Insulin resistance and diabetes are associated with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) conditions, which are distinguished by metabolic dysfunction, oxidative stress and inflammation. Sirtuin 1 (SIRT1), a NAD⁺-dependent deacetylase, is fundamental in regulating metabolic pathways, reducing inflammation, and improving antioxidant defenses. This is the first study to investigate the effects of SRT1720, a SIRT1 activator, in diabetic rats on a high-fat diet. SRT1720 significantly lowered fasting blood glucose and insulin levels and enhanced glucose tolerance and HOMA-IR and QUICKI scores, indicating increased insulin sensitivity. The treatment also reduced total cholesterol, triglycerides, and LDL levels, showing amelioration of dyslipidemia. Moreover, SRT1720 lowered markers of liver fibrosis, including TGF-β, TIMP-1, Col1a1, and hydroxyproline, and decreased inflammation by reducing NFκB activity and pro-inflammatory cytokines (TNF-α and IL-6). Furthermore, SRT1720 augmented Nrf2 activity and HO-1 levels. Consequently, the SRT1720's protective role improved liver function and histology and prolonged rats' survival. These functions were suppressed by the co-administration of the SIRT1 inhibitor EX527, confirming that the beneficial effects of SRT1720 are SIRT1-dependent. Correlation analyses uncovered that increased SIRT1 activity was strongly associated with decreased oxidative stress, inflammation, insulin resistance, and fibrosis markers. To conclude, our results find that SRT1720 represents a promising therapeutic strategy for managing Type 2 diabetes in NAFLD or NASH patients possibly through the modulation of the SIRT1/Nrf2/NFκB signaling pathwa. SRT1720 could potentially halt or reverse the progression of these conditions and associated complications and merits further investigations.

Islamic literature has indicated that daily consumption of Ajwa dates heals a variety of chronic diseases and disorders. The current research investigates the neuroprotective effect of methanolic Ajwa seed extract (MASE) on lipopolysaccharide (LPS)-induced cognitive deficits using multiple approaches. For animal studies, MASE (200 and 400 mg/kg, p.o.) was administrated for thirty consecutive days, and four doses of LPS (250 µg/kg, i.p.) were injected to induce neurotoxicity. Memory functions were evaluated using elevated plus-maze and novel object recognition tests. Acetylcholine (ACh) and neuroinflammatory markers (cyclooxygenase (COX)-2, tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10, and transforming growth factor (TGF)-β1) were estimated in brain tissues. Studies of molecular docking and dynamics were conducted to provide insight into the molecular-level mechanisms. MASE administration resulted in a significant reversal of LPS-induced memory impairment in both maze models. Both doses of MASE elevated the ACh levels in an LPS-treated rat brain. In addition, the extract lowered COX-2 and proinflammatory cytokines (TNF-α and IL-6) while increasing anti-inflammatory cytokines (IL-10 and TGF-β1) in LPS-treated brain tissues. Molecular modeling results revealed that the compound’s ellagic acid, epicatechin, catechin, kaempferol, quercetin, and apigenin have the potential to act as a dual inhibitor of acetylcholinesterase (AChE) and COX-2 and can be responsible for the improvement of both cholinergic and inflammatory conditions, while the cinnamic acid, hesperidin, hesperetin, narengin, and rutin compounds are responsible only for the improvement of cholinergic transmission. The above compounds acted by interacting with the key residues Trp84, Asp72, Gly118, Ser200, Tyr334, and His440, which are responsible for the hydrolysis of ACh in AChE, while the COX-2 is inhibited by interacting with the residues (Val349, Leu352, Tyr355, Tyr385, Ala527, Ser530, and Leu531) of the hydrophobic channel. By promoting cholinergic activity and protecting neuroinflammation in the rat brain, MASE provides neuroprotection against LPS-induced cognitive deficits. Our preliminary findings will help with further drug discovery processes related to neuroinflammation-related neurodegeneration.