Preclinical pharmacology and pharmacokinetics of curcumin tagged cilostazol nanodispersion for the management of diabetic nephropathy in wister rat model.

To evaluate the therapeutic potential of curcumin tagged cilostazol solid nano dispersion in wistar rat streptozotocin-nicotinamide-induced diabetic nephropathy. Cilostazol (CLT), a Phosphodiesterase (PDE) inhibitor has an inhibitory effect on reactive oxygen species (ROS), and Curcumin (Cur), an antioxidant, and anti-inflammatory, are water-soluble. Solid Nano dispersions were developed using the "Box-Behnken Design" and emulsion solvent evaporation procedure to improve the solubility and bioavailability. Streptozotocin (SPZ) and Nicotinamide (NA) caused diabetes in Wistar rats. DN developed 30-45 days after disease induction. All rat groups underwent histological, biochemical and pharmacokinetic evaluation. The optimized batch of Cilostazol Loaded Novel Curcumin Tagged Solid Nanodispersion (CLT-15 SND) estimated renal, lipid, and cytokine profiles better than the conventional batch. CLT-15 SND, given orally to diabetic rats for 45 days, significantly lowered fasting BGL and IL-6 levels and improved lipid and kidney-profile markers and body weight compared to plain Cilostazol Loaded Solid Nanodispersion (CLT-15 WC SND). CLT-15 SND treatment groups showed decreased blood glucose by 3.38 and 9.71 percent, increased body weight by 2.81 and 5.27 percent, improved Interleukin-6 (IL-6) by 21.36 and 18.36 percent, improved urine albumin levels by 5.67 and 14.19 percent and creatinine levels by 3.125 and 37.5 percent, improved serum urea by 30.48 percent, increased serum albumin by 2.59 and 11.18 percent, and decreased creatinine and 5.03 and 8.12 percent, respectively as compared to CLT-15 WC and MP treatment animal groups. CLT and Cur reduced IL-6, kidney, and lipid markers, demonstrating their renoprotective and pancreas-protective effects. CLT and Cur's inhibition may be the mechanism.

Nano Architect-Based Targeted Delivery Systems for Diabetic Nephropathy: A Review.

Diabetes mellitus is a long-lasting disease that is very common in the age group above 20 years and is characterized by hyperglycemia with other complications like Diabetic Nephropathy (DN). The management of DN focuses on mainly four regions: reduction of cardiovascular risks, control of blood glycemic levels, control of the blood pressure (BP) profile, and the use of therenin-angiotensin system (RAS). Although BP management and RAS-acting agents can postpone the onset of DN, they cannot prevent it. In the modern era, nanotechnological interventions have spread rapidly in the field of medicine. Patient defiance is considered important in diabetes management when long-term or continuous management is required. Nano pharmaceuticals have been shown to increase compliance of diabetic patients by providing multiple ways of drug delivery, controlling release profile, increasing biological steadiness, targeting efficacy, and decreasing toxic profile. Nanoscale formulations of botanical antidiabetic molecules improve clinical efficacy and treatment compliance by overcoming associated biopharmaceutical and pharmacokinetic barriers. Therefore, the development of nanopharmaceuticals can be considered to be a possible answer to attain the finest scientific effect of the plant-based anti-diabetic molecule. Nevertheless, further studies are needed to create clinical research-based and therapeutically effective nanoforms of antidiabetic plant-based molecules to combat the most dreaded disease of diabetes and its known present complications.

Designing regression approach for mode frequency prediction of empty and filled steel silos.

In this study the primary objective is to design prediction model for the free vibration analysis of thin circular cylindrical steel silos having various aspect ratios in empty and varying filled conditions for different types of closures. A finite element method (FEM) is used to carry out the free vibration analysis of steel silos. It is found that the effect of different aspect ratios slender, intermediate slender and squat steel silos is very significant for dynamic response of silo. The silos are considered having open, flat and cone type of closures at its top end. The clamped-free (cantilever) boundary condition is taken for this approach as actual silos are fixed at flat-base. The structural mass of thin cylindrical shell steel silo is made constant for a particular height and diameter. The eigenvalues of the thin cylindrical shell steel silos are extracted by using block Lanczos method. The free vibrations of thin cylindrical shell steel silo with different aspect ratios, radius to thickness ratio are studied. From the present studies it is seen that as aspect ratio increases the fundamental frequency is reduced in empty silo. It is more in the case of squat silo. It can be seen that the fundamental frequency is less in the case of flat closure in all the aspect ratios of the silo. The frequency values are more in the case of cone closure is observed. Also as the mode number increases the modal frequency value increases. Further, as the filling level is increased the modal frequency also increases. Finally, regression approach is adopted for predicting the mode frequency of empty and filled silos for wide range of aspect ratios.

Inhibition of ovarian cancer cell proliferation by a cell cycle inhibitory peptide fused to a thermally responsive polypeptide carrier.

Current treatment of solid tumors is limited by normal tissue tolerance, resulting in a narrow therapeutic index. To increase drug specificity and efficacy and to reduce toxicity in normal tissues, we have developed a polypeptide carrier for a cell cycle inhibitory peptide, which has the potential to be thermally targeted to the tumor site. The design of this polypeptide is based on elastin-like polypeptide (ELP). The coding sequence of ELP was modified by the addition of the cell penetrating peptide Bac-7 at the N-terminus and a 23 amino acid peptide derived from p21 at the C-terminus (Bac-ELP1-p21). Bac-ELP1-p21 is soluble in aqueous solutions below physiological temperature (37 degrees C) but aggregates when the temperature is raised above 39 degrees C, making it a promising thermally responsive therapeutic carrier that may be actively targeted to solid tumors by application of focused hyperthermia. While Bac-ELP1-p21 at 37 degrees C did not have any effect on SKOV-3 cell proliferation, the use of hyperthermia increased the antiproliferative effect of Bac-ELP1-p21 compared with a thermally unresponsive control polypeptide. Bac-ELP1-p21 displayed both a cytoplasmic and nuclear distribution in the SKOV-3 cells, with nuclear-localized polypeptide enriched in the heated cells, as revealed by confocal microscopy. Using Western blotting, we show that Bac-ELP1-p21 caused a decrease in Rb phosphorylation levels in cells treated at 42 degrees C. The polypeptide also induced caspase activation, PARP cleavage, and cell cycle arrest in S-phase and G2/M-phase. These studies indicate that ELP is a promising macromolecular carrier for the delivery of cell cycle inhibitory peptides to solid tumors.