The TRPA1 Mediated Effects of Hydrogen Sulfide and Polysulfide Compounds on Animal Models of Acute And Chronic Inflammation

Amióta ismert, hogy a H2S endogén úton is termelődik a szervezetünkben és gazotranszmitterként funkcionál, élénk kutatások folynak biológiai hatásainak feltérképezésére. Azonban hamar kiderült, hogy a H2S komplex szerepet játszik a redox rendszerekben és számos további mediátor keletkezhet belőle. Jelenleg egy olyan látszólag egyszerű kérdés, mint a hidrogén-szulfid pontos kvantitatív meghatározása a biológiai rendszerekben is heves vitákat tud kelteni tudományos körökben. Kísérleteink során három különböző hidrogén-szulfid donor vegyület hatásait kívántuk vizsgálni két különböző jellegű, egy akut- és egy krónikus gyulladásos modellt alkalmazva

Effects of sulfide and polysulfides transmitted by direct or signal transduction-mediated activation of TRPA1 channels

Hydrogen sulfide (H2 S) is a gaseous mediator in various physiological and pathological processes, including neuro-immune-modulation, metabolic pathways, cardiovascular system, tumour growth, inflammation and pain etc. Nowadays hydrogen polysulfides (H2 Sn ) have turned up as signalling molecules modulating ion channels, transcription factors and protein kinases. Transient Receptor Potential (TRP) cation channels can be activated by mechanical, thermal or chemical triggers. Here, we review the current literature regarding biological actions of sulfide and polysulfide compounds mediated by TRP-s with special emphasis on the role of TRPA1. Notwithstanding, TRPA1 is a best-known ion channel in nociceptors. Considering its regulatory role, it should not be forgotten about the function of non-neuronal receptors. Although, previous papers have particularly demonstrated sulfide and polysulfide effects in different pathological circumstances and TRPA1-mediated processes have also been investigated intensively, our review attempts to present the first comprehensive overview about potential cross-talk between TRPA1 and sulfide-activated signalling pathways

The fluorescent dye 3,3′-diethylthiatricarbocyanine iodide is unsuitable for in vivo imaging of myelination in the mouse

There is a growing interest to use non-invasive optical imaging methods to study central nervous system diseases. The application of a myelin-binding fluorescent dye, 3,3-diethylthiatricarbocyanine iodide (DBT) was recently described for in vivo optical imaging of demyelination in the mouse. In the present study we aimed at adapting the method to our optical imaging systems, the IVIS Lumina II to measure epifluorescence and the fluorescent molecular tomograph (FMT) for 3-dimensional quantification of the fluorophore. Epifluorescent imaging was performed 5−30 min after DBT injection which was followed by FMT imaging at 40 min. Two mice also underwent micro-CT imaging in the FMT cassette for the purpose of FMT-CT co-registration. Ex vivo imaging of the brain and other tissues of the head and neck was carried out 1 h after injection. Both the FMT-CT co-registration and the ex vivo imaging of organs proved that DBT poorly crossed the blood-brain barrier. The dye did not accumulate in the myelin sheath of the sciatic nerve. In contrast, there was an intense accumulation in the pituitary and salivary glands. The FMT-CT co-registration unequivocally demonstrated that the signal localized to the head did not originate from beyond the blood-brain barrier. No myelin binding was demonstrated by the ex vivo imaging either. In conclusion, DBT is unsuitable for in vivo imaging of myelination due to its poor BBB penetration, accumulation in other structures of the head and neck region and lack of selective binding towards myelin in vivo

The anti-inflammatory effect of dimethyl trisulfide in experimental acute pancreatitis

Various organosulfur compounds, such as dimethyl trisulfide (DMTS), display anti-inflammatory properties. We aimed to examine the effects of DMTS on acute pancreatitis (AP) and its mechanism of action in both in vivo and in vitro studies. AP was induced in FVB/n mice or Wistar rats by caerulein, ethanol-palmitoleic acid, or L-ornithine-HCl. DMTS treatments were administered subcutaneously. AP severity was assessed by pancreatic histological scoring, pancreatic water content, and myeloperoxidase activity measurements. The behaviour of animals was followed. Pancreatic heat shock protein 72 (HSP72) expression, sulfide, and protein persulfidation were measured. In vitro acinar viability, intracellular Ca 2+ concentration, and reactive oxygen species production were determined. DMTS dose-dependently decreased the severity of AP. It declined the pancreatic infiltration of leukocytes and cellular damage in mice. DMTS upregulated the HSP72 expression during AP and elevated serum sulfide and low molecular weight persulfide levels. DMTS exhibited cytoprotection against hydrogen peroxide and AP-inducing agents. It has antioxidant properties and modulates physiological but not pathophysiological Ca 2+ signalling. Generally, DMTS ameliorated AP severity and protected pancreatic acinar cells. Our findings indicate that DMTS is a sulfur donor with anti-inflammatory and antioxidant effects, and organosulfur compounds require further investigation into this potentially lethal disease

Amiodarone that has antibacterial effect against human pathogens may represent a novel catheter lock

