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1.  Hydrogen Sulfide Is an Endogenous Regulator of Aging in Caenorhabditis elegans 
Antioxidants & Redox Signaling  2014;20(16):2621-2630.
Abstract
Aims: To investigate the role of endogenous hydrogen sulfide (H2S) in the control of aging and healthspan of Caenorhabditis elegans. Results: We show that the model organism, C. elegans, synthesizes H2S. Three H2S-synthesizing enzymes are present in C. elegans, namely cystathionine γ lyase (CSE), cystathionine β synthetase, and 3-mercaptopyruvate transferase (MPST or 3-MST). Genetic deficiency of mpst-1 (3-MST orthologue 1), but not cth-2 (CSE orthologue), reduced the lifespan of C. elegans. This effect was reversed by a pharmacological H2S donor (GYY4137). GYY4137 also reduced detrimental age-dependent changes in a range of physiological indices, including pharyngeal contraction and defecation. Treatment of C. elegans with GYY4137 increased the expression of several age-related, stress response, and antioxidant genes, whereas MitoSOX Red fluorescence, indicative of reactive oxygen species generation, was increased in mpst-1 knockouts and decreased by GYY4137 treatment. GYY4137 additionally increased the lifespan in short-lived mev-1 mutants with elevated oxidative stress and protected wild-type C. elegans against paraquat poisoning. The lifespan-prolonging and health-promoting effects of H2S in C. elegans are likely due to the antioxidant action of this highly cell-permeable gas. Innovation: The possibility that novel pharmacological agents based on the principle of H2S donation may be able to retard the onset of age-related disease by slowing the aging process warrants further study. Conclusion: Our results show that H2S is an endogenous regulator of oxidative damage, metabolism, and aging in C. elegans and provide new insight into the mechanisms, which control aging in this model organism. Antioxid. Redox Signal. 20, 2621–2630.
doi:10.1089/ars.2013.5448
PMCID: PMC4025568  PMID: 24093496
2.  Safety and Efficacy of Flumazenil for Reversal of Iatrogenic Benzodiazepine-Associated Delirium Toxicity During Treatment of Alcohol Withdrawal, a Retrospective Review at One Center 
Journal of Medical Toxicology  2014;10(2):126-132.
Both alcohol withdrawal syndrome (AWS) and benzodiazepines can cause delirium. Benzodiazepine-associated delirium can complicate AWS and prolong hospitalization. Benzodiazepine delirium can be diagnosed with flumazenil, a GABA-A receptor antagonist. By reversing the effects of benzodiazepines, flumazenil is theorized to exacerbate symptoms of AWS and precludes its use. For patients being treated for alcohol withdrawal, flumazenil can diagnose and treat benzodiazepine delirium without precipitating serious or life-threatening adverse events. Hospital admission records were retrospectively reviewed for patients with the diagnosis of AWS who received both benzodiazepines and flumazenil from December 2006 to June 2012 at a university-affiliated inpatient toxicology center. The day of last alcohol consumption was estimated from available blood alcohol content or subjective history. Corresponding benzodiazepine, flumazenil, and adjunctive sedative pharmacy records were reviewed, as were demographic, clinical course, and outcome data. Eighty-five patients were identified (average age 50.3 years). Alcohol concentrations were detectable for 42 patients with average 261 mg/dL (10–530 mg/dL). Eighty patients were treated with adjunctive agents for alcohol withdrawal including antipsychotics (n = 57), opioids (n = 27), clonidine (n = 35), and phenobarbital (n = 23). Average time of flumazenil administration was 4.7 days (1–11 days) after abstinence, and average dose was 0.5 mg (0.2–1 mg). At the time of flumazenil administration, delirium was described as hypoactive (n = 21), hyperactive (n = 15), mixed (n = 41), or not specified (n = 8). Response was not documented in 11 cases. Sixty-two (72.9 %) patients had significant objective improvement after receiving flumazenil. Fifty-six patients required more than one dose (average 5.6 doses). There were no major adverse events and minor adverse effects included transiently increased anxiety in two patients: 1 patient who received 0.5 mg on abstinence day 2 and another patient who received 0.2 mg flumazenil on abstinence day 11. This is the largest series diagnosing benzodiazepine delirium after AWS in patients receiving flumazenil. During the treatment of AWS, if delirium is present on day 5, a test dose of flumazenil may be considered to establish benzodiazepine delirium. With the limited data set often accompanying patients with AWS, flumazenil diagnosed benzodiazepine delirium during the treatment of AWS and improved impairments in cognition and behavior without serious or life-threatening adverse events in our patients.
doi:10.1007/s13181-014-0391-6
PMCID: PMC4057541  PMID: 24619543
Alcohol withdrawal syndrome/delirium tremens; Benzodiazepine delirium/benzodiazepine toxicity; Hypoactive delirium/hyperactive delirium/agitated delirium; Flumazenil diagnostic/flumazenil therapeutic; Benzodiazepine/lorazepam/diazepam/midazolam; Pharmacovigilence
3.  Does current evidence support the use of intraoperative cell salvage in reducing the need for blood transfusion in caesarean section? 
Purpose of review
An important cause of maternal morbidity and direct maternal death is obstetric haemorrhage at caesarean section. Concerns regarding allogeneic blood safety, limited blood supplies and rising health costs have collectively generated enthusiasm for the utility of methods intended to reduce the use of allogeneic blood transfusion in cases of haemorrhage at caesarean section. This can be achieved by intraoperative cell salvage (IOCS). The aim of this review is to summarize and examine the evidence for the efficacy of IOCS during caesarean section, in women at risk of haemorrhage, in reducing the need for allogeneic blood transfusion.
