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1.
ACS Appl Mater Interfaces ; 15(37): 43332-43344, 2023 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-37671841

RESUMO

Cystinuria is an inherited autosomal recessive disease of the kidneys of recurring nature that contributes to frequent urinary tract infections due to bacterial growth and biofilm formation surrounding the stone microenvironment. In the past, commonly used strategies for managing cystinuria involved the use of (a) cystine crystal growth inhibitors such as l-cystine dimethyl ester and lipoic acid, and (b) thiol-based small molecules such as N-(2-mercaptopropionyl) glycine, commonly known as tiopronin, that reduce the formation of cystine crystals by reacting with excess cystine and generating more soluble disulfide compounds. However, there is a dearth of simplistic chemical approaches that have focused on the dual treatment of cystinuria and the associated microbial infections. This work strategically exploited a single chemical approach to develop a nitric oxide (NO)-releasing therapeutic compound, S-nitroso-2-mercaptopropionyl glycine (tiopronin-NO), for the dual management of cystine stone formation and the related bacterial infections. The results successfully demonstrated that (a) the antibacterial activity of NO rendered tiopronin-NO effective against the stone microenvironment inhabitants, Escherichia coli and Pseudomonas aeruginosa, and (b) tiopronin-NO retained the ability to undergo disulfide exchange with cystine while being reported to be safe against canine kidney and mouse fibroblast cells. Thus, the synthesis of such a facile molecule aimed at the dual management of cystinuria and related infections is unprecedented in the literature.


Assuntos
Infecções Bacterianas , Cistinúria , Camundongos , Animais , Cães , Cistinúria/tratamento farmacológico , Tiopronina/farmacologia , Tiopronina/uso terapêutico , Cistina/farmacologia , Dissulfetos , Escherichia coli , Óxido Nítrico
2.
Cardiovasc Drugs Ther ; 35(4): 745-758, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33914182

RESUMO

PURPOSE: Sonlicromanol is a phase IIB clinical stage compound developed for treatment of mitochondrial diseases. Its active component, KH176m, functions as an antioxidant, directly scavenging reactive oxygen species (ROS), and redox activator, boosting the peroxiredoxin-thioredoxin system. Here, we examined KH176m's potential to protect against acute cardiac ischemia-reperfusion injury (IRI), compare it with the classic antioxidant N-(2-mercaptopropionyl)-glycine (MPG), and determine whether protection depends on duration (severity) of ischemia. METHODS: Isolated C56Bl/6N mouse hearts were Langendorff-perfused and subjected to short (20 min) or long (30 min) ischemia, followed by reperfusion. During perfusion, hearts were treated with saline, 10 µM KH176m, or 1 mM MPG. Cardiac function, cell death (necrosis), and mitochondrial damage (cytochrome c (CytC) release) were evaluated. In additional series, the effect of KH176m treatment on the irreversible oxidative stress marker 4-hydroxy-2-nonenal (4-HNE), formed during ischemia only, was determined at 30-min reperfusion. RESULTS: During baseline conditions, both drugs reduced cardiac performance, with opposing effects on vascular resistance (increased with KH176m, decreased with MPG). For short ischemia, KH176m robustly reduced all cell death parameters: LDH release (0.2 ± 0.2 vs 0.8 ± 0.5 U/min/GWW), infarct size (15 ± 8 vs 31 ± 20%), and CytC release (168.0 ± 151.9 vs 790.8 ± 453.6 ng/min/GWW). Protection by KH176m was associated with decreased cardiac 4-HNE. MPG only reduced CytC release. Following long ischemia, IRI was doubled, and KH176m and MPG now only reduced LDH release. The reduced protection against long ischemia was associated with the inability to reduce cardiac 4-HNE. CONCLUSION: Protection against cardiac IRI by the antioxidant KH176m is critically dependent on duration of ischemia. The data suggest that with longer ischemia, the capacity of KH176m to reduce cardiac oxidative stress is rate-limiting, irreversible ischemic oxidative damage maximally accumulates, and antioxidant protection is strongly diminished.


Assuntos
Cromanos/farmacologia , Traumatismo por Reperfusão Miocárdica , Oxirredução/efeitos dos fármacos , Aldeídos/metabolismo , Animais , Antioxidantes/farmacologia , Modelos Animais de Doenças , Camundongos , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Tempo para o Tratamento , Tiopronina/farmacologia , Resultado do Tratamento
3.
Naunyn Schmiedebergs Arch Pharmacol ; 394(4): 603-617, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33079239

