Erucin exhibits vasorelaxing effects and antihypertensive activity by H2 S-releasing properties.

BACKGROUND AND PURPOSE: Hydrogen sulfide (H2 S)-releasing agents are viewed as potential antihypertensive drugs. Recently, natural isothiocyanates emerged as original H2 S-donor agents. Among them, erucin, present in some edible cruciferous plants, shows suitable H2 S-releasing properties and features of "druggability." The aim of this work was to investigate the erucin-mediated release of H2 S inside vascular cells, its vasorelaxing effects, and activity on BP of normo and hypertensive animals. EXPERIMENTAL APPROACH: Intracellular H2 S-release and the hyperpolarizing effect of erucin were tested using fluorescent dye, in human aortic smooth muscle cells (HASMCs). Its direct vasorelaxing effect and ability to inhibit noradrenaline-induced vasoconstriction were evaluated on endothelium-intact or -denuded rat aortic rings. Its vasodilator properties were tested in coronary arteries using Langendorff-perfused rat hearts. Finally, erucin's antihypertensive activity was evaluated in vivo in normotensive and spontaneously hypertensive rats (SHRs) by recording systolic BP using the tail-cuff method. KEY RESULTS: Erucin induced the release of H2 S inside HASMCs. Moreover, erucin hyperpolarized the membrane of HASMCs membrane in a concentration-dependent manner. It induced vasodilatation of rat aortic rings, in endothelium-denuded vessels. This effect was further improved by the presence of endothelial NO. When pre-incubated with rat aortic rings, erucin induced concentration-dependent inhibition of noradrenaline-induced vasoconstriction. Erucin did not affect basal coronary flow but restored the flow to normal in pre-contracted coronary vessels. Finally, in vivo, erucin decreased systolic BP in SHRs by about 25%, and restored the BP to values observed in normotensive rats. CONCLUSIONS AND IMPLICATIONS: Erucin is an H2 S donor endowed with vasorelaxing and antihypertensive effects

The effect of thermal processes on the organoleptic and nutraceutical quality of tomato fruit (Solanum lycopersicum L.)

The present study investigated the changes in the organoleptic characteristics, nutraceuticals, and antioxidant activity of tomato fruits subjected to different thermal processes: tomato sauce (80 ◦C for 30 min), blanching treatment (100 ◦C for 10 s), and the superheated steam method (SHS; 100 ◦C for 7 min) compared with fresh tomato fruit. Even though SHS negatively modified the color of the product (L* −7% than fresh tomatoes), it was the only technology able to increase the antioxidant activity compared with fresh tomatoes (e.g., +40.3% in ABTS assay), whilst lycopene and ascorbic acid contents reported similar values to fresh tomatoes. Regarding lycopene, only 5Z-lycopene (with a higher bioavailability than (all-E)-isomers) was found in all samples, and SHS maintained the same level observed in fresh tomato fruit. Furthermore, SHS technology preserved the antioxidant effects of fresh tomato extract even in human endothelial cells. This result confirmed those obtained in previous “cell-free” assays and demonstrated that SHS treatment significantly maintains the biological properties of tomato fruit in preventing oxidative stress. However, heat-treated tomato extracts did not show the same effects as fresh tomato extract against noradrenaline-induced vasoconstriction in isolated rat aortic rings. This study demonstrates that the use of SHS technology can be considered an innovative and sustainable thermal process (in terms of maintaining the nutraceutical quality) for tomato fruits, thus paving the way for future investigations on the effects of fresh and heat-treated tomatoes after intestinal absorption in vitro and in viv

