Cardiac tissue loss is one of the most important factors leading to the unsatisfactory recovery even after treatment of ischemic heart disease. Melatonin, a circadian molecule with marked antioxidant properties, protects against ischemia-reperfusion (IR) injury. In particular, the myocardial protection of melatonin is substantial. We initially focus on the cardioprotective effects of melatonin in myocardial IR. These studies showed how melatonin preserves the microstructure of the cardiomyocyte and reduces myocardial IR injury. Thereafter, downstream signaling pathways of melatonin were summarized including Janus kinase 2/signal transducers and activators of transcription 3, nitric oxide-synthase, and nuclear factor erythroid 2 related factor 2. Herein, we propose the clinical applications of melatonin in several ischemic heart diseases. Collectively, the information summarized in this review (based on in vitro, animal, and human studies) should serve as a comprehensive reference for the action of melatonin in cardioprotection and hopefully will contribute to the design of future experimental research.
Herein, we describe the precise cellular destruction of an oncogenic noncoding RNA with a small molecule—bleomycin A5 conjugate, affording reversal of phenotype and a facile method to map the cellular binding sites of a small molecule. In particular, bleomycin A5 was coupled to a small molecule that selectively binds the microRNA-96 hairpin precursor (pri-miR-96). By coupling of bleomycin A5’s free amine to the RNA binder, its affinity for binding to pri-miR-96 is >100-fold stronger than to DNA and the compound selectively cleaves pri-miR-96 in triple negative breast cancer (TNBC) cells. Indeed, selective cleavage of pri-miR-96 enhanced expression of FOXO1 protein, a proapoptotic transcription factor that miR-96 silences, and triggered apoptosis in TNBC cells. No effects were observed in healthy breast epithelial cells. Thus, conjugation of a small molecule to bleomycin A5’s free amine may provide programmable control over its cellular targets. Few approaches are available to define the binding sites of small molecules within cellular RNAs. Our targeted cleavage method provides such an approach that is straightforward to implement. That is, we determined experimentally the site cleaved within pri-miR-96 in vitro and in cells; these studies revealed that the site of cleavage is the precise site for which the small molecule cleaver was designed and in agreement with modeling. These studies demonstrate the potential of sequence-based design to provide bioactive compounds that precisely recognize and cleave RNA in cells.
Melatonin could significantly protect liver injury in mice, which was related to free radical scavenging, increased SOD activity and pro-inflammatory mediators.
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