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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.

Vascular inflammation (VI) represents a pathological condition that progressively affects the integrity and functionality of the vascular wall, thus leading to endothelial dysfunction and the onset of several cardiovascular diseases. Therefore, the research of novel compounds able to prevent VI represents a compelling need. In this study, we tested erucin, the natural isothiocyanate H

Glaucoma is a group of eye diseases consisting of optic nerve damage with corresponding loss of field vision and blindness. Hydrogen sulfide (H

Natural sulfur compounds are emerging as therapeutic options for the management of hypertension and prehypertension. They are mainly represented by polysulfides from Alliaceae (i.e., garlic) and isothiocyanates from Brassicaceae (or crucifers). The beneficial cardiovascular effects of these compounds, especially garlic polysulfides, are well known and widely reported both in preclinical and clinical studies. However, only a few authors have linked the ability of natural sulfur compounds to induce vasorelaxation and subsequent antihypertensive effects with their ability to release hydrogen sulfide (H

Adipose tissue (AT) can be classified into two different types: (i) white adipose tissue (WAT), which represents the largest amount of total AT, and has the main function of storing fatty acids for energy needs and (ii) brown adipose tissue (BAT), rich in mitochondria and specialized in thermogenesis. Many exogenous stimuli, e.g., cold, exercise or pharmacological/nutraceutical tools, promote the phenotypic change of WAT to a beige phenotype (BeAT), with intermediate characteristics between BAT and WAT; this process is called “browning”. The modulation of AT differentiation towards WAT or BAT, and the phenotypic switch to BeAT, seem to be crucial steps to limit weight gain. Polyphenols are emerging as compounds able to induce browning and thermogenesis processes, potentially via activation of sirtuins. SIRT1 (the most investigated sirtuin) activates a factor involved in mitochondrial biogenesis, peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), which, through peroxisome proliferator-activated receptor γ (PPAR-γ) modulation, induces typical genes of BAT and inhibits genes of WAT during the transdifferentiation process in white adipocytes. This review article aims to summarize the current evidence, from pre-clinical studies to clinical trials, on the ability of polyphenols to promote the browning process, with a specific focus on the potential role of sirtuins in the pharmacological/nutraceutical effects of natural compounds.

Eruca sativa Mill. is an edible plant belonging to the Brassicaceae botanical family with a long story as a medicinal material, mainly linked to the presence of glucoerucin. One of the main products of this glucosinolate is erucin, a biologicallly active isothiocyanate recently recognized as a hydrogen sulfide (H

Despite the large number of biologics currently available for moderate-to-severe psoriasis, poor adherence and persistence to therapy represent the main issues for both the clinical and economic management of psoriasis. However, the data about adherence and persistence to biologics in psoriasis patients are conflicting. Our aim was to produce summary estimates of adherence and persistence to biologics in adult patients with psoriasis. We performed a systematic review and meta-analysis of observational studies, searching two databases (PubMed and Embase). Sixty-two records met the inclusion criteria, and a meta-analysis was conducted on fifty-five studies. Overall, the proportion of adherent and persistent patients to biological therapy was 0.61 (95% confidence interval: 0.48–0.73) and 0.63 (0.57–0.68), respectively. The highest proportions were found for ustekinumab, while the lowest ones were found for etanercept. The proportions of adherence and persistence to biological drugs in psoriasis patients are sub-optimal. Notably, both proportions largely differ between drugs, suggesting that a more rational use of biologics might ensure better management of psoriasis.