Antioxidant and antisenescence effects of bergamot juice

Aging is one of the main risk factor for the onset of cardiovascular diseases; one of the possible explanations could be linked to the age-associated overproduction of free radicals. This increase of oxidative stress can be overcome with a high intake of food antioxidants. In this context, a number of studies have been addressed to assess the antiaging potential of natural antioxidant compounds. Recently, it has been shown that the juice of bergamot (Citrus bergamia Risso et Poiteau), a fruit mostly produced in the Ionian coastal areas of Southern Italy (Calabria), is a valuable source of health-promoting constituents with, among other, antioxidant properties. In order to investigate the potential antiaging effects of this Mediterranean natural antioxidant source, bergamot juices of three different cultivars ("fantastico," "femminello," and "castagnaro") were herein characterized by the mean of high-performance liquid chromatography-photodiode array-electrospray ionization-tandem mass spectrometry. Then, juices were investigated for the evaluation of total polyphenolic and flavonoid contents, cell-free model antioxidant activities, and in vitro antiaging properties on two different cellular models of induced myocardial senescence. The best performing juice was also assessed in vivo. The phytochemical profiles confirmed that juices were rich in flavonoids, both flavone and flavanone glycosides. In addition, two limonoid glycosides were also identified in all cultivars. Each cultivar showed different phenolic and flavonoid contents. In tube results showed the juice robust antioxidant activities that correlate with their phenolic and flavonoid contents. Moreover, for the first time, the ability of juice to counteract the chemical-induced senescence was here demonstrated in both cellular models. Lastly, the in vivo data obtained from mouse hearts evidenced an increase in transcription of genes involved in antiaging and antioxidant responses. The overall results suggest that bergamot juice exerts antioxidant and antisenescence effects, making it useful for nutraceutical purposes

Red Blood Cell and Endothelial eNOS Independently Regulate Circulating Nitric Oxide Metabolites and Blood Pressure

Background: Current paradigms suggest that nitric oxide (NO) produced by endothelial cells (ECs) through endothelial nitric oxide synthase (eNOS) in the vessel wall is the primary regulator of blood flow and blood pressure. However, red blood cells (RBCs) also carry a catalytically active eNOS, but its role is controversial and remains undefined. This study aimed to elucidate the functional significance of RBC eNOS compared with EC eNOS for vascular hemodynamics and nitric oxide metabolism. Methods: We generated tissue-specific loss- and gain-of-function models for eNOS by using cell-specific Cre-induced gene inactivation or reactivation. We created 2 founder lines carrying a floxed eNOS (eNOSflox/flox) for Cre-inducible knockout (KO), and gene construct with an inactivated floxed/inverted exon (eNOSinv/inv) for a Cre-inducible knock-in (KI), which respectively allow targeted deletion or reactivation of eNOS in erythroid cells (RBC eNOS KO or RBC eNOS KI mice) or in ECs (EC eNOS KO or EC eNOS KI mice). Vascular function, hemodynamics, and nitric oxide metabolism were compared ex vivo and in vivo. Results: The EC eNOS KOs exhibited significantly impaired aortic dilatory responses to acetylcholine, loss of flow-mediated dilation, and increased systolic and diastolic blood pressure. RBC eNOS KO mice showed no alterations in acetylcholine-mediated dilation or flow-mediated dilation but were hypertensive. Treatment with the nitric oxide synthase inhibitor Nγ-nitro-l-arginine methyl ester further increased blood pressure in RBC eNOS KOs, demonstrating that eNOS in both ECs and RBCs contributes to blood pressure regulation. Although both EC eNOS KOs and RBC eNOS KOs had lower plasma nitrite and nitrate concentrations, the levels of bound NO in RBCs were lower in RBC eNOS KOs than in EC eNOS KOs. Reactivation of eNOS in ECs or RBCs rescues the hypertensive phenotype of the eNOSinv/invmice, whereas the levels of bound NO were restored only in RBC eNOS KI mice. Conclusions: These data reveal that eNOS in ECs and RBCs contribute independently to blood pressure homeostasis

Pharmacological modulation of the hydrogen sulfide (H2S) system by dietary H2S-donors: A novel promising strategy in the prevention and treatment of type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) represents the most common age-related metabolic disorder, and its management is becoming both a health and economic issue worldwide. Moreover, chronic hyperglycemia represents one of the main risk factors for cardiovascular complications. In the last years, the emerging evidence about the role of the endogenous gasotransmitter hydrogen sulfide (H2S) in the pathogenesis and progression of T2DM led to increasing interest in the pharmacological modulation of endogenous “H2S-system”. Indeed, H2S directly contributes to the homeostatic maintenance of blood glucose levels; moreover, it improves impaired angiogenesis and endothelial dysfunction under hyperglycemic conditions. Moreover, H2S promotes significant antioxidant, anti-inflammatory, and antiapoptotic effects, thus preventing hyperglycemia-induced vascular damage, diabetic nephropathy, and cardiomyopathy. Therefore, H2S-releasing molecules represent a promising strategy in both clinical management of T2DM and prevention of macro- and micro-vascular complications associated to hyperglycemia. Recently, growing attention has been focused on dietary organosulfur compounds. Among them, garlic polysulfides and isothiocyanates deriving from Brassicaceae have been recognized as H2S-donors of great pharmacological and nutraceutical interest. Therefore, a better understanding of the therapeutic potential of naturally occurring H2S-donors may pave the way to a more rational use of these nutraceuticals in the modulation of H2S homeostasis in T2DM