Infection is one of the most feared hospital-acquired complications. Infusion therapy is frequently administered through a central line. Infusions facilitating bacterial growth may be a source of central line-associated bloodstream infections. On the other hand, medications that kill bacteria may protect against this kind of infection and may be used as a catheter lock.In this study, we examined the impact of amiodarone on bacterial growth. Amiodarone is used for controlling cardiac arrhythmias and can be administered as an infusion for weeks. Standard microbiological methods have been used to study the growth of laboratory strains and clinical isolates of Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, and multidrug-resistant Acinetobacter baumannii in amiodarone. The minimum inhibitory concentration (MIC) of amiodarone was determined. Bacterial growth from in use amiodarone syringes and giving sets was also investigated.Most examined strains were killed within 1 min in amiodarone. The other strains were killed within 1 h. The MICs of amiodarone were <0.5-32 μg/mL.Amiodarone infusion is unlikely to be responsible for bloodstream infections as contaminating bacteria are killed within 1 h. Amiodarone may also protect against central line infections if used as a catheter lock

Dimethyl Trisulfide Diminishes Traumatic Neuropathic Pain Acting on TRPA1 Receptors in Mice

Pharmacotherapy of neuropathic pain is still challenging. Our earlier work indicated an analgesic effect of dimethyl trisulfide (DMTS), which was mediated by somatostatin released from nociceptor nerve endings acting on SST4 receptors. Somatostatin release occurred due to TRPA1 ion channel activation. In the present study, we investigated the effect of DMTS in neuropathic pain evoked by partial ligation of the sciatic nerve in mice. Expression of the mRNA of Trpa1 in murine dorsal-root-ganglion neurons was detected by RNAscope. Involvement of TRPA1 ion channels and SST4 receptors was tested with gene-deleted animals. Macrophage activity at the site of the nerve lesion was determined by lucigenin bioluminescence. Density and activation of microglia in the spinal cord dorsal horn was verified by immunohistochemistry and image analysis. Trpa1 mRNA is expressed in peptidergic and non-peptidergic neurons in the dorsal root ganglion. DMTS ameliorated neuropathic pain in Trpa1 and Sstr4 WT mice, but not in KO ones. DMTS had no effect on macrophage activity around the damaged nerve. Microglial density in the dorsal horn was reduced by DMTS independently from TRPA1. No effect on microglial activation was detected. DMTS might offer a novel therapeutic opportunity in the complementary treatment of neuropathic pain

Nitrosopersulfide (SSNO^-) is a unique cysteine polysulfidating agent with reduction-resistant bioactivity

Aims: The aim of the present study was to investigate the biochemical properties of nitrosopersulfide (SSNO -), a key intermediate of the nitric oxide (NO)/sulfide cross talk. Results: We obtained corroborating evidence that SSNO - is indeed a major product of the reaction of S-nitrosothiols with hydrogen sulfide (H 2S). It was found to be relatively stable (t 1/2 *1 h at room temperature) in aqueous solution of physiological pH, stabilized by the presence of excess sulfide and resistant toward reduction by other thiols. Furthermore, we here show that SSNO - escapes the reducing power of the NADPH-driven biological reducing machineries, the thioredoxin and glutathione reductase systems. The slow decomposition of SSNO - produces inorganic polysulfide species, which effectively induce per/polysulfidation on glutathione or protein cysteine (Cys) residues. Our data also demonstrate that, in contrast to the transient activation by inorganic polysulfides, SSNO - induces long-term potentiation of TRPA1 (transient receptor potential ankyrin 1) channels, which may be due to its propensity to generate a slow flux of polysulfide in situ. Innovation: The characterized properties of SSNO - would seem to represent unique features in cell signaling by enabling sulfur and nitrogen trafficking within the reducing environment of the cytosol, with targeted release of both NO and polysulfide equivalents. Conclusion: SSNO - is a surprisingly stable bioactive product of the chemical interaction of S-nitrosothiol species and H 2S that is resistant to reduction by the thioredoxin and glutathione systems. As well as generating NO, it releases inorganic polysulfides, enabling transfer of sulfane sulfur species to peptide/protein Cys residues. The sustained activation of TRPA1 channels by SSNO - is most likely linked to all these properties. Antioxid. Redox Signal. 33, 1277–1294. </p

The anti-inflammatory effect of dimethyl trisulfide in experimental acute pancreatitis

Abstract Various organosulfur compounds, such as dimethyl trisulfide (DMTS), display anti-inflammatory properties. We aimed to examine the effects of DMTS on acute pancreatitis (AP) and its mechanism of action in both in vivo and in vitro studies. AP was induced in FVB/n mice or Wistar rats by caerulein, ethanol-palmitoleic acid, or L-ornithine-HCl. DMTS treatments were administered subcutaneously. AP severity was assessed by pancreatic histological scoring, pancreatic water content, and myeloperoxidase activity measurements. The behaviour of animals was followed. Pancreatic heat shock protein 72 (HSP72) expression, sulfide, and protein persulfidation were measured. In vitro acinar viability, intracellular Ca2+ concentration, and reactive oxygen species production were determined. DMTS dose-dependently decreased the severity of AP. It declined the pancreatic infiltration of leukocytes and cellular damage in mice. DMTS upregulated the HSP72 expression during AP and elevated serum sulfide and low molecular weight persulfide levels. DMTS exhibited cytoprotection against hydrogen peroxide and AP-inducing agents. It has antioxidant properties and modulates physiological but not pathophysiological Ca2+ signalling. Generally, DMTS ameliorated AP severity and protected pancreatic acinar cells. Our findings indicate that DMTS is a sulfur donor with anti-inflammatory and antioxidant effects, and organosulfur compounds require further investigation into this potentially lethal disease