Recent findings
The majority of the evidence currently available is from case reports and case series. Although this evidence appears to support the use of IOCS in obstetrics, strong clinical evidence or economic effectiveness from clinical trials are essential to support the routine practice of IOCS in obstetrics.
Summary
Current evidence is limited to reported case series and two small controlled studies. Overall, IOCS may reduce the need for allogeneic blood transfusions during caesarean section. Future large randomized trials are required to assess effectiveness, cost effectiveness and safety. The results of the current ongoing SALVO (A randomised controlled trial of intra-operative cell salvage during caesarean section in women at risk of haemorrhage) trial will shed light on these aspects.
doi:10.1097/GCO.0000000000000116
PMCID: PMC4338583  PMID: 25259949
allogeneic blood transfusion; caesarean section; intraoperative cell salvage; obstetrics
4.  Hydrogen Sulfide Donor GYY4137 Protects against Myocardial Fibrosis 
Hydrogen sulfide (H2S) is a gasotransmitter which regulates multiple cardiovascular functions. However, the precise roles of H2S in modulating myocardial fibrosis in vivo and cardiac fibroblast proliferation in vitro remain unclear. We investigated the effect of GYY4137, a slow-releasing H2S donor, on myocardial fibrosis. Spontaneously hypertensive rats (SHR) were administrated with GYY4137 by intraperitoneal injection daily for 4 weeks. GYY4137 decreased systolic blood pressure and inhibited myocardial fibrosis in SHR as evidenced by improved cardiac collagen volume fraction (CVF) in the left ventricle (LV), ratio of perivascular collagen area (PVCA) to lumen area (LA) in perivascular regions, reduced hydroxyproline concentration, collagen I and III mRNA expression, and cross-linked collagen. GYY4137 also inhibited angiotensin II- (Ang II-) induced neonatal rat cardiac fibroblast proliferation, reduced the number of fibroblasts in S phase, decreased collagen I and III mRNA expression and protein synthesis, attenuated oxidative stress, and suppressed α-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1) expression as well as Smad2 phosphorylation. These results indicate that GYY4137 improves myocardial fibrosis perhaps by a mechanism involving inhibition of oxidative stress, blockade of the TGF-β1/Smad2 signaling pathway, and decrease in α-SMA expression in cardiac fibroblasts.
doi:10.1155/2015/691070
PMCID: PMC4442292  PMID: 26078813
5.  GYY4137 protects against myocardial ischemia and reperfusion injury by attenuating oxidative stress and apoptosis in rats 
Journal of Biomedical Research  2014;29(3):203-213.
Abstract
Hydrogen sulfide (H2S) is a gasotransmitter that regulates cardiovascular functions. The present study aimed to determine the protective effect of slow-releasing H2S donor GYY4137 on myocardial ischemia and reperfusion (I/R) injury and to investigate the possible signaling mechanisms involved. Male Sprague-Dawley rats were treated with GYY4137 at 12.5 mg/(kg·day), 25 mg/(kg·day) or 50 mg/(kg·day) intraperitoneally for 7 days. Then, rats were subjected to 30 minutes of left anterior descending coronary artery occlusion followed by reperfusion for 24 hours. We found that GYY4137 increased the cardiac ejection fraction and fractional shortening, reduced the ischemia area, alleviated histological injury and decreased plasma creatine kinase after myocardial I/R. Both H2S concentration in plasma and cystathionine-γ-lyase (CSE) activity in the myocardium were enhanced in the GYY4137 treated groups. GYY4137 also decreased malondialdehyde and myeloperoxidase levels in serum, attenuated superoxide anion level and suppressed phosphorylation of mitogen activated protein kinases in the myocardium after I/R. Meanwhile, GYY4137 increased the expression of Bcl-2 but decreased the expression of Bax, caspase-3 activity and apoptosis in the myocardium. The data suggest that GYY4137 protects against myocardial ischemia and reperfusion injury by attenuating oxidative stress and apoptosis.
doi:10.7555/JBR.28.20140037
PMCID: PMC4449488  PMID: 26060444
hydrogen sulfide; ischemia and reperfusion; myocardial infarction; oxidative stress; apoptosis
6.  Hydrogen Sulfide Promotes Adipogenesis in 3T3L1 Cells 
PLoS ONE  2015;10(3):e0119511.
The effect of hydrogen sulfide (H2S) on differentiation of 3T3L1-derived adipocytes was examined. Endogenous H2S was increased after 3T3L1 differentiation. The expression of the H2S-synthesising enzymes, cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (3-MST), was increased in a time-dependent manner during 3T3L1 differentiation. Expression of genes associated with adipogenesis related genes including fatty acid binding protein 4 (FABP4/aP2), a key regulator of this process, was increased by GYY4137 (a slow-releasing H2S donor compound) and sodium hydrosulfide (NaHS, a classical H2S donor) but not by ZYJ1122 or time-expired NaHS. Furthermore expression of these genes were reduced by aminooxyacetic acid (AOAA, CBS inhibitor), DL-propargylglycine (PAG, CSE inhibitor) as well as by CSE small interference RNA (siCSE) and siCBS. The size and number of lipid droplets in mature adipocytes was significantly increased by both GYY4137 and NaHS, which also impaired the ability of CL316,243 (β3-agonist) to promote lipolysis in these cells. In contrast, AOAA and PAG had the opposite effect. Taken together, we show that the H2S-synthesising enzymes CBS, CSE and 3-MST are endogenously expressed during adipogenesis and that both endogenous and exogenous H2S modulate adipogenesis and adipocyte maturation.
doi:10.1371/journal.pone.0119511
PMCID: PMC4378953  PMID: 25822632
7.  The hydrogen sulfide donor, GYY4137, exhibits anti-atherosclerotic activity in high fat fed apolipoprotein E−/− mice 
British Journal of Pharmacology  2013;169(8):1795-1809.
