RESUMO
The efficiency of combinations of cytostatics cisplatin and adriamycin with antioxidant sodium 3-(3'-tert-butyl-4-hydroxyphenyl)propyl thiosulfate (TS-13), and nitric oxide (NO) donor NaNO2 was evaluated on two drug-resistant strains of leukemia P388 with changed redox-status of cells. Simultaneous use of both NO donor and TS-13 in combinations with the cytostatics did not increase the efficiency of therapy. In addition, antioxidant activity of TS-13, NaNO2, and their combinations was studied by the method of luminol-dependent chemiluminescence on the model systems with the use of the homogenized cells of sensitive strain and two drug-resistant strains of leukemia P388. It was shown that TS-13 and NO donor produced opposite effects: TS-13 decreased, while NO donor increased the content of free radicals in the model system. Combinations of antioxidant TS-13 and NO donor should be used with consideration for the redox-status of tumor treated.
Assuntos
Antioxidantes , Cisplatino , Doxorrubicina , Resistencia a Medicamentos Antineoplásicos , Leucemia P388 , Doadores de Óxido Nítrico , Oxirredução , Animais , Camundongos , Oxirredução/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Antioxidantes/farmacologia , Doxorrubicina/farmacologia , Leucemia P388/tratamento farmacológico , Leucemia P388/patologia , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Doadores de Óxido Nítrico/farmacologia , Tiossulfatos/farmacologia , Nitrito de Sódio/farmacologia , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologiaRESUMO
Nitrosyl iron complexes are remarkably multifactorial pharmacological agents. These compounds have been proven to be particularly effective in treating cardiovascular and oncological diseases. We evaluated and compared the antioxidant activity of tetranitrosyl iron complexes (TNICs) with thiosulfate ligands and dinitrosyl iron complexes (DNICs) with glutathione (DNIC-GS) or phosphate (DNIC-PO4-) ligands in hemoglobin-containing systems. The studied effects included the production of free radical intermediates during hemoglobin (Hb) oxidation by tert-butyl hydroperoxide, oxidative modification of Hb, and antioxidant properties of nitrosyl iron complexes. Measuring luminol chemiluminescence revealed that the antioxidant effect of TNICs was higher compared to DNIC-PO4-. DNIC-GS either did not exhibit antioxidant activity or exerted prooxidant effects at certain concentrations, which might have resulted from thiyl radical formation. TNICs and DNIC-PO4- efficiently protected the Hb heme group from decomposition by organic hydroperoxides. DNIC-GS did not exert any protective effects on the heme group; however, it abolished oxoferrylHb generation. TNICs inhibited the formation of Hb multimeric forms more efficiently than DNICs. Thus, TNICs had more pronounced antioxidant activity than DNICs in Hb-containing systems.
Assuntos
Antioxidantes , Hemoglobinas , Ferro , Fosfatos , Tiossulfatos , Tiossulfatos/farmacologia , Tiossulfatos/química , Hemoglobinas/metabolismo , Hemoglobinas/química , Ferro/metabolismo , Ferro/química , Fosfatos/química , Fosfatos/metabolismo , Ligantes , Antioxidantes/farmacologia , Compostos de Sulfidrila/química , Compostos de Sulfidrila/metabolismo , Oxirredução/efeitos dos fármacos , Óxidos de Nitrogênio/química , Óxidos de Nitrogênio/farmacologia , Óxidos de Nitrogênio/metabolismo , Glutationa/metabolismo , AnimaisRESUMO
Genetically heterogeneous UM-HET3 mice born in 2020 were used to test possible lifespan effects of alpha-ketoglutarate (AKG), 2,4-dinitrophenol (DNP), hydralazine (HYD), nebivolol (NEBI), 16α-hydroxyestriol (OH_Est), and sodium thiosulfate (THIO), and to evaluate the effects of canagliflozin (Cana) when started at 16 months of age. OH_Est produced a 15% increase (p = 0.0001) in median lifespan in males but led to a significant (7%) decline in female lifespan. Cana, started at 16 months, also led to a significant increase (14%, p = 0.004) in males and a significant decline (6%, p = 0.03) in females. Cana given to mice at 6 months led, as in our previous study, to an increase in male lifespan without any change in female lifespan, suggesting that this agent may lead to female-specific late-life harm. We found that blood levels of Cana were approximately 20-fold higher in aged females than in young males, suggesting a possible mechanism for the sex-specific disparities in its effects. NEBI was also found to produce a female-specific decline (4%, p = 0.03) in lifespan. None of the other tested drugs provided a lifespan benefit in either sex. These data bring to 7 the list of ITP-tested drugs that induce at least a 10% lifespan increase in one or both sexes, add a fourth drug with demonstrated mid-life benefits on lifespan, and provide a testable hypothesis that might explain the sexual dimorphism in lifespan effects of the SGLT2 inhibitor Cana.