Vascular inflammation (VI) represents a pathological condition that progressively affects the integrity and functionality of the vascular wall, thus leading to endothelial dysfunction and the onset of several cardiovascular diseases. Therefore, the research of novel compounds able to prevent VI represents a compelling need. In this study, we tested erucin, the natural isothiocyanate H2S-donor derived from Eruca sativa Mill. (Brassicaceae), in an in vivo mouse model of lipopolysaccharide (LPS)-induced peritonitis, where it significantly reduced the amount of emigrated CD11b positive neutrophils. We then evaluated the anti-inflammatory effects of erucin in LPS-challenged human umbilical vein endothelial cells (HUVECs). The pre-incubation of erucin, before LPS treatment (1, 6, 24 h), significantly preserved cell viability and prevented the increase of reactive oxygen species (ROS) and tumor necrosis factor alpha (TNF-α) levels. Moreover, erucin downregulated endothelial hyperpermeability and reduced the loss of vascular endothelial (VE)-Cadherin levels. In addition, erucin decreased vascular cell adhesion molecule 1 (VCAM-1), cyclooxygenase-2 (COX-2) and microsomal prostaglandin E-synthase 1 (mPGES-1) expression. Of note, erucin induced eNOS phosphorylation and counteracted LPS-mediated NF-κB nuclear translocation, an effect that was partially abolished in the presence of the eNOS inhibitor L-NAME. Therefore, erucin can control endothelial function through biochemical and genomic positive effects against VI.

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.

Type 2 diabetes (T2D) is one of the main leading causes of mortality worldwide, and its global prevalence will increase within the next years. Many pre-clinical studies demonstrated the potential effects of edible plants from Alliaceae and Brassicaceae on the regulation of blood glucose levels. Of note, secondary metabolites from Alliaceae and Brassicaceae share the ability to slowly release hydrogen sulfide (H

Supplemental Digital Content is available in the text., 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/inv mice, 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.

The bergamot (Citrus bergamia Risso & Poiteau), a small tree cultivated along the Ionian coast of the Calabria region in Southern Italy, is an ancient plant used for the production of essential oil from fruit peel, but recently evaluated also for the high content of phenolics in the fruit pulp. Indeed, the juice is rich in glycosylated flavone and flavanones, showing a wide range of pharmacological activities. Noteworthy preclinical and clinical studies reported that bergamot juice is effective in reducing plasma lipids. The aim of this study was to evaluate the beneficial effects of a C. bergamia juice using an experimental animal model of metabolic syndrome and cardiovascular risk in vivo. A significant reduction of both triglyceride levels and cardiovascular risk was observed in animals fed with a high-fat diet and bergamot juice. Daily oral treatment with bergamot juice significantly limits a high-fat-induced increase in body, visceral adipose tissue, liver, and heart weight. In addition, C. bergamia juice showed protective effects on hepatic steatosis, probably due to the reduction of oxidative stress and inflammation. Chemical constituents of administered bergamot juice, investigated by means of liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) analyses were represented by a wide range of flavonoids, with neohesperidin, neoeriocitrin, and naringin being the most abundant flavonoids according to previous studies. Furthermore, a considerable amount of brutieridin, a flavanone O-glycoside having a 3-hydroxy-3-methyl-glutaryl residue, was observed.

Plants of the Brassicaceae family are well-known for containing the glucosinolate myrosinase system, which is able to release isothiocyanates after plant biotic and abiotic lesions. Erucin (ERU; 1-isothiocyanato-4-(methylthio)-butane), an isothiocyanate particularly abundant in arugula (Eruca sativa Mill., Eruca vesicaria L., etc.), derives from the hydrolysis of the glucosinolate glucoerucin by the enzyme myrosinase. Many other natural isothiocyanates influence cancer cells and, in particular, induce antiproliferative effects at relatively high concentrations. Similar antiproliferative effects have also been shown by the newly emerging gasotransmitter hydrogen sulfide (H2 S) and by H2 S-releasing compounds. In a previous study, our group demonstrated that isothiocyanates release H2 S in biological environments. In this work, we demonstrated the H2 S-donor properties of ERU in pancreatic adenocarcinoma cells (AsPC-1) and delineated its profile as a chemopreventive or anticancer agent. Indeed, ERU showed significant antiproliferative effects: ERU inhibited AsPC-1 cell viability at relatively high concentrations (30-100 μM). Moreover, ERU inhibited cell migration, altered the AsPC-1 cell cycle, and exhibited proapoptotic effects. Finally, ERU inhibited ERK1/2 phosphorylation. This mechanism is particularly important in AsPC-1 cells because they are characterized by a mutation in KRAS that determines KRAS hyperactivation followed by MAP-kinase hyperphosphorylation, which plays a pivotal role in pancreatic cancer proliferation, growth, and survival.

