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Nikolay Bazhanov, Teodora Ivanciuc, Haotian Wu, Matteo Garofalo, Jianming Kang, Ming Xian, Antonella Casola
We have recently shown that endogenous hydrogen sulfide (H₂S), an important cellular gaseous mediator, exerts an antiviral and anti-inflammatory activity in vitro and in vivo, and that exogenous H₂S delivered via the synthetic H₂S-releasing compound GYY4137 also has similar properties. In this study, we sought to extend our findings to a novel class of H₂S donors, thiol-activated gem-dithiol-based (TAGDDs). In an in vitro model of human respiratory syncytial virus (RSV) infection, TAGDD-1 treatment significantly reduced viral replication, even when added up to six hours after infection...
May 10, 2018: Viruses
Shenzheng Mo, Yongmei Hua
Hydrogen sulfide (H2 S), a gaseous signaling molecule produced by cystathionine γ-lyase (CSE) and cystathionine β-synthase (CBS), influences bone remodeling in many ways. Osteoclasts play an important role in bone remodeling during tooth movement induced by mechanical loading, which increases the rate of tooth movement. Recently, we found that osteoclasts could produce H2 S. However, whether H2 S modulates bone remodeling by affecting osteoclasts remains unclear. In this study, we found that CSE-H2 S was a dominant H2 S generating system in osteoclasts, while CBS did not generate H2 S...
May 3, 2018: Biochemical and Biophysical Research Communications
Ricardo de Pascual, Andrés M Baraibar, Iago Méndez-López, Martín Pérez-Ciria, Ignacio Polo-Vaquero, Luis Gandía, Sunny E Ohia, Antonio G García, Antonio M G de Diego
Gasotransmitter hydrogen sulphide (H2 S) has emerged as a regulator of multiple physiological and pathophysiological processes throughout. Here, we have investigated the effects of NaHS (fast donor of H2 S) and GYY4137 (GYY, slow donor of H2 S) on the exocytotic release of catecholamines from fast-perifused bovine adrenal chromaffin cells (BCCs) challenged with sequential intermittent pulses of a K+ -depolarizing solution. Both donors caused a concentration-dependent facilitation of secretion. This was not due to an augmentation of Ca2+ entry through voltage-activated Ca2+ channels (VACCs) because, in fact, NaHS and GYY caused a mild inhibition of whole-cell Ca2+ currents...
May 2, 2018: Pflügers Archiv: European Journal of Physiology
Chadwick R Powell, Kearsley M Dillon, Yin Wang, Ryan J Carrazzone, John B Matson
Persulfides (RSSH) have been hypothesized as critical components in sulfur-mediated redox cycles and as potential signaling compounds, similar to hydrogen sulfide (H2 S). Hindering the study of persulfides is a lack of persulfide-donor compounds with selective triggers that release discrete persulfide species. Reported here is the synthesis and characterization of a ROS-responsive (ROS=reactive oxygen species), self-immolative persulfide donor. The donor, termed BDP-NAC, showed selectivity towards H2 O2 over other potential oxidative or nucleophilic triggers, resulting in the sustained release of the persulfide of N-acetyl cysteine (NAC) over the course of 2 h, as measured by LCMS...
April 26, 2018: Angewandte Chemie
Lamei Yu, Byung Mun Park, Yong Jin Ahn, Gi-Ja Lee, Suhn Hee Kim
Hydrogen sulfide (H2 S) is normally produced from L-cysteine in mammalian tissues and related to the pathogenesis of cardiovascular diseases. The aim of this study is to investigate the effects of H2 S donor on atrial natriuretic peptide (ANP) secretion and define its mechanism using normal and isoproterenol (ISP)-treated rats. Several H2 S donors were perfused into isolated beating rat atria, and atrial pressure (AP) and ANP secretion were measured. NaHS augmented high stretch-induced ANP secretion and decreased AP in a dose-dependent manner...
April 20, 2018: Peptides
Amanda R Jensen, Natalie A Drucker, Jan P Te Winkel, Michael J Ferkowicz, Troy A Markel
PURPOSE: Hydrogen sulfide (H2 S) has many beneficial properties and may serve as a novel treatment in patients suffering from intestinal ischemia-reperfusion injury (I/R). The purpose of this study was to examine the method of delivery and timing of administration of H2 S for intestinal therapy during ischemic injury. We hypothesized that 1) route of administration of hydrogen sulfide would impact intestinal recovery following acute mesenteric ischemia and 2) preischemic H2 S conditioning using the optimal mode of administration as determined above would provide superior protection compared to postischemic application...
March 6, 2018: Journal of Pediatric Surgery
Kohei Sone, Asami Mori, Kenji Sakamoto, Tsutomu Nakahara
We previously reported that systemic administration with sodium hydrogen sulfide, a rapid-release donor compound of hydrogen sulfide (H2 S), protected retinal neurons against N-methyl-D-aspartic acid (NMDA)-induced injury. For clinical application of H2 S donors for retinal neurodegeneration, topical administration with an extended-release donor compound will be better. In the present study, we histologically investigated whether GYY4137, an extended-release hydrogen sulfide donor, had a protective effect on NMDA-induced retinal injury in the mice in vivo...