Background and Purpose
Atherosclerosis is associated with reduced vascular hydrogen sulfide (H2S) biosynthesis. GYY4137 is a novel slow-releasing H2S compound that may effectively mimic the time course of H2S release in vivo. However, it is not known whether GYY4137 affects atherosclerosis.
Experimental Approach
RAW 264.7 cells and human blood monocyte-derived macrophages were incubated with oxidized low density lipoprotein (ox-LDL) with/without GYY4137. ApoE−/− mice were fed a high-fat diet for 4 weeks and administered GYY4137 for 30 days. Lipid and atherosclerotic lesions were measured by oil red O staining. Endothelium-dependent relaxation was assessed in response to acetylcholine. Superoxide production was detected by dihydroethidium staining. Expression of mRNA and protein were evaluated by quantitative real-time PCR and Western blot.
Key Results
GYY4137 inhibited ox-LDL-induced foam cell formation and cholesterol esterification in cultured cells. GYY4137 decreased the expression of lectin-like ox-LDL receptor-1, iNOS, phosphorylated IκBα, NF-κB, ICAM-1, VCAM-1 and chemokines, including CXCL2, CXCR4, CXCL10 and CCL17, but increased the scavenger protein CD36, in ox-LDL-treated RAW 264.7 cells. In vivo, GYY4137 decreased aortic atherosclerotic plaque formation and partially restored aortic endothelium-dependent relaxation in apoE−/− mice. GYY4137 decreased ICAM-1, TNF-α and IL-6 mRNA expression as well as superoxide (O2−) generation in aorta. In addition, GYY4137 increased aortic eNOS phosphorylation and expression of PI3K, enhanced Akt Ser473 phosphorylation and down-regulated the expression of LOX-1.
Conclusion and Implications
GYY4137 inhibits lipid accumulation induced by ox-LDL in RAW 264.7 cells. In vivo, GYY4137 decreased vascular inflammation and oxidative stress, improved endothelial function and reduced atherosclerotic plaque formation in apoE−/− mice.
doi:10.1111/bph.12246
PMCID: PMC3753836  PMID: 23713790
arteriosclerosis; hydrogen sulfide; inflammation; oxidative stress; endothelial dysfunction
8.  The complex effects of the slow-releasing hydrogen sulfide donor GYY4137 in a model of acute joint inflammation and in human cartilage cells 
The role of hydrogen sulfide (H2S) in inflammation remains unclear with both pro- and anti-inflammatory actions of this gas described. We have now assessed the effect of GYY4137 (a slow-releasing H2S donor) on lipopolysaccharide (LPS)-evoked release of inflammatory mediators from human synoviocytes (HFLS) and articular chondrocytes (HAC) in vitro. We have also examined the effect of GYY4137 in a complete Freund’s adjuvant (CFA) model of acute joint inflammation in the mouse. GYY4137 (0.1–0.5 mM) decreased LPS-induced production of nitrite (NO2−), PGE2, TNF-α and IL-6 from HFLS and HAC, reduced the levels and catalytic activity of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and reduced LPS-induced NF-κB activation in vitro. Using recombinant human enzymes, GYY4137 inhibited the activity of COX-2, iNOS and TNF-α converting enzyme (TACE). In the CFA-treated mouse, GYY4137 (50 mg/kg, i.p.) injected 1 hr prior to CFA increased knee joint swelling while an anti-inflammatory effect, as demonstrated by reduced synovial fluid myeloperoxidase (MPO) and N-acetyl-β-D-glucosa-minidase (NAG) activity and decreased TNF-α, IL-1β, IL-6 and IL-8 concentration, was apparent when GYY4137 was injected 6 hrs after CFA. GYY4137 was also anti-inflammatory when given 18 hrs after CFA. Thus, although GYY4137 consistently reduced the generation of pro-inflammatory mediators from human joint cells in vitro, its effect on acute joint inflammation in vivo depended on the timing of administration.
doi:10.1111/jcmm.12016
PMCID: PMC3823018  PMID: 23356870
hydrogen sulfide; GYY4137; inflammation; synoviocyte; cytokines; myeloperoxidase; lipopolysaccharide; Freund’s adjuvant; COX-2; TNF-alpha converting enzyme
9.  C. elegans Aging Is Modulated by Hydrogen Sulfide and the sulfhydrylase/cysteine Synthase cysl-2 
PLoS ONE  2013;8(11):e80135.