Preservation of vascular wall integrity against degenerative processes associated with ageing, fat-rich diet and metabolic diseases is a timely therapeutical challenge. The loss of endothelial function and integrity leads to cardiovascular diseases and multiorgan inflammation. The protective effects of the H2S-donor erucin, an isothiocyanate purified by Eruca sativa Mill. seeds, were evaluated on human endothelial and vascular smooth muscle cells. In particular, erucin actions were evaluated on cell viability, ROS, caspase 3/7, inflammatory markers levels and the endothelial hyperpermeability in an inflammatory model associated with high glucose concentrations (25 mM, HG). Erucin significantly prevented the HG-induced decrease in cell viability as well as the increase in ROS, caspase 3/7 activation, and TNF-α and IL-6 levels. Similarly, erucin suppressed COX-2 and NF-κB upregulation associated with HG exposure. Erucin also caused a significant inhibition of p22phox subunit expression in endothelial cells. In addition, erucin significantly prevented the HG-induced increase in endothelial permeability as also confirmed by the quantification of the specific markers VE-Cadherin and ZO-1. In conclusion, our results assess anti-inflammatory and antioxidant effects by erucin in vascular cells undergoing HG-induced inflammation and this protection parallels the preservation of endothelial barrier properties.

Preservation of vascular endothelium integrity and functionality represents an unmet medical need. Indeed, endothelial dysfunction leads to decreased nitric oxide biosynthesis, which is prodromic of hypertension and hypercoagulability. In this panorama, the nutraceutical supplement Taurisolo®, a polyphenolic extract from Aglianico cultivar grape, rich in catechin and procyanidins, was evaluated as a vasoprotective, vasorelaxing, anti-hypertensive and anti-coagulant agent in: cell lines, isolated vessels, in vivo models of chronic hypertension and hypercoagulability, and in clinical tests of endothelial reactivity. Taurisolo® demonstrated to fully protect vascular cell viability from oxidative stimulus at 100 µg/mL and evoke vasorelaxing effects (Emax = 80.6% ± 1.9 and pEC50 = 1.19 ± 0.03) by activation of the Sirtuins-AMPK-pathway. Moreover, Taurisolo®, chronically administered at 20 mg/Kg/die in in vivo experiments, inhibited the onset of cardiac hypertrophy (heart weight/rat weight = 3.96 ± 0.09 vs. 4.30 ± 0.03), hypercoagulability (decrease of fibrinogen vs. control: p < 0.01) and hypertension (mean of Psys: 200 ± 2 vs. control 234 ± 2 mmHg) and improved endothelial function (Emax = 88.9% ± 1.5 vs. control 59.6% ± 3.6; flow-mediated dilation in healthy volunteers after 400 mg twice daily for 8 weeks vs. baseline: p = 0.019). In conclusion, Taurisolo® preserves the vascular function against ox-inflamm-ageing process and the consequent cardiovascular accidents.

Human eye is a specialized organ with complex anatomy and physiology, because it is characterized by different cell types with specific physiological functions. Given the complexity of the eye, ocular tissues are finely organized and orchestrated. In the last few years many in vitro models have been developed, in order to meet the 3Rs principle (Replacement, Reduction and Refinement) for eye toxicity testing which is necessary to ensure that the risks associated with ophthalmic products meet appropriate safety criteria and are clearly labelled. In vitro preclinical testing is now a well-established practice of significant importance for evaluating the efficacy and safety of cosmetic, pharmaceutical, and nutraceutical products. Along with in vitro testing, also computational procedures, herein described, for evaluating the pharmacological profile of potential ocular drug candidates including their toxicity, are in rapid expansion. In this review the ocular cell types and functionality are described providing an overview about the scientific challenge for the development of three-dimensional in vitro models.