RESUMO

The current pharmacotherapy of neuropathic pain is inadequate as neuropathic pain involves varied clinical manifestations with multifactorial etiology, modulated by a cascade of physical and molecular events leading to different clinical presentations of pain. There is an accumulating evidence of the involvement of oxidative stress in neuropathy, and antioxidants have shown promise in mitigating neuropathic pain syndromes. To explore the evidence supporting this beneficial proclivity of antioxidants, this study investigated the antinociceptive effectiveness of N-(2-mercaptopropionyl)glycine or tiopronin, a well-recognized aminothiol antioxidant, in a refined chronic constriction injury (CCI) rat model of neuropathic pain. Tiopronin (10, 30, and 90 mg/kg, i.p.) and pregabalin (30 mg/kg, i.p.) were administered daily after CCI surgery. The neuropathic paradigms of mechanical/cold allodynia and mechanical/heat hyperalgesia were assessed on days 3, 7, 14, and 21 post-nerve ligation. At the end of study, malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) levels were estimated in the sciatic nerve, dorsal root ganglion, and spinal cord for assessing the extent of oxidative stress. The expression of neuropathic nociception was attenuated by tiopronin which was observed as a significant attenuation of CCI-induced allodynia and hyperalgesia. Tiopronin reversed the neuronal oxidative stress by significantly reducing MDA, and increasing SOD, CAT, and GSH levels. Pregabalin also showed similar beneficial propensity on CCI-induced neuropathic aberrations. These findings suggest prospective neuropathic pain attenuating efficacy of tiopronin and further corroborated the notion that antioxidants are effective in mitigating the development and expression of neuropathic pain and underlying neuronal oxidative stress.


Assuntos
Antioxidantes/uso terapêutico , Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Tiopronina/uso terapêutico , Animais , Antioxidantes/farmacologia , Catalase/metabolismo , Temperatura Baixa , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Glutationa/metabolismo , Temperatura Alta , Hiperalgesia/metabolismo , Masculino , Malondialdeído/metabolismo , Neuralgia/metabolismo , Ratos Sprague-Dawley , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/lesões , Nervo Isquiático/metabolismo , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Superóxido Dismutase/metabolismo , Tiopronina/farmacologia , Tato
4.
Sci Rep ; 10(1): 18632, 2020 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-33122658

RESUMO

This study evaluated the effects of different concentrations (1, 10, 25, 50, and 100 µM) of the antioxidant N-(2-mercaptopropionyl)-glycine (NMPG), during the culture of in vitro-fertilized porcine oocytes. While the highest concentrations of NMPG (50 and 100 µM) were toxic to the developing embryos during the first two days of culture, 25 µM NMPG achieved cleavage rates that were similar to those achieved by the control but did not sustain blastocyst production by Day 7 of culture. Compared to the control culture medium, the culture medium supplemented with 10 µM NMPG increased (P < 0.05) the rates of blastocyst formation, decreased (P < 0.05) the intracellular levels of reactive oxygen substances, and downregulated (P < 0.05) the expression of the oxidative stress related gene GPX1. In conclusion, these results demonstrated that supplementation of porcine embryo culture medium with 10 µM NMPG can attenuate oxidative stress and increase the yield of in vitro production of blastocysts.


Assuntos
Embrião de Mamíferos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Suínos/embriologia , Tiopronina/farmacologia , Animais , Meios de Cultura , Técnicas de Cultura Embrionária , Desenvolvimento Embrionário/efeitos dos fármacos , Estresse Oxidativo/genética
5.
Free Radic Res ; 54(5): 319-329, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32363952

RESUMO

Tiopronin (MPG) is a thiol antioxidant drug that has been explored as a treatment for various oxidative stress-related disorders. However, many of its antioxidant capabilities remain untested in well-validated cell models. To more thoroughly understand the action of this promising pharmaceutical compound against acute oxidative challenge, A549 human lung carcinoma cells were exposed to tert-butyl hydroperoxide (tBHP) and treated with MPG. Analyses of cell viability, intracellular glutathione (GSH) levels, and the prevalence of reactive oxygen species (ROS) and mitochondrial superoxide were used to examine the effects of MPG on tBHP-challenged cells. MPG treatment suppressed intracellular ROS and mitochondrial superoxide and prevented tBHP-induced GSH depletion and apoptosis. These results indicate that MPG is effective at preserving redox homeostasis against acute oxidative insult in A549 cells if present at sufficient concentrations during exposure to oxidants such as tBHP. The effects of treatment gleaned from this study can inform experimental design for future in vivo work on the therapeutic potential of MPG.


