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22 pages, 5372 KiB

Open AccessArticle

Arterial Hypertension and Plasma Glucose Modulate the Vasoactive Effects of Nitroso-Sulfide Coupled Signaling in Human Intrarenal Arteries

by Sona Cacanyiova, Katarina Krskova, Stefan Zorad, Karel Frimmel, Magdalena Drobna, Zuzana Valaskova, Anton Misak, Samuel Golas, Jan Breza, Jan Breza, Jr. and Andrea Berenyiova

Molecules 2020, 25(12), 2886; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25122886 - 23 Jun 2020

Cited by 8 | Viewed by 2108

Abstract

We have investigated the vasoactive effects of the coupled nitro-sulfide signaling pathway in lobar arteries (LAs) isolated from the nephrectomized kidneys of cancer patients: normotensive patients (NT) and patients with arterial hypertension (AH). LAs of patients with AH revealed endothelial dysfunction, which was [...] Read more.

We have investigated the vasoactive effects of the coupled nitro-sulfide signaling pathway in lobar arteries (LAs) isolated from the nephrectomized kidneys of cancer patients: normotensive patients (NT) and patients with arterial hypertension (AH). LAs of patients with AH revealed endothelial dysfunction, which was associated with an increased response to the exogenous NO donor, nitrosoglutathione (GSNO). The interaction of GSNO with the H₂S donor triggered a specific vasoactive response. Unlike in normotensive patients, in patients with AH, the starting and returning of the vasorelaxation induced by the end-products of the H₂S-GSNO interaction (S/GSNO) was significantly faster, however, without the potentiation of the maximum. Moreover, increasing glycemia shortened the time required to reach 50% of the maximum vasorelaxant response induced by S/GSNO products so modulating their final effect. Moreover, we found out that, unlike K+ channel activation, cGMP pathway and HNO as probable mediator could be involved in mechanisms of S/GSNO action. For the first time, we demonstrated the expression of genes coding H₂S-producing enzymes in perivascular adipose tissue and we showed the localization of these enzymes in LAs of normotensive patients and in patients with AH. Our study confirmed that the heterogeneity of specific nitroso-sulfide vasoactive signaling exists depending on the occurrence of hypertension associated with increased plasma glucose level. Endogenous H₂S and the end-products of the H₂S-GSNO interaction could represent prospective pharmacological targets to modulate the vasoactive properties of human intrarenal arteries. Full article

(This article belongs to the Special Issue Sulfur Compounds and Human Health)

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12 pages, 2701 KiB

Open AccessArticle

Sulfur Compounds as Inhibitors of Enzymatic Activity of a Snake Venom Phospholipase A₂: Benzyl 4-nitrobenzenecarbodithioate as a Case of Study

by Isabel Henao Castañeda, Jaime Andrés Pereañez, Lina María Preciado and Jorge Jios

Molecules 2020, 25(6), 1373; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25061373 - 18 Mar 2020

Cited by 3 | Viewed by 2189

Abstract

Snakebite is a neglected disease with a high impact in tropical and subtropical countries. Therapy based on antivenom has limited efficacy in local tissue damage caused by venoms. Phospholipases A₂ (PLA₂) are enzymes that abundantly occur in snake venoms and [...] Read more.

Snakebite is a neglected disease with a high impact in tropical and subtropical countries. Therapy based on antivenom has limited efficacy in local tissue damage caused by venoms. Phospholipases A₂ (PLA₂) are enzymes that abundantly occur in snake venoms and induce several systemic and local effects. Furthermore, sulfur compounds such as thioesters have an inhibitory capacity against a snake venom PLA₂. Hence, the objective of this work was to obtain a carbodithioate from a thioester with known activity against PLA₂ and test its ability to inhibit the same enzyme. Benzyl 4-nitrobenzenecarbodithioate (I) was synthesized, purified, and characterized using as precursor 4-nitrothiobenzoic acid S-benzyl ester (II). Compound I showed inhibition of the enzymatic activity a PLA₂ isolated from the venom of the Colombian rattlesnake Crotalus durissus cumanensis with an IC₅₀ of 55.58 μM. This result is comparable with the reported inhibition obtained for II. Computational calculations were performed to support the study, and molecular docking results suggested that compounds I and II interact with the active site residues of the enzyme, impeding the normal catalysis cycle and attachment of the substrate to the active site of the PLA₂. Full article