Assuntos
Canagliflozina , Longevidade , Tiossulfatos , Animais , Canagliflozina/farmacologia , Masculino , Feminino , Tiossulfatos/farmacologia , Longevidade/efeitos dos fármacos , Camundongos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Fatores SexuaisRESUMO
Sulfur-driven autotrophic denitrification (SdAD) is a promising nitrogen removing process, but its applications were generally constrained by conventional electron donors (i.e., thiosulfate (Na2S2O3)) with high valence and limited bioavailability. Herein, an immobilized electron donor by loading elemental sulfur on the surface of polyurethane foam (PFSF) was developed, and its feasibility for SdAD was investigated. The denitrification efficiency of PFSF was 97.3%, higher than that of Na2S2O3 (91.1%). Functional microorganisms (i.e., Thiobacillus and Sulfurimonas) and their metabolic activities (i.e., nir and nor) were substantially enhanced by PFSF. PFSF resulted in the enrichment of sulfate-reducing bacteria, which can reduce sulfate (SO42-). It attenuated the inhibitory effect of SO42-, whereas the generated product (hydrogen sulfide) also served as an electron donor for SdAD. According to the economic evaluation, PFSF exhibited strong market potential. This study proposes an efficient and low-cost immobilized electron donor for SdAD and provides theoretical support to its practical applications.
Assuntos
Processos Autotróficos , Desnitrificação , Nitrogênio , Enxofre , Enxofre/metabolismo , Enxofre/química , Elétrons , Thiobacillus/metabolismo , Poliuretanos/química , Sulfatos/metabolismo , Bactérias/metabolismo , Tiossulfatos/química , Tiossulfatos/farmacologiaRESUMO
To evaluate the effect of calcium hydroxide (CH), sodium ascorbate (SA) and sodium thiosulfate (ST) filling the pulp chamber on color stability and longevity of teeth after internal bleaching. Crowns of bovine incisors were submitted to internal bleaching and divided into groups according the material used in the pulp chamber: Control, CH, SA, ST. Each group was divided into two subgroups according to the time to perform restorative procedures (7 or 15 days). Color measurement was performed with a spectrophotometer at nine periods. The darkening (ΔE) values were calculated. The Mann-Whitney test was used to statistically analyze the data (p ⟨ 0.05). After bleaching, ΔE values were higher than 3.5, showing that the procedure was effective. After 24 hours, no difference was observed between groups. After 7 days, SA showed higher ΔE than the control group (p ⟨ 0.05). CH and TS did not differ from the control group. In restorations performed after 7/15 days, SA group showed higher values of darkening after 1 and 4 months than the control group (p ⟨ 0.05). SA induced perceptible darkening after bleaching and should not be used to fill the pulp chamber. ST and CH show color stability and longevity after 12 months.
Assuntos
Antioxidantes , Hidróxido de Cálcio , Cavidade Pulpar , Clareadores Dentários , Clareamento Dental , Animais , Bovinos , Antioxidantes/farmacologia , Clareadores Dentários/farmacologia , Espectrofotometria , Ácido Ascórbico/farmacologia , Tiossulfatos/farmacologia , Descoloração de Dente , CorRESUMO
Ethylmalonic encephalopathy (EE) is a severe inherited metabolic disorder that causes tissue accumulation of hydrogen sulfide (sulfide) and thiosulfate in patients. Although symptoms are predominantly neurological, chronic hemorrhagic diarrhea associated with intestinal mucosa abnormalities is also commonly observed. Considering that the pathophysiology of intestinal alterations in EE is virtually unknown and that sulfide and thiosulfate are highly reactive molecules, the effects of these metabolites were investigated on bioenergetic production and transfer in the intestine of rats. We observed that sulfide reduced NADH- and FADH2-linked mitochondrial respiration in the intestine, which was avoided by reduced glutathione (GSH) but not by melatonin. Thiosulfate did not change respiration. Moreover, both metabolites markedly reduced the activity of total, cytosolic and mitochondrial isoforms of creatine kinase (CK) in rat intestine. Noteworthy, the addition of GSH but not melatonin, apocynin, and Trolox (hydrosoluble vitamin E) prevented the change in the activities of total CK and its isoforms caused by sulfide and thiosulfate, suggesting a direct protein modification on CK structure by these metabolites. Sulfide further increased thiol content in the intestine, suggesting a modulation in the redox state of these groups. Finally, sulfide and thiosulfate decreased the viability of Caco-2 intestinal cells. Our data suggest that bioenergetic impairment caused by sulfide and thiosulfate is a mechanism involved in the gastrointestinal abnormalities found in EE.
