Publications by year
In Press
Curnow A, Anayo L, Magnussen A, Perry A, Wood M (In Press). AN EXPERIMENTAL INVESTIGATION OF a NOVEL IRON CHELATING PROTOPORPHYRIN IX PRODRUG FOR THE ENHANCEMENT OF PHOTODYNAMIC THERAPY. Lasers in Surgery and Medicine
Wood ME, Alexander BE, Coles SJ, Fox BC, Khan TF, Maliszewski J, Perry A, Pitak MB, Whiteman M (In Press). investigating the generation of hydrogen sulfide from the phosphonamidodithioate slow-release donor GYY4137. MedChemComm
2022
Lohakul J, Jeayeng S, Chaiprasongsuk A, Torregrossa R, Wood ME, Saelim M, Thangboonjit W, Whiteman M, Panich U (2022). Mitochondria-Targeted Hydrogen Sulfide Delivery Molecules Protect Against UVA-Induced Photoaging in Human Dermal Fibroblasts, and in Mouse Skin in Vivo.
Antioxid Redox Signal,
36(16-18), 1268-1288.
Abstract:
Mitochondria-Targeted Hydrogen Sulfide Delivery Molecules Protect Against UVA-Induced Photoaging in Human Dermal Fibroblasts, and in Mouse Skin in Vivo.
Aims: Oxidative stress and mitochondrial dysfunction play a role in the process of skin photoaging via activation of matrix metalloproteases (MMPs) and the subsequent degradation of collagen. The activation of nuclear factor E2-related factor 2 (Nrf2), a transcription factor controlling antioxidant and cytoprotective defense systems, might offer a pharmacological approach to prevent skin photoaging. We therefore investigated a pharmacological approach to prevent skin photoaging, and also investigated a protective effect of the novel mitochondria-targeted hydrogen sulfide (H2S) delivery molecules AP39 and AP123, and nontargeted control molecules, on ultraviolet a light (UVA)-induced photoaging in normal human dermal fibroblasts (NHDFs) in vitro and the skin of BALB/c mice in vivo. Results: in NHDFs, AP39 and AP123 (50-200 nM) but not nontargeted controls suppressed UVA (8 J/cm2)-mediated cytotoxicity and induction of MMP-1 activity, preserved cellular bioenergetics, and increased the expression of collagen and nuclear levels of Nrf2. In in vivo experiments, topical application of AP39 or AP123 (0.3-1 μM/cm2; but not nontargeted control molecules) to mouse skin before UVA (60 J/cm2) irradiation prevented skin thickening, MMP induction, collagen loss of oxidative stress markers 8-hydroxy-2'-deoxyguanosine (8-OHdG), increased Nrf2-dependent signaling, as well as increased manganese superoxide dismutase levels and levels of the mitochondrial biogenesis marker peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α). Innovation and Conclusion: Targeting H2S delivery to mitochondria may represent a novel approach for the prevention and treatment of skin photoaging, as well as being useful tools for determining the role of mitochondrial H2S in skin disorders and aging. Antioxid. Redox Signal. 36, 1268-1288.
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Author URL.
da Costa Marques LA, Teixeira SA, de Jesus FN, Wood ME, Torregrossa R, Whiteman M, Costa SKP, MuscarĂĄ MN (2022). Vasorelaxant Activity of AP39, a Mitochondria-Targeted H2S Donor, on Mouse Mesenteric Artery Rings in Vitro.
Biomolecules,
12(2).
Abstract:
Vasorelaxant Activity of AP39, a Mitochondria-Targeted H2S Donor, on Mouse Mesenteric Artery Rings in Vitro
Mitochondria-targeted hydrogen sulfide (H2S) donor compounds, such as compound AP39, supply H2S into the mitochondrial environment and have shown several beneficial in vitro and in vivo effects in cardiovascular conditions such as diabetes and hypertension. However, the study of their direct vascular effects has not been addressed to date. Thus, the objective of the present study was to analyze the effects and describe the mechanisms of action of AP39 on the in vitro vascular reactivity of mouse mesenteric artery. Protein and gene expressions of the H2S-producing enzymes (CBS, CSE, and 3MPST) were respectively analyzed by Western blot and qualitative RT-PCR, as well the in vitro production of H2S by mesenteric artery homogenates. Gene expression of CSE and 3MPST in the vessels has been evidenced by RT-PCR experiments, whereas the protein expression of all the three enzymes was demonstrated by Western blotting experiments. Nonselec-tive inhibition of H2S-producing enzymes by AOAA abolished H2S production, whereas it was partially inhibited by PAG (a CSE selective inhibitor). Vasorelaxation promoted by AP39 and its H2S-releasing moiety (ADT-OH) were significantly reduced after endothelium removal, specifically dependent on NO-cGMP signaling and SKCa channel opening. Endogenous H2S seems to participate in the mechanism of action of AP39, and glibenclamide-induced KATP blockade did not affect the vasorelaxant response. Considering the results of the present study and the previously demonstrated antioxidant and bioenergetic effects of AP39, we conclude that mitochondria-targeted H2S donors may offer a new promising perspective in cardiovascular disease therapeutics.
Abstract.
2021
Curnow A, Magnussen A, Reburn C, Perry A, Wood M (2021). Experimental investigation of a combinational iron chelating. protoporphyrin IX prodrug for fluorescence detection and photodynamic therapy. Lasers in Medical Science
Allen CL, Wolanska K, Malhi NK, Benest AV, Wood ME, Amoaku W, Torregrossa R, Whiteman M, Bates DO, Whatmore JL, et al (2021). Hydrogen Sulfide is a Novel Protector of the Retinal Glycocalyx and Endothelial Permeability Barrier.
Frontiers in Cell and Developmental Biology,
9Abstract:
Hydrogen Sulfide is a Novel Protector of the Retinal Glycocalyx and Endothelial Permeability Barrier
Significantly reduced levels of the anti-inflammatory gaseous transmitter hydrogen sulfide (H2S) are observed in diabetic patients and correlate with microvascular dysfunction. H2S may protect the microvasculature by preventing loss of the endothelial glycocalyx. We tested the hypothesis that H2S could prevent or treat retinal microvascular endothelial dysfunction in diabetes. Bovine retinal endothelial cells (BRECs) were exposed to normal (NG, 5.5 mmol/L) or high glucose (HG, 25 mmol/L) ± the slow-release H2S donor NaGYY4137 in vitro. Glycocalyx coverage (stained with WGA-FITC) and calcein-labeled monocyte adherence were measured. In vivo, fundus fluorescein angiography (FFA) was performed in normal and streptozotocin-induced (STZ) diabetic rats. Animals received intraocular injection of NaGYY4137 (1 μM) or the mitochondrial-targeted H2S donor AP39 (100 nM) simultaneously with STZ (prevention) or on day 6 after STZ (treatment), and the ratio of interstitial to vascular fluorescence was used to estimate apparent permeability. NaGYY4137 prevented HG-induced loss of BREC glycocalyx, increased monocyte binding to BRECs (p ≤ 0.001), and increased overall glycocalyx coverage (p ≤ 0.001). In rats, the STZ-induced increase in apparent retinal vascular permeability (p ≤ 0.01) was significantly prevented by pre-treatment with NaGYY4137 and AP39 (p < 0.05) and stabilized by their post-STZ administration. NaGYY4137 also reduced the number of acellular capillaries (collagen IV + /IB4-) in the diabetic retina in both groups (p ≤ 0.05). We conclude that NaGYY4137 and AP39 protected the retinal glycocalyx and endothelial permeability barrier from diabetes-associated loss of integrity and reduced the progression of diabetic retinopathy (DR). Hydrogen sulfide donors that target the glycocalyx may therefore be a therapeutic candidate for DR.
Abstract.
Torregrossa R (2021). Synthesis and Basic in Vitro Characterisation of Novel Mitochondria-Targeted Hydrogen Sulfide Delivering Molecules.
Abstract:
Synthesis and Basic in Vitro Characterisation of Novel Mitochondria-Targeted Hydrogen Sulfide Delivering Molecules
Hydrogen sulfide (H2S) is a human physiological mediator, enzymatically produced primarily in the mitochondria. Its administration in vitro or in vivo ameliorates mitochondrial dysfunction. Mitochondria-targeted H2S donor compounds were previously synthesised by coupling two H2S donor moieties (ADTOMe and HTB) to a known mitochondrial-targeting moiety, making AP39 and AP123, respectively. Although AP39 was effective against mitochondrial dysfunction in vitro and in vivo, its efficacy and tolerability may be improved by appropriate changes in its structure. Thus, in this work, new donors were generated by using a new donor moiety, by changing the linking approach or using a different targeting compound. Another approach to deliver H2S donor moieties inside the mitochondria, independently from the mitochondrial potential, was explored, using a known a tetrapeptide, therefore, RTP10 and RTP12 were synthesised. The H2S-releasing molecules were also linked to a compound known for its beneficial properties towards mitochondrial bioenergetics. Although the novel compounds synthesised reduced mitochondrial dysfunction more efficiently than their non-bonded equivalent control compounds, in an in vitro hyperglycaemia-induced model, only four novel molecules exerted an improvement in AP39/AP123 tolerability and had comparable efficacy thus, they might be further evaluated as drug candidates.
Another compound was synthesised using a different approach for delivering H2S in cells. The compound was evaluated in a few cell dysfunction models, in which it showed promising results.
Furthermore, studies on the stability, the reactivity and the possible H2S generation mechanism of three H2S donor moieties commonly used in H2S-releasing drug hybrids were conducted, identifying the conditions under which they may react. Indeed, despite their biological effects being widely studied, the chemical mechanisms by which they may generate H2S have never been appropriately investigated and their metabolites have never been properly characterised. Here, studies on the identification of the possible metabolites of the three donors were conducted and their activity was evaluated in the same in vitro model, in which they did not exert significant beneficial effects. Also, they did not cause toxicity at the active concentration range of their corresponding donor. The main decomposition products of ADTOMe were identified as ADOMe, plus the carboxylic acid and ketone derivatives. HTB generated primarily, the corresponding nitrile, in addition to the corresponding carboxylic acid and amide. ADOMe may form the corresponding carboxylic acid and ketone and it may also react with thiols, forming a sulfur-sulfur bond. ADTOMe, HTB and ADOMe are stable at room temperature in water/DMSO solutions. They are stable at harsh acidic pH and at pH = 8 but are susceptible to hydrolysis at strong basic pH. ADTOMe and HTB but not ADOMe, are reactive in presence of hydrogen peroxide.
Abstract.
2020
Steinberg G, Schuster M, Gurr SJ, Schrader TA, Schrader M, Wood M, Early A, Kilaru S (2020). A lipophilic cation protects crops against fungal pathogens by multiple modes of action.
Nat Commun,
11(1).
Abstract:
A lipophilic cation protects crops against fungal pathogens by multiple modes of action.
The emerging resistance of crop pathogens to fungicides poses a challenge to food security and compels discovery of new antifungal compounds. Here, we show that mono-alkyl lipophilic cations (MALCs) inhibit oxidative phosphorylation by affecting NADH oxidation in the plant pathogens Zymoseptoria tritici, Ustilago maydis and Magnaporthe oryzae. One of these MALCs, consisting of a dimethylsulfonium moiety and a long alkyl chain (C18-SMe2+), also induces production of reactive oxygen species at the level of respiratory complex I, thus triggering fungal apoptosis. In addition, C18-SMe2+ activates innate plant defense. This multiple activity effectively protects cereals against Septoria tritici blotch and rice blast disease. C18-SMe2+ has low toxicity in Daphnia magna, and is not mutagenic or phytotoxic. Thus, MALCs hold potential as effective and non-toxic crop fungicides.
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Torregrossa R, Wood M, Whiteman M (2020). Investigating the chemical reactivity, stability, and mechanisms of hydrogen sulfide (H2S) generation moieties commonly used in H2S-releasing drug hybrids.
Author URL.
Pacitti D, Brown A, Torregrossa R, Kumar V, Balachandran L, Wood M, Jong Haw T, Hansbro N, Scotton CJ, Hansbro P, et al (2020). Mitochondria-targeted H2S suppresses and reverses cigarette smoke-induced inflammasome activity and lung injury in experimental COPD. 05.01 - Airway pharmacology and treatment.
Hansbro NG, Pacitti D, Brown A, Torregrossa R, Balachandran L, Kumar V, Wood M, Haw T-J, Scotton C, Whiteman M, et al (2020). Mitochondria-targeted Sulfide Delivery Molecules - New and Novel Players that can Suppress and Reverse Cigarette Smoke-induced Inflammasome Activity.
Author URL.
Hansbro NG, Pacitti D, Brown A, Torregrossa R, Balachandran L, Kumar V, Wood M, Haw T-J, Scotton C, Whiteman M, et al (2020). Mitochondria-targeted Sulfide Delivery Molecules – New and Novel Players that can Suppress and Reverse Cigarette Smoke-induced Inflammasome Activity. The Journal of Immunology, 204(1_Supplement), 68.9-68.9.
Whiteman M, Pacitti D, Brown A, Torregrossa R, Balachandran L, Kumar V, Hansbro N, Wood ME, Haw TJ, Scotton C, et al (2020). Suppression and Reversal of Cigarette Smoke-Induced Inflammasome Activation/Activity and Lung Injury by Novel Mitochondria-Targeted Sulfide Delivery Molecules.
Author URL.
2019
Coavoy-Sanchez SA, Torregrossa R, Teixeira SA, Soares AG, Wood ME, Costa SP, Whiteman M, Muscara MN (2019). Effects of the mitochondria-targeted hydrogen sulfide (H2S) donor AP39 on atopic dermatitis in mice.
Author URL.
Reburn C, Anayo L, Magnussen A, Perry A, Wood M, Curnow A (2019). Experimental findings utilising a new iron chelating ALA prodrug to enhance protoporphyrin IX-induced photodynamic therapy.
Abstract:
Experimental findings utilising a new iron chelating ALA prodrug to enhance protoporphyrin IX-induced photodynamic therapy
Abstract.
Curnow A, Perry A, Wood M (2019). Improving in vitro photodynamic therapy through the development of a novel iron chelating aminolaevulinic acid prodrug.
Photodiagnosis Photodyn Ther,
25, 157-165.
Abstract:
Improving in vitro photodynamic therapy through the development of a novel iron chelating aminolaevulinic acid prodrug.
