Amelioration of perivascular adipose inflammation reverses vascular dysfunction in a model of nonobese prediabetic metabolic challenge: potential role of antidiabetic drugs.

The onset of vascular impairment precedes that of diagnostic hyperglycemia in diabetic patients suggesting a vascular insult early in the course of metabolic dysfunction without a well-defined mechanism. Mounting evidence implicates adipose inflammation in the pathogenesis of insulin resistance and diabetes. It is not certain whether amelioration of adipose inflammation is sufficient to preclude vascular dysfunction in early stages of metabolic disease. Recent findings suggest that antidiabetic drugs, metformin, and pioglitazone, improve vascular function in prediabetic patients, without an indication if this protective effect is mediated by reduction of adipose inflammation. Here, we used a prediabetic rat model with delayed development of hyperglycemia to study the effect of metformin or pioglitazone on adipose inflammation and vascular function. At the end of the metabolic challenge, these rats were neither obese, hypertensive, nor hyperglycemic. However, they showed increased pressor responses to phenylephrine and augmented aortic and mesenteric contraction. Vascular tissues from prediabetic rats showed increased Rho-associated kinase activity causing enhanced calcium sensitization. An elevated level of reactive oxygen species was seen in aortic tissues together with increased Transforming growth factor ß1 and Interleukin-1ß expression. Although, no signs of systemic inflammation were detected, perivascular adipose inflammation was observed. Adipocyte hypertrophy, increased macrophage infiltration, and elevated Transforming growth factor ß1 and Interleukin-1ß mRNA levels were seen. Two-week treatment with metformin or pioglitazone or switching to normal chow ameliorated adipose inflammation and vascular dysfunction. Localized perivascular adipose inflammation is sufficient to trigger vascular dysfunction early in the course of diabetes. Interfering with this inflammatory process reverses this early abnormality.

Tackling neuroinflammation and cholinergic deficit in Alzheimer's disease: Multi-target inhibitors of cholinesterases, cyclooxygenase-2 and 15-lipoxygenase.

Neuroinflammation and cholinergic deficit are key detrimental processes involved in Alzheimer's disease. Hence, in the search for novel and effective treatment strategies, the multi-target-directed ligand paradigm was applied to the rational design of two series of new hybrids endowed with anti-inflammatory and anticholinesterase activity via triple targeting properties, namely able to simultaneously hit cholinesterases, cyclooxygenase-2 (COX-2) and 15-lipoxygenase (15-LOX) enzymes. Among the synthesized compounds, triazoles 5b and 5d, and thiosemicarbazide hybrid 6e emerged as promising new hits, being able to effectively inhibit human butyrylcholinesterase (hBChE), COX-2 and 15-LOX enzymes with a higher inhibitory potency than the reference inhibitors tacrine (for hBChE inhibition), celecoxib (for COX-2 inhibition) and both NDGA and Zileuton (for 15-LOX inhibition). In addition, compound 6e proved to be a submicromolar mixed-type inhibitor of human acetylcholinesterase (hAChE). The anti-neuroinflammatory activity of the three most promising hybrids was confirmed in a cell-based assay using PC12 neuron cells, showing decreased expression levels of inflammatory cytokines IL-1ß and TNF-α. Importantly, despite the structural resemblance to tacrine, they showed ideal safety profiles on hepatic and murine brain cell lines and were safe up to 100 µM when assayed in PC12 cells. All three hybrids were also predicted to have superior BBB permeability than tacrine in the PAMPA assay, and good physicochemical properties, drug-likeness and ligand efficiency indices. Finally, molecular docking studies highlighted key structural elements impacting selectivity and activity toward the selected target enzymes. To the best of our knowledge, compounds 5b, 5d and 6e are the first balanced, safe and multi-target compounds hitting the disease at the three mentioned hubs.