Hydrogen sulfide: The hidden player of isothiocyanates pharmacology

Hydrogen sulfide (H 2 S) is an endogenous gasotransmitter that exhibits a plethora of beneficial effects in numerous systems (i.e. cardiovascular system and central nervous system). In particular, H 2 S promotes anti-inflammatory, antioxidant, anti-hypertensive, and cardioprotective properties, thus playing a crucial role in maintaining tissue homeostasis. Accordingly, an impairment in the biosynthesis of H 2 S has been described in the etiopathogenesis of many pathological conditions. Therefore, to ensure a "physiological" balance in the endogenous levels of H 2 S through H 2 S-donors represents an intriguing pharmacological strategy to prevent and/or treat several "H 2 S-poor" pathologies. Among H 2 S-releasing moieties, isothiocyanates (ITCs) have been recently recognized as "smart" H 2 S-donors, as they show a long-lasting and thiol-dependent H 2 S release. Accordingly, both natural and synthetic ITCs promote antioxidant, anti-inflammatory, antiviral, cardioprotective, anticancer, and anti-nociceptive properties. This impressive overlap in the effects exhibited by H 2 S and ITCs also helps for an understanding of their mechanism of action, as they modulate the same intracellular signaling pathways mainly through S-sulfhydration reactions. Finally, both H 2 S and ITCs show a peculiar dualism in their effects, promoting beneficial properties at low concentrations and toxic effects at high doses. This opposite behavior (known as "hormesis") further suggests that H 2 S plays a crucial role in the health-promoting effects of structurally heterogeneous ITCs, "unmasking" the hidden player in the isothiocyanate pharmacology

Resveratrol-like Compounds as SIRT1 Activators

The sirtuin 1 (SIRT1) activator resveratrol has emerged as a promising candidate for the prevention of vascular oxidative stress, which is a trigger for endothelial dysfunction. However, its clinical use is limited by low oral bioavailability. In this work, we have applied a previously developed computational protocol to identify the most promising derivatives from our in-house chemical library of resveratrol derivatives. The most promising compounds in terms of SIRT1 activation and oral bioavailability, predicted in silico, were evaluated for their ability to activate the isolated SIRT1 enzyme. Then, we assessed the antioxidant effects of the most effective derivative, compound 3d, in human umbilical vein endothelial cells (HUVECs) injured with H2O2 100 µM. The SIRT1 activator 3d significantly preserved cell viability and prevented an intracellular reactive oxygen species increase in HUVECs exposed to the oxidative stimulus. Such effects were partially reduced in the presence of a sirtuin inhibitor, sirtinol, confirming the potential role of sirtuins in the activity of resveratrol and its derivatives. Although 3d appeared less effective than resveratrol in activating the isolated enzyme, the effects exhibited by both compounds in HUVECs were almost superimposable, suggesting a higher ability of 3d to cross cell membranes and activate the intracellular target SIRT1

Adherence to Oral Antidiabetic Drugs in Patients with Type 2 Diabetes: Systematic Review and Meta-Analysis

Poor adherence to oral antidiabetic drugs (OADs) in patients with type 2 diabetes (T2D) can lead to therapy failure and risk of complications. The aim of this study was to produce an adherence proportion to OADs and estimate the association between good adherence and good glycemic control in patients with T2D. We searched in MEDLINE, Scopus, and CENTRAL databases to find observational studies on therapeutic adherence in OAD users. We calculated the proportion of adherent patients to the total number of participants for each study and pooled study-specific adherence proportions using random effect models with Freeman–Tukey transformation. We also calculated the odds ratio (OR) of having good glycemic control and good adherence and pooled study-specific OR with the generic inverse variance method. A total of 156 studies (10,041,928 patients) were included in the systematic review and meta-analysis. The pooled proportion of adherent patients was 54% (95% confidence interval, CI: 51–58%). We observed a significant association between good glycemic control and good adherence (OR: 1.33; 95% CI: 1.17–1.51). This study demonstrated that adherence to OADs in patients with T2D is sub-optimal. Improving therapeutic adherence through health-promoting programs and prescription of personalized therapies could be an effective strategy to reduce the risk of complications