No abstract

Canagliflozin (CFZ) is a sodium-glucose cotransporter-2 inhibitor (SGLT2) that lowers albuminuria in type-2 diabetic patients, cardiovascular, kidney, and liver disease. CFZ is classified as class IV in the Biopharmaceutical Classification System (BCS) and is characterized by low permeability, solubility, and bioavailability, most likely attributed to hepatic first-pass metabolism. Nanocrystal-based sublingual formulations were developed in the presence of sodium caprate, as a wetting agent, and as a permeability enhancer. This formulation is suitable for children and adults and could enhance solubility, permeability, and avoid enterohepatic circulation due to absorption through the sublingual mucosa. In the present study, formulations containing various surfactants (P237, P338, PVA, and PVP K30) were prepared by the Sono-homo-assisted precipitation ion technique. The optimized formula prepared with PVP-K30 showed the smallest particle size (157 ± 0.32 nm), Zeta-potential (−18 ± 0.01), and morphology by TEM analysis. The optimized formula was subsequently formulated into a sublingual tablet containing Pharma burst-V® with a shorter disintegration time (51s) for the in-vivo study. The selected sublingual tablet improved histological and biochemical markers (blood glucose, liver, and kidney function), AMP-activated protein kinase (AMPK), and protein kinase B (AKT) pathway compared to the market formula, increased CFZ’s antidiabetic potency in diabetic rabbits, boosted bioavailability by five-fold, and produced faster onset of action. These findings suggest successful treatment of diabetes with CFZ nanocrystal-sublingual tablets.

Background: Fibromyalgia (FM) is characterized by musculoskeletal pain, fatigue, sleep and memory disturbance. There is no definitive cure yet for FM-related health problems. Peroxisome proliferator-activated receptor's (PPAR's) activation is associated with insulin sensitisation and improved glucose metabolism. PPAR-c was reported to alleviate FM allodynia. Limited data are discussing its effect on motor disorders. Objective: To investigate the potential effect of PPAR-c agonists (pioglitazone, as one member of thiazolidinediones (TZD)) on motor dysfunction in reserpine-induced FM in a rat model. Materials and methods: Thirty-six male Wistar rats were divided into negative control (n ¼ 9) and reserpine-induced FM (n ¼ 27) groups. The latter was subdivided into three equal subgroups (n ¼ 9), positive control (untreated FM model), pioglitazone-treated and GW9662-treated. We evaluated muscle functions and activity of chloramphenicol acetyltransferase, superoxide dismutase, malondialdehyde, and serum levels of interleukin-8 and monocyte chemoattractant protein-1. Results: Pioglitazone significantly relieved fatigue, improved muscle performance, reduced inflammatory cytokines and enhanced antioxidant's activity, while GW9662, a known PPAR-c antagonist, aggravated the FM manifestations in the rat model. Conclusion: PPAR-c agonists show a promising role against FM-associated motor dysfunctions.

Aluminum, the third most plentiful metal in the Earth’s crust, has potential for human exposure and harm. Oxidative stress plays an essential role in producing male infertility by inducing defects in sperm functions. We aimed to investigate the role of endoplasmic reticulum (ER) stress and mitochondrial injury in the pathogenesis of aluminum chloride (AlCl3)-induced testicular and epididymal damage at the histological, biochemical, and molecular levels, and to assess the potential protective role of taurine. Forty-eight adult male albino rats were separated into four groups (12 in each): negative control, positive control, AlCl3, and AlCl3 plus taurine groups. Testes and epididymis were dissected. Histological and immunohistochemical (Bax and vimentin) studies were carried out. Gene expression of vimentin, PCNA, CHOP, Bcl-2, Bax, and XBP1 were investigated via quantitative real-time polymerase chain reaction (qRT-PCR), besides estimation of malondialdehyde (MDA) and total antioxidant capacity (TAC). Light and electron microscopic examinations of the testes and epididymis revealed pathological changes emphasizing both mitochondrial injury and ER stress in the AlCl3 group. Taurine-treated rats showed a noticeable improvement in the testicular and epididymal ultrastructure. Moreover, they exhibited increased gene expression of vimentin, Bcl-2, and PNCA accompanied by decreased CHOP, Bax, and XBP1 gene expression. In conclusion, male reproductive impairment is a significant hazard associated with AlCl3 exposure. Both ER stress and mitochondrial impairment are critical mechanisms of the deterioration in the testes and epididymis induced by AlCl3, but taurine can amend this.