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 (H

Increasing evidence suggests that intestinal dysfunctions may represent early events in Alzheimer&rsquo, s disease and contribute to brain pathology. This study examined the relationship between onset of cognitive impairment and colonic dysfunctions in a spontaneous AD model before the full development of brain pathology. SAMP8 mice underwent Morris water maze and assessment of faecal output at four, six and eight months of age. In vitro colonic motility was examined. Faecal and colonic A&beta, tau proteins, &alpha, synuclein and IL-1&beta, were assessed by ELISA. Colonic citrate synthase activity was assessed by spectrophotometry. Colonic NLRP3, caspase-1 and ASC expression were evaluated by Western blotting. Colonic eosinophil density and claudin-1 expression were evaluated by immunohistochemistry. The effect of A&beta, on NLRP3 signalling and mitochondrial function was tested in cultured cells. Cognitive impairment and decreased faecal output occurred in SAMP8 mice from six months. When compared with SAMR1, SAMP8 animals displayed: (1) impaired in vitro colonic contractions, (2) increased enteric AD-related proteins, IL-1&beta, active-caspase-1 expression and eosinophil density, and (3) decreased citrate synthase activity and claudin-1 expression. In THP-1 cells, A&beta, promoted IL-1&beta, release, which was abrogated upon incubation with caspase-1 inhibitor or in ASC-/- cells. A&beta, decreased mitochondrial function in THP-1 cells. In SAMP8, enteric AD-related proteins deposition, inflammation and impaired colonic excitatory neurotransmission, occurring before the full brain pathology development, could contribute to bowel dysmotility and represent prodromal events in AD.

Sirtuin 1 (SIRT1) enzyme plays a pivotal role in the regulation of many physiological functions. In particular, it is implicated in ageing-related diseases, such as cardiac hypertrophy, myocardial infarct, and endothelial dysfunction; moreover, its expression decreases with age. Therefore, an effective strategy to extend the lifespan and improve cardiovascular function is the enhancement of the expression/activity of SIRT1 with exogenous agents. The Citrus flavonoid naringenin (NAR) presents structural similarity with the natural SIRT1 activator resveratrol. In this study, we demonstrate through in vitro assays that NAR significantly activates SIRT1 enzyme and shows antisenescence effects. The binding mode of NAR into SIRT1 was detailed investigated through in silico studies. Moreover, chronic administration (for six months) of NAR (100 mg/kg/day) to 6-month-old mice leads to an enhancement of SIRT1 expression and a marked reduction of reactive oxygen species production in myocardial tissue. Furthermore, at the end of the treatment, the plasma levels of two well-known markers of cardiovascular inflammation, TNF-α and IL6, are significantly reduced in 12-month-old mice treated with NAR, as well as the cardiovascular risk (total cholesterol/HDL ratio) compared to control mice. Finally, the age-associated fibrotic remodeling, which is well detected through a Mallory trichrome staining in the vehicle-treated 12-month-old mice, is significantly reduced by the chronic treatment with NAR. Moreover, an improvement of myocardium functionality is highlighted by the enhancement of citrate synthase activity and stabilization of the mitochondrial membrane potential after NAR treatment. Taken together, these results suggest that a nutraceutical approach with NAR may have positive impacts on many critical hallmarks of myocardial senescence, contributing to improve the cardiac performance in aged subjects.