Assuntos
Antineoplásicos/farmacologia , Substâncias Protetoras/farmacologia , Tiopronina/farmacologia , Células A549 , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Relação Estrutura-Atividade , Células Tumorais Cultivadas
6.
Clin Exp Pharmacol Physiol ; 47(2): 322-332, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31663622

RESUMO

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. Oxidative stress contributes significantly to HCC pathogenesis. In this study, we investigated the possible chemoprotective effect of the thiol group-containing compound, tiopronin, against HCC induced chemically by diethylnitrosamine (DENA) in rats. In addition, we elucidated the possible underlying molecular mechanism. Adult male Wistar rats were divided into: Control group, DENA-treated group and tiopronin + DENA-treated group. Liver function tests (ALT, AST, ALP, albumin, total and direct bilirubin) as well as alpha fetoprotein (AFP) concentration were measured in the sera of samples. Oxidative stress biomarkers such as malondialdehyde, nitric oxide, catalase and glutathione peroxidase were measured in the liver tissue homogenates. Determination of the phosphorylated apoptosis signal-regulating kinase 1 (phospho-ASK1), phospho-P38 and phospho-P53 proteins by western blotting, caspase 3 by immunofluorescence in addition to histopathological examination of the liver tissues were performed. Our results showed that tiopronin prevented the DENA-induced elevation of the liver function enzymes and AFP. It also preserved the activities of antioxidant enzymes as well as providing protection from the appearance of HCC histopathological features. Interestingly, tiopronin significantly decreased the expression level of phospho-ASK1, phospho-P38 and phospho-P53, caspase 3 in the liver tissues. These novel findings suggested that tiopronin is an antioxidant drug with a chemoprotective effect against DENA-induced HCC through maintaining the normal activity of ASK1/ P38 MAPK/ P53 signalling pathway.


Assuntos
Carcinoma Hepatocelular/metabolismo , Dietilnitrosamina/toxicidade , Neoplasias Hepáticas Experimentais/metabolismo , MAP Quinase Quinase Quinase 5/metabolismo , Tiopronina/uso terapêutico , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Alquilantes/toxicidade , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/prevenção & controle , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Hepáticas Experimentais/prevenção & controle , MAP Quinase Quinase Quinase 5/antagonistas & inibidores , Masculino , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Tiopronina/farmacologia , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
7.
J Med Chem ; 63(3): 1434-1439, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-31702923

RESUMO

We previously reported that some, but not all, multidrug-resistant cells that overexpressed various drug-resistance transporters were collaterally sensitive to tiopronin. In recent follow-up studies, we discovered that sensitivity to tiopronin in the original study was mediated by infection of the cells by a human-specific strain of mycoplasma. These results strongly support the need to constantly monitor cells for mycoplasma infection and keep stored samples of all cells that are used for in vitro studies.


Assuntos
Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Infecções por Mycoplasma/fisiopatologia , Tiopronina/farmacologia , Acetilcisteína/farmacologia , Linhagem Celular Tumoral , Resistência a Múltiplos Medicamentos/fisiologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Humanos , Mycoplasma fermentans/fisiologia
8.
Drug Des Devel Ther ; 13: 2827-2832, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496659

RESUMO

OBJECTIVE: Tiopronin is an antioxidant. This study investigated the protective effect of tiopronin on oxidative stress in patients with severe burns. METHOD: Patients aged between 16 and 65 years old with >30% body surface area burns admitted to our burn unit from July 2011 to September 2016 were randomly divided into 3 groups: group A treated with tiopronin (15 mg/kg. 24 hrs), group B with vitamin C (792 mg/kg. 24 hrs), the other group with standard treatment (group C). All 3 groups also received standard treatment. Blood superoxide dismutase (SOD), malondialdehyde (MDA), and the biochemical indexes of liver, kidney, and heart were determined before treatment and 24 and 48 hrs after treatment. Samples from 8 normal healthy adult volunteers were also measured. The resuscitation fluid volume requirement for the first 24 hrs was calculated for 3 groups. RESULTS: The serum levels of MDA and the biochemical indexes in severely burned patients were higher than those in healthy volunteers (P<0.01). The serum SOD level of burn patients was lower (P<0.01). After treatment, the levels of SOD increased, the levels of MDA decreased, and the biochemical indexes of heart, liver, and kidney improved; these changes were more obvious in group A and group B compared to group C (P<0.05), and these changes were more obvious in group A compared to group B (P<0.05) at 48 hrs after treatment. There is less resuscitation fluid volume requirement to maintain adequate stable hemodynamic and urine output in the first 24 hrs in group A and group B compared to group C (P<0.05). CONCLUSION: Treatment with tiopronin could exert protective effects against burn-induced oxidative tissue damage and multiple-organ dysfunction, and also could reduce the volume of required fluid resuscitation in severely burned patients.


