Natural H2S-donors: A new pharmacological opportunity for the management of overweight and obesity.

The prevalence of overweight and obesity has progressively increased in the last few years, becoming a real threat to healthcare systems. To date, the clinical management of body weight gain is an unmet medical need, as there are few approved anti-obesity drugs and most require an extensive monitoring and vigilance due to risk of adverse effects and poor patient adherence/persistence. Growing evidence has shown that the gasotransmitter hydrogen sulfide (H2S) and, therefore, H2S-donors could have a central role in the prevention and treatment of overweight/obesity. The main natural sources of H2S-donors are plants from the Alliaceae (garlic and onion), Brassicaceae (e.g., broccoli, cabbage, and wasabi), and Moringaceae botanical families. In particular, polysulfides and isothiocyanates, which slowly release H2S, derive from the hydrolysis of alliin from Alliaceae and glucosinolates from Brassicaceae/Moringaceae, respectively. In this review, we describe the emerging role of endogenous H2S in regulating adipose tissue function and the potential efficacy of natural H2S-donors in animal models of overweight/obesity, with a final focus on the preliminary results from clinical trials. We conclude that organosulfur-containing plants and their extracts could be used before or in combination with conventional anti-obesity agents to improve treatment efficacy and reduce inflammation in obesogenic conditions. However, further high-quality studies are needed to firmly establish their clinical efficacy.

Erucin, a natural isothiocyanate, exerts pro-angiogenic properties in cultured endothelial cells and reverts angiogenic impairment induced by high glucose.

Insufficient vessel maintenance adversely impacts patients in terms of tissue reperfusion following stroke or myocardial infarction, as well as during wound healing. Angiogenesis impairment is a feature typical of metabolic disorders acting at the cardiovascular level, such as diabetes. Therapeutic angiogenesis regulation offers promising clinical implications, and natural compounds as pro-angiogenic nutraceuticals hold valuable applications in regenerative medicine. By using cultured endothelial cells from human umbilical veins (HUVEC) we studied functional and molecular responses following exposure to erucin, a natural isothiocyanate derived from Brassicaceae plants and extracted from the seeds of rocket. Erucin (at nanomolar concentrations) promotes cell migration and tube formation, similar to vascular endothelial growth factor (VEGF), through mobilizing paxillin at endothelial edges. At the molecular level, erucin induces signaling pathways typical of angiogenesis activation, namely Ras, PI3K/AKT, and ERK1/2, leading to VEGF expression and triggering its autocrine production, as pharmacological inhibition of soluble VEGF and VEGFR2 dampens endothelial functions. Furthermore, erucin, alone and together with VEGF, preserves endothelial angiogenic functions under pathological conditions, such as those induced in HUVEC by high glucose (HG) exposure. Erucin emerges as a compelling candidate for therapeutic revascularization applications, showcasing promising prospects for natural compounds in regenerative medicine, particularly in addressing angiogenesis-related disorders.

Influence of Polyphenols on Adipose Tissue: Sirtuins as Pivotal Players in the Browning Process.

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.

Anti-Proliferative Properties of the Novel Hybrid Drug Met-ITC, Composed of the Native Drug Metformin with the Addition of an Isothiocyanate H2S Donor Moiety, in Different Cancer Cell Lines.

Metformin (Met) is the first-line therapy in type 2 diabetes mellitus but, in last few years, it has also been evaluated as anti-cancer agent. Several pathways, such as AMPK or PI3K/Akt/mTOR, are likely to be involved in the anti-cancer Met activity. In addition, hydrogen sulfide (H2S) and H2S donors have been described as anti-cancer agents affecting cell-cycle and inducing apoptosis. Among H2S donors, isothiocyanates are endowed with a further anti-cancer mechanism: the inhibition of the histone deacetylase enzymes. On this basis, a hybrid molecule (Met-ITC) obtained through the addition of an isothiocyanate moiety to the Met molecule was designed and its ability to release Met has been demonstrated. Met-ITC exhibited more efficacy and potency than Met in inhibiting cancer cells (AsPC-1, MIA PaCa-2, MCF-7) viability and it was less effective on non-tumorigenic cells (MCF 10-A). The ability of Met-ITC to release H2S has been recorded both in cell-free and in cancer cells assays. Finally, its ability to affect the cell cycle and to induce both early and late apoptosis has been demonstrated on the most sensitive cell line (MCF-7). These results confirmed that Met-ITC is a new hybrid molecule endowed with potential anti-cancer properties derived both from Met and H2S.