BACKGROUND: Photodynamic therapy (PDT) is a light activated drug therapy that can be used to treat a number of cancers and precancers. It is particularly useful in its topical form in dermatology but improvement of efficacy is required to widen its application. METHODS: an ester between aminolaevulinic acid (ALA) and CP94 was synthesised (AP2-18) and experimentally evaluated to determine whether protoporphyrin IX (PpIX)-induced PDT effectiveness could be improved. A biological evaluation of AP2-18 was conducted in cultured human primary cells with both PpIX fluorescence and cell viability (as determined via the neutral red assay) being assessed in comparison to the PpIX prodrugs normally utilised in clinical practice (aminolaevulinic acid (ALA) or its methyl ester (MAL)) either administered alone or with the comparator iron chelator, CP94. RESULTS: No significant dark toxicity was observed in human lung fibroblasts but AP2-18 significantly increased PpIX accumulation above and beyond that achieved with ALA or MAL administration +/- CP94 in both human dermal fibroblasts and epithelial squamous carcinoma cells. On light exposure, the combined hydroxypyridinone iron chelating ALA prodrug AP2-18 generated significantly greater cytotoxicity than any of the other treatment parameters investigated when the lowest concentration (250 μM) was employed. CONCLUSIONS: Newly synthesised AP2-18 is therefore concluded to be an efficacious prodrug for PpIX-induced PDT in these dermatologically relevant human cells, achieving enhanced effects at lower concentrations than currently possible with existing pharmaceuticals.
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Williams E, Whiteman M, Wood ME, Wilson ID, Ladomery MR, Allainguillaume J, Teklic T, Lisjak M, Hancock JT (2019). Investigating ROS, RNS, and H2S-Sensitive Signaling Proteins.
Methods Mol Biol,
1990, 27-42.
Abstract:
Investigating ROS, RNS, and H2S-Sensitive Signaling Proteins.
The modification of proteins is a key way to alter their activity and function. Often thiols, cysteine residues, on proteins are attractive targets for such modification. Assuming that the thiol group is accessible then reactions may take place with a range of chemicals found in cells. These may include reactive oxygen species (ROS), such as hydrogen peroxide (H2O2), reactive nitrogen species such as nitric oxide (NO), hydrogen sulfide (H2S), or glutathione. Such modifications often are instrumental to important cellular signaling processes, which ultimately result in modification of physiology of the organism. Therefore, there is a need to be able to identify such modifications. There are a variety of techniques to find proteins which may be altered in this way but here the focus is on two approaches: firstly, the use of fluorescent thiol derivatives and the subsequent use of mass spectrometry to identify the thiols involved; secondly the confirmation of such changes using biochemical assays and genetic mutants. The discussion will be based on the use of two model organisms: firstly the plant Arabidopsis thaliana (both as cell cultures and whole plants) and secondly the nematode worm Caenorhabditis elegans. However, these tools, as described, may be used in a much wider range of biological systems, including human and human tissue cultures.
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2018
Stevens M, Payne M, Innes E, Torregrossa RO, Wood M, Stevens MKO, Whiteman MO, Oltean SO (2018). A novel mitochondriaâtargeted hydrogen sulfide delivery molecule prevents uraemia and diabetesâinduced renal cell oxidative stress. The FASEB Journal, 32(S1), 619.10-619.10.
Xiao AY, Brummett A, Maynard M, Pidikiti R, Miriyala S, Panchatcharam M, Sheibani N, Wood ME, Whiteman M, Harrison L, et al (2018). AP39, a Mitochondrial-Targeted Hydrogen Sulfide Donor, Protects Against Mitochondrial Dysfunction in Irradiated Mouse Retinal Endothelial Cells.
Author URL.
Brown AR, Green J, Moreman J, Gunnarsson L, Mourabit S, Ball J, Winter M, Trznadel M, Correia A, Hacker C, et al (2018). Cardiovascular Effects and Molecular Mechanisms of Bisphenol a and its Metabolite MBP in Zebrafish. Environmental Science and Technology
Moreman J, Takesono A, Trznadel M, Winter MJ, Perry A, Wood ME, Rogers NJ, Kudoh T, Tyler CR (2018). Estrogenic Mechanisms and Cardiac Responses Following Early Life Exposure to Bisphenol a (BPA) and its Metabolite 4-Methyl-2,4-bis( p-hydroxyphenyl)pent-1-ene (MBP) in Zebrafish.
Environ Sci Technol,
52(11), 6656-6665.
Abstract:
Estrogenic Mechanisms and Cardiac Responses Following Early Life Exposure to Bisphenol a (BPA) and its Metabolite 4-Methyl-2,4-bis( p-hydroxyphenyl)pent-1-ene (MBP) in Zebrafish.
Environmental exposure to Bisphenol a (BPA) has been associated with a range of adverse health effects, including on the cardiovascular system in humans. Lack of agreement on its mechanism(s) of action likely stem from comparisons between in vivo and in vitro test systems and potential multiple effects pathways. In rodents, in vivo, metabolic activation of BPA produces 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP), which is reported to be up to 1000 times more potent as an estrogen than BPA. We investigated the estrogenic effects and estrogen receptor signaling pathway(s) of BPA and MBP following early life exposure using a transgenic, estrogen responsive (ERE-TG) zebrafish and a targeted morpholino approach to knockdown the three fish estrogen receptor (ER) subtypes. The functional consequences of BPA exposure on the cardiovascular system of zebrafish larvae were also examined. The heart atrioventricular valves and the bulbus arteriosus were primary target tissues for both BPA and MBP in the ERE-TG zebrafish, and MBP was approximately 1000-fold more potent than BPA as an estrogen in these tissues. Estrogen receptor knockdown with morpholinos indicated that the estrogenic responses in the heart for both BPA and MBP were mediated via an estrogen receptor 1 (esr1) dependent pathway. At the highest BPA concentration tested (2500 μg/L), alterations in the atrial:ventricular beat ratio indicated a functional impact on the heart of 5 days post fertilization (dpf) larvae, and there was also a significantly reduced heart rate in these larvae at 14 dpf. Our findings indicate that some of the reported adverse effects on heart function associated with BPA exposure (in mammals) may act through an estrogenic mechanism, but that fish are unlikely to be susceptible to adverse effects on heart development for environmentally relevant exposures.
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Author URL.
Potor L, Nagy P, MĂ©hes G, Hendrik Z, Jeney V, PethĂł D, Vasas A, PĂĄlinkĂĄs Z, Balogh E, Gyetvai Ă, et al (2018). Hydrogen Sulfide Abrogates Hemoglobin-Lipid Interaction in Atherosclerotic Lesion.
Oxidative Medicine and Cellular Longevity,
2018Abstract:
Hydrogen Sulfide Abrogates Hemoglobin-Lipid Interaction in Atherosclerotic Lesion
The infiltration of red blood cells into atheromatous plaques is implicated in atherogenesis. Inside the lesion, hemoglobin (Hb) is oxidized to ferri-and ferrylHb which exhibit prooxidant and proinflammatory activities. Cystathione gamma-lyase-(CSE-) derived H2S has been suggested to possess various antiatherogenic actions. Expression of CSE was upregulated predominantly in macrophages, foam cells, and myofibroblasts of human atherosclerotic lesions derived from carotid artery specimens of patients. A similar pattern was observed in aortic lesions of apolipoprotein E-deficient mice on high-fat diet. We identified several triggers for inducing CSE expression in macrophages and vascular smooth muscle cells including heme, ferrylHb, plaque lipids, oxidized low-density lipoprotein, tumor necrosis factor-α, and interleukin-1β. In the interplay between hemoglobin and atheroma lipids, H2S significantly mitigated oxidation of Hb preventing the formation of ferrylHb derivatives, therefore providing a novel function as a heme-redox-intermediate-scavenging antioxidant. By inhibiting Hb-lipid interactions, sulfide lowered oxidized Hb-mediated induction of adhesion molecules in endothelium and disruption of endothelial integrity. Exogenous H2S inhibited heme and Hb-mediated lipid oxidation of human atheroma-derived lipid and human complicated lesion. Our study suggests that the CSE/H2S system represents an atheroprotective pathway for removing or limiting the formation of oxidized Hb and lipid derivatives in the atherosclerotic plaque.
Abstract.
Latorre E, Torregrossa R, Wood ME, Whiteman M, Harries LW (2018). Mitochondria-targeted hydrogen sulfide attenuates endothelial senescence by selective induction of splicing factors HNRNPD and SRSF2.
Aging (Albany NY),
10(7), 1666-1681.
Abstract:
Mitochondria-targeted hydrogen sulfide attenuates endothelial senescence by selective induction of splicing factors HNRNPD and SRSF2.
Cellular senescence is a key driver of ageing, influenced by age-related changes to the regulation of alternative splicing. Hydrogen sulfide (H2S) has similarly been described to influence senescence, but the pathways by which it accomplishes this are unclear.We assessed the effects of the slow release H2S donor Na-GYY4137 (100 µg/ml), and three novel mitochondria-targeted H2S donors AP39, AP123 and RT01 (10 ng/ml) on splicing factor expression, cell proliferation, apoptosis, DNA replication, DNA damage, telomere length and senescence-related secretory complex (SASP) expression in senescent primary human endothelial cells.All H2S donors produced up to a 50% drop in senescent cell load assessed at the biochemical and molecular level. Some changes were noted in the composition of senescence-related secretory complex (SASP); IL8 levels increased by 24% but proliferation was not re-established in the culture as a whole. Telomere length, apoptotic index and the extent of DNA damage were unaffected. Differential effects on splicing factor expression were observed depending on the intracellular targeting of the H2S donors. Na-GYY4137 produced a general 1.9 - 3.2-fold upregulation of splicing factor expression, whereas the mitochondria-targeted donors produced a specific 2.5 and 3.1-fold upregulation of SRSF2 and HNRNPD splicing factors only. Knockdown of SRSF2 or HNRNPD genes in treated cells rendered the cells non-responsive to H2S, and increased levels of senescence by up to 25% in untreated cells.Our data suggest that SRSF2 and HNRNPD may be implicated in endothelial cell senescence, and can be targeted by exogenous H2S. These molecules may have potential as moderators of splicing factor expression and senescence phenotypes.
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Author URL.
Cao X, Xiong S, Zhou Y, Wu Z, Ding L, Zhu Y, Wood ME, Whiteman M, Moore PK, Bian J-S, et al (2018). Renal Protective Effect of Hydrogen Sulfide in Cisplatin-Induced Nephrotoxicity.
Antioxid Redox Signal,
29(5), 455-470.
Abstract:
Renal Protective Effect of Hydrogen Sulfide in Cisplatin-Induced Nephrotoxicity.
AIMS: Cisplatin is a major therapeutic drug for solid tumors, but can cause severe nephrotoxicity. However, the role and therapeutic potential of hydrogen sulfide (H2S), an endogenous gasotransmitter, in cisplatin-induced nephrotoxicity remain to be defined. RESULTS: Cisplatin led to the impairment of H2S production in vitro and in vivo by downregulating the expression level of cystathionine γ-lyase (CSE), which may contribute to the subsequent renal proximal tubule (RPT) cell death and thereby renal toxicity. H2S donors NaHS and GYY4137, but not AP39, mitigated cisplatin-induced RPT cell death and nephrotoxicity. The mechanisms underlying the protective effect of H2S donors included the suppression of intracellular reactive oxygen species generation and downstream mitogen-activated protein kinases by inhibiting NADPH oxidase activity, which may be possibly through persulfidating the subunit p47phox. Importantly, GYY4137 not only ameliorated cisplatin-caused renal injury but also added on more anticancer effect to cisplatin in cancer cell lines. Innovation and Conclusion: Our study provides a comprehensive understanding of the role and therapeutic potential of H2S in cisplatin-induced nephrotoxicity. Our results indicate that H2S may be a novel and promising therapeutic target to prevent cisplatin-induced nephrotoxicity. Antioxid. Redox Signal. 29, 455-470.
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2017
Karwi QG, Bornbaum J, Boengler K, Torregrossa R, Whiteman M, Wood ME, Schulz R, Baxter GF (2017). AP39, a mitochondria-targeting hydrogen sulfide (H2 S) donor, protects against myocardial reperfusion injury independently of salvage kinase signalling.
Br J Pharmacol,
174(4), 287-301.
Abstract:
AP39, a mitochondria-targeting hydrogen sulfide (H2 S) donor, protects against myocardial reperfusion injury independently of salvage kinase signalling.
BACKGROUND AND PURPOSE: H2 S protects myocardium against ischaemia/reperfusion injury. This protection may involve the cytosolic reperfusion injury salvage kinase (RISK) pathway, but direct effects on mitochondrial function are possible. Here, we investigated the potential cardioprotective effect of a mitochondria-specific H2 S donor, AP39, at reperfusion against ischaemia/reperfusion injury. EXPERIMENTAL APPROACH: Anaesthetized rats underwent myocardial ischaemia (30 min)/reperfusion (120 min) with randomization to receive interventions before reperfusion: vehicle, AP39 (0.01, 0.1, 1 μmol·kg-1 ), or control compounds AP219 and ADT-OH (1 μmol·kg-1 ). LY294002, L-NAME or ODQ were used to investigate the involvement of the RISK pathway. Myocardial samples harvested 5 min after reperfusion were analysed for RISK protein phosphorylation and isolated cardiac mitochondria were used to examine the direct mitochondrial effects of AP39. KEY RESULTS: AP39, dose-dependently, reduced infarct size. Inhibition of either PI3K/Akt, eNOS or sGC did not affect this effect of AP39. Western blot analysis confirmed that AP39 did not induce phosphorylation of Akt, eNOS, GSK-3β or ERK1/2. In isolated subsarcolemmal and interfibrillar mitochondria, AP39 significantly attenuated mitochondrial ROS generation without affecting respiratory complexes I or II. Furthermore, AP39 inhibited mitochondrial permeability transition pore (PTP) opening and co-incubation of mitochondria with AP39 and cyclosporine a induced an additive inhibitory effect on the PTP. CONCLUSION AND IMPLICATIONS: AP39 protects against reperfusion injury independently of the cytosolic RISK pathway. This cardioprotective effect could be mediated by inhibiting PTP via a cyclophilin D-independent mechanism. Thus, selective delivery of H2 S to mitochondria may be therapeutically applicable for employing the cardioprotective utility of H2 S.
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Torregrossa R, Waters A, Gero D, Webb S, Rush C, Wood ME, Whiteman M (2017). Evaluation of a Novel Mitochondria-targeted Peptide-based H2S Donor Compound (RTP-10) in Hyperglycaemia-induced Microvascular Endothelial Cell Dysfunction.
Author URL.
Lobb I, Jiang J, Lian D, Liu W, Haig A, Saha MN, Torregrossa R, Wood ME, Whiteman M, Sener A, et al (2017). Hydrogen Sulfide Protects Renal Grafts Against Prolonged Cold Ischemia-Reperfusion Injury via Specific Mitochondrial Actions.
Am J Transplant,
17(2), 341-352.
Abstract:
Hydrogen Sulfide Protects Renal Grafts Against Prolonged Cold Ischemia-Reperfusion Injury via Specific Mitochondrial Actions.
