Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0851184 (thinning)
 11,252 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ventricular remodeling after myocardial infarction is defined as progressive chamber dilation and wall thinning, which leads to functional compromise. Remodeling is mediated by active processes of inflammation, fibrosis, and cardiomyocyte dropout over the weeks and months after infarction, and, therefore, provides a large temporal therapeutic window. In experimental models, interruption of molecular and physiological pathways that contribute to cardiomyocyte loss, and the resulting unfavorable ventricular geometry, can abrogate remodeling and prevent or improve heart failure. Remodeling is multifactorial and involves several parallel cellular pathways, which means many potential therapeutic targets exist. Of late, much attention has been given to the development of cell-based therapies; however, the abundant, promising pharmacotherapeutic developments should not be overlooked. This Review examines developments in pharmacological treatment of ventricular remodeling in preclinical models of myocardial infarction-specifically, disruption of the renin-angiotensin-aldosterone system through direct renin inhibition and blockade of aldosterone synthesis and/or uptake, enhancement of endothelial nitric oxide synthase synthesis, G-protein receptor kinase inhibition, administration of erythropoietin, and interruption of apoptosis-and highlights the challenge of translating these successes to treatment of human disease. Therapeutic targeting of multiple organ systems involved in recovery after myocardial infarction might prove to be the best approach to improve patients' cardiac outcome.
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PMID:Novel pharmacotherapies to abrogate postinfarction ventricular remodeling. 1935 32

Tuberous Sclerosis Complex (TSC) is a rare genetic disease that manifests with early symptoms, including cortical malformations, childhood epilepsy, and TSC-associated neuropsychiatric disorders (TANDs). Cortical malformations arise during embryonic development and have been linked to childhood epilepsy before, but the underlying mechanisms of this relationship remain insufficiently understood. Zebrafish have emerged as a convenient model to study elementary neurodevelopment; however, without in-depth functional analysis, the Tsc2-deficient zebrafish line cannot be used for studies of TANDs or new drug screening. In this study, we found that the lack of Tsc2 in zebrafish resulted in heterotopias and hyperactivation of the mTorC1 pathway in pallial regions, which are homologous to the mammalian cortex. We observed commissural thinning that was responsible for brain dysconnectivity, recapitulating TSC pathology in human patients. The lack of Tsc2 also delayed axonal development and caused aberrant tract fasciculation, corresponding to the abnormal expression of genes involved in axon navigation. The mutants underwent epileptogenesis that resulted in nonmotor seizures and exhibited increased anxiety-like behavior. We further mapped discrete parameters of locomotor activity to epilepsy-like and anxiety-like behaviors, which were rescued by reducing tyrosine receptor kinase B (TrkB) signaling. Moreover, in contrast to treatment with vigabatrin and rapamycin, TrkB inhibition rescued brain dysconnectivity and anxiety-like behavior. These data reveal that commissural thinning results in the aberrant regulation of anxiety, providing a mechanistic link between brain anatomy and human TANDs. Our findings also implicate TrkB signaling in the complex pathology of TSC and reveal a therapeutic target.
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PMID:TrkB hyperactivity contributes to brain dysconnectivity, epileptogenesis, and anxiety in zebrafish model of Tuberous Sclerosis Complex. 3193 27