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Dyslipidemia is a risk factor for cardiovascular diseases. Preclinical studies have shown that organosulfur compounds from the Alliaceae and Brassicaceae plants, such as garlic (Allium sativum L.) and broccoli (Brassica oleracea L.), have potential lipid-lowering effects. However, their clinical efficacy is controversial, especially in "drug-free" patients. The aim of this work was to summarize evidence on the lipid-lowering properties of extracts containing organosulfur compounds in patients with dyslipidemia. Studies were searched in four databases (Medline, Scopus, Embase, and CENTRAL), from inception to October 11, 2023.Controlled clinical studies on patients with dyslipidemia receiving Alliaceae or Brassicaceae were included. The outcome was the change in lipid parameters from baseline. Random-effect meta-analysis of the extracted data was performed using R software. The effect size was expressed as mean difference (MD) and 95% confidence interval (CI). The certainty of evidence was assessed with the GRADE approach. Out of 28 studies that were reviewed, 22 were included in the meta-analysis (publication period: 1981-2022). Results showed that Alliaceae extracts significantly reduce total cholesterol [MD: -15.2 mg/dL; 95% CI: -21.3; -9.1] and low-density lipoprotein cholesterol levels [MD: -12.0 mg/dL; 95% CI: -18.1; -5.7], although with low certainty of evidence. Conversely, the lipid-lowering properties of Brassicaceae extracts are still unexplored. Our results support the use of Alliaceae extracts in patients with hypercholesterolemia, but future high-quality studies are needed. Our work suggests further exploration of the efficacy of Brassicaceae extracts, which may have high nutraceutical/phytotherapeutic potential, opening new perspectives in the management of dyslipidemia., (© 2024 The Author(s). Phytotherapy Research published by John Wiley & Sons Ltd.)

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 (H 2 S) and, therefore, H 2 S-donors could have a central role in the prevention and treatment of overweight/obesity. The main natural sources of H 2 S-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 H 2 S, derive from the hydrolysis of alliin from Alliaceae and glucosinolates from Brassicaceae/Moringaceae, respectively. In this review, we describe the emerging role of endogenous H 2 S in regulating adipose tissue function and the potential efficacy of natural H 2 S-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., (© 2024 John Wiley & Sons Ltd.)

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 (H 2 S)-releasing moiety, suggesting that H 2 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 H 2 S could be a key player., (© 2020 John Wiley & Sons Ltd.)

The COVID-19 pandemic caused by SARS-Cov-2 demands rapid, safe and effective therapeutic options. In the last decades, the endogenous gasotransmitter hydrogen sulfide (H 2 S) has emerged as modulator of several biological functions and its deficiency has been associated with different disorders. Therefore, many H 2 S-releasing agents have been developed as potential therapeutic tools for diseases related with impaired H 2 S production and/or activity. Some of these compounds are in advanced clinical trials. Presently, the pivotal role of H 2 S in modulating the inflammatory response and pro-inflammatory cytokine cascade is well recognized, and the usefulness of some H 2 S-donors for the treatment of acute lung inflammation has been reported. Recent data is elucidating several mechanisms of action, which may account for antiviral effects of H 2 S. Noteworthy, some preliminary clinical results suggest an inverse relationship between endogenous H 2 S levels and severity of COVID-19. Therefore, repurposing of H 2 S-releasing drugs may be a potential therapeutic opportunity for treatment of COVID-19. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc., (© 2020 The British Pharmacological Society.)

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., (© 2019 The British Pharmacological Society.)

Background and Purpose: Human malignant hyperthermia (MH) syndrome is induced by volatile anaesthetics and involves increased levels of cystathionine β-synthase (CBS)-derived H 2 S within skeletal muscle. This increase contributes to skeletal muscle hypercontractility. K v 7 channels, expressed in skeletal muscle, may be a molecular target for H 2 S. Here, we have investigated the role of K v 7 channels in MH., Experimental Approach: Skeletal muscle biopsies were obtained from MH-susceptible (MHS) and MH-negative (MHN) patients. Immunohistochemistry, RT-PCR, Western blot, and in vitro contracture test (IVCT) were carried out. Development and characterization of primary human skeletal muscle cells (PHSKMC) and evaluation of cell membrane potential were also performed. The persulfidation state of K v 7 channels and polysulfide levels were measured., Key Results: K v 7 channels were similarly expressed in MHN and MHS biopsies. The IVCT revealed an anomalous contractility of MHS biopsies following exposure to the K v 7 channel opener retigabine. Incubation of negative biopsies with NaHS, prior to retigabine addition, led to an MHS-like positive response. MHS-derived PHSKMC challenged with retigabine showed a paradoxical depolarizing effect, compared with the canonical hyperpolarizing effect. CBS expression and activity were increased in MHS biopsies, resulting in a major polysulfide bioavailability. Persulfidation of K v 7.4 channels was significantly higher in MHS than in MHN biopsies., Conclusions and Implications: In skeletal muscle of MHS patients, CBS-derived H 2 S induced persulfidation of K v 7 channels. This post-translational modification switches the hyperpolarizing activity into depolarizing. This mechanism can contribute to the pathological skeletal muscle hypercontractility typical of MH syndrome., 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., (© 2019 The British Pharmacological Society.)