Ischemia-reperfusion injury is unavoidably caused by loss and subsequent restoration of blood flow during organ procurement, and prolonged ischemia-reperfusion injury IRI results in increased rates of delayed graft function and early graft loss. The endogenously produced gasotransmitter, hydrogen sulfide (H2 S), is a novel molecule that mitigates hypoxic tissue injury. The current study investigates the protective mitochondrial effects of H2 S during in vivo cold storage and subsequent renal transplantation (RTx) and in vitro cold hypoxic renal injury. Donor allografts from Brown Norway rats treated with University of Wisconsin (UW) solution + H2 S (150 μM NaSH) during prolonged (24-h) cold (4°C) storage exhibited significantly (p < 0.05) decreased acute necrotic/apoptotic injury and significantly (p < 0.05) improved function and recipient Lewis rat survival compared to UW solution alone. Treatment of rat kidney epithelial cells (NRK-52E) with the mitochondrial-targeted H2 S donor, AP39, during in vitro cold hypoxic injury improved the protective capacity of H2 S >1000-fold compared to similar levels of the nonspecific H2 S donor, GYY4137 and also improved syngraft function and survival following prolonged cold storage compared to UW solution. H2 S treatment mitigates cold IRI-associated renal injury via mitochondrial actions and could represent a novel therapeutic strategy to minimize the detrimental clinical outcomes of prolonged cold IRI during RTx.
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Author URL.
Allen C, Whatmore JL, Wood ME, Whiteman M, Bates DO (2017). Hydrogen sulfide as a novel therapeutic for diabetic retinopathy.
Author URL.
Neale H, Deshappriya N, Arnold D, Wood ME, Whiteman M, Hancock JT (2017). Hydrogen sulfide causes excision of a genomic island in Pseudomonas syringae pv. phaseolicola.
European Journal of Plant Pathology,
149(4), 911-921.
Abstract:
Hydrogen sulfide causes excision of a genomic island in Pseudomonas syringae pv. phaseolicola
Hydrogen sulfide (H2S) is known to be an important signalling molecule in both animals and plants, despite its toxic nature. In plants it has been seen to control stomatal apertures, so altering the ability of bacteria to invade plant tissues. Bacteria are known to generate H2S as well as being exposed to plant-generated H2S. During their interaction with plants pathogenic bacteria are known to undergo alterations to their genomic complement. For example Pseudomonas syringae pv. phaseolicola (Pph) strain 1302A undergoes loss of a section of DNA known as a genomic island (PPHGI-1) when exposed to the plants resistance response. Loss of PPHGI-1 from Pph 1302A enables the pathogen to overcome the plants resistance response and cause disease. Here, with the use of H2S donor molecules, changes induced in Pph 1302A genome, as demonstrated by excision of PPHGI-1, were investigated. Pph 1302A cells were found to be resistant to low concentrations of H2S. However, at sub-lethal H2S concentrations an increase in the expression of the PPHGI-1 encoded integrase gene (xerC), which is responsible for island excision, and a subsequent increase in the presence of the circular form of PPHGI-1 were detected. This suggests that H2S is able to initiate excision of PPHGI-1 from the Pph genome. Therefore, H2S that may emanate from the plant has an effect on the genome structure of invading bacteria and their ability to cause disease in plants. Modulation of such plant signals may be a way to increase plant defence responses for crops in the future.
Abstract.
NuĂbaum BL, Vogt J, Wachter U, McCook O, Wepler M, Matallo J, Calzia E, Gröger M, Georgieff M, Wood ME, et al (2017). Metabolic, Cardiac, and Renal Effects of the Slow Hydrogen Sulfide-Releasing Molecule GYY4137 During Resuscitated Septic Shock in Swine with Pre-Existing Coronary Artery Disease.
Shock,
48(2), 175-184.
Abstract:
Metabolic, Cardiac, and Renal Effects of the Slow Hydrogen Sulfide-Releasing Molecule GYY4137 During Resuscitated Septic Shock in Swine with Pre-Existing Coronary Artery Disease.
Decreased levels of endogenous hydrogen sulfide (H2S) contribute to atherosclerosis, whereas equivocal data are available on H2S effects during sepsis. Moreover, H2S improved glucose utilization in anaesthetized, ventilated, hypothermic mice, but normothermia and/or sepsis blunted this effect. The metabolic effects of H2S in large animals are controversial. Therefore, we investigated the effects of the H2S donor GYY4137 during resuscitated, fecal peritonitis-induced septic shock in swine with genetically and diet-induced coronary artery disease (CAD). Twelve and 18âh after peritonitis induction, pigs received either GYY4137 (10âmgâkg, nâ=â9) or vehicle (nâ=â8). Before, at 12 and 24âh of sepsis, we assessed left ventricular (pressure-conductance catheters) and renal (creatinine clearance, blood NGAL levels) function. Endogenous glucose production and glucose oxidation were derived from the plasma glucose isotope and the expiratory CO2/CO2 enrichment during continuous i.v. 1,2,3,4,5,6-C6-glucose infusion. GYY4137 significantly increased aerobic glucose oxidation, which coincided with higher requirements of exogenous glucose to maintain normoglycemia, as well as significantly lower arterial pH and decreased base excess. Apart from significantly lower cardiac eNOS expression and higher troponin levels, GYY4137 did not significantly influence cardiac and kidney function or the systemic inflammatory response. During resuscitated septic shock in swine with CAD, GYY4137 shifted metabolism to preferential carbohydrate utilization. Increased troponin levels are possibly due to reduced local NO availability. Cautious dosing, the timing of GYY4137 administration, and interspecies differences most likely account for the absence of any previously described anti-inflammatory or organ-protective effects of GYY4137 in this model.
Abstract.
Author URL.
Whiteman M, Karwi QG, Wood ME, Baxter GF (2017). Mitochondria-targeted Hydrogen Sulfide (H2S), but not Untargeted H2S, Reverses Ventricular Arrhythmia at Reperfusion.
Author URL.
Etheridge T, Gaffney C, Szewczyk N, Torregrossa R, Wood ME, Whiteman M (2017). Mitochondria-targeting hydrogen sulfide donors prolong healthspan: lifespan ratio in Caenorhabditis elegans.
Author URL.
Karwi QG, Whiteman M, Wood M, Baxter G (2017). Postconditioning with H2S donors: effect on reperfusion-induced ventricular arrhythmias.
Author URL.
Rodrigues L, Ekundi-Valentim E, Florenzano J, Cerqueira ARA, Soares AG, Schmidt TP, Santos KT, Teixeira SA, Ribela MTCP, Rodrigues SF, et al (2017). Protective effects of exogenous and endogenous hydrogen sulfide in mast cell-mediated pruritus and cutaneous acute inflammation in mice.
Pharmacol Res,
115, 255-266.
Abstract:
Protective effects of exogenous and endogenous hydrogen sulfide in mast cell-mediated pruritus and cutaneous acute inflammation in mice.
The recently described 'gasomediator' hydrogen sulfide (H2S) has been involved in pain mechanisms, but its effect on pruritus, a sensory modality that similarly to pain acts as a protective mechanism, is poorly known and controversial. The effects of the slow-releasing (GYY4137) and spontaneous H2S donors (Na2S and Lawesson's reagent, LR) were evaluated in histamine and compound 48/80 (C48/80)-dependent dorsal skin pruritus and inflammation in male BALB/c mice. Animals were intradermally (i.d.) injected with C48/80 (3μg/site) or histamine (1μmol/site) alone or co-injected with Na2S, LR or GYY4137 (within the 0.3-100nmol range). The involvement of endogenous H2S and KATP channel-dependent mechanism were also evaluated. Pruritus was assessed by the number of scratching bouts, whilst skin inflammation was evaluated by the extravascular accumulation of intravenously injected 125I-albumin (plasma extravasation) and myeloperoxidase (MPO) activity (neutrophil recruitment). Histamine or C48/80 significantly evoked itching behavior paralleled by plasma extravasation and increased MPO activity. Na2S and LR significantly ameliorated histamine or C48/80-induced pruritus and inflammation, although these effects were less pronounced or absent with GYY4137. Inhibition of endogenous H2S synthesis increased both Tyrode and C48/80-induced responses in the skin, whereas the blockade of KATP channels by glibenclamide did not. H2S-releasing donors significantly attenuate C48/80-induced mast cell degranulation either in vivo or in vitro. We provide first evidences that H2S donors confer protective effect against histamine-mediated acute pruritus and cutaneous inflammation. These effects can be mediated, at least in part, by stabilizing mast cells, known to contain multiple mediators and to be primary initiators of allergic processes, thus making of H2S donors a potential alternative/complementary therapy for treating inflammatory allergic skin diseases and related pruritus.
Abstract.
Author URL.
Waters A, Torregrossa R, Gero D, Perry A, Wood ME, Whiteman M (2017). RT01, a Novel Derivative of the Mitochondria-targeted Hydrogen Sulfide Donor AP39, Reversed Hyperglycaemia-induced Mitochondrial Dysfunction in Murine Brain Microvascular Endothelial Cells.
Author URL.
Karwi QG, Whiteman M, Wood M, Baxter G (2017). The effect of hydrogen sulfide (H2S) on reperfusion-induced ventricular arrhythmias.
Author URL.
2016
Ahmad A, Olah G, Szczesny B, Wood ME, Whiteman M, Szabo C (2016). AP39, a mitochondrially targeted hydrogen sulfide donor, exerts protective effects in renal epithelial cells subjected to oxidative stress in vitro and in acute renal injury in vivo.
Shock,
45(1), 88-97.
Abstract:
AP39, a mitochondrially targeted hydrogen sulfide donor, exerts protective effects in renal epithelial cells subjected to oxidative stress in vitro and in acute renal injury in vivo
This study evaluated the effects of AP39 [(10-oxo-10-(4-(3-Thioxo-3H-1,2-dithiol-5yl) phenoxy)decyl) triphenyl phosphonium bromide], a mitochondrially targeted donor of hydrogen sulfide (H2S) in an in vitro model of hypoxia/oxidative stress injury in NRK-49F rat kidney epithelial cells (NRK cells) and in a rat model of renal ischemia-reperfusion injury. Renal oxidative stresswas induced by the addition of glucose oxidase, which generates hydrogen peroxide in the culture medium at a constant rate. Glucose oxidase (GOx)-induced oxidative stress led to mitochondrial dysfunction, decreased intracellular ATP content, and, at higher concentrations, increased intracellular oxidant formation (estimated by the fluorescent probe 2, 7-dichlorofluorescein, DCF) and promoted necrosis (estimated by the measurement of lactate dehydrogenase release into the medium) of the NRK cells in vitro. Pretreatment with AP39 (30-300 nM) exerted a concentration-dependent protective effect against all of the above effects of GOx. Most of the effects of AP39 followed a bell-shaped concentration-response curve; at the highest concentration of GOx tested, AP39 was no longer able to afford cytoprotective effects. Rats subjected to renal ischemia/reperfusion responded with a marked increase (over four-fold over sham control baseline) blood urea nitrogen and creatinine levels in blood, indicative of significant renal damage. This was associated with increased neutrophil infiltration into the kidneys (assessed by the myeloperoxidase assay in kidney homogenates), increased oxidative stress (assessed by the malondialdehyde assay in kidney homogenates), and an increase in plasma levels of IL-12. Pretreatment with AP39 (0.1, 0.2, and 0.3 mg/kg) provided a dose-dependent protection against these pathophysiological alterations; the most pronounced protective effect was observed at the 0.3 mg/kg dose of the H2S donor; nevertheless, AP39 failed to achieve a complete normalization of any of the injury markers measured. The partial protective effects of AP39 correlated with a partial improvement of kidney histological scores and reduced TUNEL staining (an indicator of DNA damage and apoptosis). In summary, the mitochondria-Targeted H2S donor AP39 exerted dose-dependent protective effects against renal epithelial cell injury in vitro and renal ischemia-reperfusion injury in vivo. We hypothesize that the beneficial actions of AP39 are related to the reduction of cellular oxidative stress, and subsequent attenuation of various positive feed-forward cycles of inflammatory and oxidative processes.
Abstract.
Wood ME, Chatzianastasiou A, Bibli S-I, Andreadou I, Efentakis P, Kaludercic N, Whiteman M, Di Lisa F, Daiber A, Manolopoulos VG, et al (2016). Cardioprotection by H2S donors: nitric oxide-dependent and -independent mechanisms. Journal of Pharmacology and Experimental Therapeutics
Lin S, Visram F, Liu W, Haig A, Jiang J, Mok A, Lian D, Wood ME, Torregrossa R, Whiteman M, et al (2016). GYY4137, a Slow-Releasing Hydrogen Sulfide Donor, Ameliorates Renal Damage Associated with Chronic Obstructive Uropathy.
J Urol,
196(6), 1778-1787.
Abstract:
GYY4137, a Slow-Releasing Hydrogen Sulfide Donor, Ameliorates Renal Damage Associated with Chronic Obstructive Uropathy.
PURPOSE: Chronic obstructive uropathy can cause irreversible kidney injury, atrophy and inflammation, which can ultimately lead to fibrosis. Epithelial-mesenchymal transition is a key trigger of fibrosis that is caused by up-regulation of TGF-β1 (transforming growth factor-β1) and ANGII (angiotensin II). H2S is an endogenously produced gasotransmitter with cytoprotective properties. We sought to elucidate the effects of the slow-releasing H2S donor GYY4137 on chronic ureteral obstruction and evaluate the potential mechanisms. MATERIALS AND METHODS: Following unilateral ureteral obstruction male Lewis rats were given daily intraperitoneal administration of phosphate buffered saline vehicle (obstruction group) or phosphate buffered saline plus 200 μmol/kg GYY4137 (obstruction plus GYY4137 group) for 30 days. Urine and serum samples were collected to determine physiological parameters of renal function and injury. Kidneys were removed on postoperative day 30 to evaluate histopathology and protein expression. Epithelial-mesenchymal transition in LLC-PK1 pig kidney epithelial cells was induced with TGF-β1 and treated with GYY4137 to evaluate potential mechanisms via in vitro scratch wound assays. RESULTS: H2S treatment decreased serum creatinine and the urine protein-to-creatinine excretion ratio after unilateral ureteral obstruction. In addition, H2S mitigated cortical loss, inflammatory damage and tubulointerstitial fibrosis. Tissues showed decreased expression of epithelial-mesenchymal transition markers upon H2S treatment. Epithelial-mesenchymal transition progression in LLC-PK1 was alleviated upon in vitro administration of GYY4137. CONCLUSIONS: to our knowledge our findings demonstrate for the first time the protective effects of H2S in chronic obstructive uropathy. This may represent a potential therapeutic solution to ameliorate renal damage and improve the clinical outcomes of urinary obstruction.
Abstract.
Author URL.
Coavoy-SĂĄnchez SA, Rodrigues L, Teixeira SA, Soares AG, Torregrossa R, Wood ME, Whiteman M, Costa SKP, MuscarĂĄ MN (2016). Hydrogen sulfide donors alleviate itch secondary to the activation of type-2 protease activated receptors (PAR-2) in mice.
Pharmacol Res,
113(Pt A), 686-694.
Abstract:
Hydrogen sulfide donors alleviate itch secondary to the activation of type-2 protease activated receptors (PAR-2) in mice.
