Amlodipine rescues advanced iron overload cardiomyopathy in hemojuvelin knockout murine model: Clinical implications.

Background: Iron overload cardiomyopathy (IOC) is a major co-morbidity of genetic hemochromatosis and secondary iron overload with limited therapeutic options. We aim to investigate mechanisms of rescue action of amlodipine in the murine model of iron overload, characterize changes in human cardiac tissue due to IOC, and compare them to the changes in the animal model of IOC. Methods and results: As an animal model, we used male hemojuvelin knockout (HJVKO) mice, which lacked hemojuvelin (a co-receptor protein for hepcidin expression). The mice were fed a high-iron diet from 4 weeks to 1 year of age. As a rescue, iron-fed mice received the Ca2+ channel blocker, amlodipine, from 9 to 12 months. Iron overload resulted in systolic and diastolic dysfunctions and changes in the cardiac tissue similar to the changes in the explanted human heart with IOC. An IOC patient (ß-thalassemia) with left-ventricular ejection fraction (LVEF) 25% underwent heart transplantation. The murine model and the explanted heart showed intra-myocyte iron deposition, fibrosis, hypertrophy, oxidative stress, remodeling of Ca2+ cycling proteins, and metabolic kinases typical of heart failure. Single-myocyte contractility and Ca2+ release were diminished in the murine model. The amlodipine-treated group exhibited normalization of cellular function and reversed fibrosis, hypertrophy, oxidative stress, and metabolic remodeling. We also report a clinical case of primary hemochromatosis successfully treated with amlodipine. Conclusions: The aged HJVKO murine model on the iron-rich diet reproduced many features of the human case of IOC. The use of amlodipine in the murine model and clinical case reversed IOC remodeling, demonstrating that amlodipine is effective adjuvant therapy for IOC.

Comparative temporal metabolomics studies to investigate interspecies variation in three Ocimum species.

Ocimum is one of the most revered medicinally useful plants which have various species. Each of the species is distinct in terms of metabolite composition as well as the medicinal property. Some basil types are used more often as an aromatic and flavoring ingredient. It would be informative to know relatedness among the species which though belong to the same genera while exclusively different in terms of metabolic composition and the operating pathways. In the present investigation the similar effort has been made in order to differentiate three commonly occurring Ocimum species having the high medicinal value, these are Ocimum sanctum, O. gratissimum and O. kilimandscharicum. The parameters for the comparative analysis of these three Ocimum species comprised of temporal changes in number leaf trichomes, essential oil composition, phenylpropanoid pathway genes expression and the activity of important enzymes. O. gratissimum was found to be richest in phenylpropanoid accumulation as well as their gene expression when compared to O. sanctum while O. kilimandscharicum was found to be accumulating terpenoid. In order to get an overview of this qualitative and quantitative regulation of terpenes and phenylpropenes, the expression pattern of some important transcription factors involved in secondary metabolism were also studied.

Ocimum metabolomics in response to abiotic stresses: Cold, flood, drought and salinity.

Ocimum tenuiflorum is a widely used medicinal plant since ancient times and still continues to be irreplaceable due to its properties. The plant has been explored chemically and pharmacologically, however, the molecular studies have been started lately. In an attempt to get a comprehensive overview of the abiotic stress response in O. tenuiflorum, de novo transcriptome sequencing of plant leaves under the cold, drought, flood and salinity stresses was carried out. A comparative differential gene expression (DGE) study was carried out between the common transcripts in each stress with respect to the control. KEGG pathway analysis and gene ontology (GO) enrichment studies exhibited several modifications in metabolic pathways as the result of four abiotic stresses. Besides this, a comparative metabolite profiling of stress and control samples was performed. Among the cold, drought, flood and salinity stresses, the plant was most susceptible to the cold stress. Severe treatments of all these abiotic stresses also decreased eugenol which is the main secondary metabolite present in the O. tenuiflorum plant. This investigation presents a comprehensive analysis of the abiotic stress effects in O. tenuiflorum. Current study provides an insight to the status of pathway genes' expression that help synthesizing economically valuable phenylpropanoids and terpenoids related to the adaptation of the plant. This study identified several putative abiotic stress tolerant genes which can be utilized to either breed stress tolerant O. tenuiflorum through pyramiding or generating transgenic plants.