/NLRP3 pathway is associated with metabolic stress and inflammation, both facilitating neurodegeneration. Conversely, the AMPK/pGSK3β pathway is crucial for neuroprotection, regulating cellular responses to oxidative stress and promoting neuronal survival. Additionally, the BACE/Aβ pathway exacerbates neuronal damage by triggering inflammatory and oxidative stress responses, highlighting critical targets for therapeutic strategies. Hispidulin and diosmin have emerged as promising agents in the modulation of mediators involved in neuroinflammation and neurodegenerative diseases. Oxidative stress and inflammatory pathways, including those driven by Aβ/BACE1 and JAK/STAT signaling, are central to neuronal damage and disease progression. Recent studies highlight that hispidulin and diosmin exhibit notable neuroprotective effects by targeting these mediators. Hispidulin has been shown to impact key inflammatory cytokines and adhesion molecules, while diosmin influences proinflammatory cytokine production and inflammasome activation. Both compounds offer potential therapeutic benefits by modulating crucial mediators linked to neuroinflammation and neurodegeneration. This review article is designed to explore the intricate mechanistic interplay underlying the neuroprotective effects of hispidulin and diosmin. Show less

Although the activity of telomerase, an enzyme which synthesizes telomeres de novo and stabilizes telomere length has been demonstrated in the testis, the precise expression of activity in different germ cell types is not known. We examined telomerase activity using a PCR-based telomeric repeat amplification protocol during development of the rat testis from birth to adulthood. Telomerase activity was relatively high from birth to the 4th week of age, and then low between the 5th to 10th week, suggesting that the type A spermatogonial stem cells may be the population which is expressing the highest levels of telomerase activity. To ascertain which germ cells expresses the telomerase activity, purified populations of type A spermatogonia from 9-day old rats, and pachytene spermatocytes, round spermatids and epididymal spermatozoa from adult rats were isolated. While type A spermatogonia expressed very strong telomerase activity, the fractions containing pachytene spermatocytes and round spermatids also expressed telomerase activity, but at comparatively lower levels. Telomerase activity was totally absent in epididymal spermatozoa. Thus, it appears that the telomerase activity is expressed at high levels in the type A spermatogonial stem cells, is down-regulated during spermatogenesis, and is absent in the differentiated spermatozoa. Show less