Hydrogen sulfide (H2S) has been highlighted as an endogenous signaling molecule and we have previously found that it can inhibit histamine-mediated itching. Pruritus is the most common symptom of cutaneous diseases and anti-histamines are the usual treatment; however, anti-histamine-resistant pruritus is common in some clinical settings. In this way, the involvement of mediators other than histamine in the context of pruritus requires new therapeutic targets. Considering that the activation of proteinase-activated receptor 2 (PAR-2) is involved in pruritus both in rodents and humans, in this study we investigated the effect of H2S donors on the acute scratching behavior mediated by PAR-2 activation in mice, as well as some of the possible pharmacological mechanisms involved. The intradermal injection of the PAR-2 peptide agonist SLIGRL-NH2 (8-80nmol) caused a dose-dependent scratching that was unaffected by intraperitoneal pre-treatment with the histamine H1 antagonist pyrilamine (30mg/kg). Co-injection of SLIGRL-NH2 (40nmol) with either the slow-release H2S donor GYY4137 (1 and 3nmol) or the spontaneous donor NaHS (1 and 0.3nmol) significantly reduced pruritus. Co-treatment with the KATP channel blocker glibenclamide (200nmol) or the nitric oxide (NO) donor sodium nitroprusside (10nmol) abolished the antipruritic effects of NaHS; however, the specific soluble guanylyl cyclase inhibitor ODQ (30μg) had no significant effects. The transient receptor potential ankyrin type 1 (TRPA1) antagonist HC-030031 (20μg) significantly reduced SLIGRL-NH2-induced pruritus; however pruritus induced by the TRPA1 agonist AITC (1000nmol) was unaffected by NaHS. Based on these data, we conclude that pruritus secondary to PAR-2 activation can be reduced by H2S, which acts through KATP channel opening and involves NO in a cyclic guanosine monophosphate (cGMP)-independent manner. Furthermore, TRPA1 receptors mediate the pruritus induced by activation of PAR-2, but H2S does not interfere with this pathway. These results provide additional support for the development of new therapeutical alternatives, mainly intended for treatment of pruritus in patients unresponsive to anti-histamines.
Abstract.
Author URL.
Wedmann R, Onderka C, Wei S, SzijĂĄrtĂł IA, Miljkovic JL, Mitrovic A, Lange M, Savitsky S, Yadav PK, Torregrossa R, et al (2016). Improved tag-switch method reveals that thioredoxin acts as depersulfidase and controls the intracellular levels of protein persulfidation.
Chemical Science,
7(5), 3414-3426.
Abstract:
Improved tag-switch method reveals that thioredoxin acts as depersulfidase and controls the intracellular levels of protein persulfidation
H2S signalsviaprotein persulfidation. To be regulatory the modification will have to be reversible. Using a new method for persulfide detection, we discover this missing link and show that thioredoxin system acts as depersulfidasein vivo.
Abstract.
Hedegaard ER, Gouliaev A, Winther AK, Arcanjo DDR, Aalling M, Renaltan NS, Wood ME, Whiteman M, Skovgaard N, Simonsen U, et al (2016). Involvement of Potassium Channels and Calcium-Independent Mechanisms in Hydrogen Sulfide-Induced Relaxation of Rat Mesenteric Small Arteries.
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS,
356(1), 53-63.
Author URL.
Lin S, Visram F, Lobb I, Liu W, Haig A, Jiang J, Mok A, Lian D, Wood ME, Whiteman M, et al (2016). MP58-18 EXOGENOUS HYDROGEN SULFIDE TREATMENT REDUCES RENAL FIBROSIS ASSOCIATED WITH CHRONIC URETERAL OBSTRUCTION BY ATTENUATING EPITHELIAL-MESENCHYMAL TRANSITION. Journal of Urology, 195(4S).
Gero D, Torregrossa R, Waters A, Perry A, Wood ME, Whiteman M (2016). Mitochondria-Targeted Hydrogen Sulfide Donors Protect Microvascular Endothelial Cells from Hyperglycaemia-Induced Metabolic Changes and Oxidative Damage.
Author URL.
Karwi QG, Whiteman M, Wood ME, Torregrossa R, Baxter GF (2016). Pharmacological postconditioning against myocardial infarction with a slow-releasing hydrogen sulfide donor, GYY4137. Pharmacological Research, 111, 442-451.
GerĆ D, Torregrossa R, Perry A, Waters A, Le-Trionnaire S, Whatmore JL, Wood M, Whiteman M (2016). The novel mitochondria-targeted hydrogen sulfide (H2S) donors AP123 and AP39 protect against hyperglycemic injury in microvascular endothelial cells in vitro.
Pharmacol Res,
113(Pt A), 186-198.
Abstract:
The novel mitochondria-targeted hydrogen sulfide (H2S) donors AP123 and AP39 protect against hyperglycemic injury in microvascular endothelial cells in vitro.
The development of diabetic vascular complications is initiated, at least in part, by mitochondrial reactive oxygen species (ROS) production in endothelial cells. Hyperglycemia induces superoxide production in the mitochondria and initiates changes in the mitochondrial membrane potential that leads to mitochondrial dysfunction. Hydrogen sulfide (H2S) supplementation has been shown to reduce the mitochondrial oxidant production and shows efficacy against diabetic vascular damage in vivo. However, the half-life of H2S is very short and it is not specific for the mitochondria. We have therefore evaluated two novel mitochondria-targeted anethole dithiolethione and hydroxythiobenzamide H2S donors (AP39 and AP123 respectively) at preventing hyperglycemia-induced oxidative stress and metabolic changes in microvascular endothelial cells in vitro. Hyperglycemia (HG) induced significant increase in the activity of the citric acid cycle and led to elevated mitochondrial membrane potential. Mitochondrial oxidant production was increased and the mitochondrial electron transport decreased in hyperglycemic cells. AP39 and AP123 (30-300nM) decreased HG-induced hyperpolarisation of the mitochondrial membrane and inhibited the mitochondrial oxidant production. Both H2S donors (30-300nM) increased the electron transport at respiratory complex III and improved the cellular metabolism. Targeting H2S to mitochondria retained the cytoprotective effect of H2S against glucose-induced damage in endothelial cells suggesting that the molecular target of H2S action is within the mitochondria. Mitochondrial targeting of H2S also induced >1000-fold increase in the potency of H2S against hyperglycemia-induced injury. The high potency and long-lasting effect elicited by these H2S donors strongly suggests that these compounds could be useful against diabetic vascular complications.
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Author URL.
2015
Perry A, Green SJ, Horsell DW, Hornett SM, Wood ME (2015). A pyrene-appended spiropyran for selective photo-switchable binding of Zn(II): UV-visible and fluorescence spectroscopy studies of binding and non-covalent attachment to graphene, graphene oxide and carbon nanotubes.
TetrahedronAbstract:
A pyrene-appended spiropyran for selective photo-switchable binding of Zn(II): UV-visible and fluorescence spectroscopy studies of binding and non-covalent attachment to graphene, graphene oxide and carbon nanotubes
Synthesis of photo-switchable, Zn2+ sensitive hybrid materials was achieved by facile non-covalent functionalization of graphene, graphene oxide and carbon nanotubes with a pyrene-appended spiropyran. Solution phase binding studies, using UV-visible and fluorescence spectroscopy, indicated that the pyrene-spiropyran dyad was highly selective for Zn2+ over a range of potentially competitive cations and that binding occurred with 1:1 stoichiometry and a binding constant of K=1.4×104mol-1dm3 at 295K. Zn2+ binding was promoted by UV irradiation or in darkness and reversed upon irradiation with visible light.
Abstract.
Ahmad A, Olah G, Szczesny B, Wood ME, Whiteman M, Szabo C (2015). AP39, a mitochondrially targeted hydrogen sulfide donor, exerts protective effects in a rat model of renal ischemia-reperfusion.
Author URL.
Schmidt TP, Lopes LB, Rodrigues L, Wood M, Whiteman M, Muscara MN, Costa SKP (2015). Antipsoriatic activity of GYY4137 (a slow-releasing hydrogen sulphide donor) microemulsion system using a mouse skin model of psoriasis.
Author URL.
Williams E, Pead S, Whiteman M, Wood ME, Wilson ID, Ladomery MR, Teklic T, Lisjak M, Hancock JT (2015). Detection of thiol modifications by hydrogen sulfide.
,
555, 233-251.
Abstract:
Detection of thiol modifications by hydrogen sulfide
Hydrogen sulfide (H2S) is an important gasotransmitter in both animals and plants. Many physiological events, including responses to stress, have been suggested to involve H2S, at least in part. On the other hand, numerous responses have been reported following treatment with H2S, including changes in the levels of antioxidants and the activities of transcription factors. Therefore, it is important to understand and unravel the events that are taking place downstream of H2S in signaling pathways. H2S is known to interact with other reactive signaling molecules such as reactive oxygen species (ROS) and nitric oxide (NO). One of the mechanisms by which ROS and NO have effects in a cell is the modification of thiol groups on proteins, by oxidation or S-nitrosylation, respectively. Recently, it has been reported that H2S can also modify thiols. Here we report a method for the determination of thiol modifications on proteins following the treatment with biological samples with H2S donors. Here, the nematode Caenorhabditis elegans is used as a model system but this method can be used for samples from other animals or plants.
Abstract.
Chatzianastasiou A, Bibli SI, Wood ME, Whiteman M, Andreadou I, Manolopoulos VG, Papapetropoulos A (2015). Distinct mechanisms of cardioprotection by different H2S donors.
Author URL.
Chatzianastasiou A, Bibli S-I, Wood ME, Whiteman M, Andreadou I, Manolopoulos VG, Papapetropoulos A (2015). Distinct mechanisms of cardioprotection by different hydrogen sulfide donors.
Author URL.
Tomasova L, Pavlovicova M, Malekova L, Misak A, Kristek F, Grman M, Cacanyiova S, Tomasek M, Tomaskova Z, Perry A, et al (2015). Effects of AP39, a novel triphenylphosphonium derivatised anethole dithiolethione hydrogen sulfide donor, on rat haemodynamic parameters and chloride and calcium Cav3 and RyR2 channels.
Nitric Oxide,
46, 131-144.
Abstract:
Effects of AP39, a novel triphenylphosphonium derivatised anethole dithiolethione hydrogen sulfide donor, on rat haemodynamic parameters and chloride and calcium Cav3 and RyR2 channels.
H2S donor molecules have the potential to be viable therapeutic agents. The aim of this current study was (i) to investigate the effects of a novel triphenylphosphonium derivatised dithiolethione (AP39), in the presence and absence of reduced nitric oxide bioavailability and (ii) to determine the effects of AP39 on myocardial membrane channels; CaV3, RyR2 and Cl(-). Normotensive, L-NAME- or phenylephrine-treated rats were administered Na2S, AP39 or control compounds (AP219 and ADT-OH) (0.25-1 µmol kg(-1)i.v.) and haemodynamic parameters measured. The involvement of membrane channels T-type Ca(2+) channels CaV3.1, CaV3.2 and CaV3.3 as well as Ca(2+) ryanodine (RyR2) and Cl(-) single channels derived from rat heart sarcoplasmic reticulum were also investigated. In anaesthetised Wistar rats, AP39 (0.25-1 µmol kg(-1) i.v) transiently decreased blood pressure, heart rate and pulse wave velocity, whereas AP219 and ADT-OH and Na2S had no significant effect. In L-NAME treated rats, AP39 significantly lowered systolic blood pressure for a prolonged period, decreased heart rate and arterial stiffness. In electrophysiological studies, AP39 significantly inhibited Ca(2+) current through all three CaV3 channels. AP39 decreased RyR2 channels activity and increased conductance and mean open time of Cl(-) channels. This study suggests that AP39 may offer a novel therapeutic opportunity in conditions whereby (•)NO and H2S bioavailability are deficient such as hypertension, and that CaV3, RyR2 and Cl(-) cardiac membrane channels might be involved in its biological actions.
Abstract.
Author URL.
Kulkarni-Chitnis M, Njie-Mbye YF, Mitchell L, Robinson J, Whiteman M, Wood ME, Opere CA, Ohia SE (2015). Inhibitory action of novel hydrogen sulfide donors on bovine isolated posterior ciliary arteries.
Exp Eye Res,
134, 73-79.
Abstract:
Inhibitory action of novel hydrogen sulfide donors on bovine isolated posterior ciliary arteries.
In the present study, we investigate the inhibitory effect of novel H2S donors, AP67 and AP72 on isolated bovine posterior ciliary arteries (PCAs) under conditions of tone induced by an adrenoceptor agonist. Furthermore, we examined the possible mechanisms underlying the AP67- and AP72-induced relaxations. Isolated bovine PCA were set up for measurement of isometric tension in organ baths containing oxygenated Krebs solution. The relaxant action of H2S donors was studied on phenylephrine-induced tone in the absence or presence of enzyme inhibitors for the following pathways: cyclooxygenase (COX); H2S; nitric oxide and the ATP-sensitive K(+) (KATP) channel. The H2S donors, NaSH (1 nM - 10 μM), AP67 (1 nM - 10 μM) and AP72 (10 nM - 1 μM) elicited a concentration-dependent relaxation of phenylephrine-induced tone in isolated bovine PCA. While the COX inhibitor, flurbiprofen (3 μM) blocked significantly (p
Abstract.
Author URL.
Emerson M, Ilkan Z, Mustafa F, Solomon A, Wood ME, Whiteman M (2015). Inhibitory regulation of platelets by hydrogen sulphide.
Author URL.
Alexander BE, Coles SJ, Khan TF, Maliszewsi J, Perry A, Pitak MP, Whiteman M, Wood ME (2015). Investigating the generation of hydrogen sulphide from the phosphinodithioate slow-release donor GYY4137: Novel products and experimental tools.
Author URL.
Hedegaard ER, Gouliaev A, Winther AK, Aalling M, Sivasubramaniam N, Whiteman M, Skovgaard N, Simonsen U (2015). Involvement of K channels and calcium-independent mechanisms in hydrogen sulfide relaxation of rat mesenteric small arteries.
Author URL.
Ikeda K, Marutani E, Hirai S, Wood ME, Whiteman M, Ichinose F (2015). Mitochondria-targeted hydrogen sulfide donor AP39 improves neurological outcomes after cardiac arrest in mice.
Nitric Oxide - Biology and Chemistry,
49, 90-96.