Assuntos
Queimaduras/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Tiopronina/farmacologia , Adolescente , Adulto , Idoso , Queimaduras/sangue , Relação Dose-Resposta a Droga , Feminino , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Substâncias Protetoras/administração & dosagem , Índice de Gravidade de Doença , Tiopronina/administração & dosagem , Adulto Jovem
9.
Pharmazie ; 74(9): 536-542, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31484593

RESUMO

Glutathione peroxidase (GPx), an important antioxidative enzmye, can be inhibited by various thiols, including of tiopronin and mercaptosuccinic acid (MSA). Recently, there has been discussion regarding the combination of tiopronin in anticancer therapy to overcome acquired resistance to anticancer drugs. However, thiols are also known to act as antioxidants, which can be contraindicated in cancer chemotherapy. This article focuses on the inhibitory effects of tiopronin and MSA on bovine and human glutathione peroxidase activities, and their effects on the redox status of cancer cells. IC50 values for the inhibition for the bovine erythrocyte enzyme were 356 and 24.7 µM for tiopronin and MSA, respectively, with the corresponding Ki values of 343 µM and 14.6 µM, respectively at pH 7.4 and 25 °C. MSA inhibited human GPx activity in human cancer cell lysates at its IC50 while tiopronin did not. Both compounds were cytotoxic to human cancer cell lines GUMBUS and HL-60, with IC50 values between 42.7 and 149.4 µM. Neither had an effect on cell cycle. Only MSA induced apoptosis in HL-60 cells but not in GUMBUS cells, while tiopronin resulted in no apoptosis in either cell line. Combination studies of the MSA with hydrogen peroxide in living cells enhanced the production of reactive oxygen species in GUMBUS cells while tiopronin acted as antioxidant in HL-60 cells. MSA and tiopronin antagonized the cytotoxic effect of cisplatin, doxorubicin and methotrexate in combination studies. Our findings indicate that the antioxidant properties of both thiols prevail over their GPx inhibitory activity in human cancer cell lines.


Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Tiomalatos/farmacologia , Tiopronina/farmacologia , Animais , Antineoplásicos/administração & dosagem , Antioxidantes/administração & dosagem , Apoptose/efeitos dos fármacos , Bovinos , Linhagem Celular Tumoral , Glutationa Peroxidase/efeitos dos fármacos , Glutationa Peroxidase/metabolismo , Células HL-60 , Humanos , Concentração Inibidora 50 , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/patologia , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/patologia , Oxirredução/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Tiomalatos/administração & dosagem , Tiopronina/administração & dosagem
10.
Urolithiasis ; 47(6): 549-555, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30980122

RESUMO

Appropriate dosing of cystine-binding thiol drugs in the management of cystinuria has been based on clinical stone activity. When new stones form, the dose is increased. Currently, there is no method of measuring urinary drug levels to guide the titration of therapy. Increasing cystine capacity, a measure of cystine solubility, has been promoted as a method of judging the effects of therapy. In this study, we gave increasing doses of tiopronin or D-penicillamine, depending on the patients' own prescriptions, to ten patients with cystinuria and measured cystine excretion and cystine capacity. The doses were 0, 1, 2, 3 g per day, given in two divided doses, and administered in a random order. Going from 0 to 1 g/day led to an increase in cystine capacity from - 39.1 to 130.4 mg/L (P < 0.009) and decreased 24 h cystine excretion from 1003.9 to 834.8 mg/day (P = 0.039). Increasing the doses from 1 to 2 to 3 g/day had no consistent or significant effect to further increase cystine capacity or decrease cystine excretion. Whether doses higher than 1 g/day have additional clinical benefit is not clear from this study. Limiting doses might be associated with fewer adverse effects without sacrificing the benefit of higher doses if higher doses do not offer clinical importance. However, trials with stone activity as an outcome would be desirable.


Assuntos
Cistina/química , Cistinúria/tratamento farmacológico , Penicilamina/administração & dosagem , Tiopronina/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Cross-Over , Cistina/análise , Cistina/efeitos dos fármacos , Cistinúria/metabolismo , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Penicilamina/farmacologia , Solubilidade/efeitos dos fármacos , Tiopronina/farmacologia , Adulto Jovem
11.
J Pharmacol Sci ; 133(4): 232-239, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28363413

RESUMO

Bacopa monnieri (BM, family Scrophulariaceae) is used in several traditional systems of medicine for the management of epilepsy, depression, neuropathic pain, sleep disorders and memory deficits. The present study investigated the potential of BM methanol (BM-MetFr) and BM n-butanol fractions (BM-ButFr) to reduce chemotherapy-induced emesis in Suncus murinus (house musk shrew). Cisplatin (30 mg/kg, i.p.) reliably induced retching and/or vomiting over a 2 day period. BM-MetFr (10-40 mg/kg, s.c.) and BM-ButFr (5-20 mg/kg, s.c.) antagonized the retching and/or vomiting response by ∼59.4% (p < 0.05) and 78.9% (p < 0.05), respectively, while the 5-HT3 receptor antagonist, palonosetron (0.5 mg/kg, s.c.), reduced the response by ∼71% (p < 0.05). The free radical scavenger/antioxidant, N-(2-mercaptopropionyl)-glycine (30-300 mg/kg, s.c.) reduced the retching and/or vomiting response occurring on day one non-significantly by 44% (p > 0.05). In conclusion, the n-butanol fractions of BM have anti-emetic activity comparable with palonosetron and MPG. BM may be useful alone or in combination with other anti-emetic drugs for the treatment of chemotherapy-induced emesis in man.


