Assessment of sub-chronic oral toxicity of Nityanand Rasa: An ayurvedic herbo-metallic formulation.

ETHNOPHARMACOLOGICAL RELEVANCE: Nityananda Rasa (NR) is an ayurvedic herbo-metallic formulation used to treat gout, obesity, hypothyroidism, elephantiasis, and other diseases. However, its safety is a concern owing to the use of heavy metals like mercury and arsenic. AIM OF THE STUDY: To study the sub-chronic oral toxicity of NR on albino wistar rats for safety evaluation. MATERIALS AND METHODS: The male and female albino wistar rats were administered a daily dose of 30 (low), 300 (medium) and 600 (high) mg/kg BW/day of NR for 90-day period. The body weight and feed consumption were monitored once a week. After 90 days, blood and vital organs were harvested for genotoxicity, hematology, biochemistry, histopathology, gene expression and the biodistribution analysis. RESULTS: There was no mortality or severe behavioural changes observed in rats. Significant changes in biochemical enzyme levels were seen at medium and high doses of NR i. e. 300 and 600 mg/kg BW/day respectively. No hematological changes were observed. Mild histopathological changes seen at high dose of NR which were found in concurrence with the biochemical alterations in liver and brain. There was mild genotoxicity and no detectable level of mercury but significant arsenic level in blood at high dose. Gene expression was mildly affected. CONCLUSIONS: NR induced moderate toxic effects at high dose but can be considered safe at therapeutic doses.

Secretagogin Regulates Insulin Signaling by Direct Insulin Binding.

Secretagogin (SCGN) is a ß-cell enriched, secretory/cytosolic Ca2+-binding protein with unknown secretory regulation and functions. Recent findings suggest that SCGN deficiency correlates with compromised insulin response and diabetes. However, the (patho)physiological SCGN-insulin nexus remains unexplored. We here report that SCGN is an insulin-interacting protein. The protein-protein interaction between SCGN and insulin regulates insulin stability and increases insulin potency in vitro and in vivo. Mutagenesis studies suggest an indispensable role for N-terminal domain of SCGN in modulating insulin stability and function. SCGN supplementation in diabetogenic-diet-fed mice preserves physiological insulin responsiveness while relieving obesity and cardiovascular risk. SCGN-insulin interaction mediated alleviation of hyperinsulinemia by increased insulin internalization, which translates to reduced body fat and hepatic lipid accumulation, emerges as a plausible mechanism for the preservation of insulin responsiveness. These findings establish SCGN as a functional insulin-binding protein (InsBP) with therapeutic potential against diabetes.

An innovative in situ method of creating hybrid dendrimer nano-assembly: An efficient next generation dendritic platform for drug delivery.

Dendrimers have proven to be effective for drug delivery and their biodisposition varies with change on their surface, generation and core. In an effort to understand the role of critical nanoscale design parameters, we developed a novel hybrid dendrimer approach to harness unique features of individual dendrimers and create a nano-assembly. We report an easy in situ method of creating hybrid dendrimer nano-assembly by mixing G4.0 PAMAM (-NH2) and G3.5 PAMAM (-COONa) dendrimers with a chemotherapeutic drug docetaxel (DTX). Zeta potential, HR-TEM, 1H-NMR proved the formation of nano-assembly. In vitro dissolution, release studies revealed pH dependent dissolution and sustained drug release. Cellular uptake, cytotoxicity, and flow cytometric analysis in human/mouse glioblastoma cells indicated the effectiveness of hybrid dendrimers. The oral administration of the hybrid dendrimers showed pharmacokinetic equivalence to intravenous injection of commercially available Taxotere®. Hybrid dendrimer concept provides much needed fine-tuning to create multistage next-generation dendritic platform in nanomedicine.