Abstract:
Mitochondria-targeted hydrogen sulfide donor AP39 improves neurological outcomes after cardiac arrest in mice
Abstract Aims Mitochondria-targeted hydrogen sulfide donor AP39, [(10-oxo-10-(4-(3-thioxo-3H-1,2-dithiol-5yl)phenoxy)decyl) triphenylphosphonium bromide], exhibits cytoprotective effects against oxidative stress in vitro. We examined whether or not AP39 improves the neurological function and long term survival in mice subjected to cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). Methods Adult C57BL/6 male mice were subjected to 8 min of CA and subsequent CPR. We examined the effects of AP39 (10, 100, 1000 nmol kg-1) or vehicle administered intravenously at 2 min before CPR (Experiment 1). Systemic oxidative stress levels, mitochondrial permeability transition, and histological brain injury were assessed. We also examined the effects of AP39 (10, 1000 nmol kg-1) or vehicle administered intravenously at 1 min after return of spontaneous circulation (ROSC) (Experiment 2). ROSC was defined as the return of sinus rhythm with a mean arterial pressure >40 mm Hg lasting at least 10 seconds. Results Vehicle treated mice subjected to CA/CPR had poor neurological function and 10-day survival rate (Experiment 1; 15%, Experiment 2; 23%). Administration of AP39 (100 and 1000 nmol kg-1) 2 min before CPR significantly improved the neurological function and 10-day survival rate (54% and 62%, respectively) after CA/CPR. Administration of AP39 before CPR attenuated mitochondrial permeability transition pore opening, reactive oxygen species generation, and neuronal degeneration after CA/CPR. Administration of AP39 1 min after ROSC at 10 nmol kg-1, but not at 1000 nmol kg-1, significantly improved the neurological function and 10-day survival rate (69%) after CA/CPR. Conclusion the current results suggest that administration of mitochondria-targeted sulfide donor AP39 at the time of CPR or after ROSC improves the neurological function and long term survival rates after CA/CPR by maintaining mitochondrial integrity and reducing oxidative stress.
Abstract.
Aboalsamh G, Saha M, Lobb I, Grewal J, Luke P, Wood M, Whiteman M, Sener A (2015). Mitochondrial Hydrogen Sulphide Donor Molecules Are More Effective Against Hypoxic Injury in Renal Tubular Epithelial Cells.
Author URL.
Whiteman M, Perry A, Zhou Z, Bucci M, Papapetropoulos A, Cirino G, Wood ME (2015). Phosphinodithioate and Phosphoramidodithioate Hydrogen Sulfide Donors.
Handb Exp Pharmacol,
230, 337-363.
Abstract:
Phosphinodithioate and Phosphoramidodithioate Hydrogen Sulfide Donors.
Hydrogen sulfide is rapidly emerging as a key physiological mediator and potential therapeutic tool in numerous areas such as acute and chronic inflammation, neurodegenerative and cardiovascular disease, diabetes, obesity and cancer. However, the vast majority of the published studies have employed crude sulfide salts such as sodium hydrosulfide (NaSH) and sodium sulfide (Na2S) as H2S "donors" to generate H2S. Although these salts are cheap, readily available and easy to use, H2S generated from them occurs as an instantaneous and pH-dependent dissociation, whereas endogenous H2S synthesis from the enzymes cystathionine γ-lyase, cystathionine-β-synthase and 3-mercaptopyruvate sulfurtransferase is a slow and sustained process. Furthermore, sulfide salts are frequently used at concentrations (e.g. 100 μM to 10 mM) far in excess of the levels of H2S reported in vivo (nM to low μM). For the therapeutic potential of H2S is to be properly harnessed, pharmacological agents which generate H2S in a physiological manner and deliver physiologically relevant concentrations are needed. The phosphorodithioate GYY4137 has been proposed as "slow-release" H2S donors and has shown promising efficacy in cellular and animal model diseases such as hypertension, sepsis, atherosclerosis, neonatal lung injury and cancer. However, H2S generation from GYY4137 is inefficient necessitating its use at high concentrations/doses. However, structural modification of the phosphorodithioate core has led to compounds (e.g. AP67 and AP105) with accelerated rates of H2S generation and enhanced biological activity. In this review, the therapeutic potential and limitations of GYY4137 and related phosphorodithioate derivatives are discussed.
Abstract.
Author URL.
Emerson M, Ahmad O, Rauzi F, Smyth E, Wood ME, Whiteman M (2015). Physiological regulation of platelet aggregation by the gasotransmitter hydrogen sulfide.
Author URL.
Penn TJ, Wood ME, Soanes DM, Csukai M, Corran AJ, Talbot NJ (2015). Protein kinase C is essential for viability of the rice blast fungus Magnaporthe oryzae.
Mol Microbiol,
98(3), 403-419.
Abstract:
Protein kinase C is essential for viability of the rice blast fungus Magnaporthe oryzae.
Protein kinase C constitutes a family of serine-threonine kinases found in all eukaryotes and implicated in a wide range of cellular functions, including regulation of cell growth, cellular differentiation and immunity. Here, we present three independent lines of evidence which indicate that protein kinase C is essential for viability of Magnaporthe oryzae. First, all attempts to generate a target deletion of PKC1, the single copy protein kinase C-encoding gene, proved unsuccessful. Secondly, conditional gene silencing of PKC1 by RNA interference led to severely reduced growth of the fungus, which was reversed by targeted deletion of the Dicer2-encoding gene, MDL2. Finally, selective kinase inhibition of protein kinase C by targeted allelic replacement with an analogue-sensitive PKC1(AS) allele led to specific loss of fungal viability in the presence of the PP1 inhibitor. Global transcriptional profiling following selective PKC inhibition identified significant changes in gene expression associated with cell wall re-modelling, autophagy, signal transduction and secondary metabolism. When considered together, these results suggest protein kinase C is essential for growth and development of M. oryzae with extensive downstream targets in addition to the cell integrity pathway. Targeting protein kinase C signalling may therefore prove an effective means of controlling rice blast disease.
Abstract.
Author URL.
Rodrigues L, Schmidt TR, Florenzano J, dos Santos KT, Cerqueira ARA, Teixeira SA, Wood ME, Whiteman M, Muscara MN, Costa SKP, et al (2015). The slow-releasing hydrogen sulphide donor, GYY4137, exhibits novel anti-skin symptoms of psoriasis and related itch.
Author URL.
2014
Szczesny B, MĂłdis K, Yanagi K, Coletta C, Le Trionnaire S, Perry A, Wood ME, Whiteman M, Szabo C (2014). AP39, a novel mitochondria-targeted hydrogen sulfide donor, stimulates cellular bioenergetics, exerts cytoprotective effects and protects against the loss of mitochondrial DNA integrity in oxidatively stressed endothelial cells in vitro.
Nitric Oxide,
41, 120-130.
Abstract:
AP39, a novel mitochondria-targeted hydrogen sulfide donor, stimulates cellular bioenergetics, exerts cytoprotective effects and protects against the loss of mitochondrial DNA integrity in oxidatively stressed endothelial cells in vitro.
The purpose of the current study was to investigate the effect of the recently synthesized mitochondrially-targeted H2S donor, AP39 [(10-oxo-10-(4-(3-thioxo-3H-1,2-dithiol-5yl)phenoxy)decyl) triphenylphosphonium bromide], on bioenergetics, viability, and mitochondrial DNA integrity in bEnd.3 murine microvascular endothelial cells in vitro, under normal conditions, and during oxidative stress. Intracellular H2S was assessed by the fluorescent dye 7-azido-4-methylcoumarin. For the measurement of bioenergetic function, the XF24 Extracellular Flux Analyzer was used. Cell viability was estimated by the combination of the MTT and LDH methods. Oxidative protein modifications were measured by the Oxyblot method. Reactive oxygen species production was monitored by the MitoSOX method. Mitochondrial and nuclear DNA integrity were assayed by the Long Amplicon PCR method. Oxidative stress was induced by addition of glucose oxidase. Addition of AP39 (30-300 nM) to bEnd.3 cells increased intracellular H2S levels, with a preferential response in the mitochondrial regions. AP39 exerted a concentration-dependent effect on mitochondrial activity, which consisted of a stimulation of mitochondrial electron transport and cellular bioenergetic function at lower concentrations (30-100 nM) and an inhibitory effect at the higher concentration of 300 nM. Under oxidative stress conditions induced by glucose oxidase, an increase in oxidative protein modification and an enhancement in MitoSOX oxidation was noted, coupled with an inhibition of cellular bioenergetic function and a reduction in cell viability. AP39 pretreatment attenuated these responses. Glucose oxidase induced a preferential damage to the mitochondrial DNA; AP39 (100 nM) pretreatment protected against it. In conclusion, the current paper documents antioxidant and cytoprotective effects of AP39 under oxidative stress conditions, including a protection against oxidative mitochondrial DNA damage.
Abstract.
Author URL.
Szczesny B, Modis K, Yanagi K, Le Trionnaire S, Wood ME, Whiteman M, Szabo C (2014). Cytoprotective effects of AP39, a mitochondrially targeted hydrogen sulfide donor in oxidatively stressed endothelial cells: Protection against the loss of cell viability and bioenergetics and attenuation of mitochondrial DNA injury.
Author URL.
Hafner S, Matallo J, Groeger M, Wachter U, McCook O, Wood M, Whiteman M, Georgieff M, Calzia E, Radermacher P, et al (2014). EFFECTS OF THE SLOW-RELEASING SULFIDE DONOR GYY4137 DURING RESUSCITATED SEPTIC SHOCK IN ATHEROSCLEROTIC SWINE.
Author URL.
Tomasova L, Misak A, Kristek F, Perry A, Wood ME, Ondrias K, Whiteman M (2014). Effects of a Novel Triphenylphosphonium Derivatised Anethole Dithiolethione Hydrogen Sulfide (H2S) Donor, AP39, on Cardiac Ion Channels and on Haemodynamic Parameters in Normotensive and Hypertensive Rats in Vivo.
Author URL.
McCook O, Radermacher P, Volani C, Asfar P, Ignatius A, Kemmler J, Möller P, Szabó C, Whiteman M, Wood ME, et al (2014). H2S during circulatory shock: some unresolved questions.
Nitric Oxide,
41, 48-61.
Abstract:
H2S during circulatory shock: some unresolved questions.
Numerous papers have been published on the role of H2S during circulatory shock. Consequently, knowledge about vascular sulfide concentrations may assume major importance, in particular in the context of "acute on chronic disease", i.e. during circulatory shock in animals with pre-existing chronic disease. This review addresses the questions (i) of the "real" sulfide levels during circulatory shock, and (ii) to which extent injury and pre-existing co-morbidity may affect the expression of H2S producing enzymes under these conditions. In the literature there is a huge range on sulfide blood levels during circulatory shock, in part as a result of the different analytical methods used, but also due to the variable of the models and species studied. Clearly, some of the very high levels reported should be questioned in the context of the well-known H2S toxicity. As long as "real" sulfide levels during circulatory shock are unknown and/or undetectable "on line" due to the lack of appropriate techniques, it appears to be premature to correlate the measured blood levels of hydrogen sulfide with the severity of shock or the H2S therapy-related biological outcomes. The available data on the tissue expression of the H2S-releasing enzymes during circulatory shock suggest that a "constitutive" CSE expression may play a crucial role of for the maintenance of organ function, at least in the kidney. The data also indicate that increased CBS and CSE expression, in particular in the lung and the liver, represents an adaptive response to stress states.
Abstract.
Author URL.
Whiteman M, Perry A, Wood ME (2014). H2S in inflammation: Time for resolution?.
Author URL.
Jeney V, Potor L, Petho D, Whiteman M, Wood ME, Balla G, Balla J (2014). HYDROGEN-SULFIDE RELEASING MOLECULES INHIBIT INTRAPLAQUE HEMORRHAGE-ASSOCIATED OXIDATIVE BURST IN THE HUMAN ATHEROMA AND SUBSEQUENT ENDOTHELIAL REACTIONS.
Author URL.
Szczesny B, Wood ME, Whiteman M, Szabo C (2014). Hydrogen Sulfide is an Endogenous Stimulator of Mitochondrial DNA Repair.
Author URL.
Yang H-Y, Wu Z-Y, Wood M, Whiteman M, Bian J-S (2014). Hydrogen sulfide attenuates opioid dependence by suppression of adenylate cyclase/cAMP pathway.
Antioxid Redox Signal,
20(1), 31-41.
Abstract:
Hydrogen sulfide attenuates opioid dependence by suppression of adenylate cyclase/cAMP pathway.
AIMS: the best-established mechanism of opioid dependence is the up-regulation of adenylate cyclase (AC)/cAMP pathway, which was reported to be negatively regulated by hydrogen sulfide (H2S), a novel endogenous neuromodulator. The present study was, therefore, designed to determine whether H2S is able to attenuate the development of opioid dependence via down-regulating AC/cAMP pathway. RESULTS: We demonstrated that application of sodium hydrosulphide (NaHS) and GYY4137, two donors of H2S, significantly alleviated naloxone-induced robust withdrawal jumping (the most sensitive and reliable index of opioid physical dependence) in morphine-treated mice. Repeated treatment with NaHS inhibited the up-regulated protein expression of AC in the striatum of morphine-dependent mice. Furthermore, NaHS also attenuated morphine/naloxone-elevated mRNA levels of AC isoform 1 and 8, production of cAMP, and phosphorylation of cAMP response element-binding protein (CREB) in mice striatum. These effects were mimicked by the application of exogenous H2S or over-expression of cystathione-β-synthase, an H2S -producing enzyme, in SH-SY5Y neuronal cells on treatment with [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-Enkephalin, a selective μ-opioid receptor agonist. Blockade of extracellular-regulated protein kinase 1/2 (ERK1/2) with its specific inhibitor attenuated naloxone-induced CREB phosphorylation. Pretreatment with NaHS or stimulation of endogenous H2S production also significantly suppressed opioid withdrawal-induced ERK1/2 activation in mice striatum or SH-SY5Y cells. INNOVATION: H2S treatment is important in prevention of the development of opioid dependence via suppression of cAMP pathway in both animal and cellular models. CONCLUSION: Our data suggest a potential role of H2S in attenuating the development of opioid dependence, and the underlying mechanism is closely related to the inhibition of AC/cAMP pathway.
Abstract.
Author URL.
Jeney V, Potor L, Petho D, Whiteman M, Wood ME, Balla G, Balla J (2014). Hydrogen-sulfide releasing molecules inhibit intraplaque hemorrhage-associated oxidative burst in the human atheroma and subsequent endothelial reactions.
Author URL.
Emerson M, Solomon A, Smyth E, Wood ME, Whiteman M (2014). Inhibition of platelet aggregation in vitro and in vivo by the H2S releasing compound GYY4137.
Author URL.
Jamroz-WiĆniewska A, Gertler A, Solomon G, Wood ME, Whiteman M, BeĆtowski J (2014). Leptin-induced endothelium-dependent vasorelaxation of peripheral arteries in lean and obese rats: role of nitric oxide and hydrogen sulfide.
PLoS One,
9(1).
Abstract:
Leptin-induced endothelium-dependent vasorelaxation of peripheral arteries in lean and obese rats: role of nitric oxide and hydrogen sulfide.