BACKGROUND AND PURPOSE: Hydrogen sulfide (H(2)S)‐releasing agents are viewed as potential antihypertensive drugs. Recently, natural isothiocyanates emerged as original H(2)S‐donor agents. Among them, erucin, present in some edible cruciferous plants, shows suitable H(2)S‐releasing properties and features of “druggability.” The aim of this work was to investigate the erucin‐mediated release of H(2)S inside vascular cells, its vasorelaxing effects, and activity on BP of normo and hypertensive animals. EXPERIMENTAL APPROACH: Intracellular H(2)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 H(2)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 H(2)S donor endowed with vasorelaxing and antihypertensive effects. LINKED ARTICLES: This article is part of a themed section on Hydrogen Sulfide in Biology & Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc

Obesity is currently considered a major source of morbidity, with dramatic complications on health status and life expectancy. Several studies demonstrated the positive effects of Brassicaceae vegetables on obesity and related diseases, partially attributing these beneficial properties to glucosinolates and their derivatives isothiocyanates. Recently, isothiocyanates have been described as a hydrogen sulfide (H2 S)-releasing moiety, suggesting that H2 S may be at least in part responsible for the beneficial effects of Brassicaceae. In this work, the metabolic effects of an extract obtained from Eruca sativa Mill. seeds (E.S., Brassicaceae), containing high levels of glucoerucin, were evaluated in an experimental model of obesity. Male balb/c mice were fed for 10 weeks with standard (Std) diet or high fat (HF) diet supplemented with E.S. E.S. significantly contained the body weight gain in this obesity model, improving also glucose homeostasis. Interestingly, lower values of white adipose tissue mass and a significant reduction of adipocytes size were also observed. Moreover, E.S. enhanced the adipocytes metabolism, improving the citrate synthase activity and reduced triglyceride levels in mice fed with HF diet. Taken together, these results suggest that E.S. is endowed with an interesting translational and nutraceutical value in the prevention of metabolic disorders, suggesting that H2 S could be a key player.

The gasotransmitter hydrogen sulfide (H2S) is an important tuner of the cardiovascular homeostasis, and its deficiency is etiologically associated with a number of cardiovascular diseases. Therefore, the research of original moieties able to release H2S represents a timely issue for drug discovery. In this work, we developed a collection of iminothioethers (ITEs), exhibiting H2S-releasing properties and producing vasorelaxing effects on rat aortic rings. Derivatives 4 and 11, selected as representative of slow and fast rate H2S donors, respectively, produced a complete recovery of the basal coronary flow, reverting the AngII-induced effects in isolated rat hearts. In addition, studies on human aortic smooth muscle cells (HASMCs) demonstrated membrane hyperpolarizing effects, well related to the intracellular generation of H2S. Taken together, the results obtained support ITEs 4 and 11 as new pharmacological tools, as well as effective and innovative H2S donors for cardiovascular drug discovery.

The gasotransmitter hydrogen sulfide (H2S) is involved in the regulation of the vascular tone and an impairment of its endogenous production may play a role in hypertension. Thus, the administration of exogenous H2S may be a possible novel and effective strategy to control blood pressure. Some natural and synthetic sulfur compounds are suitable H2S-donors, exhibiting long-lasting H2S release; however, novel H2S-releasing agents are needed to improve the pharmacological armamentarium for the treatment of cardiovascular diseases. For this purpose, N-phenylthiourea (PTU) and N,N'-diphenylthiourea (DPTU) compounds have been investigated as potential H2S-donors. The thioureas showed long-lasting H2S donation in cell free environment and in human aortic smooth muscle cells (HASMCs). In HASMCs, DPTU caused membrane hyperpolarization, mediated by activation of KATP and Kv7 potassium channels. The thiourea derivatives promoted vasodilation in rat aortic rings, which was abolished by KATP and Kv7 blockers. The vasorelaxing effects were also observed in angiotensin II-constricted coronary vessels. In conclusion, thiourea represents an original H2S-donor functional group, which releases H2S with slow and long lasting kinetic, and promotes typical H2S-mediated vascular effects. Such a moiety will be extremely useful for developing original cardiovascular drugs and new chemical tools for investigating the pharmacological roles of H2S.