Assuntos
Sulfeto de Hidrogênio , Humanos , Ratos , Animais , Ratos Wistar , Tiossulfatos/farmacologia , Células CACO-2 , Metabolismo Energético , Sulfetos , Intestinos , Diarreia , Isoformas de Proteínas/metabolismoRESUMO
OBJECTIVE: To investigate the effect of sodium thiosulfate (STS) on serum calcification factors in patients undergoing maintenance hemodialysis. METHODS: Forty-four Patients were randomly divided into control group (n = 22) and observation group (n = 22) by envelope method (block 4 randomization). The control group received routine treatment while observation group was treated with STS on the basis of routine treatment. The biochemical indicators, including BUN, UA, SCr, Ca2+ , P3- , calcium-phosphorus product, PTH, hs-CRP, TG, TC, HDL, LDL, and serum calcification factor MGP, FA, FGF-23, and OPG levels were compared before and after treatment. RESULTS: Control group had no statistically significant difference in the levels of vascular calcification factors MGP, FA, FGF-23, and OPG before and after treatment (p > 0.05). Whereas observation group had higher levels of MGP and FA, and lower levels of FGF-23 and OPG after treatment than before treatment (p < 0.05). The levels of MGP and FA in observation group were higher than those in control group, and FGF-23 and OPG were lower than those in control group (p < 0.05). CONCLUSION: It is speculated that sodium thiosulfate can alleviate the progression of vascular calcification by changing the levels of calcification factors.
Assuntos
Diálise Renal , Calcificação Vascular , Humanos , Diálise Renal/métodos , Tiossulfatos/farmacologia , Tiossulfatos/uso terapêutico , Calcificação Vascular/etiologia , Proteína C-ReativaRESUMO
1,4-Napththoquinones (NQs) are clinically relevant therapeutics that affect cell function through production of reactive oxygen species (ROS) and formation of adducts with regulatory protein thiols. Reactive sulfur species (RSS) are chemically and biologically similar to ROS and here we examine RSS production by NQ oxidation of hydrogen sulfide (H2S) using RSS-specific fluorophores, liquid chromatography-mass spectrometry, UV-Vis absorption spectrometry, oxygen-sensitive optodes, thiosulfate-specific nanoparticles, HPLC-monobromobimane derivatization, and ion chromatographic assays. We show that NQs, catalytically oxidize H2S to per- and polysulfides (H2Sn, n = 2−6), thiosulfate, sulfite and sulfate in reactions that consume oxygen and are accelerated by superoxide dismutase (SOD) and inhibited by catalase. The approximate efficacy of NQs (in decreasing order) is, 1,4-NQ ≈ juglone ≈ plumbagin > 2-methoxy-1,4-NQ ≈ menadione >> phylloquinone ≈ anthraquinone ≈ menaquinone ≈ lawsone. We propose that the most probable reactions are an initial two-electron oxidation of H2S to S0 and reduction of NQ to NQH2. S0 may react with H2S or elongate H2Sn in variety of reactions. Reoxidation of NQH2 likely involves a semiquinone radical (NQ·−) intermediate via several mechanisms involving oxygen and comproportionation to produce NQ and superoxide. Dismutation of the latter forms hydrogen peroxide which then further oxidizes RSS to sulfoxides. These findings provide the chemical background for novel sulfur-based approaches to naphthoquinone-directed therapies.