Assuntos
Antieméticos/farmacologia , Antineoplásicos/efeitos adversos , Bacopa/química , Cisplatino/efeitos adversos , Extratos Vegetais/farmacologia , Vômito/induzido quimicamente , Vômito/tratamento farmacológico , Animais , Isoquinolinas/farmacologia , Isoquinolinas/uso terapêutico , Masculino , Palonossetrom , Quinuclidinas/farmacologia , Quinuclidinas/uso terapêutico , Antagonistas da Serotonina/farmacologia , Antagonistas da Serotonina/uso terapêutico , Musaranhos , Tiopronina/farmacologia , Tiopronina/uso terapêutico , Vômito/prevenção & controle
12.
Drug Res (Stuttg) ; 67(4): 204-210, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28142160

RESUMO

Drug safety- and drug-alcohol interaction studies have mainly been conducted for frequently prescribed drugs with high financial interests. Orphan drugs such as tiopronin (ORPHA25073) are often neglected in terms of clinical research. Tiopronin is a drug that is mainly used for the treatment of cystinuria. In this study, the interaction of tiopronin regarding the metabolism of alcohol (primary objective), and the safety of tiopronin in combination with alcohol was tested in healthy volunteers.In this randomised, double-blind, cross-over study, 13 healthy subjects received 500 mg tiopronin or an identical looking placebo 1 h before the intake of 0.8 g of alcohol per kg of bodyweight. Blood alcohol concentrations were measured over the course of 12 h after consumption. The experiment was repeated 7 days later with the previous placebo group receiving the active drug and vice-versa. Changes in blood alcohol AUC and elimination rate k were analysed using a 2-tailed t-test. Further acetaldehyde concentrations were measured. Additionally, the concentration ability of the subjects was tested and any adverse effects were recorded.There was no significant change in blood alcohol or acetaldehyde concentration. Significant differences in concentration tests refer presumably to learning effects. No serious adverse event occurred. All adverse events were reversible and there was no significant difference in occurrence between drug and placebo group.It was demonstrated that tiopronin does not affect the metabolism of alcohol. Intake of tiopronin in combination with alcohol has no safety implications on healthy subjects.


Assuntos
Etanol/metabolismo , Interações Alimento-Droga , Tiopronina/farmacologia , Acetaldeído/sangue , Adulto , Atenção , Estudos Cross-Over , Método Duplo-Cego , Etanol/administração & dosagem , Etanol/sangue , Etanol/farmacologia , Feminino , Voluntários Saudáveis , Humanos , Masculino , Produção de Droga sem Interesse Comercial , Tiopronina/administração & dosagem , Tiopronina/efeitos adversos , Adulto Jovem
13.
Am J Physiol Heart Circ Physiol ; 311(3): H713-24, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27422983

RESUMO

Previous results from our laboratory showed that phosphorylation of ryanodine receptor 2 (RyR2) by Ca(2+) calmodulin-dependent kinase II (CaMKII) was a critical but not the unique event responsible for the production of reperfusion-induced arrhythmogenesis, suggesting the existence of other mechanisms cooperating in an additive way to produce these rhythm alterations. Oxidative stress is a prominent feature of ischemia/reperfusion injury. Both CaMKII and RyR2 are proteins susceptible to alteration by redox modifications. This study was designed to elucidate whether CaMKII and RyR2 redox changes occur during reperfusion and whether these changes are involved in the genesis of arrhythmias. Langendorff-perfused hearts from rats or transgenic mice with genetic ablation of CaMKII phosphorylation site on RyR2 (S2814A) were subjected to ischemia-reperfusion in the presence or absence of a free radical scavenger (mercaptopropionylglycine, MPG) or inhibitors of NADPH oxidase and nitric oxide synthase. Left ventricular contractile parameters and monophasic action potentials were recorded. Oxidation and phosphorylation of CaMKII and RyR2 were assessed. Increased oxidation of CaMKII during reperfusion had no consequences on the level of RyR2 phosphorylation. Avoiding the reperfusion-induced thiol oxidation of RyR2 with MPG produced a reduction in the number of arrhythmias and did not modify the contractile recovery. Conversely, selective prevention of S-nitrosylation and S-glutathionylation of RyR2 was associated with higher numbers of arrhythmias and impaired contractility. In S2814A mice, treatment with MPG further reduced the incidence of arrhythmias. Taken together, the results suggest that redox modification of RyR2 synergistically with CaMKII phosphorylation modulates reperfusion arrhythmias.


