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Perivascular adipose tissue (PVAT) is a specialized type of adipose tissue that surrounds most mammalian blood vessels. PVAT is a metabolically active, endocrine organ capable of regulating blood vessel tone, endothelium function, vascular smooth muscle cell growth and proliferation, and contributing critically to cardiovascular disease onset and progression. In the context of vascular tone regulation, under physiological conditions, PVAT exerts a potent anticontractile effect by releasing a plethora of vasoactive substances, including NO, H2S, H2O2, prostacyclin, palmitic acid methyl ester, angiotensin 1-7, adiponectin, leptin, and omentin. However, under certain pathophysiological conditions, PVAT exerts pro-contractile effects by decreasing the production of anticontractile and increasing that of pro-contractile factors, including superoxide anion, angiotensin II, catecholamines, prostaglandins, chemerin, resistin, and visfatin. The present review discusses the regulatory effect of PVAT on vascular tone and the factors involved. In this scenario, dissecting the precise role of PVAT is a prerequisite to the development of PVAT-targeted therapies.

Several studies demonstrate the beneficial effects of dietary flavonoids on the cardiovascular system. Since perivascular adipose tissue (PVAT) plays an active role in the regulation of vascular tone in both health and diseases, the present study aimed to assess the functional interaction between PVAT and flavonoids in vitro on rat aorta rings. Several flavonoids proved to display both antispasmodic and spasmolytic activities towards noradrenaline-induced contraction of rings deprived of PVAT (-PVAT). However, on PVAT-intact (+PVAT) rings, both actions of some flavonoids were lost and/or much decreased. In rings-PVAT, the superoxide donor pyrogallol mimicked the effect of PVAT, while in rings+PVAT the antioxidant mito-tempol restored both activities of the two most representative flavonoids, namely apigenin and chrysin. The Rho-kinase inhibitor fasudil, or apigenin and chrysin concentration-dependently relaxed the vessel active tone induced by the Rho-kinase activator NaF; the presence of PVAT counteracted apigenin spasmolytic activity, though only in the absence of mito-tempol. Similar results were obtained in rings pre-contracted by phenylephrine. Finally, when β3 receptors were blocked by SR59230A, vasorelaxation caused by both flavonoids was unaffected by PVAT. These data are consistent with the hypothesis that both noradrenaline and apigenin activated adipocyte β3 receptors with the ensuing release of mitochondrial superoxide anion, which once diffused toward myocytes, counteracted flavonoid vasorelaxant activity. This phenomenon might limit the beneficial health effects of dietary flavonoids in patients affected by either obesity and/or other pathological conditions characterized by sympathetic nerve overactivity.

A growing body of evidence underlines the crucial role of GPR55 in physiological and pathological conditions. In fact, GPR55 has recently emerged as a therapeutic target for several diseases, including cancer and neurodegenerative and metabolic disorders. Several lines of evidence highlight GPR55′s involvement in the regulation of microglia-mediated neuroinflammation, although the exact molecular mechanism has not been yet elucidated. Nevertheless, there are only a limited number of selective GPR55 ligands reported in the literature. In this work, we designed and synthesized a series of novel GPR55 ligands based on the 3-benzylquinolin-2(1H)-one scaffold, some of which showed excellent binding properties (with Ki values in the low nanomolar range) and almost complete selectivity over cannabinoid receptors. The full agonist profile of all the new derivatives was assessed using the p-ERK activation assay and a computational study was conducted to predict the key interactions with the binding site of the receptor. Our data outline a preliminary structure–activity relationship (SAR) for this class of molecules at GPR55. Some of our compounds are among the most potent GPR55 agonists developed to date and could be useful as tools to validate this receptor as a therapeutic target.

Si306, a pyrazolo[3,4-d]pyrimidine derivative recently identified as promising anticancer agent, has shown favorable in vitro and in vivo activity profile against neuroblastoma (NB) models by acting as a competitive inhibitor of c-Src tyrosine kinase. Nevertheless, Si306 antitumor activity is associated with sub-optimal aqueous solubility, which might hinder its further development. Drug delivery systems were here developed with the aim to overcome this limitation, obtaining suitable formulations for more efficacious in vivo use. Si306 was encapsulated in pegylated stealth liposomes, undecorated or decorated with a monoclonal antibody able to specifically recognize and bind to the disialoganglioside GD2 expressed by NB cells (LP[Si306] and GD2-LP[Si306], respectively). Both liposomes possessed excellent morphological and physio-chemical properties, maintained over a period of two weeks. Compared to LP[Si306], GD2-LP[Si306] showed in vitro specific cellular targeting and increased cytotoxic activity against NB cell lines. After intravenous injection in healthy mice, pharmacokinetic profiles showed increased plasma exposure of Si306 when delivered by both liposomal formulations, compared to that obtained when Si306 was administered as free form. In vivo tumor homing and cytotoxic effectiveness of both liposomal formulations were finally tested in an orthotopic animal model of NB. Si306 tumor uptake resulted significantly higher when encapsulated in GD2-LP, compared to Si306, either free or encapsulated into untargeted LP. This, in turn, led to a significant increase in survival of mice treated with GD2-LP[Si306]. These results demonstrate a promising antitumor efficacy of Si306 encapsulated into GD2-targeted liposomes, supporting further therapeutic developments in pre-clinical trials and in the clinic for NB.

Oxidative stress (OS) and the resulting reactive oxygen species (ROS) generation and inflammation play a pivotal role in the neuronal loss occurring during the onset of neurodegenerative diseases. Therefore, promising future drugs that would prevent or slow down the progression of neurodegeneration should possess potent radical-scavenging activity. Acacia catechu Willd. heartwood extract (AC), already characterized for its high catechin content, is endowed with antioxidant properties. The aim of the present study was to assess AC neuroprotection in both human neuroblastoma SH-SY5Y cells and rat brain slices treated with hydrogen peroxide. In SH-SY5Y cells, AC prevented a decrease in viability, as well as an increase in sub-diploid-, DAPI positive cells, reduced ROS formation, and recovered the mitochondrial potential and caspase-3 activation. AC related neuroprotective effects also occurred in rat brain slices as a reversal prevention in the expression of the main proteins involved in apoptosis and signalling pathways related to calcium homeostasis following OS-mediated injury. Additionally, unbiased quantitative mass spectrometry allowed for assessing that AC partially prevented the hydrogen peroxide-induced altered proteome, including proteins belonging to the synaptic vesicle fusion apparatus. In conclusion, the present results suggest the possibility of AC as a nutraceutical useful in preventing neurodegenerative diseases.