Assuntos
Sulfeto de Hidrogênio , Naftoquinonas , Tiossulfatos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Oxirredução , Naftoquinonas/farmacologia , Naftoquinonas/metabolismo , Sulfeto de Hidrogênio/metabolismo , Enxofre/metabolismo , Oxigênio/metabolismoRESUMO
There are some limitations in date palm micropropagation. These include low multiplication efficiency, low rooting rate, and high mortality experienced by in vitro raised plantlets during laboratory to soil transfer. The objective of the study was to determine the effect of the polyamines and Silver Thiosulphate (STS) on the enhancement of shoot multiplication and genetic stability of in vitro cultures of date palm cultivar Quntar. Media supplemented with 75 mg L-1 SPD in combination with 10 mg L-1 STS gave the highest percentage of callus producing buds (83.34%) and average bud formation (16.3) per jar. The addition of PUT and STS to the medium was most effective on root formation and the number of roots per shoot, where the best result, 91.67% and 6.37 roots per shoot, respectively, were obtained using 75 mg L-1 PUT and 10 mg L-1 STS, resulting in fast-growing plantlets during acclimatization phase, reaching 80% of plant survival. The genetic fidelity assessment of plants derived from micropropagation was confirmed by RAPD analysis. Four operon primers were used, and all of them showed amplified unambiguous (OPA02, OPC-04, OPD-07, and OPE-15). All generated bands were monomorphic and had no variation among the tissue culture-derived plants tested. Accordingly, these results indicate that adding polyamines and silver thiosulfate to the nutrient medium of date palm cv. Quntar was beneficial to improving shoot organogenesis, rooting, and production of genetically stable date palm plants.
Assuntos
Phoeniceae , Meios de Cultura/farmacologia , Poliaminas/farmacologia , Técnica de Amplificação ao Acaso de DNA Polimórfico/métodos , Tiossulfatos/farmacologiaRESUMO
Ever since the discovery of endogenous H2S and the identification of its cytoprotective properties, efforts have been made to develop strategies to use H2S as a therapeutic agent. The ability of H2S to regulate vascular tone, inflammation, oxidative stress, and apoptosis might be particularly useful in the therapeutic management of critical illness. However, neither the inhalation of gaseous H2S, nor the administration of inorganic H2S-releasing salts or slow-releasing H2S-donors are feasible for clinical use. Na2S2O3 is a clinically approved compound with a good safety profile and is able to release H2S, in particular under hypoxic conditions. Pre-clinical studies show promise for Na2S2O3 in the acute management of critical illness. A current clinical trial is investigating the therapeutic potential for Na2S2O3 in myocardial infarct. Pre-eclampsia and COVID-19 pneumonia might be relevant targets for future clinical trials.
Assuntos
Tratamento Farmacológico da COVID-19 , Sulfeto de Hidrogênio , Estado Terminal , Humanos , Sulfeto de Hidrogênio/uso terapêutico , Tiossulfatos/farmacologia , Tiossulfatos/uso terapêuticoRESUMO
INTRODUCTION: Cold ischemia-reperfusion injury (IRI) is an inevitable event that increases post-transplant complications. We have previously demonstrated that supplementation of University of Wisconsin (UW) solution with non-FDA-approved hydrogen sulfide (H2S) donor molecules minimizes cold IRI and improves renal graft function after transplantation. The present study investigates whether an FDA-approved H2S donor molecule, sodium thiosulfate (STS), will have the same or superior effect in a clinically relevant rat model of syngeneic orthotopic kidney transplantation. METHOD: Thirty Lewis rats underwent bilateral nephrectomy followed by syngeneic orthotopic transplantation of the left kidney after 24-hour preservation in either UW or UW+STS solution at 4 °C. Rats were monitored to post-transplant day 14 and sacrificed to assess renal function (urine output, serum creatinine and blood urea nitrogen). Kidney sections were stained with H&E, TUNEL, CD68, and myeloperoxidase (MPO) to detect acute tubular necrosis (ATN), apoptosis, macrophage infiltration, and neutrophil infiltration. RESULT: UW+STS grafts showed significantly improved graft function immediately after transplantation, with improved recipient survival compared to UW grafts (p < 0.05). Histopathological examination revealed significantly reduced ATN, apoptosis, macrophage and neutrophil infiltration and downregulation of pro-inflammatory and pro-apoptotic genes in UW+STS grafts compared to UW grafts (p < 0.05). CONCLUSION: We show for the first time that preservation of renal grafts in STS-supplemented UW solution protects against prolonged cold IRI by suppressing apoptotic and inflammatory pathways, and thereby improving graft function and prolonging recipient survival. This could represent a novel clinically applicable therapeutic strategy to minimize the detrimental clinical outcome of prolonged cold IRI in kidney transplantation.