Adipose tissue hormone leptin induces endothelium-dependent vasorelaxation mediated by nitric oxide (NO) and endothelium-derived hyperpolarizing factors (EDHF). Previously it has been demonstrated that in short-term obesity the NO-dependent and the EDHF-dependent components of vascular effect of leptin are impaired and up-regulated, respectively. Herein we examined the mechanism of the EDHF-dependent vasodilatory effect of leptin and tested the hypothesis that alterations of acute vascular effects of leptin in obesity are accounted for by chronic hyperleptinemia. The study was performed in 5 groups of rats: (1) control, (2) treated with exogenous leptin for 1 week to induce hyperleptinemia, (3) obese, fed highly-palatable diet for 4 weeks, (4) obese treated with pegylated superactive rat leptin receptor antagonist (PEG-SRLA) for 1 week, (5) fed standard chow and treated with PEG-SRLA. Acute effect of leptin on isometric tension of mesenteric artery segments was measured ex vivo. Leptin relaxed phenylephrine-preconstricted vascular segments in NO- and EDHF-dependent manner. The NO-dependent component was impaired and the EDHF-dependent component was increased in the leptin-treated and obese groups and in the latter group both these effects were abolished by PEG-SRLA. The EDHF-dependent vasodilatory effect of leptin was blocked by either the inhibitor of cystathionine γ-lyase, propargylglycine, or a hydrogen sulfide (H2S) scavenger, bismuth (III) subsalicylate. The results indicate that NO deficiency is compensated by the up-regulation of EDHF in obese rats and both effects are accounted for by chronic hyperleptinemia. The EDHF-dependent component of leptin-induced vasorelaxation is mediated, at least partially, by H2S.
Abstract.
Author URL.
Gero D, Szczesny B, Modis K, Yanagi K, Wood ME, Perry A, Szabo C, Whiteman M (2014). Mitochondira-targeted hydrogen sulfide donors AP39 and AP123 attenuate hyperglycaemia-induced oxidative stress and loss of bioenergetics in microvascular endothelial cells.
Author URL.
Gero D, Szczesny B, Perry A, Modis K, Wood ME, Szabo C, Whiteman M (2014). Novel Mitochondria-Targeted Hydrogen Sulfide (H2S) Donors AP39 and AP123 Attenuate Hyperglycaemia-Induced Oxidative Stress and Loss of Bioenergetics in Microvascular Endothelial Cells.
Author URL.
Ferguson D, Perry A, Wood ME, Winyard PG, Whiteman M (2014). Potentiation of Methyl Aminolevulinate (MAL)-Induced Photodynamic Therapy (PDT) Killing of Skin Cancer Cells by Mitochondria-Targeted Hydrogen Sulfide (H2S) Donors.
Author URL.
Le Trionnaire S, Perry A, Szczesny B, Szabo C, Winyard PG, Whatmore JL, Wood ME, Whiteman M (2014). The synthesis and functional evaluation of a mitochondria-targeted hydrogen sulfide donor, (10-oxo-10-(4-(3-thioxo-3H-1,2-dithiol-5-yl)phenoxy)decyl) triphenylphosphonium bromide (AP39).
MedChemComm,
5(6), 728-736.
Abstract:
The synthesis and functional evaluation of a mitochondria-targeted hydrogen sulfide donor, (10-oxo-10-(4-(3-thioxo-3H-1,2-dithiol-5-yl)phenoxy)decyl) triphenylphosphonium bromide (AP39)
Synthesis and bioavailability of the endogenous gasomediator hydrogen sulfide (H2S) is perturbed in many disease states, including those involving mitochondrial dysfunction. There is intense interest in developing pharmacological agents to generate H2S. We have synthesised a novel H2S donor molecule coupled to a mitochondria-targeting moiety (triphenylphosphonium; TPP+) and compared the effectiveness of the compound against a standard non-TPP+ containing H2S donor (GYY4137) in the inhibition of oxidative stress-induced endothelial cell death. Our study suggests mitochondria-targeted H2S donors are useful pharmacological tools to study the mitochondrial physiology of H2S in health and disease. © 2014 the Partner Organisations.
Abstract.
2013
Fox B, Holland T, Wood ME, Winyard PG, Whiteman M (2013). Comparing the differential effects of novel, slow-release H2S donors on inflammatory mediators and cell proliferation in human joint and immune cells.
Author URL.
Rodrigues L, Santos BC, Florenzano J, dos Santos KT, Lopes KC, Lira FBC, Teixeira SA, Wood ME, Whiteman M, Muscara MN, et al (2013). Does the slow-releasing hydrogen sulfide donor GYY4137 controls inflammation and pruritogen responses in mouse skin?.
Author URL.
Malekova L, Pavlovicova M, Kristek F, Tomasova L, Wood ME, Whiteman M, Ondrias K (2013). Effects of H2S-donors on membrane channels.
Author URL.
Radermacher P, McCook O, Asfar P, Calzia E, Wood ME, Szabo C, Whiteman M, Wang R (2013). Expression of H2S-catalyzing enzymes during "acute chronic disease".
Author URL.
Le Trionnaire S, Perry A, Whatmore JL, Wood ME, Whiteman M (2013). Mitochondria-targeted hydrogen sulfide donors: a novel twist to an old "tail"?.
Author URL.
Whiteman M, Perry A, Le Trionnaire S, Whatmore JL, Ahmed T, Fox B, Kerr P, Haigh R, Winyard PG, Wood ME, et al (2013). Modulation of inflammatory and vascular signalling by novel slow release and mitochondria-targeted H2S donors.
Author URL.
Chitnis MK, Njie-Mbye YF, Opere CA, Wood ME, Whiteman M, Ohia SE (2013). Pharmacological actions of the slow release hydrogen sulfide donor GYY4137 on phenylephrine-induced tone in isolated bovine ciliary artery.
Exp Eye Res,
116, 350-354.
Abstract:
Pharmacological actions of the slow release hydrogen sulfide donor GYY4137 on phenylephrine-induced tone in isolated bovine ciliary artery.
Hydrogen sulfide (H2S), a colorless gas characterized by its pungent odor of rotten eggs has been reported to elicit relaxation effects on basal and pre-contracted non-ocular smooth muscles of several mammalian species. In the present study, we investigated the pharmacological actions of a H2S donor, GYY4137 on isolated bovine posterior ciliary artery after contraction with the adrenergic receptor agonist, phenylephrine. Furthermore, we studied the underlying mechanism of inhibitory action of GYY4137 on the posterior ciliary arteries. Isolated bovine posterior ciliary arteries were mounted in oxygenated organ baths and changes in isometric tension were measured with a Grass FT03 transducer connected to a recorder using a Grass Polyview Software. The relaxant actions of GYY4137 on phenylephrine pre-contracted arteries were observed in the absence and presence of an inhibitor of cyclo-oxygenase, flurbiprofen. Furthermore, the inhibitory effects of GYY4137 were studied in the absence or presence of inhibitors/activators of biosynthetic enzymes for H2S and nitric oxide production, as well as specific ion channel blockers. In the concentration range, 100 nM to 100 μM, GYY4137 elicited a concentration-dependant relaxation of phenylephrine-induced tone in isolated posterior ciliary arteries, with IC50 value of 13.4 ± 1.9 μM (n = 6). The cyclo-oxygenase inhibitor, flurbiprofen, significantly (p < 0.01) enhanced the relaxation induced by GYY4137 yielding IC50 value of 0.13 ± 0.08 μM (n = 6). Both the inhibitors of cystathionine β-synthase (aminooxyacetic acid, AOAA, 30 μM) and cystathionine γ-lyase (propargylglycine, PAG, 1 mM) caused significant (p < 0.05) rightward shifts in the concentration-response curve to GYY4137. Furthermore, the KATP channel antagonist, glibenclamide (100 μM) significantly (p < 0.01) attenuated the relaxant action induced by GYY4137 on bovine ciliary artery. Conversely, the activator of cystathionine β-synthase, SAM (100 μM) and an inhibitor of nitric oxide synthase, L-NAME (100 μM) had no significant effect on relaxations induced by GYY4137. We conclude that the inhibitory action of GYY4137 on isolated bovine ciliary artery is dependent upon the endogenous production of both prostanoids and H2S. Furthermore, the observed vascular smooth muscle relaxation induced by GYY4137 is mediated, at least in part, by KATP channels.
Abstract.
Author URL.
Jeney V, Potor L, Whiteman M, Wood ME, Balla G, Balla J (2013). Potential anti-atherogenic effects of hydrogen-sulfide releasing molecules.
Author URL.
Whatmore JL, Wolanska KI, Perry A, Wood ME, Whiteman M (2013). Slow release hydrogen sulfide (H2S) donors prevent hyperglycaemia-induced glycocalyx loss in retinal mirovascular endothelial cells.
Author URL.
Lencesova L, Hudecova S, Markova J, Soltysova A, Sedlak J, Wood ME, Whiteman M, Ondrias K, Krizanova O (2013). Sulfide signalling potentiates apoptosis through the up-regulation of IP3 receptors type 1 and 2.
Author URL.
Lencesova L, Hudecova S, Csaderova L, Markova J, Soltysova A, Pastorek M, Sedlak J, Wood ME, Whiteman M, Ondrias K, et al (2013). Sulphide signalling potentiates apoptosis through the up-regulation of IP3 receptor types 1 and 2.
Acta Physiol (Oxf),
208(4), 350-361.
Abstract:
Sulphide signalling potentiates apoptosis through the up-regulation of IP3 receptor types 1 and 2.
AIM: to investigate an interaction between the calcium and sulphide signalling pathways, particularly effects of the slow H2 S release donor morpholin-4-ium-4-methoxyphenyl-(morpholino)-phosphinodithioate (GYY4137) on the expression of inositol 1,4,5-trisphosphate receptors (IP3 R) with the possible impact on the apoptosis induction in HeLa cells. METHODS: Gene expression, Western blot analysis, apoptosis determination by Annexin-V-FLUOS and drop in mitochondrial membrane potential by 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolyl-carbocyanine iodide (JC1) and immunofluorescence were used to determine differences in control and GYY4137-treated HeLa cells. RESULTS: in HeLa cell line, GYY4137 (10 μm) up-regulated expression of the IP3 R1 and IP3 R2, but not IP3 R3 on both mRNA and protein levels. Concurrently, cytosolic calcium increased and reticular calcium was depleted in concentration-dependent manner, partially by the involvement of IP3 R. Depletion of calcium from reticulum was accompanied by increase in endoplasmic reticulum (ER) stress markers, such as X-box, CHOP and ATF4, thus pointing to the development of ER stress due to GYY4137 treatment. Also, GYY4137 treatment of HeLa cells increased the number of apoptotic cells. CONCLUSION: These results suggest an involvement of H2 S in both IP3 -induced calcium signalling and induction of apoptosis, possibly through the activation of ER stress.
Abstract.
Author URL.
Wood ME, Bissiriou S, Lowe C, Windeatt KM (2013). Synthetic use of the primary kinetic isotope effect in hydrogen atom transfer 2: generation of captodatively stabilised radicals.
Org Biomol Chem,
11(16), 2712-2723.
Abstract:
Synthetic use of the primary kinetic isotope effect in hydrogen atom transfer 2: generation of captodatively stabilised radicals.
Using C-3 di-deuterated morpholin-2-ones bearing N-2-iodobenzyl and N-3-bromobut-3-enyl radical generating groups, only products derived from the more stabilised C-3, rather than the less stabilised C-5 translocated radicals, were formed after intramolecular 1,5-hydrogen atom transfer, suggesting that any kinetic isotope effect present was not sufficient to offset captodative stabilisation.
Abstract.
Author URL.
Li L, Fox B, Keeble J, Salto-Tellez M, Winyard PG, Wood ME, Moore PK, Whiteman M (2013). The complex effects of the slow-releasing hydrogen sulfide donor GYY4137 in a model of acute joint inflammation and in human cartilage cells.
J Cell Mol Med,
17(3), 365-376.
Abstract:
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 (H2 S) 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 H2 S 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.
Abstract.
Author URL.
Lisjak M, Teklic T, Wilson I, Wood ME, Whiteman M, Spoljarevic M, Hancock JT (2013). The role of H2S in pepper leaves under salt stress conditions.
Author URL.
2012
Fox B, Perry A, Winyard P, Wood ME, Whiteman M (2012). Characterising the effect of novel slow-release H2S donors on pro-inflammatory enzyme activity in human cartilage cells.
Author URL.
Fox B, Holland T, Perry A, Wood ME, Whiteman M (2012). Characterising the effect of novel slow-release H2S donors on pro-inflammatory enzyme activity in human cartilage cells.
Author URL.
Whiteman ML, Wood ME, Perry A (2012). Compounds for use in the treatment of plants.
Abstract:
Compounds for use in the treatment of plants
The invention relates to use of a compound in a treatment of a plant to promote plant growth wherein the compound is a salt comprising an anion of formula (1): or a conjugate acid thereof, wherein: R1, R2, R3, R4 and R5 are each independently selected from H, halogen, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2- C10 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 cycloalkenyl, optionally substituted C3-Ci0 cycloalkynyl, hydroxy, optionally substituted C1 -C10 alkoxy, amino, mono-(C1-C10 alkyl)amino and di-(C1-C10 alkyl)amino groups; and Y is a nitrogen containing heterocyclyl group having from 3 to 14 ring atoms, a nitrogen containing heteroaryl group having from 3 to 14 ring atoms, an optionally substituted mono-(C1-C10 alkyl)amino group, an optionally substituted di-(C1-C10 alkyl)amino group or an optionally substituted tri-(C1-C10 alkyl)amino group. The compounds can be used to prevent or reduce stomatal closure or to cause stomatal opening in a plant. The invention further provides compounds for use in a herbicidal treatment of a plant. New compounds and a method for their manufacture are also described.
Abstract.
Author URL.
Fox B, Holland T, Perry A, Winyard PG, Wood ME, Whiteman M (2012). Defining the Effect of Novel Slow-Release H2S Donors on Pro-Inflammatory Mediators and Enzymes in Human Joint Cells.
Author URL.
Yong QC, Cheong JL, Hua F, Deng LW, Khoo YM, Lee HS, Perry A, Wood M, Whiteman M, Bian JS, et al (2012). Erratum: Regulation of heart function by endogenous gaseous mediators-crosstalk between nitric oxide and hydrogen sulfide (Antioxidants and Redox Signaling (2011) 14 (2081-2091)). Antioxidants and Redox Signaling, 16(7).
Wolanska K, Perry A, Wood ME, Chibber R, Whatmore J, Whiteman M (2012). Hydrogen sulfide - a novel guardian of the endothelial glycocalyx?.
Author URL.
Fox B, Schantz J-T, Haigh R, Wood ME, Moore PK, Viner N, Spencer JPE, Winyard PG, Whiteman M (2012). Inducible hydrogen sulfide synthesis in chondrocytes and mesenchymal progenitor cells: is H2S a novel cytoprotective mediator in the inflamed joint?.
J Cell Mol Med,
16(4), 896-910.
Abstract:
Inducible hydrogen sulfide synthesis in chondrocytes and mesenchymal progenitor cells: is H2S a novel cytoprotective mediator in the inflamed joint?