(This article belongs to the Special Issue Sulfur Compounds and Human Health)

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14 pages, 3225 KiB

Open AccessFeature PaperArticle

Effects of Manganese Porphyrins on Cellular Sulfur Metabolism

by Kenneth R. Olson, Yan Gao, Andrea K. Steiger, Michael D. Pluth, Charles R. Tessier, Troy A. Markel, David Boone, Robert V. Stahelin, Ines Batinic-Haberle and Karl D. Straubg

Molecules 2020, 25(4), 980; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25040980 - 22 Feb 2020

Cited by 8 | Viewed by 3015

Abstract

Manganese porphyrins (MnPs), MnTE-2-PyP⁵⁺, MnTnHex-2-PyP⁵⁺ and MnTnBuOE-2-PyP⁵⁺, are superoxide dismutase (SOD) mimetics and form a redox cycle between O₂ and reductants, including ascorbic acid, ultimately producing hydrogen peroxide (H₂O₂). We previously found that [...] Read more.

Manganese porphyrins (MnPs), MnTE-2-PyP⁵⁺, MnTnHex-2-PyP⁵⁺ and MnTnBuOE-2-PyP⁵⁺, are superoxide dismutase (SOD) mimetics and form a redox cycle between O₂ and reductants, including ascorbic acid, ultimately producing hydrogen peroxide (H₂O₂). We previously found that MnPs oxidize hydrogen sulfide (H₂S) to polysulfides (PS; H₂S_n, n = 2–6) in buffer. Here, we examine the effects of MnPs for 24 h on H₂S metabolism and PS production in HEK293, A549, HT29 and bone marrow derived stem cells (BMDSC) using H₂S (AzMC, MeRho-AZ) and PS (SSP4) fluorophores. All MnPs decreased intracellular H₂S production and increased intracellular PS. H₂S metabolism and PS production were unaffected by cellular O₂ (5% versus 21% O₂), H₂O₂ or ascorbic acid. We observed with confocal microscopy that mitochondria are a major site of H₂S production in HEK293 cells and that MnPs decrease mitochondrial H₂S production and increase PS in what appeared to be nucleoli and cytosolic fibrillary elements. This supports a role for MnPs in the metabolism of H₂S to PS, the latter serving as both short- and long-term antioxidants, and suggests that some of the biological effects of MnPs may be attributable to sulfur metabolism. Full article

(This article belongs to the Special Issue Sulfur Compounds and Human Health)

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14 pages, 1724 KiB

Open AccessArticle

Higher Levels of Low Molecular Weight Sulfur Compounds and Homocysteine Thiolactone in the Urine of Autistic Children

by Paulina Gątarek, Angelina Rosiak, Kamila Borowczyk, Rafał Głowacki and Joanna Kałużna-Czaplińska

Molecules 2020, 25(4), 973; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25040973 - 21 Feb 2020

Cited by 7 | Viewed by 2583

Abstract

In this study, the levels of concentration of homocysteine thiolactone (HTL), cysteine (Cys), and cysteinylglycine (CysGly) in the urine of autistic and non-autistic children were investigated and compared. HTL has never been analyzed in autistic children. The levels of low molecular weight sulfur [...] Read more.

In this study, the levels of concentration of homocysteine thiolactone (HTL), cysteine (Cys), and cysteinylglycine (CysGly) in the urine of autistic and non-autistic children were investigated and compared. HTL has never been analyzed in autistic children. The levels of low molecular weight sulfur compounds in the urine of both groups were determined by validated methods based on high-performance liquid chromatography with spectrofluorometric and diode-array detectors. The statistical data show a significant difference between the examined groups. Children with autism were characterized by a significantly higher level of HTL (p = 5.86 × 10⁻⁸), Cys (p = 1.49 × 10⁻¹⁰) and CysGly (p = 1.06 × 10⁻⁸) in urine compared with the control group. A difference in the p-value of <0.05 is statistically significant. Higher levels of HTL, Cys, and CysGly in the urine of 41 children with autism, aged 3 to 17, were observed. The obtained results may indicate disturbances in the metabolism of methionine, Cys, and glutathione in some autistic patients. These preliminary results suggest that further research with more rigorous designs and a large number of subjects is needed. Full article