Exogenous hydrogen sulfide (H2S) administration and endogenous H2S metabolism were explored in the nematode C. elegans. Chronic treatment with a slow-releasing H2S donor, GYY4137, extended median survival by 17-23% and increased tolerance towards oxidative and endoplasmic reticulum (ER) stress. Also, cysl-2, a sulfhydrylase/cysteine synthase in C. elegans, was transcriptionally upregulated by GYY4137 treatment and the deletion of cysl-2 resulted in a significant reduction in lifespan which was partially recovered by the supplementation of GYY4137. Likewise, a mammalian cell culture system, GYY4137 was able to protect bovine aortic endothelial cells (BAECs) from oxidative stress and (H2O2)-induced cell death. Taken together, this provides further support that H2S exerts a protective function which is consistent with the longevity dividend theory. Overall, this study underlines the therapeutic potential of a slow-releasing H2S donor as regulators of the aging and cellular stress pathways.
doi:10.1371/journal.pone.0080135
PMCID: PMC3832670  PMID: 24260346
10.  The complex effects of the slow-releasing hydrogen sulfide donor GYY4137 in a model of acute joint inflammation and in human cartilage cells 
The role of hydrogen sulfide (H2S) in inflammation remains unclear with both pro- and anti-inflammatory actions of this gas described. We have now assessed the effect of GYY4137 (a slow-releasing H2S donor) on lipopolysaccharide (LPS)-evoked release of inflammatory mediators from human synoviocytes (HFLS) and articular chondrocytes (HAC) in vitro. We have also examined the effect of GYY4137 in a complete Freund's adjuvant (CFA) model of acute joint inflammation in the mouse. GYY4137 (0.1–0.5 mM) decreased LPS-induced production of nitrite (NO2−), PGE2, TNF-α and IL-6 from HFLS and HAC, reduced the levels and catalytic activity of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and reduced LPS-induced NF-κB activation in vitro. Using recombinant human enzymes, GYY4137 inhibited the activity of COX-2, iNOS and TNF-α converting enzyme (TACE). In the CFA-treated mouse, GYY4137 (50 mg/kg, i.p.) injected 1 hr prior to CFA increased knee joint swelling while an anti-inflammatory effect, as demonstrated by reduced synovial fluid myeloperoxidase (MPO) and N-acetyl-β-D-glucosaminidase (NAG) activity and decreased TNF-α, IL-1β, IL-6 and IL-8 concentration, was apparent when GYY4137 was injected 6 hrs after CFA. GYY4137 was also anti-inflammatory when given 18 hrs after CFA. Thus, although GYY4137 consistently reduced the generation of pro-inflammatory mediators from human joint cells in vitro, its effect on acute joint inflammation in vivo depended on the timing of administration.
doi:10.1111/jcmm.12016
PMCID: PMC3823018  PMID: 23356870
hydrogen sulfide; GYY4137; inflammation; synoviocyte; cytokines; myeloperoxidase; lipopolysaccharide; Freund's adjuvant; COX-2; TNF-alpha converting enzyme
11.  Multifaceted role of nitric oxide in an in vitro mouse neuronal injury model: transcriptomic profiling defines the temporal recruitment of death signalling cascades 
Abstract
Nitric oxide is implicated in the pathogenesis of various neuropathologies characterized by oxidative stress. Although nitric oxide has been reported to be involved in the exacerbation of oxidative stress observed in several neuropathologies, existent data fail to provide a holistic description of how nitrergic pathobiology elicits neuronal injury. Here we provide a comprehensive description of mechanisms contributing to nitric oxide induced neuronal injury by global transcriptomic profiling. Microarray analyses were undertaken on RNA from murine primary cortical neurons treated with the nitric oxide generator DETA-NONOate (NOC-18, 0.5 mM) for 8–24 hrs. Biological pathway analysis focused upon 3672 gene probes which demonstrated at least a ±1.5-fold expression in a minimum of one out of three time-points and passed statistical analysis (one-way anova, P < 0.05). Numerous enriched processes potentially determining nitric oxide mediated neuronal injury were identified from the transcriptomic profile: cell death, developmental growth and survival, cell cycle, calcium ion homeostasis, endoplasmic reticulum stress, oxidative stress, mitochondrial homeostasis, ubiquitin-mediated proteolysis, and GSH and nitric oxide metabolism. Our detailed time-course study of nitric oxide induced neuronal injury allowed us to provide the first time a holistic description of the temporal sequence of cellular events contributing to nitrergic injury. These data form a foundation for the development of screening platforms and define targets for intervention in nitric oxide neuropathologies where nitric oxide mediated injury is causative.
doi:10.1111/j.1582-4934.2011.01288.x
PMCID: PMC3823092  PMID: 21352476
nitric oxide; neuronal injury; oxidative stress; microarray; reactive oxygen species; reactive nitrogen species
12.  The Slow-Releasing Hydrogen Sulfide Donor, GYY4137, Exhibits Novel Anti-Cancer Effects In Vitro and In Vivo 
PLoS ONE  2011;6(6):e21077.
The slow-releasing hydrogen sulfide (H2S) donor, GYY4137, caused concentration-dependent killing of seven different human cancer cell lines (HeLa, HCT-116, Hep G2, HL-60, MCF-7, MV4-11 and U2OS) but did not affect survival of normal human lung fibroblasts (IMR90, WI-38) as determined by trypan blue exclusion. Sodium hydrosulfide (NaHS) was less potent and not active in all cell lines. A structural analogue of GYY4137 (ZYJ1122) lacking sulfur and thence not able to release H2S was inactive. Similar results were obtained using a clonogenic assay. Incubation of GYY4137 (400 µM) in culture medium led to the generation of low (<20 µM) concentrations of H2S sustained over 7 days. In contrast, incubation of NaHS (400 µM) in the same way led to much higher (up to 400 µM) concentrations of H2S which persisted for only 1 hour. Mechanistic studies revealed that GYY4137 (400 µM) incubated for 5 days with MCF-7 but not IMR90 cells caused the generation of cleaved PARP and cleaved caspase 9, indicative of a pro-apoptotic effect. GYY4137 (but not ZYJ1122) also caused partial G2/M arrest of these cells. Mice xenograft studies using HL-60 and MV4-11 cells showed that GYY4137 (100–300 mg/kg/day for 14 days) significantly reduced tumor growth. We conclude that GYY4137 exhibits anti-cancer activity by releasing H2S over a period of days. We also propose that a combination of apoptosis and cell cycle arrest contributes to this effect and that H2S donors should be investigated further as potential anti-cancer agents.
doi:10.1371/journal.pone.0021077
PMCID: PMC3119065  PMID: 21701688
13.  The Effect of Hydrogen Sulfide Donors on Lipopolysaccharide-Induced Formation of Inflammatory Mediators in Macrophages 
Antioxidants & Redox Signaling  2010;12(10):1147-1154.