Assuntos
Arritmias Cardíacas/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Contração Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Potenciais de Ação , Animais , Arritmias Cardíacas/metabolismo , Western Blotting , Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/efeitos dos fármacos , Eletroforese , Sequestradores de Radicais Livres/farmacologia , Glutationa/metabolismo , Preparação de Coração Isolado , Masculino , Camundongos , Camundongos Transgênicos , Contração Miocárdica/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/metabolismo , NADPH Oxidases/antagonistas & inibidores , Óxido Nítrico Sintase/antagonistas & inibidores , Oxirredução , Estresse Oxidativo , Fosforilação , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/efeitos dos fármacos , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Retículo Sarcoplasmático/metabolismo , Tiopronina/farmacologia
14.
Drug Metab Pharmacokinet ; 31(3): 249-51, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27155909

RESUMO

When the biosynthesis of homocysteine (Hcy), an amino acid containing thiol, exceeds its elimination, plasma Hcy concentration increases and results in hyperhomocysteinemia (HHC). Most of the Hcy in plasma covalently binds to the cysteine residues of albumin by disulfide bonds. Meanwhile tiopronin (TP), a thiol-containing compound, is used for treatment of cysteinuria to decrease the amount of insoluble cystine in urine, by replacing a cysteine molecule in cystine with TP to form soluble TP-cysteine complexes. The present study investigated the effect of TP on the total (protein-unbound and protein-bound) Hcy concentration and the ratio of protein-unbound Hcy to total Hcy in plasma, and the urinary excretion of Hcy. Methionine was administered orally to rats to induce temporary hyperhomocysteinemia, and then TP was administered and the plasma and urine were collected. The amount of Hcy excreted in urine was higher but the plasma concentration of Hcy was lower in the TP group than in the control group until 3 h after TP administration. In addition the ratio of protein-unbound Hcy in plasma tended to be increased by TP administration. These results demonstrated that TP enhanced the urinary excretion of Hcy, which might cause the decrease of its plasma concentration in rats.


Assuntos
Homocisteína/metabolismo , Tiopronina/farmacologia , Animais , Homocisteína/sangue , Homocisteína/urina , Masculino , Ratos Sprague-Dawley
15.
Carbohydr Polym ; 134: 516-23, 2015 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-26428153

RESUMO

The ability to protect hyaluronic acid (HA) from oxidative degradation by cupric ions and ascorbate (production of (•)OH and peroxy-type radicals) during acute phase joint inflammation has been investigated using the following drugs: tiopronin, captopril, and levamisole. Radical scavenging activity, i.e. the propensity for donation of electrons was assessed for the drugs by ABTS and DPPH assays. The kinetics of HA degradation have been measured in the presence of each drug using rotational viscometry. The results of ABTS and DPPH assays show the highest radical scavenging activity for captopril, followed by tiopronin. For levamisole, no effect was observed. Captopril and tiopronin prevented HA degradation induced by (•)OH radicals in a similar manner, while tiopronin was more effective in scavenging peroxy-type radicals. On the other hand, levamisole was shown to be a pro-oxidant. Recovered HA fragments were characterized using FT-IR analysis, the incorporation of a sulphur atom from captopril and tiopronin but not from levamisole into the HA molecule was demonstrated.


Assuntos
Sequestradores de Radicais Livres/farmacologia , Ácido Hialurônico/metabolismo , Benzotiazóis/química , Compostos de Bifenilo/química , Captopril/química , Captopril/farmacologia , Transporte de Elétrons/efeitos dos fármacos , Sequestradores de Radicais Livres/química , Cinética , Levamisol/química , Levamisol/farmacologia , Picratos/química , Ácidos Sulfônicos/química , Tiopronina/química , Tiopronina/farmacologia , Viscosidade
16.
J Mol Cell Cardiol ; 81: 150-61, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25731682

