Challenges for Cardiovascular Drug Research

Scriabine, Alexander

doi:10.1111/j.1527-3466.2007.00015.x

Cited by 4 publications

(2 citation statements)

References 16 publications

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“…Considering that PARP-1 is recognized as an essential co-factor in gene expression regulation by modulating the binding of transcription factors to specific promoter regions, the lack or inhibition of it under pathological conditions could also exert a protective effect on cell survival, maintenance of tissue homeostasis, or preservation of extracellular matrix integrity [26,27]. This protective effect has been documented in several referred studies [28,29].…”

Section: Discussionmentioning

confidence: 97%

Stress-Induced Changes in Nucleocytoplasmic Localization of Crucial Factors in Gene Expression Regulation

Khamit,

Chakraborty,

Zahorán

et al. 2024

IJMS

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This study investigates the toxic effect of harmful materials, unfiltered by the placenta, on neonatal umbilical cord (UC) vessels, focusing on stress-induced adaptations in transcriptional and translational processes. It aims to analyze changes in pathways related to mRNA condensate formation, transcriptional regulation, and DNA damage response under maternal smoking-induced stress. UC vessels from neonates born to smoking (Sm) and nonsmoking mothers (Ctr) were examined. Immunofluorescence staining and confocal microscopy assessed the localization of key markers, including Transcription Complex Subunit 1 (CNOT1) and the largest subunit of RNA polymerase II enzyme (RPB1). Additionally, markers of DNA damage response, such as Poly(ADP-ribose) polymerase-1, were evaluated. In Sm samples, dissolution of CNOT1 granules in UC vessels was observed, potentially aiding stalled translation and enhancing transcription via RPB1 assembly and translocation. Control vessels showed predominant cytoplasmic RPB1 localization. Despite adaptive responses, Sm endothelial cells exhibited significant damage, indicated by markers like Poly(ADP-ribose) polymerase-1. Ex vivo metal treatment on control vessels mirrored Sm sample alterations, emphasizing marker roles in cell survival under toxic exposure. Maternal smoking induces specific molecular adaptations in UC vessels, affecting mRNA condensate formation, transcriptional regulation, and DNA damage response pathways. Understanding these intricate molecular mechanisms could inform interventions to improve neonatal health outcomes and mitigate adverse effects of toxic exposure during pregnancy.

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Section: Discussionmentioning

confidence: 97%

Stress-Induced Changes in Nucleocytoplasmic Localization of Crucial Factors in Gene Expression Regulation

Khamit,

Chakraborty,

Zahorán

et al. 2024

IJMS

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“…Challenges to CV drug development include a scarcity of accepted surrogates for CV outcomes and a lack of useful platforms to assess direct vascular effects of promising new drug candidates (8). The most prominent gaps are the lack of 1) valid drug targets and pre-clinical models that predict efficacy and safety in humans; 2) biomarkers that predict CV clinical outcomes such as myocardial infarction (MI) and unstable angina; 3) responder patient segments that can increase the efficiency and probability of success of outcome trials; and 4) drug/diagnostic combinations.…”

mentioning

confidence: 99%

Genomics and Cardiovascular Drug Development

Plump

Lum²

2009

Journal of the American College of Cardiology

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In the last half century, phenomenal advances have been made in understanding the pathophysiology of cardiovascular disease and in developing therapies to reduce cardiovascular risk. Nevertheless, cardiovascular disease remains the leading cause of death and morbidity in the industrialized world, with rapidly rising prevalence in developing countries, accounting for approximately 30% of all deaths worldwide. Since the initial availability of statin drugs in 1987, few novel cardiovascular therapies have emerged. Whereas statins reduce the mortality and morbidity from atherosclerotic heart disease by approximately 30%, the staggering 70% residual cardiovascular risk underscores the persistent need for novel therapies. Substantial advances in genomic research offer promise to greatly facilitate cardiovascular drug development. Over the past decade, often termed "the genomics revolution," such advancements as the emergence of genome-wide genotyping in humans, the industrialization of messenger ribonucleic acid expression profiling, and the maturation of proteomic and metabolomic methodologies have been made. In addition, the advancement of informatics to allow the intersection of multiple complex datasets has led to the field of systems biology. Genomic approaches are already being utilized to drive novel compound pipelines by helping with the identification and validation of novel targets. In the future, the study of genomics is expected to support biomarker discovery and development and the identification of responder patient segments. The focus of the present review is the application of genomics to the development of novel atherosclerosis therapies.

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