2018: Biological & Pharmaceutical Bulletin
Yun Qiu, Yichen Wu, Min Meng, Man Luo, Hongmei Zhao, Hong Sun, Sumin Gao
BACKGROUND: This study explores the protective effects of a hydrogen sulfide donor, morpholin-4-ium 4-methoxyphenyl-morpholino-phosphinodithioate (GYY4137), in the hearts of diabetic mice that had been subjected to myocardial ischemia/reperfusion injury. Diabetes impairs the Akt pathway, in which the Akt protein is dephosphorylated and inactivated by PH domain leucine-rich repeat protein phosphatase-1 (PHLPP-1). However, the function of PHLPP-1 and molecular mechanism that underlies the cardiac protection exerted by GYY4137 remains unknown...
May 2018: Journal of Surgical Research
Shouzhe Lin, Dameng Lian, Weihua Liu, Aaron Haig, Ian Lobb, Ahmed Hijazi, Hassan Razvi, Jeremy Burton, Matthew Whiteman, Alp Sener
OBJECTIVES: To assess the effects of slow-releasing H2 S donor GYY4137 on post-obstructive renal function and injury following unilateral ureteral obstruction (UUO) by using the UUO and reimplantation (UUO-R) model in rats and to elucidate potential mechanisms by using an in vitro model of epithelial-mesenchymal transition (EMT). METHODS: Male Lewis rats underwent UUO at the left ureterovesical junction. From post-obstructive day (POD) 1-13, rats received daily intraperitoneal (IP) injection of phosphate buffered saline (PBS, 1 mL) or GYY4137 (200 μmol/kg/day in 1 mL PBS, IP)...
March 6, 2018: Nitric Oxide: Biology and Chemistry
Shubhangi Prabhudesai, Chris Koceja, Anindya Dey, Shahram Eisa-Beygi, Noah R Leigh, Resham Bhattacharya, Priyabrata Mukherjee, Ramani Ramchandran
The cystathionine ß-synthase (CBS) is a critical enzyme in the transsulfuration pathway and is responsible for the synthesis of cystathionine from serine and homocysteine. Cystathionine is a precursor to amino acid cysteine. CBS is also responsible for generation of hydrogen sulfide (H2 S) from cysteine. Mutation in CBS enzyme causes homocysteine levels to rise, and gives rise to a condition called hyperhomocysteinuria. To date, numerous mouse knockout models for CBS enzyme has been generated, which show panoply of defects, reflecting the importance of this enzyme in development...
2018: Frontiers in Cell and Developmental Biology
Changnan Wang, Jiankui Du, Shufang Du, Yujian Liu, Dongxia Li, Xiaoyan Zhu, Xin Ni
In a previous study, we showed that endogenous hydrogen sulfide (H2 S) plays a key role in the maintenance of intact adrenal cortex function via the protection of mitochondrial function during endoxemia. We further investigated whether mitochondria-mediated apoptosis is involved in H2 S protection of adrenal function. LPS treatment resulted in mitochondria-mediated apoptosis in the adrenal glands of male mice, and these effects were prevented by the H2 S donor GYY4137. In the model of Y1 cells, the LPS-induced mitochondria-mediated apoptosis and blunt response to ACTH were rescued by GYY4137...
February 24, 2018: Molecular and Cellular Endocrinology
Jin-Zhuo Ning, Wei Li, Fan Cheng, Ting Rao, Wei-Min Yu, Yuan Ruan, Run Yuan, Xiao-Bin Zhang, Yang Du, Cheng-Cheng Xiao
The aim of the present study was to evaluate whether morpholin-4-ium 4 methoxyphenyl (morpholino) phosphonodithioate (GYY4137) exhibits a protective effect on ipsilateral testicular injury in experimentally varicocele (VC)-induced rats. A total of 48 rats were randomly divided into the following 6 groups (n=8 each): Group A (control group); group B (sham group); group C (VC group); group D (VC group administered 5 mg/kg/day GYY4137); group E (VC group administered 10 mg/kg/day GYY4137) and group F (VC group administered 20 mg/kg/day GYY4137)...
January 2018: Experimental and Therapeutic Medicine
R Zhuang, L Guo, J Du, S Wang, J Li, Y Liu
OBJECTIVE: This study includes exploring (i) the production of endogenous hydrogen sulfide (H2 S) after mucosal wound generation and (ii) the role of compensating the change in H2 S level postmucosal wound generation. METHODS AND MATERIALS: A mucosal wound model was established in female C57BL/6J mice. Wound tissues were collected to examine the change in the endogenous H2 S level. To examine the effect of decreased H2 S, GYY4137 was intraperitoneally injected into mice at 50 mg kg-1  day-1 before mucosal wounding to compensate for the decreased endogenous H2 S...
