Inflammation is the response of the body's immune system to harmful stimuli. The expression of phosphodiesterase 4 enzyme (PDE4) was demonstrated in many inflammatory cells. Thus, it was considered an attractive therapeutic target for combating inflammatory disorders. In the present study, a novel class of quinazolin‐2,4‐dione analogues 1‐17a,b was synthesized. Structures of the newly synthesized compounds were characterized by means of spectral and elemental analysis. Additionally, molecular docking studies for the new synthetic compounds were performed using PyRx—virtual screening tool to demonstrate the possible binding pattern mode of interactions within the active site region of the PDE4 enzyme. The antiinflammatory activity of the synthesized compounds was also in vitro examined using inhibition of protein denaturation, anti‐proteinase effect, and membrane stabilization assay. The in silico docking studies revealed that the newly synthesized compounds were well accommodated by the active site region of the target protein through a network of noncovalent interactions such as hydrogen bonds and pi‐stacking, which contributed to the enhancement of affinity and stability between the compounds and the target protein. They exhibited better docking scores when compared with reference drugs diclofenac and coumarin. In addition, in vitro testing revealed that the compounds had moderate to good antiinflammatory effects. The biological study agreed with in silico approach, which revealed that the compounds had promising antiinflammatory activity. Hence, our detailed results can facilitate the rational drug design targeting PDE4 enzyme.

Non-alcoholic fatty liver disease (NAFLD) constitutes a major health problem worldwide and intimately links with obesity and diabetes. This study aimed to explore the therapeutic impact of early treatment with metformin (MTF) alone or in combination with Lactobacillus reuteri DSM 17938 ( L. reuteri) + metronidazole (MTZ) in male Sprague Dawley rats with high-fat diet (HFD)-induced NAFLD. Hepatic steatosis was induced by feeding rats HFD for 6 weeks. MTF (150 mg/kg/day) or L. reuteri (2 × 109 colony forming unit/day) were given orally for 4 weeks; meanwhile, MTZ (15 mg/kg/day, p.o.) was administered for 1 week. Administration of L. reuteri + MTZ in combination with MTF produced a superior effect concerning insulin resistance (IR), lipid profile, liver function, oxidative stress, inflammatory and autophagic markers than using each treatment alone. Besides, this combination resulted in disappearance of steatosis, inflammation and vacuolation within hepatic architecture. Moreover, it normalized short chain fatty acids (SCFAs) as well as Firmicutes and Bacteroidetes faecal contents. In conclusion, early treatment with L. reuteri + MTZ in combination with MTF could prevent NAFLD progression and liver injury through targeting gut dysbiosis, inflammation and autophagic pathways.

IFN-β (Rebif) is a drug with valuable cancer therapeutic potential as it mediates anti-proliferation and apoptosis induction. Therefore, this study aimed to evaluate the anti-proliferation of IFN-β through assessing gene expression of p53 and caspase-3 in hepatocellular carcinoma cell (HCC) line (HepG2). The 50% inhibition viability concentration (IC50) of IFN-β was calculated by cytotoxicity assay, and it was tested on normal cell line (Vero). After treating HepG2 cells with IFN-β, p53 and caspase-3 expression was analyzed, at time intervals of 2, 4, 6, and 24 hrs, by real-time PCR, histopathology and immunohistochemistry. IC50 of IFN-β was 420 µg/ml, which wasn't cytotoxic on normal cells. P53 expression was gradually up-regulated by time, and then, it was decreased after 24 hrs incubation. However, no expression of caspase-3 was detected compared to cell control. Histopathologically, cells degeneration was remarkable after 24 hrs while no change was noticed in control. Immunohistochemical analysis revealed a decline of p53 and caspase-3 expression in treated cells with IFN-β, after 24 hrs, to 30% compared to cell control (50% and 60%, respectively). IFN-β has the potential to be utilized as a suppressor of HCC proliferation and inducer of malignant cells apoptosis.

No abstract

No abstract