Abstract
The role of hydrogen sulfide (H2S) in inflammation is controversial, with both pro- and antiinflammatory effects documented. Many studies have used simple sulfide salts as the source of H2S, which give a rapid bolus of H2S in aqueous solutions and thus do not accurately reflect the enzymatic generation of H2S. We therefore compared the effects of sodium hydrosulfide and a novel slow-releasing H2S donor (GYY4137) on the release of pro- and antiinflammatory mediators in lipopolysaccharide (LPS)-treated murine RAW264.7 macrophages. For the first time, we show that GYY4137 significantly and concentration-dependently inhibits LPS-induced release of proinflammatory mediators such as IL-1β, IL-6, TNF-α, nitric oxide (•NO), and PGE2 but increased the synthesis of the antiinflammatory chemokine IL-10 through NF-κB/ATF-2/HSP-27–dependent pathways. In contrast, NaHS elicited a biphasic effect on proinflammatory mediators and, at high concentrations, increased the synthesis of IL-1β, IL-6, NO, PGE2 and TNF-α. This study clearly shows that the effects of H2S on the inflammatory process are complex and dependent not only on H2S concentration but also on the rate of H2S generation. This study may also explain some of the apparent discrepancies in the literature regarding the pro- versus antiinflammatory role of H2S. Antioxid. Redox Signal. 12, 1147–1154.
doi:10.1089/ars.2009.2899
PMCID: PMC2875982  PMID: 19769459
14.  Hydrogen sulfide and the vasculature: a novel vasculoprotective entity and regulator of nitric oxide bioavailability? 
Abstract
Hydrogen sulfide (H2S) is a well known and pungent toxic gas that has recently been shown to be synthesised in man from the amino acids cystathionine, homocysteine and cysteine by at least two distinct enzymes; cystathionine-γ-lyase and cystathionine-β-synthase. In the past few years, H2S has emerged as a novel and increasingly important mediator in the cardiovascular system but delineating the precise physiology and pathophysiology of H2S is proving to be complex and difficult to unravel with disparate findings reported with cell types, tissue types and animal species reported. Therefore, in this review we summarize the mechanisms by which H2S has been proposed to regulate blood pressure and cardiac function, discuss the mechanistic discrepancies reported in the literature as well as the therapeutic potential of H2S. We also examine the methods of H2S detection in biological fluids, processes for H2S removal and discuss the reported blood levels of H2S in man and animal models of cardiovascular pathology. We also highlight the complex interaction of H2S with nitric oxide in regulating cardiovascular function in health and disease.
doi:10.1111/j.1582-4934.2009.00645.x
PMCID: PMC3822510  PMID: 19374684
nitrosothiol; cardioprotection; KATP; vasodilator; gaseous mediators; reactive nitrogen species; sulfur
16.  The role of urotensin II in cardiovascular and renal physiology and diseases 
British Journal of Pharmacology  2006;148(7):884-901.
Urotensin II (U-II) is a cyclic neuropeptide that was first isolated from teleost fish some 35 years ago. Mammalian U-II is a powerful vasoconstrictor with a potency greater than that of endothelin-1.Nevertheless, unlike endothelin-1, which constricts all or nearly all vascular beds, the vasoactive effects of U-II are reported to be dependent both on the species and on the regional vascular bed examined. Typical regional variability occurs in the rat in which vasoconstriction to U-II is most robust in thoracic aorta proximal to the aortic arch and decreases gradually towards the distal peripheral arteries. As small peripheral arteries but not larger arteries such as the aorta play a major role in regulating peripheral resistance and consequent blood pressure as well as workload on the heart, doubts have been raised concerning the importance of this peptide in cardiovascular physiology. Moreover, an interaction between U-II and other endogenous vasoactive molecules may add a level of complexity to the vascular actions of U-II.On the other hand, recent experimental and clinical studies have revealed increased expression of U-II and urotensin receptor (UT receptor) in animals with experimentally induced myocardial infarction, heart failure, and in patients with hypertension, atherosclerosis, and diabetic nephropathy, which suggests a potential role for U-II in both cardiovascular and renal diseases. A series of peptidic and nonpeptidic UT receptor ligands have been shown to be effective in antagonizing the effects of U-II in the cardiorenal system.This article aims to review recent advances in our understanding of the physiology and pathophysiology of U-II with particular references to its role in cardiovascular health and disease.
doi:10.1038/sj.bjp.0706800
PMCID: PMC1751922  PMID: 16783414
Urotensin II; urotensin receptor; vasoactive effects; signalling mechanisms; interaction
17.  Nitric oxide-releasing flurbiprofen reduces formation of proinflammatory hydrogen sulfide in lipopolysaccharide-treated rat 
British Journal of Pharmacology  2006;147(8):966-974.