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/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.

Potential effects of Alliaceae and Brassicaceae edible plants on blood glucose levels in patients with type 2 diabetes: A systematic review and meta-analysis of clinical trials.

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 (H2S), which is emerging as a crucial modulator of the "glucose-insulin system". However, the results of clinical studies evaluating the effects of such edible plants on glycaemic control in patients with T2D are quite conflicting. We performed a systematic review and meta-analysis of controlled clinical trials, both parallel and cross-over, searching four databases (Pubmed, Embase, Scopus and the Cochrane library). Only English-written papers evaluating the effects of Alliaceae and Brassicaceae on glycaemic parameters in diabetic patients have been included. 16 studies met the inclusion criteria, and 12 were included in the random-effects meta-analysis. Consumption of Alliaceae or Brassicaceae significantly reduced fasting blood glucose (FBG) levels compared with the placebo group (mean reduction: -12.67 mg/dl [95% confidence interval (CI) - 19.66; - 5.68]). Moreover, Alliaceae and Brassicaceae significantly improved the effects of standard antidiabetic therapy (mean reduction in FBG levels in patients receiving combination therapy compared with patients only receiving standard antidiabetic therapy: -6.75 mg/dl [-12.62; -0.88]). Overall, the regular consumption of these edible plants was safe and well-tolerated. We suggest that edible plants containing organosulfur compounds are endowed with promising nutraceutical potential in the treatment of T2D.

Cardiovascular benefits of Eruca sativa mill. Defatted seed meal extract: Potential role of hydrogen sulfide.

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 (H2 S) donor. In this work, an Eruca sativa extract has been obtained from a defatted seed meal (DSM), achieving a powder rich in thiofunctionalized glucosinolates, glucoerucin, and glucoraphanin, accounting for 95% and 5% of the total glucosinolate content (17% on a dry weight basis), associated with 13 identified phenolic acids and flavonoids accounting for 2.5%. In a cell-free model, Eruca sativa DSM extract slowly released H2 S. Moreover, this extract promoted significant hypotensive effects in hypertensive rats, and evoked dose-dependent cardioprotection in in vivo model of acute myocardial infarct, obtained through a reversible coronary occlusion. This latter effect was sensitive to blockers of mitochondrial KATP and Kv7.4 potassium channels, suggesting a potential role of these mitochondrial channels in the protective effects of Eruca sativa DSM extract. Accordingly, Eruca sativa DSM extract reduced calcium uptake and apoptotic cell death in isolated cardiac mitochondria. Taken together, these results demonstrate that Eruca sativa DSM extract is endowed with an interesting nutraceutical profile on the cardiovascular system due to, at least in part, its H2 S releasing properties. These results pave the way for future investigations on active metabolites.

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.

Design, Synthesis and Evaluation of Novel Molecular Hybrids between Antiglaucoma Drugs and H2S Donors.