Assuntos
Transplante de Rim/métodos , Soluções para Preservação de Órgãos/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Tiossulfatos/farmacologia , Adenosina/administração & dosagem , Adenosina/farmacologia , Alopurinol/administração & dosagem , Alopurinol/farmacologia , Animais , Apoptose/fisiologia , Nitrogênio da Ureia Sanguínea , Isquemia Fria/efeitos adversos , Creatinina/sangue , Glutationa/administração & dosagem , Glutationa/farmacologia , Insulina/administração & dosagem , Insulina/farmacologia , Testes de Função Renal , Masculino , Soluções para Preservação de Órgãos/administração & dosagem , Rafinose/administração & dosagem , Rafinose/farmacologia , Ratos , Ratos Endogâmicos Lew , Taxa de Sobrevida , Tiossulfatos/administração & dosagemRESUMO
BACKGROUND: Sodium thiosulfate (Na2S2O3) is a clinically established drug with antioxidant and sulphide-releasing properties. Na2S2O3 mediated neuro- and cardioprotective effects in ischemia/reperfusion models and anti-inflammatory effects in LPS-induced acute lung injury. Moreover, Na2S2O3 improved lung function during resuscitation from hemorrhagic shock in swine with pre-existing atherosclerosis, characterized by decreased expression of cystathionine γ-lyase (CSE), a major source of hydrogen sulfide (H2S) synthesis in the vasculature. Based on these findings, we investigated the effects of Na2S2O3 administration during resuscitation from trauma-and-hemorrhage in mice under conditions of whole body CSE deficit. METHODS: After blast wave-induced blunt chest trauma and surgical instrumentation, CSE knockout (CSE-/-) mice underwent 1 h of hemorrhagic shock (MAP 35â±â5 mm Hg). At the beginning of resuscitation comprising retransfusion, norepinephrine support and lung-protective mechanical ventilation, animals received either i.v. Na2S2O3 (0.45âmgâg-1, nâ=â12) or vehicle (saline, nâ=â13). Hemodynamics, acid-base status, metabolism using stable isotopes, and visceral organ function were assessed. Blood and organs were collected for analysis of cytokines, mitochondrial respiratory capacity, and immunoblotting. RESULTS: Na2S2O3 treatment improved arterial paO2 (Pâ=â0.03) coinciding with higher lung tissue glucocorticoid receptor expression. Norepinephrine requirements were lower in the Na2S2O3 group (Pâ<â0.05), which was associated with lower endogenous glucose production and higher urine output. Na2S2O3 significantly increased renal tissue IκBα and heme oxygenase-1 expression, whereas it lowered kidney IL-6 and MCP-1 levels. CONCLUSION: Na2S2O3 exerted beneficial effects during resuscitation of murine trauma-and-hemorrhage in CSE-/- mice, confirming and extending the previously described organ-protective and anti-inflammatory properties of Na2S2O3. The findings make Na2S2O3 a potentially promising therapeutic option in the context of impaired CSE activity and/or reduced endogenous H2S availability.
Assuntos
Antioxidantes/farmacologia , Ressuscitação , Tiossulfatos/farmacologia , Animais , Quimiocina CCL2/metabolismo , Cistationina gama-Liase/genética , Glucose/metabolismo , Heme Oxigenase-1/metabolismo , Interleucina-6/metabolismo , Rim/metabolismo , Pulmão/metabolismo , Camundongos Knockout , Inibidor de NF-kappaB alfa/metabolismo , Norepinefrina/administração & dosagem , Oxigênio/sangue , Receptores de Glucocorticoides/metabolismo , Choque Hemorrágico/terapia , Traumatismos Torácicos/terapia , Urina , Vasoconstritores/administração & dosagemRESUMO
Uremic pruritus is a distressful complication of chronic kidney disease and results in impaired quality of life and higher mortality rates. Intravenous sodium thiosulfate has been reported to alleviate pruritus in hemodialysis patients. We performed a systematic review and meta-analysis to estimate the efficacy of intravenous sodium thiosulfate in patients with uremic pruritus. A systematic search of electronic databases up to June 2021 was conducted for randomized controlled trials that evaluated the clinical effects of sodium thiosulfate in the management of patients with uremic pruritus. Two reviewers selected eligible articles and evaluated the risk of bias; the results of pruritus assessment and uremic pruritus-related laboratory parameters in selected studies were analyzed. There are four trials published between 2018 and 2021, which include 222 participants. The sodium thiosulfate group displayed significant decrease in the pruritus score (standardized mean difference = -3.52, 95% confidence interval = -5.63 to -1.41, p = 0.001), without a significant increase in the adverse effects (risk ratio = 2.44, 95% confidence interval = 0.37 to 15.99, p = 0.35) compared to the control group. Administration of sodium thiosulfate is found to be a safe and efficacious complementary therapy in improving uremic pruritus in patients with chronic kidney disease.
