Novel Cell-Penetrating Peptide Conjugated Proteasome Inhibitors: Anticancer and Antifungal Investigations.

Cell-penetrating peptide conjugated peptide aldehydes Tat-A and Tat-B showed low micromolar anticancer and antifungal activities and synergistic action in combination with cisplatin and amphotericin B against cancer and fungal cells, respectively. Tat-A and Tat-B were significantly more potent than Ixazomib in inhibiting the human 20S proteasomes with IC50 values in the low nanomolar range. Treatment with Tat-A and Tat-B caused membrane disruption and pore formation in HeLa and BE(2)-C cells and inhibition and eradication of C. albicans biofilms. Apoptotic cell death of the treated HeLa and BE(2)-C cells was demonstrated by Annexin V/PI staining. Flow cytometry analyses showed that more than 78% (HeLa) and 92% (BE(2)-C cells showed signs of apoptosis and necrosis upon treatment with Tat-A and Tat-B. This study forms the first report that documents the benefits of cell-penetrating peptide conjugation to enhance the potential of peptide aldehydes as therapeutics

Initial hyperinsulinemia and subsequent β-cell dysfunction is associated with elevated palmitate levels

BACKGROUND: The prevalence of obesity-related diabetes in childhood is increasing and circulating levels of nonesterified fatty acids may constitute a link. Here, the association between palmitate and insulin secretion was investigated in vivo and in vitro.METHODS: Obese and lean children and adolescents (n = 80) were included. Palmitate was measured at fasting; insulin and glucose during an oral glucose tolerance test (OGTT). Human islets were cultured for 0 to 7 d in presence of 0.5 mmol/l palmitate. Glucose-stimulated insulin secretion (GSIS), insulin content and apoptosis were measured.RESULTS: Obese subjects had fasting palmitate levels between 0.10 and 0.33 mmol/l, with higher average levels compared to lean subjects. While obese children with elevated palmitate (&gt;0.20 mmol/l) had accentuated insulin levels during OGTT, obese adolescents with high palmitate had delayed first-phase insulin response. In human islets exposed to palmitate for 2 d GSIS was twofold enhanced, but after 7 d attenuated. Intracellular insulin content decreased time-dependently in islets cultured in the presence of palmitate and cleaved caspase 3 increased.CONCLUSION: The rapid accentuated and delayed insulin secretory responses observed in obese children and adolescents, respectively, with high palmitate levels may reflect changes in islet secretory activity and integrity induced by extended exposure to the fatty acid.</p

Decades of research in drug targeting using gastroretentive drug delivery systems for antihypertensive therapy

ABSTRACT The limitations in absorption of drugs with narrow absorption window, or those unstable in the intestinal pH or those exhibiting low solubility at high pH are primary candidates for gastroretentive drug delivery systems (GRDDS). The delivery system has been widely explored for its commercial potential for a wide variety of therapeutic agents. GRDDS offer clinical therapeutics for acute and chronic management. Hypertension is a chronic disease that requires long term treatment and its management by patient compliant dosage forms would be clinically useful. Antihypertensives belonging to different classes have proved good candidates for the formulation of GRDDS. The review aims to discuss various GRDDS researched for antihypertensive drugs to increase the gastric residing time, bioavailability, henceforth to reduce the dose of the drug, dosing frequency and increase patient compliance. It also explores various marketed products and the patents filed/granted for GRRDS of antihypertensives. The GRDDS investigated include effervescent and non-effervescent floating drug delivery systems, swelling and expanding systems and bio/mucoadhesive systems. Many other systems that provided research platforms include high density systems, raft forming systems and osmotic delivery systems. In clinical context, wherein combination of antihypertensives is indicated, dual release delivery systems may also be explored