The ability of sulfhydryl compounds to provide protection against the acute toxicity of morphinone was investigated in mice. Subcutaneous administration of morphinone produced a reduction of hepatic non-protein sulfhydryl concentration. Pretreatments of mice with glutathione or cysteine significantly increased the survival rate of mice given a lethal dose of morphinone, whereas morphinone lethality was markedly potentiated by diethyl maleate. On the other hand, the administration of morphine produce a dose dependent reduction of hepatic non-protein sulfhydryl contents. However, neither glutathione nor cysteine protected mice from the acute toxicity of morphine. A possible explanation for these observations was proposed as follows: morphine is oxidized by morphine 6-dehydrogenase to morphinone, and the morphinone thus produced decreases the sulfhydryl contents in the liver. This mechanism is supported by the fact that morphinone reacts easily with glutathione and cysteine in vitro.

6-Shogaol and 6-gingerol are ginger components with similar chemical structures. However, while 6-shogaol damages microtubules, 6-gingerol does not. We have investigated the molecular mechanism of 6-shogaol-induced microtubule damage and found that the action of 6-shogaol results from the structure of alpha,beta-unsaturated carbonyl compounds. alpha,beta-Unsaturated carbonyl compounds such as 6-shogaol react with sulfhydryl groups of cysteine residues in tubulin, and impair tubulin polymerization. The reaction with sulfhydryl groups depends on the chain length of alpha,beta-unsaturated carbonyl compounds. In addition, alpha,beta-unsaturated carbonyl compounds are more reactive with sulfhydryl groups in tubulin than in 2-mercaptoethanol, dithiothreitol, glutathione and papain, a cysteine protease.

The concepts of mucoadhesion and mucoadhesive polymers were introduced in the 20th century, leading to several advantages. These included enhanced drug absorption and extended residence at specific site of action. Polymeric excipients underwent chemical modification with sulfhydryl groups on the polymeric backbone so as to improve mucoadhesive features as well as potential. This modification resulted in compounds mimicking the nature of secreted mucus glycoproteins. Thus, these thiol group-bearing excipients presented the ability to attach covalently to the mucosa by the disulfide bonding. Nevertheless, the first generation of these thiol-modified polymers, named thiomers, presented disadvantages such as low stability in aqueous media and/or the high susceptibility towards oxidation along with the drawback of low sufficient reactive functional moieties on the polymeric backbone at lower pH. Therefore, in the 21st century, a second generation of preactivated or S-protected polymers with protected thiol moieties were developed, as well as a third generation of thiomers, solving some of the previously described problems. This review article aimed to highlight the progess on a potent sulfhydryl modification during the last decades and the posterior characterization and in vitro/ex vivo/in vivo mucoadhesiveness.

Mitrella kentii (M. kentii) (Bl.) Miq, is a tree-climbing liana that belongs to the family Annonaceae. The plant is rich with isoquinoline alkaloids, terpenylated dihydrochalcones and benzoic acids and has been reported to possess anti-inflammatory activity. The purpose of this study is to assess the gastroprotective effects of desmosdumotin C (DES), a new isolated bioactive compound from M. kentii, on gastric ulcer models in rats.

Significant resources in early drug discovery are spent unknowingly pursuing artifacts and promiscuous bioactive compounds, while understanding the chemical basis for these adverse behaviors often goes unexplored in pursuit of lead compounds. Nearly all the hits from our recent sulfhydryl-scavenging high-throughput screen (HTS) targeting the histone acetyltransferase Rtt109 were such compounds. Herein, we characterize the chemical basis for assay interference and promiscuous enzymatic inhibition for several prominent chemotypes identified by this HTS, including some pan-assay interference compounds (PAINS). Protein mass spectrometry and ALARM NMR confirmed these compounds react covalently with cysteines on multiple proteins. Unfortunately, compounds containing these chemotypes have been published as screening actives in reputable journals and even touted as chemical probes or preclinical candidates. Our detailed characterization and identification of such thiol-reactive chemotypes should accelerate triage of nuisance compounds, guide screening library design, and prevent follow-up on undesirable chemical matter.

