ABSTRACT
Nutritional overload in the form of high-fat and nonglycolysis sugar intake contributes towards the accelerated creation of reactive oxygen species (ROS), hyperglycemia, and dyslipidemia. Glucose absorption and its subsequent oxidation processes in fat and muscle tissues alter as a consequence of these modifications. Insulin resistance (IR) caused glucose transporter 4 (GLUT4) translocation to encounter a challenge that manifested itself as changes in glycolytic pathways and insulin signaling. We previously found that beta (ß)-sitosterol reduces IR in fat tissue via IRS-1/PI3K/Akt facilitated signaling due to its hypolipidemic and hypoglycemic activity. The intention of this research was to see whether the phytosterol ß-sitosterol can aid in the translocation of GLUT4 in rats fed on high-fat diet (HFD) and sucrose by promoting Rab/IRAP/Munc 18 signaling molecules. The rats were labeled into four groups, namely control rats, HFD and sucrose-induced diabetic control rats, HFD and sucrose-induced diabetic rats given oral dose of 20 mg/kg body wt./day of ß-sitosterol treatment for 30 days, and HFD and sucrose-induced diabetic animals given oral administration of 50 mg/kg body wt./day metformin for 30 days. Diabetic rats administered with ß-sitosterol and normalized the titers of blood glucose, serum insulin, serum testosterone, and the status of insulin tolerance and oral glucose tolerance. In comparison with the control group, ß-sitosterol effectively regulated both glycolytic and gluconeogenesis enzymes. Furthermore, qRT-PCR analysis of the mRNA levels of key regulatory genes such as SNAP23, VAMP-2, syntaxin-4, IRAP, vimentin, and SPARC revealed that ß-sitosterol significantly regulated the mRNA levels of the above genes in diabetic gastrocnemius muscle. Protein expression analysis of Rab10, IRAP, vimentin, and GLUT4 demonstrated that ß-sitosterol had a positive effect on these proteins, resulting in effective GLUT4 translocation in skeletal muscle. According to the findings, ß-sitosterol reduced HFD and sucrose-induced IR and augmented GLUT4 translocation in gastrocnemius muscle through insulin signaling modulation via Rab/IRAP/Munc 18 and glucose metabolic enzymes. The present work is the first of its kind to show that ß-sitosterol facilitates GLUT4 vesicle fusion on the plasma membrane via Rab/IRAP/Munc 18 signaling molecules in gastrocnemius muscle.
ABSTRACT
The impact of a soluble complex (SC) of curcumin (CuR) synthesized using hot melt (HM) and hot-melt extrusion (HE) technologies on adenocarcinoma cells for the treatment of colorectal cancer by enhancing CuR solubility is investigated in this work. In silico molecular modelling, solubility, drug release, and physicochemical analysis were all part of the phase solubility (PS) study, which featured a novel dyeing test and a central composite design to optimize the best complex (CDD). The optimal HE-SC (1 : 5) enhances solubility (0.8521 ± 0.016 mg·mL-1) and dissolution (91.87 ± 0.208% at 30 min), and it has an ideal stability constant (309 and 377 M-1) at 25 and 37°C and an AL type of isotherm, implying 1 : 1 stoichiometry according to the findings. An intermolecular hydrogen bond that has not undergone any chemical change and has resulted in the complete conversion of the amorphous form aids in the creation of SC. In vitro cytotoxicity was measured at IC50 on the SW480 (72 M·mL-1) and Caco-2 (40 M·mL-1) cells. According to apoptotic studies, apoptosis was responsible for the vast majority of cell death, with necrosis accounting for a small proportion of the total. In vivo toxicity was established using a zebrafish model, and a western blot examination revealed apoptosis at the molecular level. It was argued that the novel formulations developed using HE technology are more significant and effective than existing pure CuR formulations.