Assuntos
Antioxidantes/efeitos adversos , Prurido/tratamento farmacológico , Tiossulfatos/efeitos adversos , Uremia/tratamento farmacológico , Vasodilatadores/efeitos adversos , Antioxidantes/farmacologia , Humanos , Prurido/etiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Tiossulfatos/farmacologia , Uremia/complicações , Vasodilatadores/farmacologiaRESUMO
Nitric oxide (NO) mediates diverse physiological processes in living organisms. Small molecular NO donors usually lack stability and have a short half-life in human tissues, limiting the therapeutic application. The anionic tetranitrosyl iron complex with thiosulfate ligands (TNIC) is one of the most promising NO donors. This study shows that bovine serum albumin (BSA) can effectively stabilize the TNIC complex under aerobic (physiological) conditions, which contributes to its prolonged action as NO donor. Our results demonstrated that TNIC-BSA inhibits formation of TBARS - standard biomarker for the lipid peroxidation induced oxidative stress. Also, it was found that TNIC-BSA inhibits the catalytic activity of mitochondrial membrane-bound enzymes: cytochrome c oxidase and monoamine oxidase A. Together, these results demonstrate that, stabilization of TNIC with BSA opens up the possibility of its practical application in chemotherapy of socially significant diseases.
Assuntos
Ferro , Peroxidação de Lipídeos/efeitos dos fármacos , Mitocôndrias , Óxidos de Nitrogênio , Soroalbumina Bovina , Tiossulfatos , Animais , Encéfalo/citologia , Ferro/química , Ferro/farmacologia , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/enzimologia , Mitocôndrias/metabolismo , Monoaminoxidase/metabolismo , Óxidos de Nitrogênio/química , Óxidos de Nitrogênio/farmacologia , Soroalbumina Bovina/química , Soroalbumina Bovina/farmacologia , Tiossulfatos/química , Tiossulfatos/farmacologiaRESUMO
Introduction: In the immunology of sepsis microcirculatory and mitochondrial dysfunction in the gastrointestinal system are important contributors to mortality. Hydrogen sulfide (H2S) optimizes gastrointestinal oxygen supply and mitochondrial respiration predominantly via K(ATP)-channels. Therefore, we tested the hypothesis that sodium thiosulfate (STS), an inducer of endogenous H2S, improves intestinal and hepatic microcirculation and mitochondrial function via K(ATP)-channels in sepsis. Methods: In 40 male Wistar rats colon ascendens stent peritonitis (CASP) surgery was performed to establish sepsis. Animals were randomized into 4 groups (1: STS 1 g ⢠kg-1 i.p., 2: glibenclamide (GL) 5 mg ⢠kg-1 i.p., 3: STS + GL, 4: vehicle (VE) i.p.). Treatment was given directly after CASP-surgery and 24 hours later. Microcirculatory oxygenation (µHBO2) and flow (µflow) of the colon and the liver were continuously recorded over 90 min using tissue reflectance spectrophotometry. Mitochondrial oxygen consumption in tissue homogenates was determined with respirometry. Statistic: two-way ANOVA + Dunnett´s and Tukey post - hoc test (microcirculation) and Kruskal-Wallis test + Dunn's multiple comparison test (mitochondria). p < 0.05 was considered significant. Results: STS increased µHbO2 (colon: 90 min: + 10.4 ± 18.3%; liver: 90 min: + 5.8 ± 9.1%; p < 0.05 vs. baseline). Furthermore, STS ameliorated µflow (colon: 60 min: + 51.9 ± 71.1 aU; liver: 90 min: + 22.5 ± 20.0 aU; p < 0.05 vs. baseline). In both organs, µHbO2 and µflow were significantly higher after STS compared to VE. The combination of STS and GL increased colonic µHbO2 and µflow (µHbO2 90 min: + 8.7 ± 11.5%; µflow: 90 min: + 41.8 ± 63.3 aU; p < 0.05 vs. baseline), with significantly higher values compared to VE. Liver µHbO2 and µflow did not change after STS and GL. GL alone did not change colonic or hepatic µHbO2 or µflow. Mitochondrial oxygen consumption and macrohemodynamic remained unaltered. Conclusion: The beneficial effect of STS on intestinal and hepatic microcirculatory oxygenation in sepsis seems to be mediated by an increased microcirculatory perfusion and not by mitochondrial respiratory or macrohemodynamic changes. Furthermore, the effect of STS on hepatic but not on intestinal microcirculation seems to be K(ATP)-channel-dependent.