(This article belongs to the Special Issue Sulfur Compounds and Human Health)

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9 pages, 3355 KiB

Open AccessArticle

Modulation of Allicin-Free Garlic on Gut Microbiome

by Keyu Chen, Yasushi Nakasone, Kun Xie, Kozue Sakao and De-Xing Hou

Molecules 2020, 25(3), 682; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25030682 - 05 Feb 2020

Cited by 14 | Viewed by 4038

Abstract

The allicin diallyldisulfid-S-oxide, a major garlic organosulfur compound (OSC) in crushed garlic (Allium sativum L.), possesses antibacterial effects, and influences gut bacteria. In this study, we made allicin-free garlic (AFG) extract and investigated its effects on gut microbiome. C57BL/6N male [...] Read more.

The allicin diallyldisulfid-S-oxide, a major garlic organosulfur compound (OSC) in crushed garlic (Allium sativum L.), possesses antibacterial effects, and influences gut bacteria. In this study, we made allicin-free garlic (AFG) extract and investigated its effects on gut microbiome. C57BL/6N male mice were randomly divided into 6 groups and fed normal diet (ND) and high-fat diet (HFD) supplemented with or without AFG in concentrations of 1% and 5% for 11 weeks. The genomic DNAs of feces were used to identify the gut microbiome by sequencing 16S rRNA genes. The results revealed that the ratio of p-Firmicutes to p-Bacteroidetes increased by aging and HFD was reduced by AFG. In particular, the f-Lachnospiraceae, g-Akkermansia, and g-Lactobacillus decreased by aging and HFD was enhanced by AFG. The g-Dorea increased by aging and HFD decreased by AFG. In addition, the ratio of glutamic-pyruvic transaminase to glutamic-oxaloacetic transaminase (GPT/GOT) in serum was significantly increased in the HFD group and decreased by AFG. In summary, our data demonstrated that dietary intervention with AFG is a potential way to balance the gut microbiome disturbed by a high-fat diet. Full article

(This article belongs to the Special Issue Sulfur Compounds and Human Health)

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27 pages, 2446 KiB

Open AccessArticle

Glutathione Deficiency and Alterations in the Sulfur Amino Acid Homeostasis during Early Postnatal Development as Potential Triggering Factors for Schizophrenia-Like Behavior in Adult Rats

by Magdalena Górny, Agnieszka Wnuk, Adrianna Kamińska, Kinga Kamińska, Grażyna Chwatko, Anna Bilska-Wilkosz, Małgorzata Iciek, Małgorzata Kajta, Zofia Rogóż and Elżbieta Lorenc-Koci

Molecules 2019, 24(23), 4253; https://doi.org/10.3390/molecules24234253 - 22 Nov 2019

Cited by 16 | Viewed by 3519

Abstract

Impaired glutathione (GSH) synthesis and dopaminergic transmission are important factors in the pathophysiology of schizophrenia. Our research aimed to assess the effects of l-buthionine-(S,R)-sulfoximine (BSO), a GSH synthesis inhibitor, and GBR 12909, a dopamine reuptake inhibitor, administered alone [...] Read more.

Impaired glutathione (GSH) synthesis and dopaminergic transmission are important factors in the pathophysiology of schizophrenia. Our research aimed to assess the effects of l-buthionine-(S,R)-sulfoximine (BSO), a GSH synthesis inhibitor, and GBR 12909, a dopamine reuptake inhibitor, administered alone or in combination, to Sprague–Dawley rats during early postnatal development (p5–p16), on the levels of GSH, sulfur amino acids, global DNA methylation, and schizophrenia-like behavior. GSH, methionine (Met), homocysteine (Hcy), and cysteine (Cys) contents were determined in the liver, kidney, and in the prefrontal cortex (PFC) and hippocampus (HIP) of 16-day-old rats. DNA methylation in the PFC and HIP and schizophrenia-like behavior were assessed in adulthood (p90–p93). BSO caused the tissue-dependent decreases in GSH content and alterations in Met, Hcy, and Cys levels in the peripheral tissues and in the PFC and HIP. The changes in these parameters were accompanied by alterations in the global DNA methylation in the studied brain structures. Parallel to changes in the global DNA methylation, deficits in the social behaviors and cognitive functions were observed in adulthood. Only BSO + GBR 12909-treated rats exhibited behavioral alterations resembling positive symptoms in schizophrenia patients. Our results suggest the usefulness of this neurodevelopmental model for research on the pathomechanism of schizophrenia. Full article