The biosynthesis of both nitric oxide (NO) and hydrogen sulfide (H2S) is increased in lipopolysaccharide (LPS)-injected mice and rats but their interaction in these models is not known. In this study we examined the effect of the NO donor, nitroflurbiprofen (and the parent molecule flurbiprofen) on NO and H2S metabolism in tissues from LPS-pretreated rats.Administration of LPS (10 mg kg−1, i.p.; 6 h) resulted in an increase (P<0.05) in plasma TNF-α, IL-1β and nitrate/nitrite (NOx) concentrations, liver H2S synthesis (from added cysteine), CSE mRNA, inducible nitric oxide synthase (iNOS), myeloperoxidase (MPO) activity (marker for neutrophil infiltration) and nuclear factor-kappa B (NF-κB) activation.Nitroflurbiprofen (3–30 mg kg−1, i.p.) administration resulted in a dose-dependent inhibition of the LPS-mediated increase in plasma TNF-α, IL-1β and NOx concentration, liver H2S synthesis (55.00±0.95 nmole mg protein−1, c.f. 62.38±0.47 nmole mg protein−1, n=5, P<0.05), CSE mRNA, iNOS, MPO activity and NF-κB activation.Flurbiprofen (21 mg kg−1, i.p.) was without effect.These results show for the first time that nitroflurbiprofen downregulates the biosynthesis of proinflammatory H2S and suggest that such an effect may contribute to the augmented anti-inflammatory activity of this compound.These data also highlight the existence of ‘crosstalk' between NO and H2S in this model of endotoxic shock.
doi:10.1038/sj.bjp.0706696
PMCID: PMC1760720  PMID: 16491094
Nitric oxide; nitroflurbiprofen; flurbiprofen; hydrogen sulphide; lipopolysaccharide-induced endotoxic shock; interleukin-1β; tumour necrosis factor-α cystathionine γ lyase
18.  Hydrogen sulfide acts as a mediator of inflammation inacute pancreatitis: in vitro studies using isolated mouse pancreatic acinar cells 
Abstract
Hydrogen sulphide (H2S) is synthesized from L-cysteine via the action of cystathionine-γ-lyase (CSE) and cystathionine-β-synthase (CBS). We have earlier shown that H2S acts as a mediator of inflammation. However the mechanism remains unclear. In this study, we investigated the presence of H2S and the expression of H2S synthesizing enzymes, CSE and CBS, in isolated mouse pancreatic acini. Pancreatic acinar cells from mice were incubated with or without caerulein (10−7 M for 30 and 60 min). Caerulein increased the levels of H2S and CSE mRNA expression while CBS mRNA expression was decreased. In addition, cells pre-treated with DL-propargylglycine (PAG, 3 mM), a CSE inhibitor, reduced the formation of H2S in caerulein treated cells, suggesting that CSE may be the main enzyme involved in H2S formation in mouse acinar cells. Furthermore, substance P (SP) concentration in the acini and expression of SP gene (preprotachykinin-A, PPT-A) and neurokinin-1 receptor (NK-1R), the primary receptor for SP, are increased in secretagogue caerulein-treated acinar cells. Inhibition of endogenous production of H2S by PAG significantly suppressed SP concentration, PPT-A expression and NK1-R expression in the acini. To determine whether H2S itself provoked inflammation in acinar cells, the cells were treated with H2S donor drug, sodium hydrosulphide (NaHS), (10, 50 and 100 μM), that resulted in a significant increase in SP concentration and expression of PPT-A and NK1-R in acinar cells. These results suggest that the pro-inflammatory effect of H2S may be mediated by SP-NK-1R related pathway in mouse pancreatic acinar cells.
doi:10.1111/j.1582-4934.2007.00024.x
PMCID: PMC3822830  PMID: 17488480
cystathionine-γ-lyase; cystathionine-β-synthase; H2S; Substance P; pancreatic acinar cells
19.  Inhibition of endogenous hydrogen sulfide formation reduces the organ injury caused by endotoxemia 
British Journal of Pharmacology  2005;146(4):498-505.
Hydrogen sulfide (H2S) is a naturally occurring gaseous transmitter, which may play important roles in normal physiology and disease. Here, we investigated the role of H2S in the organ injury caused by severe endotoxemia in the rat.Male Wistar rats were subjected to acute endotoxemia (Escherichia coli lipopolysaccharide (LPS) 6 mg kg−1 intravenously (i.v.) for 6 h) and treated with vehicle (saline, 1 ml kg−1 i.v.) or DL-propargylglycine (PAG, 10–100 mg kg−1 i.v.), an inhibitor of the H2S-synthesizing enzyme cystathionine-γ-lyase (CSE). PAG was administered either 30 min prior to or 60 min after the induction of endotoxemia.Endotoxemia resulted in circulatory failure (hypotension and tachycardia) and an increase in serum levels of alanine aminotransferase and aspartate aminotransferase (markers for hepatic injury), lipase (indicator of pancreatic injury) and creatine kinase (indicator of neuromuscular injury). In the liver, endotoxemia induced a significant increase in the myeloperoxidase (MPO) activity, and in the expression and activity of the H2S-synthesizing enzymes CSE and cystathionine-β-synthase.Administration of PAG either prior to or after the injection of LPS dose-dependently reduced the hepatocellular, pancreatic and neuromuscular injury caused by endotoxemia, but not the circulatory failure. Pretreatment of rats with PAG abolished the LPS-induced increase in the MPO activity and in the formation of H2S and in the liver.These findings support the view that an enhanced formation of H2S contributes to the pathophysiology of the organ injury in endotoxemia. We propose that inhibition of H2S synthesis may be a useful therapeutic strategy against the organ injury associated with sepsis and shock.
doi:10.1038/sj.bjp.0706367
PMCID: PMC1751176  PMID: 16100527
Hydrogen sulfide; DL-propargylglycine; LPS; cystathionine-γ-lyase; CSE; rat
20.  Hydrogen sulphide is a mediator of carrageenan-induced hindpaw oedema in the rat 
British Journal of Pharmacology  2005;145(2):141-144.