Glaucoma is a group of eye diseases consisting of optic nerve damage with corresponding loss of field vision and blindness. Hydrogen sulfide (H2S) is a gaseous neurotransmitter implicated in various pathophysiological processes. It is involved in the pathological mechanism of glaucomatous neuropathy and exerts promising effects in the treatment of this disease. In this work, we designed and synthetized new molecular hybrids between antiglaucoma drugs and H2S donors to combine the pharmacological effect of both moieties, providing a heightened therapy. Brinzolamide, betaxolol and brimonidine were linked to different H2S donors. The H2S-releasing properties of the new compounds were evaluated in a phosphate buffer solution by the amperometric approach, and evaluated in human primary corneal epithelial cells (HCEs) by spectrofluorometric measurements. Experimental data showed that compounds 1c, 1d and 3d were the hybrids with the best properties, characterized by a significant and long-lasting production of the gasotransmitter both in the aqueous solution (in the presence of L-cysteine) and in the intracellular environment. Because, to date, the donation of H2S by antiglaucoma H2S donor hybrids using non-immortalized corneal cells has never been reported, these results pave the way to further investigation of the potential efficacy of the newly synthesized compounds.

Anti-Inflammatory Effect of the Natural H2S-Donor Erucin in Vascular Endothelium.

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.

Pharmacological modulation of the hydrogen sulfide (H2 S) system by dietary H2 S-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 (H2 S) in the pathogenesis and progression of T2DM led to increasing interest in the pharmacological modulation of endogenous "H2 S-system". Indeed, H2 S directly contributes to the homeostatic maintenance of blood glucose levels; moreover, it improves impaired angiogenesis and endothelial dysfunction under hyperglycemic conditions. Moreover, H2 S promotes significant antioxidant, anti-inflammatory, and antiapoptotic effects, thus preventing hyperglycemia-induced vascular damage, diabetic nephropathy, and cardiomyopathy. Therefore, H2 S-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 H2 S-donors of great pharmacological and nutraceutical interest. Therefore, a better understanding of the therapeutic potential of naturally occurring H2 S-donors may pave the way to a more rational use of these nutraceuticals in the modulation of H2 S homeostasis in T2DM.

Eruca sativa Mill. seed extract promotes anti-obesity and hypoglycemic effects in mice fed with a high-fat diet.

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.

Searching for novel hydrogen sulfide donors: The vascular effects of two thiourea derivatives.

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.

Protective Effects of Bergamot (Citrus bergamia Risso & Poiteau) Juice in Rats Fed with High-Fat Diet.

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.

Prodromal Intestinal Events in Alzheimer's Disease (AD): Colonic Dysmotility and Inflammation Are Associated with Enteric AD-Related Protein Deposition.

Increasing evidence suggests that intestinal dysfunctions may represent early events in Alzheimer'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 Aß, tau proteins, α-synuclein and IL-1ß 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 Aß 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-1ß, active-caspase-1 expression and eosinophil density; and (3) decreased citrate synthase activity and claudin-1 expression. In THP-1 cells, Aß promoted IL-1ß release, which was abrogated upon incubation with caspase-1 inhibitor or in ASC-/- cells. Aß 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.

Anticancer properties of erucin, an H2 S-releasing isothiocyanate, on human pancreatic adenocarcinoma cells (AsPC-1).

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.

Matrix metalloproteinase-12 inhibitors: synthesis, structure-activity relationships and intestinal absorption of novel sugar-based biphenylsulfonamide carboxylates.

MMP-12 is a validated target in pulmonary and cardiovascular diseases. The principal obstacles to clinical development of MMP-12 inhibitors are an inadequate selectivity for the target enzyme and a poor water solubility, with consequent poor oral bioavailability. We recently reported a new class of sugar-based arylsulfonamide carboxylates with a nanomolar activity for MMP-12, a good selectivity and an improved water solubility. In this study, we designed and synthesized new derivatives to characterize the structure-activity relationship (SAR) within this class of glycoconjugate inhibitors. All the new derivatives were tested on human recombinant MMP-12 and MMP-9 in order to evaluate their affinity and the selectivity for the target enzyme. Among them, the four most promising compounds were selected to assess their intestinal permeability using an ex vivo everted gut sac model. Given the high polarity and structural similarity to glucose, compound 3 was demonstrated to cross the intestinal membrane by using the facilitative GLUT2 transport.

Role of hydrogen sulfide in the regulation of lipid metabolism: Implications on cardiovascular health.

