Improved bioavailability of targeted Curcumin delivery efficiently regressed cardiac hypertrophy by modulating apoptotic load within cardiac microenvironment
| Autor: | Santanu Rana, Sagartirtha Sarkar, Ritwik Datta, Durba Banerjee, Arkadeep Mitra, Aramita Ray, Shaon Naskar |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cardiac function curve medicine.medical_specialty Curcumin Cell Survival Biological Availability Down-Regulation Apoptosis Cardiomegaly Caspase 3 Pharmacology Toxicology Muscle hypertrophy 03 medical and health sciences chemistry.chemical_compound Drug Delivery Systems Bcl-2-associated X protein Internal medicine medicine Animals Myocyte Myocytes Cardiac Rats Wistar bcl-2-Associated X Protein Chitosan TUNEL assay Dose-Response Relationship Drug biology Chemistry Myocardium Cytochromes c Acetylation medicine.disease Rats Disease Models Animal 030104 developmental biology Endocrinology Heart failure biology.protein Nanoparticles Tumor Suppressor Protein p53 E1A-Associated p300 Protein |
| Zdroj: | Toxicology and Applied Pharmacology. 290:54-65 |
| ISSN: | 0041-008X |
| DOI: | 10.1016/j.taap.2015.11.011 |
| Popis: | Cardiomyocyte apoptosis acts as a prime modulator of cardiac hypertrophy leading to heart failure, a major cause of human mortality worldwide. Recent therapeutic interventions have focussed on translational applications of diverse pharmaceutical regimes among which, Curcumin (from Curcuma longa) is known to have an anti-hypertrophic potential but with limited pharmacological efficacies due to low aqueous solubility and poor bioavailability. In this study, Curcumin encapsulated by carboxymethyl chitosan (CMC) nanoparticle conjugated to a myocyte specific homing peptide was successfully delivered in bioactive form to pathological myocardium for effective regression of cardiac hypertrophy in a rat (Rattus norvegicus) model. Targeted nanotization showed higher cardiac bioavailability of Curcumin at a low dose of 5 mg/kg body weight compared to free Curcumin at 35 mg/kg body weight. Moreover, Curcumin/CMC-peptide treatment during hypertrophy significantly improved cardiac function by downregulating expression of hypertrophy marker genes (ANF, β-MHC), apoptotic mediators (Bax, Cytochrome-c) and activity of apoptotic markers (Caspase 3 and PARP); whereas free Curcumin in much higher dose showed minimal improvement during compromised cardiac function. Targeted Curcumin treatment significantly lowered p53 expression and activation in diseased myocardium via inhibited interaction of p53 with p300-HAT. Thus attenuated acetylation of p53 facilitated p53 ubiquitination and reduced the apoptotic load in hypertrophied cardiomyocytes; thereby limiting cardiomyocytes' need to enter the regeneration cycle during hypertrophy. This study elucidates for the first time an efficient targeted delivery regimen for Curcumin and also attributes towards probable mechanistic insight into its therapeutic potential as a cardio-protective agent for regression of cardiac hypertrophy. |
| Databáze: | OpenAIRE |
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