We previously showed that oxidative stress inhibits leukemia inhibitory factor (LIF) signaling by targeting JAK1, and the catalytic domains of JAK 1 and 2 have a cysteine-based redox switch. Thus, we postulated that the NO sibling and thiophylic compound, nitroxyl (HNO), would inhibit LIF-induced JAK-STAT3 activation. Pretreatment of human microvascular endothelial cells (HMEC-1) or neonatal rat cardiomyocytes with the HNO donors Angeli's salt or nitrosocyclohexyl acetate (NCA) inhibited LIF-induced STAT3 activation. NCA pretreatment also blocked the induction of downstream inflammatory genes (e.g. intercellular adhesion molecule 1, CCAAT/enhancer binding protein delta). The related 1-nitrosocyclohexyl pivalate (NCP; not a nitroxyl donor) was equally effective in inhibiting STAT3 activation, suggesting that these compounds act as thiolate targeting electrophiles. The JAK1 redox switch is likely not a target of acyloxy nitroso compounds, as NCA had no effect on JAK1 catalytic activity and only modestly affected JAK1-induced phosphorylation of the LIF receptor. However, pretreatment of recombinant human STAT3 with NCA or NCP reduced labeling of free sulfhydryl residues. We show that NCP in the presence of diamide enhanced STAT3 glutathionylation and dimerization in adult mouse cardiac myocytes and altered STAT3 under non-reducing conditions. Finally, we show that monomeric STAT3 levels are decreased in the Gαq model of heart failure in a redox-sensitive manner. Altogether, our evidence indicates that STAT3 has redox-sensitive cysteines that regulate its activation and are targeted by HNO donors and acyloxy nitroso compounds. These findings raise the possibility of new therapeutic strategies to target STAT3 signaling via a redox-dependent manner, particularly in the context of cardiac and non-cardiac diseases with prominent pro-inflammatory signaling.

Evidence indicates that inflammation in Inflammatory Bowel Disease (IBD) is associated with increased systemic levels of reactive oxygen species. Systemic oxidative stress has been associated with reduced levels of plasma thiols. Less invasive tests capable of reflecting and predicting IBD activity are increasingly sought after. We sought to systematically review the evidence inherent in serum thiol levels as a marker of Crohn's Disease and Ulcerative Colitis activity (PROSPERO: CRD42021255521).

The effects of sulfhydryl reduction/oxidation on the gating of large-conductance, Ca(2+)-activated K+ (maxi-K) channels were examined in excised patches from tracheal myocytes. Channel activity was modified by sulfhydryl redox agents applied to the cytosolic surface, but not the extracellular surface, of membrane patches. Sulfhydryl reducing agents dithiothreitol, beta-mercaptoethanol, and GSH augmented, whereas sulfhydryl oxidizing agents diamide, thimerosal, and 2,2'-dithiodipyridine inhibited, channel activity in a concentration-dependent manner. Channel stimulation by reduction and inhibition by oxidation persisted following washout of the compounds, but the effects of reduction were reversed by subsequent oxidation, and vice versa. The thiol-specific reagents N-ethylmaleimide and (2-aminoethyl)methanethiosulfonate inhibited channel activity and prevented the effect of subsequent sulfhydryl oxidation. Measurements of macroscopic currents in inside-out patches indicate that reduction only shifted the voltage/nP0 relationship without an effect on the maximum conductance of the patch, suggesting that the increase in nP0 following reduction did not result from recruitment of more functional channels but rather from changes of channel gating. We conclude that redox modulation of cysteine thiol groups, which probably involves thiol/disulfide exchange, alters maxi-K channel gating, and that this modulation likely affects channel activity under physiological conditions.

The influence of lipid content and pretreatment methods (blanching and brining) on proteins conformation in fish (Capelin, Mallotus villosus) during drying and smoking were assessed. Soluble protein fractions were examined through changes in salt-soluble proteins, sulfhydryl groups, and disulfide bonds contents. The salt level and moisture content were also evaluated. Conformational changes in muscle protein were significant (p < 0.05) after blanching and during initial drying when moisture content and dryness rates were high. Salt-soluble proteins and total sulfhydryl groups contents reduced, whereas available sulfhydryl group and disulfide bonds contents intensified. The conformational changes were explained by muscle protein denaturation and aggregation ascribed to high temperature and dehydration during processing. The study reports fish protein denaturation to have reduced protein solubility as well as the nutritional value (loss of thermolabile compounds) and yield after smoking. More so, protein aggregation that was significantly (p < 0.05) higher in dried blanched fish could have reduced the dried fish sensory quality. Blanching pretreatment is thus not suitable for commercial capelin drying. Lipids were found to have protective effect against fish protein conformation.