Preservation of vascular endothelium integrity and functionality represents an unmet medical need. Indeed, endothelial dysfunction leads to decreased nitric oxide biosynthesis, which is prodromic of hypertension and hypercoagulability. In this panorama, the nutraceutical supplement Taurisolo®, a polyphenolic extract from Aglianico cultivar grape, rich in catechin and procyanidins, was evaluated as a vasoprotective, vasorelaxing, anti-hypertensive and anti-coagulant agent in: cell lines, isolated vessels, in vivo models of chronic hypertension and hypercoagulability, and in clinical tests of endothelial reactivity. Taurisolo® demonstrated to fully protect vascular cell viability from oxidative stimulus at 100 µg/mL and evoke vasorelaxing effects (Emax = 80.6% ± 1.9 and pEC50 = 1.19 ± 0.03) by activation of the Sirtuins-AMPK-pathway. Moreover, Taurisolo®, chronically administered at 20 mg/Kg/die in in vivo experiments, inhibited the onset of cardiac hypertrophy (heart weight/rat weight = 3.96 ± 0.09 vs. 4.30 ± 0.03), hypercoagulability (decrease of fibrinogen vs. control: p &lt, 0.01) and hypertension (mean of Psys: 200 ± 2 vs. control 234 ± 2 mmHg) and improved endothelial function (Emax = 88.9% ± 1.5 vs. control 59.6% ± 3.6, flow-mediated dilation in healthy volunteers after 400 mg twice daily for 8 weeks vs. baseline: p = 0.019). In conclusion, Taurisolo® preserves the vascular function against ox-inflamm-ageing process and the consequent cardiovascular accidents.

Retinal diseases can be induced by a variety of factors, including gene mutations, environmental stresses and dysmetabolic processes. The result is a progressive deterioration of visual function, which sometimes leads to blindness. Many treatments are under investigation, though results are still mostly unsatisfactory and restricted to specific pathologies, particularly in the case of gene therapy. The majority of treatments have been tested in animal models, but very few have progressed to human clinical trials. A relevant approach is to study the relation between the type of treatments and the degenerative characteristics of the animal model to better understand the effectiveness of each therapy. Here we compare the results obtained from different animal models treated with natural compounds (saffron and naringenin) to anticipate the potentiality of a single treatment in different pathologies.

The human eye is a specialized organ with a complex anatomy and physiology, because it is characterized by different cell types with specific physiological functions. Given the complexity of the eye, ocular tissues are finely organized and orchestrated. In the last few years, many in vitro models have been developed in order to meet the 3Rs principle (Replacement, Reduction and Refinement) for eye toxicity testing. This procedure is highly necessary to ensure that the risks associated with ophthalmic products meet appropriate safety criteria. In vitro preclinical testing is now a well-established practice of significant importance for evaluating the efficacy and safety of cosmetic, pharmaceutical, and nutraceutical products. Along with in vitro testing, also computational procedures, herein described, for evaluating the pharmacological profile of potential ocular drug candidates including their toxicity, are in rapid expansion. In this review, the ocular cell types and functionality are described, providing an overview about the scientific challenge for the development of three-dimensional (3D) in vitro models.

In the last four decades, the several classes of diuretics, currently available for clinical use, have been the first line option for the therapy of widespread cardiovascular and non-cardiovascular diseases. Diuretic drugs generally exhibit an overall favourable risk/benefit balance. However, they are not devoid of side effects. In particular, all the classes of diuretics cause alteration of potassium homeostasis. In recent years, understanding of the physiological role of the renal outer medullary potassium (ROMK) channels, has shown an intriguing pharmacological target for developing an innovative class of diuretic agents: the ROMK inhibitors. This novel class is expected to promote diuretic activity comparable to (or even higher than) that provided by the most effective drugs used in clinics (such as furosemide), with limited effects on potassium homeostasis. In this review, the physio-pharmacological roles of ROMK channels in the renal function are reported, along with the most representative molecules which have been currently developed as ROMK inhibitors.

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.