The World Health Organization (WHO) defines obesity as an urgency for health and a social emergency. Today around 39 % of people is overweight, of these over 13 % is obese. It is well-consolidated that the adipose cells are deputy to lipid storage under caloric excess; however, despite the classical idea that adipose tissue has exclusively a passive function, now it is known to be deeply involved in the regulation of systemic metabolism in physiological as well as under obesogenic conditions, with consequences on cardiovascular health. Beside two traditional types of adipose cells (white and brown), recently the beige one has been highlighted as the consequence of the healthy remodeling of white adipocytes, confirming their metabolic adaptability. In this direction, pharmacological, nutraceutical and nutrient-based approaches are addressed to positively influence inflammation and metabolism, thus contributing to reduce the obese-associated cardiovascular risk. In this scenario, hydrogen sulfide emerges as a new mediator that may regulate crucial targets involved in the regulation of metabolism. The current evidence demonstrates that hydrogen sulfide may induce peroxisome proliferator activated receptor γ (PPARγ), a crucial mediator of adipogenesis, inhibit the phosphorylation of perlipin-1 (plin-1), a protein implicated in the lipolysis, and finally promote browning process, through the release of irisin from skeletal muscle. The results summarized in this review suggest an important role of hydrogen sulfide in the regulation of metabolism and in the prevention/treatment of obese-associated cardiovascular diseases and propose new insight on the putative mechanisms underlying the release of hydrogen sulfide or its biosynthesis, delineating a further exciting field of application.

The Citrus flavanone naringenin prolongs the lifespan in C. elegans and slows signs of brain aging in mice.

Aging is one of the main risk factors for neurodegenerative disorders, which represent a global burden on healthcare systems. Therefore, identifying new strategies to slow the progression of brain aging is a compelling challenge. In this article, we first assessed the potential anti-aging effects of the Citrus flavanone naringenin (NAR), an activator of the enzyme sirtuin-1 (SIRT1), in a 3R-compliant and short-lived aging model (i.e., the nematode C. elegans). Then, we investigated the preventive effects of a 6-month treatment with NAR (100 mg/kg, orally) against brain aging and studied its mechanism of action in middle-aged mice. We demonstrated that NAR (100 µM) extends lifespan and improves healthspan in C. elegans. In the brain of middle-aged mice, NAR promotes the activity of metabolic enzymes (citrate synthase, cytochrome C oxidase) and increases the expression of the SIRT1 enzyme. Consistently, NAR up-regulates the expression of downstream antioxidant (Foxo3, Nrf2, Ho-1), anti-senescence (p16), and anti-inflammatory (Il-6, Il-18) markers. Our findings support NAR supplementation to slow the signs of brain aging.

Circulating Levels of Hydrogen Sulfide (H2S) in Patients with Age-Related Diseases: A Systematic Review and Meta-Analysis.

Hydrogen sulfide (H2S) is an endogenous gasotransmitter that promotes multiple biological effects in many organs and tissues. An imbalanced biosynthesis of H2S has been observed in animal models of age-related pathological conditions. However, the results from human studies are inconsistent. We performed a systematic review with meta-analysis of studies searched in Medline, Embase, Scopus, and CENTRAL databases. We included observational studies on patients with age-related diseases showing levels of H2S in blood, plasma, or serum. All the analyses were carried out with R software. 31 studies were included in the systematic review and 21 in the meta-analysis. The circulating levels of H2S were significantly reduced in patients with progressive, chronic, and degenerative diseases compared with healthy people (standardized mean difference, SMD: -1.25; 95% confidence interval, CI: -1.98; -0.52). When we stratified results by type of disorder, we observed a significant reduction in circulating levels of H2S in patients with vascular disease (e.g., hypertension) (SMD: -1.32; 95% CI: -2.43; -0.22) or kidney disease (SMD: -2.24; 95% CI: -4.40; -0.08) compared with the control group. These results could support the potential use of compounds targeting the "H2S system" to slow down the progression of many diseases in the elderly.