January 30, 2018: Oral Diseases
Congkuo Du, Xianjuan Lin, Wenjing Xu, Fengjiao Zheng, Junyan Cai, Jichun Yang, Qinghua Cui, Chaoshu Tang, Jun Cai, Guoheng Xu, Bin Geng
AIMS: Hydrogen sulfide (H2S) has a protective role in the pathogenesis of atherosclerosis by multiple pathways. Sirtuin-1 (SIRT1) is a histone deacetylase, as an essential mediated longevity gene, and has an anti-atherogenic effect by regulating the acetylation of some functional proteins. Whether SIRT1 is involved in protecting H2S in atherosclerosis and its mechanism remains unclear. RESULTS: In ApoE-knockout atherosclerosis mice, treatment with an H2S donor (NaHS or GYY4137) reduced atherosclerotic plaque area, macrophage infiltration, aortic inflammation and plasma lipid level...
January 17, 2018: Antioxidants & Redox Signaling
Natalie A Drucker, Amanda R Jensen, Michael Ferkowicz, Troy A Markel
BACKGROUND: Necrotizing enterocolitis (NEC) continues to be a morbid surgical condition among preterm infants. Novel therapies for this condition are desperately needed. Hydrogen sulfide (H2 S) is an endogenous gasotransmitter that has been found to have beneficial properties. We therefore hypothesized that intraperitoneal injection of various H2 S donors would improve clinical outcomes, increase intestinal perfusion, and reduce intestinal injury in an experimental mouse model of necrotizing enterocolitis...
December 24, 2017: Journal of Pediatric Surgery
Xu Cao, Siping Xiong, Yebo Zhou, Zhiyuan Wu, Lei Ding, Yike Zhu, Mark E Wood, Matthew Whiteman, Philip K Moore, Jin-Song Bian
AIMS: Cisplatin is a major therapeutic drug for solid tumors, but can cause severe nephrotoxicity. However, the role and therapeutic potential of hydrogen sulfide (H2 S), an endogenous gasotransmitter, in cisplatin-induced nephrotoxicity remain to be defined. RESULTS: Cisplatin led to the impairment of H2 S 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...
February 21, 2018: Antioxidants & Redox Signaling
Mariela Castelblanco, Jérôme Lugrin, Driss Ehirchiou, Sonia Nasi, Isao Ishii, Alexander So, Fabio Martinon, Nathalie Busso
A variety of stimuli, including monosodium urate (MSU) crystals, activate the NLRP3 inflammasome, and this activation involves several molecular mechanisms including xanthine oxidase (XO) up-regulation and mitochondrial dysfunction. Upon oligomerization of apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1 becomes active and cleaves the proinflammatory cytokine IL-1β into its active secreted form. Hydrogen sulfide (H2 S), a gasotransmitter mainly produced by cystathionine γ-lyase (CSE) in macrophages, could modulate inflammation...
February 16, 2018: Journal of Biological Chemistry
Patrick B Murphy, Aurelia Bihari, Neil G Parry, Ian Ball, Ken Leslie, Kelly Vogt, Abdel-Rahman Lawendy
BACKGROUND: Carbon monoxide (CO)- and hydrogen sulphide-releasing molecules (CORM-3 and GYY4137, respectively) have been shown to be potent antioxidant and antiinflammatory agents at the tissue and systemic level. We hypothesized that both CORM-3 and GYY4137 would reduce the significant organ dysfunction associated with abdominal compartment syndrome (ACS). MATERIAL AND METHODS: Randomized trial was conducted where ACS was maintained for 2 hours in 27 rats using an abdominal plaster cast and intraperitoneal CO2 insufflation at 20 mmHg...
February 2018: Journal of Surgical Research
Meng Lu, Xian Jiang, Liquan Tong, Feng Zhang, Lin Ma, Xuesong Dong, Xueying Sun
Maintaining a certain level of hydrogen sulfide (H2 S) in ischemia-reperfusion (I/R) is essential for limiting injury to the liver. Exogenous H2 S exerts protective effects against this injury, but the mechanisms remain unclear. Liver injury was induced in Wistar rats undergoing hepatic I/R for 30 min, followed by a 3-h reperfusion. Administration of GYY4137 (a slow-releasing H2 S donor) significantly attenuated the severity of liver injury and was reflected by reduced inflammatory cytokine production and cell apoptosis, the levels of which were elevated by I/R, while DL-propargylglycine (PAG, an inhibitor of cystathionine γ-lyase [CSE]) aggravated liver injury...
February 1, 2018: Biological & Pharmaceutical Bulletin
Zheng-Wei Lee, Xin-Yi Teo, Zhi J Song, Dawn S Nin, Wisna Novera, Bok A Choo, Brian W Dymock, Philip K Moore, Ruby Y-J Huang, Lih-Wen Deng
Slow and continuous release of H2 S by GYY4137 has previously been demonstrated to kill cancer cells by increasing glycolysis and impairing anion exchanger and sodium/proton exchanger activity. This action is specific for cancer cells. The resulting lactate overproduction and defective pH homeostasis bring about intracellular acidification-induced cancer cell death. The present study investigated the potency of H2 S released by GYY4137 against invasive and radio- as well as chemo-resistant cancers, known to be glycolytically active...
2017: Frontiers in Pharmacology
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