Hydrogen sulfide (H(2)S) has recently been proposed as an endogenous mediator of inflammation and is present in human synovial fluid. This study determined whether primary human articular chondrocytes (HACs) and mesenchymal progenitor cells (MPCs) could synthesize H(2)S in response to pro-inflammatory cytokines relevant to human arthropathies, and to determine the cellular responses to endogenous and pharmacological H(2)S. HACs and MPCs were exposed to IL-1β, IL-6, TNF-α and lipopolysaccharide (LPS). The expression and enzymatic activity of the H(2)S synthesizing enzymes cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE) were determined by Western blot and zinc-trap spectrophotometry, respectively. Cellular oxidative stress was induced by H(2)O(2), the peroxynitrite donor SIN-1 and 4-hydroxynonenal (4-HNE). Cell death was assessed by 3-(4,5-dimethyl-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. Mitochondrial membrane potential (DCm) was determined in situ by flow cytometry. Endogenous H(2) S synthesis was inhibited by siRNA-mediated knockdown of CSE and CBS and pharmacological inhibitors D,L-propargylglycine and aminoxyacetate, respectively. Exogenous H(2)S was generated using GYY4137. Under basal conditions HACs and MPCs expressed CBS and CSE and synthesized H(2)S in a CBS-dependent manner, whereas CSE expression and activity was induced by treatment of cells with IL-1β, TNF-α, IL-6 or LPS. Oxidative stress-induced cell death was significantly inhibited by GYY4137 treatment but increased by pharmacological inhibition of H(2)S synthesis or by CBS/CSE-siRNA treatment. These data suggest CSE is an inducible source of H(2)S in cultured HACs and MPCs. H(2)S may represent a novel endogenous mechanism of cytoprotection in the inflamed joint, suggesting a potential opportunity for therapeutic intervention.
Abstract.
Author URL.
Le Trionnaire S, Perry A, Whatmore JL, Winyard PG, Wood ME, Whiteman M (2012). Mitochondria-Targeted Slow Release Hydrogen Donors: a Novel Link to an Old 'tail'?.
Author URL.
Lo Faro ML, Whatmore J, More J, Wood ME, Whiteman M, Winyard PG (2012). Mutual regulation of (NO)-N-center dot/H2S bioavailability and cell signalling in the cardiovascular system.
Author URL.
Le Trionnaire S, Whatmore J, Perry A, Wood ME, Matthew W (2012). Slow release H2S donors protect human microvascular endothelial cells from oxidative stress induced cell death: Markedly increased potency by mitochondria-targeting.
Author URL.
Le Trionnaire S, Whatmore JL, Perry A, Wood ME, Whiteman M (2012). Slow release H2S donors protect human microvascular endothelial cells from oxidative stress induced cell death: Markedly increased potency by mitochondria-targetting.
Author URL.
Fox B, Li L, Keeble J, Winyard P, Wood M, Moore P, Whiteman M (2012). The complex effects of a slow-releasing hydrogen sulifde donor (GYY4137) in a model of inflammatory arthritis and in primary human cartilage cells.
Author URL.
2011
Le Trionnaire S, Whatmore JL, Perry A, Wood ME, Whiteman M (2011). Endogenous hydrogen sulfide (H2 S) and novel slow release H2S donors protect human endothelial cells from oxidative stress-induced cell death.
Author URL.
Le Trionnaire S, Whatmore J, Perry A, Wood ME, Whiteman M (2011). Endogenous hydrogen sulphide (H2S) and novel slow release H2S donors protect human microvascular endothelial cells from oxidative stress-induced cell death.
Author URL.
Lisjak M, TekliÄ T, Wilson ID, Wood M, Whiteman M, Hancock JT (2011). Hydrogen sulfide effects on stomatal apertures.
Plant Signal Behav,
6(10), 1444-1446.
Abstract:
Hydrogen sulfide effects on stomatal apertures.
Hydrogen sulfide (H(2)S) has recently been reported to be a signaling molecule in plants. It has been well established that is has such roles in animals and it has been suggested that it is included into the group of gasotransmitters. We have recently shown that hydrogen sulfide causes stomatal opening in the model plant Arabidopsis thaliana. H(2)S can be supplied to the plant tissues from donors such as sodium hydrosulfide (NaSH) or more recently from slow release H(2)S donor molecules such as GYY4137. Both give similar effects, that is, they cause stomatal opening. Furthermore both H(2)S donors reduced the accumulation of nitric oxide (NO) induced by abscisic acid (ABA) treatment of leaf tissues. Here similar work has been repeated in a crop plant, Capsium anuum, and similar data has been obtained, suggesting that such effects of hydrogen sulfide on plants is not confined to model species.
Abstract.
Author URL.
Perry MM, Hui CK, Whiteman M, Wood ME, Adcock I, Kirkham P, Michaeloudes C, Chung KF (2011). Hydrogen sulfide inhibits proliferation and release of IL-8 from human airway smooth muscle cells.
Am J Respir Cell Mol Biol,
45(4), 746-752.
Abstract:
Hydrogen sulfide inhibits proliferation and release of IL-8 from human airway smooth muscle cells.
Hydrogen sulfide (H(2)S) is synthesized intracellularly by the enzymes cystathionine-γ-lyase and cystathionine-β-synthase (CBS), and is proposed to be a gasotransmitter with effects in modulating inflammation and cellular proliferation. We determined a role of H(2)S in airway smooth muscle (ASM) function. ASM were removed from resection or transplant donor lungs and were placed in culture. Proliferation of ASM was induced by FCS and the proinflammatory cytokine, IL-1β. Proliferation of ASM and IL-8 release were measured by bromodeoxyuridine incorporation and ELISA, respectively. Exposure of ASM to H(2)S "donors" inhibited this proliferation and IL-8 release. Methemoglobin, a scavenger of endogenous H(2)S, increased DNA synthesis induced by FCS and IL-1β. In addition, methemoglobin increased IL-8 release induced by FCS, but not by IL-1β, indicating a role for endogenous H(2)S in these systems. Inhibition of CBS, but not cystathionine-γ-lyase, reversed the inhibitory effect of H(2)S on proliferation and IL-8 release, indicating that this is dependent on CBS. CBS mRNA and protein expression were inhibited by H(2)S donors, and were increased by methemoglobin, indicating that CBS is the main enzyme responsible for endogenous H(2)S production. Finally, we found that exogenous H(2)S inhibited the phosphorylation of extracellular signal-regulated kinase-1/2 and p38, which could represent a mechanism by which H(2)S inhibited cellular proliferation and IL-8 release. In summary, H(2)S production provides a novel mechanism for regulation of ASM proliferation and IL-8 release. Therefore, regulation of H(2)S may represent a novel approach to controlling ASM proliferation and cytokine release that is found in patients with asthma.
Abstract.
Author URL.
Yong Q-C, Cheong JL, Hua F, Deng L-W, Khoo YM, Lee H-S, Perry A, Wood M, Whiteman M, Bian J-S, et al (2011). Regulation of heart function by endogenous gaseous mediators-crosstalk between nitric oxide and hydrogen sulfide. Antioxidants & Redox Signaling, 14(11), 2081-2091.
2010
Lisjak M, Srivastava N, Teklic T, Civale L, Lewandowski K, Wilson I, Wood ME, Whiteman M, Hancock JT (2010). A novel hydrogen sulfide donor causes stomatal opening and reduces nitric oxide accumulation.
Plant Physiol Biochem,
48(12), 931-935.
Abstract:
A novel hydrogen sulfide donor causes stomatal opening and reduces nitric oxide accumulation.
Effects of hydrogen sulfide (H(2)S) on plant physiology have been previously studied, but such studies have relied on the use of NaSH as a method for supplying H(2)S to tissues. Now new compounds which give a less severe H(2)S shock and a more prolonged exposure to H(2)S have been developed. Here the effects of one such compound, GYY4137, has been investigated to determine its effects on stomatal closure in Arabidopsis thaliana. It was found that both NaSH and GYY4137 caused stomatal opening in the light and prevented stomatal closure in the dark. Nitric oxide (NO) has been well established as a mediator of stomatal movements and here it was found that both NaSH and GYY4137 reduced the accumulation of NO in guard cells, perhaps suggesting a mode of action for H(2)S in this system. GYY4137, and future related compounds, will be important tools to unravel the effects of plant exposure to H(2)S and to determine how H(2)S may fit into plant cell signalling pathways.
Abstract.
Author URL.
CaneâHoneysett DJ, Dowle MD, Wood ME (2010). ChemInform Abstract: 1,2,4âDithiazolidineâ3,5âdione: a Nucleophilic Isocyanate “Building Block”. ChemInform, 32(8), no-no.
BALDWIN JE, FRYER AM, PRITCHARD GJ, SPYVEE MR, WHITEHEAD RC, WOOD ME (2010). ChemInform Abstract: a Biomimetic Approach to the Pyridone Rings of the Acromelic Acids: a Concise Synthesis of Acromelic Acid a and an Approach to Acromelic Acid B. ChemInform, 29(41), no-no.
Gosain R, Norrish AM, Wood ME (2010). ChemInform Abstract: a Concise Method for the Functionalization of Ethanolamine α to Nitrogen Using Free Radical Methodology. ChemInform, 32(25), no-no.
SHIBATA N, BALDWIN JE, JACOBS A, WOOD ME (2010). ChemInform Abstract: a Stereocontrolled Synthesis of Protected (2R,3R)â3âMercaptoaspartic Acid via a βâAspartyl Enolate Sulfenylation. ChemInform, 27(42), no-no.
BALDWIN JE, BAMFORD SJ, FRYER AM, WOOD ME (2010). ChemInform Abstract: a Versatile Approach to Acromelic Acid Analogues. ChemInform, 26(48), no-no.
BALDWIN JE, FRYER AM, PRITCHARD GJ, SPYVEE MR, WHITEHEAD RC, WOOD ME (2010). ChemInform Abstract: Concise Syntheses of Acromelic Acid a and AlloâAcromelic Acid A. ChemInform, 29(19), no-no.
SHIBATA N, BALDWIN JE, JACOBS A, WOOD ME (2010). ChemInform Abstract: Electrophilic Sulfenylation in a Stereocontrolled Synthesis of Protected (2R,3R)â3âMercaptoaspartic Acid from LâAspartic Acid. ChemInform, 28(4), no-no.
Gosain R, Norrish AM, Wood ME (2010). ChemInform Abstract: FreeâRadical Functionalization of βâAmino Alcohols via 1,5âHydrogen Atom Abstraction in 1,3âOxazolidines. ChemInform, 30(50), no-no.
BALDWIN JE, FRYER AM, SPYVEE MR, WHITEHEAD RC, WOOD ME (2010). ChemInform Abstract: Stereocontrol in the Synthesis of Kainoids. ChemInform, 28(4), no-no.
BALDWIN JE, ADLINGTON RM, CROUCH NP, KEEPING JW, LEPPARD SW, PITLIK J, SCHOFIELD CJ, SOBEY WJ, WOOD ME (2010). ChemInform Abstract: Studies on the Mechanism of DeacetoxyâDeacetylcephalosporin C Synthase Using Cyclopropyl Substituted Cephalosporin Probes. ChemInform, 23(10), no-no.
Wood ME, Fryer AM (2010). ChemInform Abstract: Synthesis of Kainoids and Kainoid Analogues. ChemInform, 30(24), no-no.
BALDWIN JE, BAMFORD SJ, FRYER AM, RUDOLPH MPW, WOOD ME (2010). ChemInform Abstract: Towards a Versatile Synthesis of Kainoids. Part 1. Introduction of the Câ3 and Câ4 Substituents. ChemInform, 28(32), no-no.
BALDWIN JE, BAMFORD SJ, FRYER AM, RUDOLPH MPW, WOOD ME (2010). ChemInform Abstract: Towards a Versatile Synthesis of Kainoids. Part 2. Two Methods for Establishment of Câ4 Stereochemistry. ChemInform, 28(32), no-no.
BALDWIN JE, FRYER AM, SPYVEE MR, WHITEHEAD RC, WOOD ME (2010). ChemInform Abstract: Towards a Versatile Synthesis of Kainoids. Part 3. Efficient Methods for Control of Câ4 Stereochemistry. ChemInform, 28(32), no-no.
Chopra M, Perry A, Hodgkinson A, Wood ME, Whiteman M (2010). Contrasting Effects of 'Fast' and 'Slow' Releasing H2S Donors on beta Cell Viability in the Diabetic Milieu.
Author URL.
Whiteman M, Chopra M, Wood ME, Whatmore JL (2010). ENDOGENOUS HYDROGEN SULFIDE (H2S) AND NOVEL SLOW RELEASING H2S DONOR COMPOUNDS INHIBIT ENDOTHELIAL DYSFUNCTION INDUCED BY TNF- alpha, OXIDATIVE AND NITROSATIVE STRESS.
Author URL.
Perry MM, Hui C, Whiteman M, Wood ME, Adcock I, Kirkham P, Chung KF (2010). Hydrogen Sulfide Inhibits Proliferation and Release of IL-8 from Human Airway Smooth Muscle Cells.
Author URL.
Whiteman M, Wood ME, Whatmore JL (2010). Novel Slow Releasing Hydrogen Sulfide (H2S) Donor Compounds Inhibit Endothelial Dysfunction Induced by TNF-alpha, Oxidative and Nitrosative Stress.
Author URL.
Wood ME, Bissiriou S, Lowe C, Norrish AM, SĂ©nĂ©chal K, Windeatt KM, Coles SJ, Hursthouse MB (2010). Synthetic use of the primary kinetic isotope effect in hydrogen atom transfer: generation of α-aminoalkyl radicals.
Org Biomol Chem,
8(20), 4653-4665.
Abstract:
Synthetic use of the primary kinetic isotope effect in hydrogen atom transfer: generation of α-aminoalkyl radicals.
The extent to which deuterium can act as a protecting group to prevent unwanted 1,5-hydrogen atom transfer to aryl and vinyl radical intermediates was examined in the context of the generation of α-aminoalkyl radicals in a pyrrolidine ring. Intra- and intermolecular radical trapping following hydrogen atom transfer provides an illustration of the use of the primary kinetic isotope effect in directing the outcome of synthetic C-C bond-forming processes.
Abstract.
Author URL.
2009
Wood ME, Annis VM, Jones CD (2009). ChemInform Abstract: Unusual Reactivity of NâAcyl Imides: NâAroylâ1,2,4âdithiazolidineâ3,5âdiones as Acyl Isocyanate Equivalents. ChemInform, 40(13), no-no.
Chowdhry MI, Horton PN, Hursthouse MB, Wood ME (2009). α-Allylation of α-amino acids via 1,5-hydrogen atom transfer.
Tetrahedron Letters,
50(26), 3400-3403.
Abstract:
α-Allylation of α-amino acids via 1,5-hydrogen atom transfer
A straightforward method for the radical-based α-allylation of proteinogenic α-amino acids is described in which the key step involves 1,5-hydrogen atom transfer from the C-4 position of an oxazolidin-5-one. © 2009 Elsevier Ltd. All rights reserved.
Abstract.
2008
Mark E. Wood, Sabine Bissiriou, Christopher Lowe and Kim M. Windeatt (2008). Investigations into the effectiveness of deuterium as a protecting group for C–H bonds in radical reactions involving hydrogen atom transfer.