RESUMO

Moderate enhanced reactive oxygen species (ROS) during early reperfusion trigger the cardioprotection against ischemia/reperfusion (I/R) injury, while the mechanism is largely unknown. Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) contributes to the cardioprotection but whether it is activated by ROS and how it regulates Ca(2+) homeostasis remain unclear. Here we investigated whether the ROS generated during early reperfusion protect the heart/cardiomyocyte against I/R-induced Ca(2+) overload and contractile dysfunction via the activation of JAK2/STAT3 signaling pathway by using a cardioprotective model of intermittent hypobaric hypoxia (IHH) preconditioning. IHH improved the postischemic recovery of myocardial contractile performance in isolated rat I/R hearts as well as Ca(2+) homeostasis and cell contraction in simulated I/R cardiomyocytes. Meanwhile, IHH enhanced I/R-increased STAT3 phosphorylation at tyrosine 705 in the nucleus and reversed I/R-suppressed STAT3 phosphorylation at serine 727 in the nucleus and mitochondria during reperfusion. Moreover, IHH improved I/R-suppressed sarcoplasmic reticulum (SR) Ca(2+)-ATPase 2 (SERCA2) activity, enhanced I/R-increased Bcl-2 expression, and promoted the co-localization and interaction of Bcl-2 with SERCA2 during reperfusion. These effects were abolished by scavenging ROS with N-(2-mercaptopropionyl)-glycine (2-MPG) and/or by inhibiting JAK2 with AG490 during the early reperfusion. Furthermore, IHH-improved postischemic SERCA2 activity and Ca(2+) homeostasis as well as cell contraction were reversed after Bcl-2 knockdown by short hairpin RNA. In addition, the reversal of the I/R-suppressed mitochondrial membrane potential by IHH was abolished by 2-MPG and AG490. These results indicate that during early reperfusion the ROS/JAK2/STAT3 pathways play a crucial role in (i) the IHH-maintained intracellular Ca(2+) homeostasis via the improvement of postischemic SERCA2 activity through the increase of SR Bcl-2 and its interaction with SERCA2; and (ii) the IHH-improved mitochondrial function.


Assuntos
Cálcio/metabolismo , Hipóxia/genética , Janus Quinase 2/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT3/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Animais , Sequestradores de Radicais Livres/farmacologia , Regulação da Expressão Gênica , Hipóxia/metabolismo , Precondicionamento Isquêmico Miocárdico/métodos , Janus Quinase 2/genética , Masculino , Contração Miocárdica , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fosforilação , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/antagonistas & inibidores , Fator de Transcrição STAT3/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , Transdução de Sinais , Tiopronina/farmacologia
17.
Genet Mol Res ; 13(2): 4516-22, 2014 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-25036356

RESUMO

This study aimed to investigate the effects of mitochondrial ATP-sensitive potassium (MitoKATP) channel opening on the translocation of protein kinase C epsilon (PKCε). In addition, we aimed to determine the relationship between PKCε translocation and the production of reactive oxygen species (ROS). PKCε protein expression in cultured adult rat ventricular myocytes was investigated by immunofluorescence and Western blotting. Diazoxide (DZ), a selective MitoKATP channel activator, caused a significant translocation to myofibrillar-like structures in cultured adult rat ventricular myocytes. N-2-Mercaptopropionylglycine, a free radical scavenger, could partially inhibit the translocation of PKCε induced by DZ. By contrast, chelerythrine, a selective PKC inhibitor, could completely block the translocation of PKCε induced by DZ. The opening of MitoKATP channels might activate and cause PKCε to translocate into myofibrillar-like structures. PKCε activation occurred downstream of the MitoKATP channel, possibly as a result of ROS production that occurred after the MitoKATP channels opened.


Assuntos
Diazóxido/farmacologia , Canais KATP/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Proteína Quinase C-épsilon/metabolismo , Animais , Benzofenantridinas/farmacologia , Membrana Celular/metabolismo , Células Cultivadas , Mitocôndrias/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Tiopronina/farmacologia
18.
J Exp Biol ; 217(Pt 18): 3346-55, 2014 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-25063855

RESUMO

Oxygen deprivation triggers excitotoxic cell death in mammal neurons through excessive calcium loading via over-activation of N-methyl-d-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. This does not occur in the western painted turtle, which overwinters for months without oxygen. Neurological damage is avoided through anoxia-mediated decreases in NMDA and AMPA receptor currents that are dependent upon a modest rise in intracellular Ca(2+) concentrations ([Ca(2+)]i) originating from mitochondria. Anoxia also blocks mitochondrial reactive oxygen species (ROS) generation, which is another potential signaling mechanism to regulate glutamate receptors. To assess the effects of decreased intracellular [ROS] on NMDA and AMPA receptor currents, we scavenged ROS with N-2-mercaptopropionylglycine (MPG) or N-acetylcysteine (NAC). Unlike anoxia, ROS scavengers increased NMDA receptor whole-cell currents by 100%, while hydrogen peroxide decreased currents. AMPA receptor currents and [Ca(2+)]i concentrations were unaffected by ROS manipulation. Because decreases in [ROS] increased NMDA receptor currents, we next asked whether mitochondrial Ca(2+) release prevents receptor potentiation during anoxia. Normoxic activation of mitochondrial ATP-sensitive potassium (mKATP) channels with diazoxide decreased NMDA receptor currents and was unaffected by subsequent ROS scavenging. Diazoxide application following ROS scavenging did not rescue scavenger-mediated increases in NMDA receptor currents. Fluorescent measurement of [Ca(2+)]i and ROS levels demonstrated that [Ca(2+)]i increases before ROS decreases. We conclude that decreases in ROS concentration are not linked to anoxia-mediated decreases in NMDA/AMPA receptor currents but are rather associated with an increase in NMDA receptor currents that is prevented during anoxia by mitochondrial Ca(2+) release.