Sulfhydryl-containing compounds, including thiols and hydrogen sulfide (H2S), play important but differential roles in biological structure and function. One major challenge in separating the biological roles of thiols and H2S is developing tools to effectively separate the reactivity of these sulfhydryl-containing compounds. To address this challenge, we report the differential responses of common electrophilic fluorescent thiol labeling reagents, including nitrobenzofurazan-based scaffolds, maleimides, alkylating agents, and electrophilic aldehydes, toward cysteine and H2S. Although H2S reacted with all of the investigated scaffolds, the photophysical response to each scaffold was significantly different. Maleimide-based, alkylating, and aldehydic thiol labeling reagents provided a diminished fluorescence response when treated with H2S. By contrast, nitrobenzofurazan-based labeling reagents were deactivated by H2S addition. Furthermore, the addition of H2S to thiol-activated nitrobenzofurazan-based reagents reduced the fluorescence signal, thus establishing the incompatibility of nitrobenzofurazan-based thiol labeling reagents in the presence of H2S. Taken together, these studies highlight the differential reactivity of thiols and H2S toward common thiol-labeling reagents and suggest that sufficient care must be taken when labeling or measuring thiols in cellular environments that produce H2S due to the potential for both false-positive and eroded responses.

Previous studies have examined the conjugation of sulfhydryl compounds such as L-cysteine and glutathione with DOPA-quinone following the oxidation of tyrosine and DOPA by tyrosinase. These covalent reactions play a key role in the regulation and metabolism of pigment cells. We report on the first direct evidence for the formation of lipoyl adducts in reactions of thiol groups with DOPA-quinone in dihydrolipoic acid (6,8-dimercaptooctanoic acid [DHLA]). Incubating DHLA with DOPA-quinone followed by tyrosinase-catalyzed oxidation resulted in the three products predicted by HPLC-UV and LC-ESI(-)-MS analyses for DHLA DOPA conjugates. In the current study, we identified 5-S-lipoyl-DOPA among the principal products isolated by HPLC and characterized by FAB(-)-MS, ESI(-)-MS/MS, and 1H NMR, 2D-COSY studies. Collectively, these results suggest that DHLA undergoes sulfhydryl conjugation with DOPA-quinone, pointing to the involvement of thiol-reactive metabolites.

Life-history strategies play a critical role in susceptibility to environmental stresses for Scleractinia coral. Metabolomics, which is capable of determining the metabolic responses of biological systems to genetic and environmental changes, is competent for the characterization of species’ biological traits. In this study, two coral species (Pocillopora meandrina and Seriatopora hystrix in the South China Sea) with different life-history strategies (“competitive” and “weedy”) were targeted, and untargeted mass spectrometry metabolomics combined with molecular networking was applied to characterize their differential metabolic pathways. The results show that lyso-platelet activating factors (lyso-PAFs), diacylglyceryl carboxyhydroxymethylcholine (DGCC), aromatic amino acids, and sulfhydryl compounds were more enriched in P. meandrina, whereas new phospholipids, dehydrated phosphoglycerol dihydroceramide (de-PG DHC), monoacylglycerol (MAG), fatty acids (FA) (C < 18), short peptides, and guanidine compounds were more enriched in S. hystrix. The metabolic pathways involved immune response, energy metabolism, cellular membrane structure regulation, oxidative stress system, secondary metabolite synthesis, etc. While the immune system (lysoPAF) and secondary metabolite synthesis (aromatic amino acids and sulfhydryl compounds) facilitates fast growth and resistance to environmental stressors of P. meandrina, the cell membrane structure (structural lipids), energy storage (storage lipids), oxidative stress system (short peptides), and secondary metabolite synthesis (guanidine compounds) are beneficial to the survival of S. hystrix in harsh conditions. This study contributes to the understanding of the potential molecular traits underlying life-history strategies of different coral species.