Assuntos
Colo/efeitos dos fármacos , Fígado/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Sepse , Tiossulfatos/farmacologia , Animais , Antioxidantes/farmacologia , Colo/irrigação sanguínea , Modelos Animais de Doenças , Fígado/irrigação sanguínea , Masculino , Microcirculação/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
BACKGROUND: Silver is a transition metal that is known to be less toxic than platinum. However, only few studies have reported the anticancer effects of some silver complexes and their possibility as an alternative to platinum complex. This study investigated the anticancer effects of the silver thiosulfate complex (STS), [Ag(S2O3)2]3-, consisting of silver and sodium thiosulfate. METHODS: In vitro cytotoxic activity of STS was investigated comparatively in human cancer cell lines (K562 and MCF-7) and normal human cells (mesenchymal stem cells and mammary epithelial cells). For its anticancer effects, cell cycle, mode of cell death, morphological changes, and accumulation of intracellular ROS and GSH were evaluated in MCF-7 to provide mechanistic insights. RESULTS: STS showed a concentration-dependent cytotoxicity in MCF-7 cell, which was abolished by pretreatment with N-acetylcysteine, suggesting ROS accumulation by STS. Moreover, STS caused cell cycle arrest at the G1 phase, decrease in the GSH levels, and morphological changes in MCF-7. Direct measurement of ROS demonstrated the elevation of intracellular ROS accumulation in cancer cells treated with STS; however, neither cytotoxicity nor ROS accumulation was observed in normal human cells. CONCLUSION: The results obtained here are the first evidence to show that STS exhibited an anticancer activity through ROS-induced mechanisms, and that its cytotoxicity is highly selective to cancer cells. The results of the present study warrant further investigation on the detailed mechanism of STS actions, as well as its in vivo effectiveness and safety for clinical application.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Morte Celular/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Prata/farmacologia , Tiossulfatos/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Fase G1/efeitos dos fármacos , Humanos , Células K562 , Células MCF-7RESUMO
Ethylene is a gaseous phytohormone involved in various physiological processes, including fruit ripening, senescence, root hair development and stress responses. Recent genomics studies have suggested that most homologous genes of ethylene biosynthesis and signaling are conserved from algae to angiosperms, whereas the function and biosynthesis of ethylene remain unknown in basal plants. Here, we examined the physiological effects of ethylene, an ethylene precursor, 1-aminocyclopropane-1-carboxylic acid (ACC) and an inhibitor of ethylene perception, silver thiosulfate (STS), in a basal land plant, Marchantia polymorpha. M. polymorpha plants biosynthesized ethylene, and treatment with high concentrations of ACC slightly promoted ethylene production. ACC remarkably suppressed the growth of thalli (vegetative organs) and rhizoids (root-hair-like cells), whereas exogenous ethylene slightly promoted thallus growth. STS suppressed thallus growth and induced ectopic rhizoid formation on the dorsal surface of thalli. Thus, ACC and ethylene have different effects on the vegetative growth of M. polymorpha. We generated single and double mutants of ACC synthase-like (ACSL) genes, MpACSL1 and MpACSL2. The mutants did not show obvious defects in thallus growth, ACC content and ethylene production, indicating that MpACSL genes are not essential for the vegetative growth and biosynthesis of ACC and ethylene. Gene expression analysis suggested the involvement of MpACSL1 and MpACSL2 in stress responses. Collectively, our results imply ethylene-independent function of ACC and the absence of ACC-mediated ethylene biosynthesis in M. polymorpha.