Organic and Biomolecular Chemistry,
6 Author URL.
Wood ME, Annis VM, Jones CD (2008). Unusual reactivity of N-acyl imides: N-aroyl-1,2,4-dithiazolidine-3,5-diones as acyl isocyanate equivalents.
Org Biomol Chem,
6(22), 4099-4101.
Abstract:
Unusual reactivity of N-acyl imides: N-aroyl-1,2,4-dithiazolidine-3,5-diones as acyl isocyanate equivalents.
Crystalline samples of three N-aroyl-1,2,4-dithiazolidine-3,5-diones have been prepared as the first examples of a novel class of compound that displays the reactivity of an acyl isocyanate when treated with nucleophiles.
Abstract.
Author URL.
2006
Penny, M.J. Steere, J.S. Horton, P.N. (2006). "A General Route to Protected Quaternary alpha-Amino Acids from alpha-Amino Alcohols via a Stereocontrolled Radical Approach". Chemical Communications, 2983-2985.
Wood ME, Penny MJ, Steere JS, Horton PN, Light ME, Hursthouse MB (2006). A General Route to Protected Quaternary αâAmino Acids from βâAmino Alcohols via a Stereocontrolled Radical Approach. ChemInform, 37(49), no-no.
2005
CaneâHoneysett DJ, Dowle MD, Wood ME (2005). A Stereocontrolled Route to Protected Isocyanates from Alcohols. ChemInform, 36(26), no-no.
Dowle, M.D. Wood, M.E. (2005). A stereocontrolled route to protected isocyanates from alcohols. Tetrahedron, 61, 2141-2148.
2004
Wood ME (2004). Tin Halides and Organotin Halides. ChemInform, 35(6), no-no.
2003
Wood ME, CaneâHoneysett DJ, Dowle MD (2003). 1,2,4âDithiazolidineâ3,5âdione as an Isocyanate Equivalent in the Mitsunobu Reaction. ChemInform, 34(8), no-no.
Wood ME, CaneâHoneysett DJ, Dowle MD, Coles SJ, Hursthouse MB (2003). Synthetic and Structural Studies on 1,2,4âDithiazolidineâ3,5âdione Derivatives. ChemInform, 35(1), no-no.
Cane-Honeysett, D.J. Dowle, M.D. (2003). Synthetic and structural studies on 1,2,4-dithiazolidine-3,5-dione derivatives. Organic and Biomolecular Chemistry, 1, 3015-3023.
2002
Cane-Honeysett, D.J. Dowle, M.D. (2002). 1,2,4-Dithiazolidine-3,5-dione as an isocyanate equivalent in the Mitsunobu reaction. Journal of the Chemical Society
2001
Norrish, A.M. Wood, M.E. (2001). A concise method for the functionalisation of ethanolamine alpha-to nitrogen using free radical methodology. Tetrahedron, 57
2000
Cane-Honeysett DJ, Dowle MD, Wood ME (2000). 1,2,4-Dithiazolidine-3,5-dione: a nucleophilic isocyanate 'building block'.
Synlett(11), 1622-1624.
Abstract:
1,2,4-Dithiazolidine-3,5-dione: a nucleophilic isocyanate 'building block'
Mild conditions are described for the direct N-alkylation of 1,2,4-dithiazolidine-3,5-dione 1 using a variety of alkyl halides with subsequent conversion of the products 2 into alkyl isocyanates using triphenylphosphine.
Abstract.
1999
Gosain R, Norrish AM, Wood ME (1999). Free-radical functionalisation of β-amino alcohols via 1,5-hydrogen atom abstraction in 1,3-oxazolidines.
Tetrahedron Letters,
40(36), 6673-6676.
Abstract:
Free-radical functionalisation of ÎČ-amino alcohols via 1,5-hydrogen atom abstraction in 1,3-oxazolidines
Functionalisation of ethanolamine at the carbon atom α- to nitrogen can be achieved in a diastereoselective C-4 alkylation of 1,3-oxazolidines using free-radical methodology.
Abstract.
1998
Baldwin JE, Fryer AM, Pritchard GJ, Spyvee MR, Whitehead RC, Wood ME (1998). A biomimetic approach to the pyridone rings of the acromelic acids: a concise synthesis of acromelic acid a and an approach to acromelic acid B.
Tetrahedron,
54(26), 7465-7484.
Abstract:
A biomimetic approach to the pyridone rings of the acromelic acids: a concise synthesis of acromelic acid a and an approach to acromelic acid B.
The syntheses of acromelic acid a 1, allo-acromelic acid a 19 and an approach towards acromelic acid B 2 are described. Palladium (0) catalysed cross-coupling reactions were used to generate C-4 catechol precursors and formation of the pyridone rings was investigated using a biomimetic oxidative cleavage - recyclisation strategy.
Abstract.
Baldwin JE, Fryer AM, Pritchard GJ, Spyvee MR, Whitehead RC, Wood ME (1998). Concise syntheses of acromelic acid a and allo-acromelic acid A.
Tetrahedron Letters,
39(7), 707-710.
Abstract:
Concise syntheses of acromelic acid a and allo-acromelic acid A
Acromelic acid a 1 and allo-acromelic acid a 12 were synthesised in a biomimetic fashion. An oxidative cleavage-recyclisation strategy was used to construct the requisite C-4 pyridone from an intermediate catechol.
Abstract.
1997
Baldwin JE, Adlington RM, Crouch NP, Hill RL, Wood ME, Lloyd MD (1997). Competing pathways in the oxidation of Z-3-ethylidine cephalosporin C by the enzyme deacetoxycephalosporin C synthase (DAOCS).
Bioorganic and Medicinal Chemistry Letters,
7(5), 593-596.
Abstract:
Competing pathways in the oxidation of Z-3-ethylidine cephalosporin C by the enzyme deacetoxycephalosporin C synthase (DAOCS)
DAOCS converts Z-3-ethylidene cephalosporin C to two diastereomeric alcohols in the ratio 7:2 with nearly complete incorporation of 18O from 18O2.
Abstract.
Shibata N, Baldwin JE, Wood ME (1997). Resin-bound peptide libraries showing specific metal ion binding.
Bioorganic and Medicinal Chemistry Letters,
7(4), 413-416.
Abstract:
Resin-bound peptide libraries showing specific metal ion binding
A library of 7240 TentaGel® resin-bound peptides all containing the active site residues of isopenicillin N synthase was prepared. Several peptides showed a high binding affinity for Co2+.
Abstract.
Baldwin JE, Bamford SJ, Fryer AM, Rudolph MPW, Wood ME (1997). Towards a versatile synthesis of kainoids I: Introduction of the C-3 and C-4 substituents.
Tetrahedron,
53(14), 5233-5254.
Abstract:
Towards a versatile synthesis of kainoids I: Introduction of the C-3 and C-4 substituents
The first stages in the synthesis of acromelic acid analogues from trans-4-hydroxy-L-proline are described. An enamine alkylation was used to stereospecifically introduce the C-3 substituent, Grignard addition to a ketone or Pd(0) catalysed cross-coupling procedures adding C-4 aryl substituents for further manipulation. A number of versatile intermediates were generated.
Abstract.
Baldwin JE, Bamford SJ, Fryer AM, Rudolph MPW, Wood ME (1997). Towards a versatile synthesis of kainoids II: Two methods for establishment of C-4 stereochemistry.
Tetrahedron,
53(14), 5255-5272.
Abstract:
Towards a versatile synthesis of kainoids II: Two methods for establishment of C-4 stereochemistry
Benzylic lactone hydrogenolysis and enamide reduction were used to generate protected C-4 aryl substituted kainoid analogues which were deprotected to their corresponding free amino acids. X-ray crystographic data were obtained for the C-4 2-MeOPh- analogue.
Abstract.
Baldwin JE, Fryer AM, Spyvee MR, Whitehead RC, Wood ME (1997). Towards a versatile synthesis of kainoids III: Efficient methods for control of C-4 stereochemistry.
Tetrahedron,
53(14), 5273-5290.
Abstract:
Towards a versatile synthesis of kainoids III: Efficient methods for control of C-4 stereochemistry
Halo- and selenolactonisation methods were used to prepare benzylic lactones from enamide carboxylic acids. The lactones were subsequently cleaved with predominantly inversion of configuration at the benzylic centre to give protected acromelic analogues with the correct C-4 stereochemistry. Hydroxyl directed heterogeneous hydrogenation of related enamide carbinols gave total stereocontrol at C-4.
Abstract.
1996
Shibata N, Baldwin JE, Jacobs A, Wood ME (1996). A Stereocontrolled Synthesis of Protected (2R, 3R)-3-Mercaptoaspartic Acid via a β-Aspartyl Enolate Sulfenylation.
Synlett,
1996(6), 519-520.
Abstract:
A Stereocontrolled Synthesis of Protected (2R, 3R)-3-Mercaptoaspartic Acid via a ÎČ-Aspartyl Enolate Sulfenylation
The unnatural α-amino acid (2R, 3R)-3-mercaptoaspartic acid was prepared stereoselectively in protected form (15) via electrophilic sulfenylation of a β-aspartate dianion2. A novel sulfenylating agent, 2,4-dimethoxybenzylthio-4-methylphenyl sulfonate (12) was developed and an application of (15) in the preparation of a tripeptide was investigated.
Abstract.
Shibata N, Baldwin JE, Jacobs A, Wood ME (1996). Electrophilic sulfenylation in a stereocontrolled synthesis of protected (2R,3R)-3-mercaptoaspartic acid from L-aspartic acid.
Tetrahedron,
52(39), 12839-12852.
Abstract:
Electrophilic sulfenylation in a stereocontrolled synthesis of protected (2R,3R)-3-mercaptoaspartic acid from L-aspartic acid
A novel electrophilic sulfenylating agent, (2,4-dimethoxybenzylthio)-4-methylphenyl sulfonate (13) was developed to give thiols bearing an acid labile protecting group. This was subsequently used to prepare in a stereocontrolled manner, a protected form of (2R,3R)-3-mercaptoaspartic acid which was incorporated into a tripeptide.
Abstract.
Baldwin JE, Fryer AM, Spyvee MR, Whitehead RC, Wood ME (1996). Stereocontrol in the synthesis of kainoids.
Tetrahedron Letters,
37(38), 6923-6924.
Abstract:
Stereocontrol in the synthesis of kainoids
A stereoselective synthesis of acromelic acid analogues is described in which the C-3/C-4 cis-relative stereochemistry is established by a hydroxyl directed heterogeneous catalytic hydrogenation of an enamide.
Abstract.
1995
Wood ME (1995). 1,2,4âDithiazolidineâ3,5âdione. In (Ed) Encyclopedia of Reagents for Organic Synthesis.
BALDWIN JE, BAMFORD SJ, FRYER AM, WOOD ME (1995). A VERSATILE APPROACH TO ACROMELIC ACID ANALOGS.
TETRAHEDRON LETTERS,
36(27), 4869-4872.
Author URL.
Baldwin JE, Brown D, Scudder PH, Wood ME (1995). A chemical model for the activation of pyruvate-formate-lyase.
Tetrahedron Letters,
36(12), 2105-2108.
Abstract:
A chemical model for the activation of pyruvate-formate-lyase
A chemical model is described for the activation of the carbon-centred radical-based enzyme, pyruvate-formate-lyase. The feasibility of a 5′-deoxyadenosyl radical abstracting a hydrogen atom from C-2 of a peptideglycine residue has been demonstrated in an intramolecular process. © 1995.
Abstract.
Baldwin JE, Bamford SJ, Fryer AM, Wood ME (1995). A versatile approach to acromelic acid analogues. Tetrahedron Letters, 36(27), 4869-4872.
1991
Baldwin JE, Adlington RM, Crouch NP, Keeping JW, Leppard SW, Pitlik J, Schofield CJ, Sobey WJ, Wood ME (1991). Studies on the mechanism of deacetoxy-deacetylcephalosporin C synthase using cyclopropyl substituted cephalosporin probes.
Journal of the Chemical Society, Chemical Communications(11), 768-770.
Abstract:
Studies on the mechanism of deacetoxy-deacetylcephalosporin C synthase using cyclopropyl substituted cephalosporin probes
Cyclopropyl substituted cephalosporin analogues were prepared and evaluated as substrates for the FeII/α-ketoglutarate dependent oxygenase, DAOC-DAC synthase; the first example of catalytic product formation from a Cyclopropyl ring cleavage pathway by an α-ketoglutarate dependent oxygenase is reported.
Abstract.
Baldwin JE, Goh KC, Wood ME, Schofield CJ, Cooper RDG, Huffman GW (1991). The role of sulphur in cephalosporin biosynthesis.
Bioorganic and Medicinal Chemistry Letters,
1(8), 421-424.
Abstract:
The role of sulphur in cephalosporin biosynthesis
The role of sulphur in cephalosporin biosynthesis was probed by evaluation of a carbocyclic analogue of deacetoxycephalosporin C as a substrate for DAOC/DAC synthase. © 1991.
Abstract.
1989
Baldwin JE, Adlington RM, Russell MA, Schofield CJ, Wood ME (1989). Syntheses of [2â<sup>13</sup>C] and [1,2â<sup>13</sup>C] labelled αâketoglutaric acid.
Journal of Labelled Compounds and Radiopharmaceuticals,
27(9), 1091-1099.
Abstract:
Syntheses of [2â13C] and [1,2â13C] labelled αâketoglutaric acid
The syntheses of αâketo[2â13C]glutaric acid and αâketo[1,2â13C]glutaric acid were each achieved from commercial 13CH3I in 5 steps. 13CH3NO2, prepared in situ from 13CH3I and AgNO2, was treated with magnesium methyl carbonate, followed by acidified methanol to give O2N13CH2CO2CH3. Michael addition to methyl acrylate, followed by in situ nitronate formation and ozonolysis gave the dimethyl ester of αâketo [2â13C]glutaric acid, which was deprotected with hydrochloric acid. O2N13CH213CO2CH3 was prepared from 13CH3NO2 by reaction with aqueous KOH, followed by treatment with acidified methanol, and was converted to 1,2â13Câαâketoglutaric acid in a similar fashion to that used for monoâlabelled material. Copyright © 1989 John Wiley & Sons, Ltd.
Abstract.
Baldwin JE, Adlington RM, Schofield CJ, Sobey WJ, Wood ME (1989). The role of α-ketoglutarate in cephalosporin biosynthesis.
Journal of the Chemical Society, Chemical Communications(15), 1012-1015.
Abstract:
The role of α-ketoglutarate in cephalosporin biosynthesis
13C Labelled α-ketoglutarates in conjuction with 18O2 were used to investigate the role of α-ketoglutarate in cephalosporin biosynthesis.
Abstract.
1986
JONES JH, WOOD ME (1986). L-HISTIDINE BENZYL ESTER.
SYNTHETIC COMMUNICATIONS,
16(12), 1515-1516.
Author URL.
JONES JH, THOMAS DW, THOMAS RM, WOOD ME (1986). TERT-BUTYL CHLOROMETHYL ETHER.
SYNTHETIC COMMUNICATIONS,
16(13), 1607-1610.
Author URL.