Corryocactus brevistylus (K. Schum. ex Vaupel) Britton & Rose (Cactaceae) is a shrubby or often arborescent cactus popularly known as "sancayo" and produce an edible fruit known as "Sanky" which is consumed in Arequipa-Perú. The purpose of this study was to report the gastroprotective activity and relate this activity to the antioxidant capacity and presence of phenolic compounds for the first time. A metabolomic profiling based on Ultrahigh-pressure liquid chromatography and electrospray high resolution mass spectrometry, and the antioxidant activities (DPPH, ABTS, and FRAP), ascorbic acid content, total phenolics and flavonoids contents, and the mode of gastroprotective action of the Sanky fruit including the involvement of prostaglandins, nitric oxide, and sulfhydryl compounds is reported. Thirty-eight compounds were detected in the ethanolic extract including 12 organic acids, nine hydroxycinnamic acids, three isoamericanol derivatives, six flavonoids, five fatty acids, and two sterols. The results of the biological tests showed that the ethanolic extract had antioxidant capacity and gastroprotective activity on the model of HCl/EtOH-induced gastric lesions in mice (at 10, 25, 50, and 100 mg/kg). The effect elicited by the extract at 50 mg/kg was reversed by indometacin and N-ethylmaleimide but not by NG-nitro-L-arginine methyl ester suggesting that sulfhydryl groups and prostaglandins are involved in the mode of gastroprotective action. In conclusion, our study proves that C. brevistylus pears have some gastroprotective and antioxidant capacities and consumption is recommended for the presence of several bioactive compounds.

Ethnomedicinal studies in the Amazon community and in the Northeast region of Brazil highlight the use of Libidibia ferrea fruits for the treatment of gastric problems. However, there are no data in the literature of this pharmacological activity. Thus, the aim of this paper is to provide a scientific basis for the use of the dry extract of L. ferrea pods (DELfp) for the treatment of peptic ulcers. Phytochemical characterization was performed by HPLC/MS. In vitro antioxidant activity was assessed using DPPH, ABTS, phosphomolybdenum, and superoxide radical scavenging activity. The gastroprotective activity, the ability to stimulate mucus production, the antisecretory activity, and the influence of -SH and NO compounds on the antiulcerogenic activity of DELfp were evaluated. The healing activity was determined by the acetic acid-induced chronic ulcer model. Anti-Helicobacter pylori activity was investigated. HPLC/MS results identified the presence of phenolic compounds, gallic acid and ellagic acid, in DELfp. The extract showed antioxidant activity in vitro. In ulcers induced by absolute ethanol and acidified ethanol, the ED50 values of DELfp were 113 and 185.7 mg/kg, respectively. DELfp (100, 200, and 400 mg/kg) inhibited indomethacin-induced lesions by 66.7, 69.6, and 65.8%, respectively. DELfp (200 mg/kg) reduced gastric secretion and H+ concentration in the gastric contents and showed to be independent of nitric oxide (NO) and dependent on sulfhydryl (-SH) compounds in the protection of the gastric mucosa. In the chronic ulcer model, DELfp reduced the area of the gastric lesion. DELfp also showed anti-H. pylori activity. In conclusion, DELfp showed antioxidant, gastroprotective, healing, and antiulcerogenic activities. The mechanism of these actions seems to be mediated by different pathways and involves the reduction of gastric secretion and H+ concentration, dependence on sulfhydryl compounds, and anti-H. pylori activity. All these actions support the medicinal use of this species in the management of peptic ulcers.

In the presence of hydrogen peroxide cytochrome c can perform the oxidation of catecholamines and their S-cysteinyl-derivatives yielding melanins as final products. The initial reaction rate is linearly dependent on cytochrome c and H2O2 concentration; the reaction follows the Michaelis and Menten kinetics both for H2O2 and hydrogen donors. Sulfhydryl compounds inhibit the formation of the pigment. The reported data indicate that a heme-containing protein belonging to the mitochondrial chain can accelerate the oxidation of catecholamines to eumelanins.

Bromelain and N-acetylcysteine are two natural, sulfhydryl-containing compounds with good safety profiles which have been investigated for their benefits and application in health and disease for more than fifty years. As such, the potential values of these agents in cancer therapy have been variably reported in the literature. In the present study, the efficacy of bromelain and N-acetylcysteine in single agent and combination treatment of human gastrointestinal carcinoma cells was evaluated in vitro and the underlying mechanisms of effect were explored.