Assuntos
Aminoácidos Cíclicos/metabolismo , Etilenos/metabolismo , Marchantia/metabolismo , Aminoácidos Cíclicos/farmacologia , Etilenos/biossíntese , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Marchantia/efeitos dos fármacos , Marchantia/genética , Marchantia/crescimento & desenvolvimento , Mutação , Compostos Organofosforados/farmacologia , Reguladores de Crescimento de Plantas/farmacologia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Tiossulfatos/farmacologiaRESUMO
Nutraceutical polyphenol catechins in green tea oxidize H2S to polysulfides (PS) in buffer and in cells thereby conveying their cytoprotective effects. Here we measure H2S oxidation in buffer and HEK293 cells by over-the-counter nutraceuticals, blueberry, bilberry and cranberry, and by polyphenols, cyanadin (Cya), quercetin (Que), rosmarinic acid (RA) and resveratrol (Res). H2S and PS were measured with specific fluorophores, AzMc and SSP4 respectively, and thiosulfate (TS) production was measured in buffer using silver nanoparticles (AgNPs). All compounds increased polysulfide production from H2S in buffer and increased polysufides in cells. Decreasing oxygen from 100% to 21% and 0% progressively decreased PS production by Que and RA in buffer and Que decreased PS production in cells incubated in 5% O2 compared to 21% O2. Que, RA and Res, but not Cya, increased TS production from H2S in 21% O2 but not in 0% O2. Superoxide dismutase did not affect PS production from H2S by Que or TS production from H2S by Que, RA or Res, whereas catalase inhibited TS production by all three polyphenols. Conversely, these polyphenols only slightly reduce a mixed polysulfide (K2Sn) or thiosulfate to H2S in 0% O2. Collectively, our results suggest that polyphenols are autoxidized to a semiquinone radical and that this, in turn, oxidizes H2S to a thiyl radical from which polysulfides and thiosulfate derived. They also suggest that this is catalyzed by a semiquinone radical and it is independent of either superoxide or hydrogen peroxide concomitantly produced during polyphenol autoxidation. The polysulfides produced in these reactions are potent antioxidants and also initiate a variety of downstream cytoprotective effector mechanisms. It is also possible that H2S can be regenerated from the thiosulfate produced in these reactions by other cellular reductants and reused in subsequent reactions.
Assuntos
Sulfeto de Hidrogênio , Nanopartículas Metálicas , Antocianinas , Antioxidantes/farmacologia , Cinamatos , Depsídeos , Frutas , Células HEK293 , Humanos , Resveratrol/farmacologia , Prata , Sulfetos/farmacologia , Tiossulfatos/farmacologia , Ácido RosmarínicoRESUMO
BACKGROUND/AIMS: Arterial stenosis activates the renin-angiotensin-aldosterone system subsequently resulting in renovascular hypertension (RVHT) and renal oxidative injury. We explored the effect of sodium thiosulfate (STS, Na2S2O3), a developed antioxidant in clinical trial, on RVHT-induced hypertension and renal oxidative injury in rats. METHODS: We induced RVHT in male Wistar rats with bilaterally partial ligation of renal arteries in the 2-kidney 2-clip model. We evaluated the STS effect on RVHT-induced oxidative injury and apoptosis by a chemiluminescence amplification method, Western blot, and immunohistochemistry. RESULTS: We found STS displayed a dose-dependent antioxidant H2O2 activity and adapted the maximal scavenging H2O2 activity of STS at the dosage of 0.1 g/kg intraperitoneally 3 times/week for 4 weeks in RVHT rats. RVHT induced a significant elevation of arterial blood pressure, blood reactive oxygen species amount, neutrophil infiltration, 4-HNE and NADPH oxidase gp91 expression, Bax/Bcl-2/poly(ADP-ribose) polymerase (PARP)-mediated apoptosis formation, blue Masson-stained fibrosis, and urinary protein level. STS treatment significantly reduced hypertension, oxidative stress, neutrophil infiltration, fibrosis, and Bax/Bcl-2/PARP-mediated apoptosis formation and depressed the urinary protein level in the RVHT models. CONCLUSION: Our results suggest that STS treatment could ameliorate RVHT hypertension and renal oxidative injury through antioxidant, antifibrotic, and antiapoptotic mechanisms.
Assuntos
Antioxidantes/uso terapêutico , Hipertensão Renovascular/tratamento farmacológico , Rim/efeitos dos fármacos , Tiossulfatos/uso terapêutico , Animais , Antioxidantes/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Hipertensão Renovascular/metabolismo , Hipertensão Renovascular/fisiopatologia , Rim/metabolismo , Rim/fisiopatologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Tiossulfatos/farmacologiaRESUMO
Nrf2 is a key transcription factor responsible for antioxidant defense in many tissues and cells, including alveolar epithelium, endothelium, and macrophages. Furthermore, Nrf2 functions as a transcriptional repressor that inhibits expression of the inflammatory cytokines in macrophages. Critically ill patients with COVID-19 infection often present signs of high oxidative stress and systemic inflammation - the leading causes of mortality. This article suggests rationale for the use of Nrf2 inducers to prevent development of an excessive inflammatory response in COVID-19 patients.