(This article belongs to the Special Issue Sulfur Compounds and Human Health)

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Review

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17 pages, 2428 KiB

Open AccessFeature PaperReview

An Appraisal of Developments in Allium Sulfur Chemistry: Expanding the Pharmacopeia of Garlic

by Peter Rose, Philip Keith Moore, Matthew Whiteman and Yi-Zhun Zhu

Molecules 2019, 24(21), 4006; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24214006 - 05 Nov 2019

Cited by 22 | Viewed by 4502

Abstract

Alliums and allied plant species are rich sources of sulfur compounds that have effects on vascular homeostasis and the control of metabolic systems linked to nutrient metabolism in mammals. In view of the multiple biological effects ascribed to these sulfur molecules, researchers are [...] Read more.

Alliums and allied plant species are rich sources of sulfur compounds that have effects on vascular homeostasis and the control of metabolic systems linked to nutrient metabolism in mammals. In view of the multiple biological effects ascribed to these sulfur molecules, researchers are now using these compounds as inspiration for the synthesis and development of novel sulfur-based therapeutics. This research has led to the chemical synthesis and biological assessment of a diverse array of sulfur compounds representative of derivatives of S-alkenyl-l-cysteine sulfoxides, thiosulfinates, ajoene molecules, sulfides, and S-allylcysteine. Many of these synthetic derivatives have potent antimicrobial and anticancer properties when tested in preclinical models of disease. Therefore, the current review provides an overview of advances in the development and biological assessment of synthetic analogs of allium-derived sulfur compounds. Full article

(This article belongs to the Special Issue Sulfur Compounds and Human Health)

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27 pages, 17890 KiB

Open AccessReview

Hydrogen Sulfide: Recent Progression and Perspectives for the Treatment of Diabetic Nephropathy

by Hai-Jian Sun, Zhi-Yuan Wu, Lei Cao, Meng-Yuan Zhu, Teng-Teng Liu, Lei Guo, Ye Lin, Xiao-Wei Nie and Jin-Song Bian

Molecules 2019, 24(15), 2857; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24152857 - 06 Aug 2019

Cited by 68 | Viewed by 15074

Abstract

Diabetic kidney disease develops in approximately 40% of diabetic patients and is a major cause of chronic kidney diseases (CKD) and end stage kidney disease (ESKD) worldwide. Hydrogen sulfide (H₂S), the third gasotransmitter after nitric oxide (NO) and carbon monoxide (CO), [...] Read more.

Diabetic kidney disease develops in approximately 40% of diabetic patients and is a major cause of chronic kidney diseases (CKD) and end stage kidney disease (ESKD) worldwide. Hydrogen sulfide (H₂S), the third gasotransmitter after nitric oxide (NO) and carbon monoxide (CO), is synthesized in nearly all organs, including the kidney. Though studies on H₂S regulation of renal physiology and pathophysiology are still in its infancy, emerging evidence shows that H₂S production by renal cells is reduced under disease states and H₂S donors ameliorate kidney injury. Specifically, aberrant H₂S level is implicated in various renal pathological conditions including diabetic nephropathy. This review presents the roles of H₂S in diabetic renal disease and the underlying mechanisms for the protective effects of H₂S against diabetic renal damage. H₂S may serve as fundamental strategies to treat diabetic kidney disease. These H₂S treatment modalities include precursors for H₂S synthesis, H₂S donors, and natural plant-derived compounds. Despite accumulating evidence from experimental studies suggests the potential role of the H₂S signaling pathway in the treatment of diabetic nephropathy, these results need further clinical translation. Expanding understanding of H₂S in the kidney may be vital to translate H₂S to be a novel therapy for diabetic renal disease. Full article

(This article belongs to the Special Issue Sulfur Compounds and Human Health)

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