Hydrogen sulphide (H2S) is a naturally occurring gas, with potent vasodilator activity. In this report, we identify a role for H2S in carrageenan-induced hindpaw oedema in the rat. Intraplantar injection of carrageenan (150 μl, 2% (w v−1)) resulted in an increase in hindpaw H2S synthesising enzyme activity and increased myeloperoxidase (MPO) activity. Pretreatment (i.p. 60 min before carrageenan) with DL-propargylglycine (PAG, 25–75 mg kg−1), an inhibitor of the H2S synthesising enzyme cystathionine-γ-lyase (CSE), significantly reduced carrageenan-induced hindpaw oedema in a dose-dependent manner (e.g. increase in hindpaw weight at 3 h, saline: 0.12±0.017 g; carrageenan, 1.39±0.037 g; PAG, 50 mg kg−1, 1.11±0.06 g, n=10) and MPO activity (fold increase) in the hindpaw (saline: 1.0±0.12; carrageenan, 2.92±0.45 g; PAG, 50 mg kg−1, 1.1±0.22, n=10); PAG (50 mg kg−1) also inhibited H2S synthesising enzyme activity (nmol μg DNA−1) in the hindpaw in a dose-dependent manner (saline, 0.46±0.05; carrageenan, 0.71±0.08 g; PAG, 50 mg kg−1, 0.17±0.05, n=10).
doi:10.1038/sj.bjp.0706186
PMCID: PMC1576135  PMID: 15753944
Hydrogen sulphide; oedema; inflammation; carrageenan
21.  Role of hydrogen sulphide in haemorrhagic shock in the rat: protective effect of inhibitors of hydrogen sulphide biosynthesis 
British Journal of Pharmacology  2004;143(7):881-889.
Haemorrhagic shock (60 min) in the anaesthetized rat resulted in a prolonged fall in the mean arterial blood pressure (MAP) and heart rate (HR).Pre-treatment (30 min before shock) or post-treatment (60 min after shock) with inhibitors of cystathionine γ lyase (CSE; converts cysteine into hydrogen sulphide (H2S)), dl-propargylglycine or β-cyanoalanine (50 mg kg−1, i.v.), or glibenclamide (40 mg kg−1, i.p.), produced a rapid, partial restoration in MAP and HR. Neither saline nor DMSO affected MAP or HR.Plasma H2S concentration was elevated 60 min after blood withdrawal (37.5±1.3 μm, n=18 c.f. 28.9±1.4 μm, n=15, P<0.05).The conversion of cysteine to H2S by liver (but not kidney) homogenates prepared from animals killed 60 min after withdrawal of blood was significantly increased (52.1±1.6 c.f. 39.8±4.1 nmol mg protein−1, n=8, P<0.05), as was liver CSE mRNA (2.7 ×). Both PAG (IC50, 55.0±3.2 μm) and BCA (IC50, 6.5±1.2 μm) inhibited liver H2S synthesizing activity in vitro.Pre-treatment of animals with PAG or BCA (50 mg kg−1, i.p.) but not glibenclamide (40 mg kg−1, i.p., KATP channel inhibitor) abolished the rise in plasma H2S in animals exposed to 60 min haemorrhagic shock and prevented the augmented biosynthesis of H2S from cysteine in liver.These results demonstrate that H2S plays a role in haemorrhagic shock in the rat. CSE inhibitors may provide a novel approach to the treatment of haemorrhagic shock.
doi:10.1038/sj.bjp.0706014
PMCID: PMC1575944  PMID: 15504752
Hydrogen sulphide; haemorrhagic shock; DL-propargylglycine; β-cyanoalanine; glibenclamide
22.  Hydrogen sulfide protects colon cancer cells from chemopreventative agent β-phenylethyl isothiocyanate induced apoptosis 
AIM: Hydrogen sulfide (H2S) is a prominent gaseous constituent of the gastrointestinal (GI) tract with known cytotoxic properties. Endogenous concentrations of H2S are reported to range between 0.2-3.4 mmol/L in the GI tract of mice and humans. Considering such high levels we speculate that, at non-toxic concentrations, H2S may interact with chemical agents and alter the response of colonic epithelium cells to such compounds. The GI tract is a major site for the absorption of phytochemical constituents such as isothiocyanates, flavonoids, and carotenoids, with each group having a role in the prevention of human diseases such as colon cancer. The chemopreventative properties of the phytochemical agent β-phenyethyl isothiocyanate (PEITC) are well recognized. However, little is currently known about the physiological or biochemical factors present in the GI tract that may influence the biological properties of ITCs. The current study was undertaken to determine the effects of H2S on PEITC mediated apoptosis in colon cancer cells.
METHODS: Induction of apoptosis by PEITC in human colon cancer HCT116 cells was assessed using classic apoptotic markers namely SubG1 population analysis, caspase-3 like activity and nuclear fragmentation and condensation coupled with the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrasodium bromide] viability assay and LDH leakage.
RESULTS: PEITC significantly induced apoptosis in HCT116 cells as assessed by SubG1 population formation, nuclear condensation, LDH leakage and caspase-3 activity after 24 h, these data being significant from control groups (P < 0.01). In contrast, co-treatment of cells with physiological concentrations of H2S (0.1-1 mmol/L) prevented PEITC mediated apoptosis as assessed using the parameters described.