Assuntos
Córtex Cerebral/citologia , Neurônios/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Receptores de N-Metil-D-Aspartato/fisiologia , Tartarugas/fisiologia , Acetilcisteína/análogos & derivados , Acetilcisteína/farmacologia , Animais , Cálcio/metabolismo , Córtex Cerebral/fisiologia , Feminino , Sequestradores de Radicais Livres , Peróxido de Hidrogênio , Potenciais da Membrana/fisiologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neurônios/citologia , Neurônios/fisiologia , Oxigênio , Técnicas de Patch-Clamp , Rotenona , Tiopronina/farmacologia
19.
J Biol Chem ; 289(31): 21473-89, 2014 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-24930045

RESUMO

Multidrug resistance (MDR) is a major obstacle to the successful chemotherapy of cancer. MDR is often the result of overexpression of ATP-binding cassette transporters following chemotherapy. A common ATP-binding cassette transporter that is overexpressed in MDR cancer cells is P-glycoprotein, which actively effluxes drugs against a concentration gradient, producing an MDR phenotype. Collateral sensitivity (CS), a phenomenon of drug hypersensitivity, is defined as the ability of certain compounds to selectively target MDR cells, but not the drug-sensitive parent cells from which they were derived. The drug tiopronin has been previously shown to elicit CS. However, unlike other CS agents, the mechanism of action was not dependent on the expression of P-glycoprotein in MDR cells. We have determined that the CS activity of tiopronin is mediated by the generation of reactive oxygen species (ROS) and that CS can be reversed by a variety of ROS-scavenging compounds. Specifically, selective toxicity of tiopronin toward MDR cells is achieved by inhibition of glutathione peroxidase (GPx), and the mode of inhibition of GPx1 by tiopronin is shown in this report. Why MDR cells are particularly sensitive to ROS is discussed, as is the difficulty in exploiting this hypersensitivity to tiopronin in the clinic.


Assuntos
Inibidores Enzimáticos/farmacologia , Glutationa Peroxidase/antagonistas & inibidores , Tiopronina/farmacologia , Sequência de Aminoácidos , Sequência de Bases , Linhagem Celular Tumoral , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Glutationa Peroxidase/química , Humanos , Dados de Sequência Molecular , Oligodesoxirribonucleotídeos , Espécies Reativas de Oxigênio/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Espectrometria de Massas em Tandem , Tiomalatos/farmacologia
20.
Biochem Biophys Res Commun ; 443(3): 1008-13, 2014 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-24361888

RESUMO

We investigated anti-colitic effects of N-(2-mercaptopropionyl)-glycine (NMPG), a diffusible antioxidant, in TNBS-induced rat colitis model and a potential molecular mechanism underlying the pharmacologic effect of the antioxidant. NMPG alleviated colonic injury and effectively lowered myeloperoxidase activity. Moreover, NMPG substantially attenuated expression of pro-inflammatory mediators in the inflamed colon. NMPG induced hypoxia-inducible factor-1α (HIF-1α) in human colon carcinoma cells, leading to elevated secretion of vascular endothelial growth factor (VEGF), a target gene product of HIF-1 involved in ulcer healing of gastrointestinal mucosa. NMPG induction of HIF-1α occurred by inhibiting HIF prolyl hydroxylase-2 (HPH-2), an enzyme that plays a major role in negatively regulating HIF-1α protein stability. In in vitro Von Hippel-Lindau protein binding assay, the inhibitory effect of NMPG on HPH-2 was attenuated by escalating dose of ascorbate but not 2-ketoglutarate, cofactors of the enzyme. Consistent with this, cell-permeable ascorbate significantly attenuated NMPG induction of HIF-1α in cells. Our data suggest that NMPG is an anti-colitic antioxidant that exerts its pharmacologic effects at least partly through activation of an ulcer healing pathway, HIF-1-VEGF.


Assuntos
Antioxidantes/uso terapêutico , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Colite/tratamento farmacológico , Colite/enzimologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Prolil Hidroxilases/metabolismo , Tiopronina/uso terapêutico , Animais , Antioxidantes/farmacologia , Ácido Ascórbico/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Colite/patologia , Difusão , Ativação Enzimática/efeitos dos fármacos , Células HCT116 , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Tiopronina/farmacologia , Ácido Trinitrobenzenossulfônico , Fator A de Crescimento do Endotélio Vascular/metabolismo
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