Analysis of the Efficacy of Metformin Against Doxorubicin Cardiotoxicity and Exploration of its Molecular Mechanism

Doxorubicin is a very effective broad-spectrum anti-tumor drug, but it can cause dose-dependent cardiotoxicity and ultimately lead to heart failure. Previous studies have found that metformin exerts a cardioprotective effect through AMP-activated protein kinase (AMPK), but its effect on doxorubicin cardiotoxicity is still unclear. In order to investigate whether and how AMPK affects the ability of metformin to regulate the cardiotoxicity of doxorubicin, we have conducted two parts: clinical research and basic research. We found that metformin can reduce doxorubicin cardiotoxicity through clinical retrospective case-control study. Based on this, animal experiments were conducted to explore the molecular mechanism, and it was found that metformin was not associated with AMPK pathway, an important pathway of energy metabolism in the body, and this pathway did not play a protective role in doxorubicin induced cardiotoxicity. The reason may be related to decreased glucose utilization and mitochondrial autophagy of cardiomyocytes.

Evaluation of Cardioprotective action of Suvarna gairik (Redochre) in Indian Cobra Envenomation, Aluminium Phosphide Poisoning and Doxorubicin Cardiotoxicity in Albino Rats- A Protocol

Background: Poisoning is major health issue all over the world. Poisoning is one of basic causes for Out Hospital cardiac arrest (OHCA). P-OHCA (Poison induced Out Hospital cardiac arrest) can be prevented by immediate primary management. The agent for poisoning is unknown in most cases, which leads to difficulty deciding the emergency antidote. In Ayurveda Hridyavaranchikitsa (Cardio protection) is one of the treatment modalities mentioned in all types of poisoning as first aid treatment. Suvarna Gairik (Red ochre) is one of drugs mentioned for the cardioprotection. Snake bite and organophosphate poisoning are the threats to life in India. Doxorubicin is commonly used drug for Chemotherapy in malignancies, and its major side effect is cardiotoxicity. Hence these poisonings are included in study. Aim and Objective: Evaluation of cardioprotective activity of Suvarna Gairik (Red ochre) in cardiac biomarker like Lactate dehydrogenase, Creatinine phosphokinase, Alkaline transferase, Cardiac Troponins and Survival Time in Indian Cobra Envenomation, Aluminium phosphide poisoning and Doxorubicin cardiotoxicity in Albino Rats. Methodology: Animal study is designed. 56 wistar rats will be divided in 7 groups as Vehicle Control Group, Disease control Group -1 Indian Cobra envenomation, Disease control Group -2Aluminium Phosphide poisoning, Disease control Group -3 Inj. Doxorubicin induced cardiotoxicity, Test Group -1 Indian Cobra Envenomation and Suvarna gairik Test Group -2 Aluminium Phosphide poisoning and Suvarna gairik Test control Group 3- Inj. Doxorubicin cardiotoxicity and Suvarna gairik. Results: Outcome will be assessed in between groups and among groups. Conclusion: Suvarna Gairik (Red ochre) may show statistical significant cardioprotective activity.

Genome-wide CRISPR/Cas9 screening in human iPS derived cardiomyocytes uncovers novel mediators of doxorubicin cardiotoxicity

Human induced pluripotent stem (iPS) cell technologies coupled with genetic engineering now facilitate the study of the molecular underpinnings of disease in relevant human cell types. Application of CRISPR/Cas9-based approaches for genome-scale functional screening in iPS-derived cells, however, has been limited by technical constraints, including inefficient transduction in pooled format, loss of library representation, and poor cellular differentiation. Herein, we present optimized approaches for whole-genome CRISPR/Cas9 based screening in human iPS derived cardiomyocytes with near genome-wide representation at both the iPS and differentiated cell stages. As proof-of-concept, we perform a screen to investigate mechanisms underlying doxorubicin mediated cell death in iPS derived cardiomyocytes. We identified two poorly characterized, human-specific transporters (SLCO1A2, SLCO1B3) whose loss of function protects against doxorubicin-cardiotoxicity, but does not affect cell death in cancer cells. This study provides a technical framework for genome-wide functional screening in iPS derived cells and identifies new targets to mitigate doxorubicin-cardiotoxicity in humans.