Abstract:Since impaired mitochondrial ATP production in cardiomyocytes is thought to lead to heart failure, a drug that protects mitochondria and improves ATP production under disease conditions would be an attractive treatment option. In this study, we identified small-molecule drugs, including the anti-parasitic agent, ivermectin, that maintain mitochondrial ATP levels under hypoxia in cardiomyocytes. Mechanistically, transcriptomic analysis and gene silencing experiments revealed that ivermectin increased mitochondr… Show more
“…This prevents pathological hypertrophy and improves cardiac function. Nagai H et al 2017 [ 67 ] *available as preprint; Clinical trials of IVM on COVID-19 available on https://clinicaltrials.gov[ 7 ]; Ivermectin for COVID-19: real-time meta-analysis available on https://ivmmeta.com [ 8 ] Fig. 1 A schematic of the key cellular and biomolecular interactions between Ivermectin, host cell, and SARS-CoV-2 in COVID-19 pathogenesis and prevention of complications.…”
Considering the urgency of the ongoing COVID-19 pandemic, detection of various new mutant strains and future potential re-emergence of novel coronaviruses, repurposing of approved drugs such as Ivermectin could be worthy of attention. This evidence-based review article aims to discuss the mechanism of action of ivermectin against SARS-CoV-2 and summarizing the available literature over the years. A schematic of the key cellular and biomolecular interactions between Ivermectin, host cell, and SARS-CoV-2 in COVID-19 pathogenesis and prevention of complications have been proposed.
“…This prevents pathological hypertrophy and improves cardiac function. Nagai H et al 2017 [ 67 ] *available as preprint; Clinical trials of IVM on COVID-19 available on https://clinicaltrials.gov[ 7 ]; Ivermectin for COVID-19: real-time meta-analysis available on https://ivmmeta.com [ 8 ] Fig. 1 A schematic of the key cellular and biomolecular interactions between Ivermectin, host cell, and SARS-CoV-2 in COVID-19 pathogenesis and prevention of complications.…”
Considering the urgency of the ongoing COVID-19 pandemic, detection of various new mutant strains and future potential re-emergence of novel coronaviruses, repurposing of approved drugs such as Ivermectin could be worthy of attention. This evidence-based review article aims to discuss the mechanism of action of ivermectin against SARS-CoV-2 and summarizing the available literature over the years. A schematic of the key cellular and biomolecular interactions between Ivermectin, host cell, and SARS-CoV-2 in COVID-19 pathogenesis and prevention of complications have been proposed.
“…Samples in different dilutions and positive control (40-mM propranolol hydrochloride, VWR, Radnor, Pennsylvania, USA) and EarlyTox Cardiotoxicity Kit (Molecular Devices, San-Jose, California, USA) were added for 2 hours at 37 C according to the manufacturer's protocol. 30 Spontaneous calcium transients were captured in single cells at Ex 470 nm/Em 500-530 nm for 30 seconds using a Nikon high content screening system (Nikon CEE GmbH) prior and after the addition of samples and positive control. After subtraction of the background, the number of spikes (only those with amplitudes >30 AFU) per 30 seconds was manually counted before and after the treatment.…”
Section: Cell Line Characterization In Vitro Exposure Technique and mentioning
Spherical nanoparticles (NPs) of cadmium and lead sulfides (diameter 37 ± 5 and 24 ± 4 nm, respectively) have been found to be cytotoxic for HL-1 cardiomyocytes as evidenced by decrease in adenosine triphosphate–dependent luminescence. Cadmium sulfide (CdS)-NPs were discovered to produce a much greater cytotoxic impact than lead sulphide (PbS)-NP. Given the same dose range, CdS-NP reduced the number of calcium spikes. A similar effect was observed for small doses of PbS-NP. In addition to cell hypertrophy under the impact of certain doses of CdS-NP and PbS-NP, doses causing cardiomyocyte size reduction were identified. For these 3 outcomes, we obtained both monotonic “dose–response” functions (well approximated by the hyperbolic function) and different variants of non-monotonic ones for which we found adequate mathematical expressions by modifying certain models of hormesis available in the literature. Data analysis using a response surface linear model with a cross-term provided new support to the previously established postulate that a diversity of types of joint action characteristic of one and the same pair of damaging agents is one of the important assertions of the general theory of combined toxicity.
“…A recent study showed that hypoxic activation of HIF1α may occur due to mitochondrial dysfunction in response to increased intracellular Ca 2+ (ref. 64 ). Notably, similar to altered cardiomyocytes, Ca 2+ cycling was observed in the HIP rats 23 and mitochondrial disarrangement was observed in control RVCMs incubated with exogenous aggregated human amylin 24 .…”
Hyperamylinemia induces amylin aggregation and toxicity in the pancreas and contributes to the development of type-2 diabetes (T2D). Cardiac amylin deposition in patients with obesity and T2D was found to accelerate heart dysfunction. Non-human primates (NHPs) have similar genetic, metabolic, and cardiovascular processes as humans. However, the underlying mechanisms of cardiac amylin in NHPs, particularly related to the hypoxia inducible factor (HIF)1α and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) signaling pathways, are unknown. Here, we demonstrate that in NHPs, amylin deposition in heart failure (HF) contributes to cardiac dysfunction via activation of HIF1α and PFKFB3 signaling. This was confirmed in two in vitro cardiomyocyte models. Furthermore, alterations of intracellular Ca2+, reactive oxygen species, mitochondrial function, and lactate levels were observed in amylin-treated cells. Our study demonstrates a pathological role for amylin in the activation of HIF1α and PFKFB3 signaling in NHPs with HF, establishing amylin as a promising target for heart disease patients.
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