Mutations in human bestrophin-1 are linked to various kinds of retinal degeneration. Although it has been proposed that bestrophins are Ca(2+)-activated Cl(-) channels, definitive proof is lacking partly because mice with the bestrophin-1 gene deleted have normal Ca(2+)-activated Cl(-) currents. Here, we provide compelling evidence to support the idea that bestrophin-1 is the pore-forming subunit of a cell volume-regulated anion channel (VRAC) in Drosophila S2 cells. VRAC was abolished by treatment with RNAi to Drosophila bestrophin-1. VRAC was rescued by overexpressing bestrophin-1 mutants with altered biophysical properties and responsiveness to sulfhydryl reagents. In particular, the ionic selectivity of the F81C mutant changed from anionic to cationic when the channel was treated with the sulfhydryl reagent, sodium (2-sulfonatoethyl) methanethiosulfonate (MTSES(-)) (P(Cs)/P(Cl) = 0.25 for native and 2.38 for F81C). The F81E mutant was 1.3 times more permeable to Cs(+) than Cl(-). The finding that VRAC was rescued by F81C and F81E mutants with different biophysical properties shows that bestrophin-1 is a VRAC in S2 cells and not simply a regulator or an auxiliary subunit. F81C overexpressed in HEK293 cells also exhibits a shift of ionic selectivity after MTSES(-) treatment, although the effect is quantitatively smaller than in S2 cells. To test whether bestrophins are VRACs in mammalian cells, we compared VRACs in peritoneal macrophages from wild-type mice and mice with both bestrophin-1 and bestrophin-2 disrupted (best1(-/-)/best2(-/-)). VRACs were identical in wild-type and best1(-/-)/best2(-/-) mice, showing that bestrophins are unlikely to be the classical VRAC in mammalian cells.

Dietary isothiocyanates (ITCs) are electrophilic compounds that have diverse biological activities including induction of apoptosis and effects on cell cycle. They protect against experimental carcinogenesis in animals, an activity believed to result from the transcriptional induction of "Phase 2" enzymes. The molecular mechanism of action of ITCs is unknown. Since ITCs are electrophiles capable of reacting with sulfhydryl groups on amino acids, we hypothesized that ITCs induce their biological effects through covalent modification of proteins, leading to changes in cell regulatory events. We previously demonstrated that stress-signaling kinase pathways are inhibited by other electrophilic compounds such as menadione. We therefore tested the effects of nutritional ITCs on MEKK1, an upstream regulator of the SAPK/JNK signal transduction pathway.

Reducing or replacing sodium nitrite without compromising the sensory attributes of meat products has always been a focus of the meat industry. In this study, five treatments, CT (without nitrite and plasma treatment), NT (with nitrite treatment), PT15, PT30, and PT45 (without nitrite and with plasma treatment for 15, 30, and 45 min, respectively), were designed to investigate the effect of atmospheric nonthermal plasma treatment replacing nitrite on the sensory attributes of roasted lamb. Results showed that PT45 decreased the residual nitrite of roasted lamb by 30% compared with NT, and nitrite was not detected in the PT15 and PT30 samples. The inhibition effect of plasma treatment on the lipid oxidation reached values from 86.69% to 89.89% compared with NT. Compared with CT, the redness of plasma-treated samples was increased by 9.30% to 31.40%, and the redness of NT samples was increased by 30.87%. In addition, the volatile compounds (OAVs > 1) of the PT30 sample were higher than those of the NT sample. The overall sensory score of the PT30 sample was higher than that of the CT sample and was similar to that of the NT samples. In conclusion, the sensory attributes of roasted lamb were enhanced by plasma treatment, and the 30 min plasma treatment is recommended.

Liver disease has become one of the serious health problems as it is exposed to many kinds of xenobiotics and therapeutic agents. Moreover the rapidly growing morbidity and mortality from liver disease are attributable to the increasing number of chemical compounds and environmental pollution. Unfortunately, so far, in the modern era of medicine there is no specific treatment to counter the menacing impact of these dreaded diseases. Many polyherbal formulations are used widely to treat these disorders. Livactine is a polyherbal formulation and is claimed to be useful in jaundice and biliary dysfunctions. Most of these formulations do not have standard and approved reports stating their pharmacological action or therapeutic efficacy. Therefore, there is a need for experimental confirmation of the pharmacological effects of this formulation. The rationale behind the selection of carbon tetrachloride is due to its free radical mechanism based liver injury, and paracetamol is consumed widely by the human population and it is also a potential liver hazard.