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 (H 2 S) and by H 2 S-releasing compounds. In a previous study, our group demonstrated that isothiocyanates release H 2 S in biological environments. In this work, we demonstrated the H 2 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., (© 2019 John Wiley & Sons, Ltd.)

The beneficial effects of isothiocyanate-based compounds, as well as their safety, have been shown in neuropathological disorders, such as neuropathic pain. Aim of the present work was to study the efficacy of the glucosinolate glucoraphanin (GRA) and the derived isothiocyanate sulforaphane (SFN), secondary metabolites occurring exclusively in Brassicales, on chemotherapy-induced neuropathic pain. Mice were repeatedly treated with oxaliplatin (2.4 mg kg -1 ip) for 14 days to induce neuropathic pain. GRA and SFN effects were evaluated after a single administration on Day 15 or after a daily repeated oral and subcutaneous treatment starting from the first day of oxaliplatin injection until the 14 th day. Single subcutaneous and oral administrations of GRA (4.43-119.79 μmol kg -1 ) or SFN (1.33-13.31 μmol kg -1 ) reduced neuropathic pain in a dose-dependent manner. The repeated administration of GRA and SFN (respectively 13.31 and 4.43 μmol kg -1 ) prevented the chemotherapy-induced neuropathy. The co-administration of GRA and SFN in mixture with the H 2 S binding molecule, haemoglobin, abolished their pain-relieving effect, which was also reverted by pretreating the animals with the selective blocker of Kv7 potassium channels, XE991. GRA and SFN reduce neuropathic pain by releasing H 2 S and modulating Kv7 channels and show a protective effect on the chemotherapy-induced neuropathy., (© 2018 John Wiley & Sons, Ltd.)

Background and Purpose: Hydrogen sulfide (H 2 S) modulates many pathophysiological processes, including inflammation and allergic reactions, in which mast cells act as major effector cells. IgE receptor (FcεRI) cross linking leads to an increase in intracellular calcium ([Ca +2 ] i ), a critical step in mast cell degranulation. The aim of this study was to investigate the role of H 2 S in [Ca +2 ] i -dependent mast cell activation., Experimental Approach: We investigated the effects of H 2 S, either endogenously produced or released by the slow H 2 S donor 4-carboxy-phenyl isothiocyanate (PhNCS-COOH), on antigenic- and non-antigenic degranulation of native murine mast cells, and human and rat (RBL-2H3) mast cell lines. We measured the release of specific mast cell degranulation markers (β-hexosaminidase and renin), as well as changes in [Ca +2 ] i and phosphorylation of proteins downstream of FcεRI activation., Key Results: Endogenously produced H 2 S inhibited antigen-induced degranulation in RBL-2H3. Similarly, H 2 S released by PhNCS-COOH (10-300 μM) reduced, in a concentration-dependent manner, antigenic and non-antigenic degranulation and renin release in all mast cell types. Notably, PhNCS-COOH also prevented in a concentration-dependent mode the increase in [Ca +2 ] i elicited by Ca +2 ionophore, thapsigargin and FcεRI activation. Moreover, PhNCS-COOH attenuated the phosphorylation of Syk, cPLA-2 and PLCγ1 in antigen-stimulated RBL-2H3 cells., Conclusion and Implications: Collectively, our results demonstrate that, by attenuating the phosphorylation of proteins downstream of FcεRI cross-linking on mast cells, H 2 S diminishes [Ca +2 ] i availability and thus mast cell degranulation and renin release. These findings suggest that PhNCS-COOH could be a strategic therapeutic tool in mast cell-mediated allergic conditions., (© 2016 The British Pharmacological Society.)

Hydrogen sulphide (H(2)S) is emerging as an important endogenous modulator, which exhibits the beneficial effects of nitric oxide (NO) on the cardiovascular (CV) system, without producing toxic metabolites. H(2)S is biosynthesized in mammalian tissues by cystathionine-β-synthase and cystathionine-γ-lyase. H(2)S exhibits the antioxidant properties of inorganic and organic sulphites, behaving as a scavenger of reactive oxygen species. There is also clear evidence that H(2)S triggers other important effects, mainly mediated by the activation of ATP-sensitive potassium channels (K(ATP)). This mechanism accounts for the vasorelaxing and cardioprotective effects of H(2)S. Furthermore, H(2)S inhibits smooth muscle proliferation and platelet aggregation. In non-CV systems, H(2)S regulates the functions of the central nervous system, as well as respiratory, gastroenteric, and endocrine systems. Conversely, H(2)S deficiency contributes to the pathogenesis of hypertension. Likewise, impairment of H(2)S biosynthesis is involved in CV complications associated with diabetes mellitus. There is also evidence of a cross-talk between the H(2)S and the endothelial NO pathways. In particular, recent observations indicate a possible pathogenic link between deficiencies of H(2 S activity and the progress of endothelial dysfunction. These biological aspects of endogenous H(2)S have led several authors to look at this mediator as "the new NO" that has given attractive opportunities to develop innovative classes of drugs. In this review, the main biological actions of H(2)S are discussed. Moreover, some examples of H(2)S-donors are shown, as well as some hybrids, in which H(2)S-releasing moieties are added to well-known drugs, for improving their pharmacodynamic profile or reducing the potential for adverse effects, are reported., (© 2010 Wiley Periodicals, Inc.)