CONCLUSION: PEITC effectively induced cell death in the human adenocarcinoma cell line HCT116 in vitro through classic apoptotic mechanisms. However, in the presence of H2S, apoptosis was abolished. These data suggest that H2S may play a significant role in the response of colonic epithelial cells to beneficial as well as toxic agents present within the GI tract.
doi:10.3748/wjg.v11.i26.3990
PMCID: PMC4502092  PMID: 15996021
Apoptosis; Colon cancer; Hydrogen sulfide; β-phenylethyl isothiocyanate
23.  Medical malpractice 
Western Journal of Medicine  2000;173(4):244-250.
Objective To examine the causal effects of doctor-patient relations and the severity of a medical outcome on medical patient perceptions and malpractice intentions in the event of an adverse medical outcome. Design Randomized between-subjects experimental design. Patients were given scenarios depicting interactions between an obstetric patient and her physician throughout the patient's pregnancy, labor, and delivery. Participants One hundred twenty-eight postpartum obstetric patients were approached for participation, of whom 104 completed the study. Main outcome measures Patients' perceptions of physician competence and intentions to file a malpractice claim. Results Positive physician communication behaviors increased patients' perceptions of physician competence and decreased malpractice claim intentions toward both the physician and the hospital. A more severe outcome increased only patients' intentions to sue the hospital. Conclusion These results provide empiric evidence for a direct, causal effect of the doctor-patient relationship on medical patients' treatment perceptions and malpractice claim intentions in the event of an adverse medical outcome.
PMCID: PMC1071103  PMID: 11017984
24.  A comparison of the effects of L-NAME, 7-NI and L-NIL on carrageenan-induced hindpaw oedema and NOS activity 
British Journal of Pharmacology  1998;123(6):1119-1126.
Intraplantar injection of carrageenan (150 μl, 1–3% w/v) in the rat resulted in a dose-related increase in hindpaw weight (oedema) characterized by a rapid ‘early' phase (up to 2.5 h) response followed by a more sustained ‘late' phase (2–6 h) response. No change in weight of either the contralateral (i.e. noninjected) hindpaw or hindpaws injected with saline was observed.Six hours after intraplantar injection of carrageenan (1–3% w/v) hindpaw constitutive (i.e. calcium-dependent) nitric oxide synthase (cNOS) activity (determined ex vivo as the conversion of radiolabelled L-arginine to radiolabelled citrulline) was increased (e.g. 2% w/v; 0.64±0.08 pmol citrulline mg−1 protein 15 min−1 c.f. 0.08±0.04 pmol citrulline mg−1 protein 15 min−1 in saline-injected, control animals, n=4, P<0.05). Carrageenan injection also resulted in the appearance in hindpaw homogenates of inducible (i.e. calcium-independent) nitric oxide synthase (iNOS, e.g. 2% w/v; 0.67±0.14 pmol citrulline mg−1 protein 15 min−1, n=4). Hindpaw cyclic GMP concentration was also significantly increased 6 h after intraplantar injection of carrageenan (e.g. 2% w/v; 379.6±26.8 fmol mg−1 protein c.f. 261.8±42.2 fmol mg−1 protein, in saline-injected, control animals, n=4, P<0.05).Pretreatment (5–25 mg kg−1, i.p., 30 min before carrageenan, 2% w/v) of animals with L-NG nitro arginine methyl ester (L-NAME; isoform nonselective inhibitor of NOS) or 7-nitro indazole (7-NI; inhibitor of neuronal NOS, nNOS) caused dose-related inhibition of both the early (2 h) and late (6 h) phase hindpaw oedema, associated with reduced hindpaw iNOS and cNOS activity and cyclic GMP concentration in animals killed at 6 h. Administration of 7-NI (5–25 mg kg−1, i.p.) to animals 2.5 h after intraplantar carrageenan (2% w/v) injection (i.e. at the end of the early phase oedema response) produced dose-related inhibition of the late phase response.Pretreatment (5–25 mg kg−1, i.p., 30 min before carrageenan, 2% w/v) of animals with L-N6-iminoethyllysine (L-NIL, selective inhibitor of iNOS) (5–25 mg kg−1) failed to affect the early phase hindpaw oedema response but did produce a dose-related inhibition of the late phase oedema. L-NIL pretreatment also inhibited the carrageenan-induced increase in both hindpaw iNOS and cNOS activity as well as the rise in hindpaw cyclic GMP concentration.The present experiments demonstrate an anti-inflammatory effect of 7-NI as evidenced by inhibition of carrageenan-induced hindpaw oedema in the rat. Inhibition of nNOS (early phase) and iNOS (late phase) at the site of inflammation most probably accounts for the anti-inflammatory activity observed. These data suggest a role for nitric oxide synthesized by the nNOS isoform (most probably within sensory nerves) in this model of inflammation.
doi:10.1038/sj.bjp.0701735
PMCID: PMC1565282  PMID: 9559895
Hindpaw oedema; nitric oxide synthase; nitric oxide; 7-nitro indazole; L-NAME; inflammation
25.  Patients' knowledge of heart disease in general practice 
Interviews with 400 consecutive patients attending a general practice sought their knowledge of the signs and symptoms of an acute heart attack, what action they would take for such an event, and their understanding of the predisposing factors contributing to heart disease. The survey revealed poor recognition of the relevant signs and symptoms of an acute heart attack and lack of knowledge of some of the main predisposing factors associated with heart disease.
PMCID: PMC2157977  PMID: 618352

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