Amelioration of endothelial integrity by 3,5,4'-trihydroxy-trans-stilbene against high-fat-diet-induced obesity and -associated vasculopathy and myocardial infarction in rats, targeting TLR4/MyD88/NF-κB/iNOS signaling cascade.

Exacerbated expression of TLR4 protein (foremost pattern recognition receptor) during obesity could trigger NF-κB/iNOS signaling through linker protein (MyD88), predisposed to an indispensable inflammatory response. The induction of this detrimental cascade leads to myocardial and vascular abnormalities. Molecular docking was studied for protein-ligand interaction between these potential targets and resveratrol. The pre-treatment of resveratrol (20 mg/kg/p.o/per day for ten weeks) was given to investigate the therapeutic effect against HFD-induced obesity and associated vascular endothelial dysfunction (VED) and myocardial infarction (MI) in Wistar rats. In addition to accessing the levels of serum biomarkers for VED and MI, oxidative stress, inflammatory cytokines, and histopathology of these tissues were investigated. Lipopolysaccharide (for receptor activation) and protein expression analysis were introduced to explore the mechanistic involvement of TLR4/MyD88/NF-κB/iNOS signaling. Assessment of in-silico analysis showed significant interaction between protein and ligand. The involvement of this proposed signaling (TLR4/MyD88/NF-κB/iNOS) was further endorsed by the impact of lipopolysaccharide and protein expression analysis in obese and treated rats. Moreover, resveratrol pre-treated rats showed significantly lowered cardio and vascular damage measured by the distinct down expression of the TLR4/MyD88/NF-κB/iNOS pathway by resveratrol treatment endorses its ameliorative effect against VED and MI.

Dysbiosis versus diabesity: Pathological signaling and promising therapeutic strategies.

A healthy life depends on the inseparable relationship between a host and the gut microbiota. A healthy gut microbiota regulates intestinal integrity, whereas an unbalanced gut microbiota contributes to junctional remodeling and leads to dysbiosis. Bacterial infiltration and dysbiosis are reported to activate a series of pathological cascades that trigger metabolic abnormalities, including diabesity. Conversely, recent studies revealed that the incidence of dysbiosis itself is fuelled by diabesity. In this review, we highlight the molecular aspects of multifaceted pathological signaling between dysbiosis and diabetes that could pave the way for new drug discovery. Moreover, to reinstate the gut microbiota and restrict the epidemic of dysbiosis and diabesity, we also scrutinize a promising therapeutic strategy that can challenge the pathological interlink.