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1.
Matrix Biol ; 102: 37-69, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34508852

RESUMO

Dysregulation of proteolytic enzymes has huge impact on epidermal homeostasis, which can result in severe pathological conditions such as fibrosis or Netherton syndrome. The metalloprotease meprin ß was found to be upregulated in hyperproliferative skin diseases. AP-1 transcription factor complex has been reported to induce Mep1b expression. Since AP-1 and its subunit fos-related antigen 2 (fra-2) are associated with the onset and progression of psoriasis, we wanted to investigate if this could partially be attributed to increased meprin ß activity. Here, we demonstrate that fra-2 transgenic mice show increased meprin ß expression and proteolytic activity in the epidermis. To avoid influence by other fra-2 regulated genes, we additionally generated a mouse model that enabled tamoxifen-inducible expression of meprin ß under the Krt5-promotor to mimic the pathological condition. Interestingly, induced meprin ß expression in the epidermis resulted in hyperkeratosis, hair loss and mottled pigmentation of the skin. Employing N-terminomics revealed syndecan-1 as a substrate of meprin ß in skin. Shedding of syndecan-1 at the cell surface caused delayed calcium-induced differentiation and impaired adhesion of keratinocytes, which was blocked by the meprin ß inhibitor fetuin-B.


Assuntos
Sindecana-1 , Tiopronina , Animais , Diferenciação Celular , Membrana Celular , Queratinócitos , Metaloendopeptidases/genética , Camundongos
2.
Nephrol Ther ; 17S: S100-S107, 2021 Apr.
Artigo em Francês | MEDLINE | ID: mdl-33910689

RESUMO

Cystinuria is the most common monogenic nephrolithiasis disorder. Because of its poor solubility at a typical urine pH of less than 7, cystine excretion results in recurrent urinary cystine stone formation. A high prevalence of high blood pressure and of chronic kidney disease has been reported in these patients. Alkaline hyperdiuresis remains the cornerstone of the preventive medical treatment. To reach a urine pH between 7.5 and 8 and a urine specific gravity less than or equal to 1.005 should be the goal of medical treatment. D-penicillamine and tiopronin, two cysteine-binding thiol agents, should be considered as second line treatments with frequent adverse events that should be closely monitored.


Assuntos
Cistinúria , Cálculos Renais , Cistina , Cistinúria/diagnóstico , Cistinúria/epidemiologia , Cistinúria/terapia , Humanos , Penicilamina , Tiopronina
3.
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
4.
J Cereb Blood Flow Metab ; 41(1): 31-44, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32065075

RESUMO

The metalloprotease meprin ß (Mep1b) is capable of cleaving cell-adhesion molecules in different tissues (e.g. skin, kidney and intestine) and is dysregulated in several diseases associated with barrier breakdown (Alzheimer´s disease, kidney disruption, inflammatory bowel disease). In this study, we demonstrate that Mep1b is a novel regulator of tight junction (TJ) composition and blood-brain barrier (BBB) integrity in brain endothelium. In Mep1b-transfected mouse brain endothelial cells (bEnd.3), we observed a reduction of the TJ protein claudin-5, decreased transendothelial electrical resistance (TEER) and an elevated permeability to paracellular diffusion marker [14C]-inulin. Analysis of global Mep1b knock-out (Mep1b-/-) mice showed increased TJ protein expression (claudin-5, occludin, ZO-1) in cerebral microvessels and increased TEER in cultivated primary mouse brain endothelial compared to wild-type (wt) mice. Furthermore, we investigated the IgG levels in cerebrospinal fluid (CSF) and the brain water content as additional permeability markers and detected lower IgG levels and reduced brain water content in Mep1b-/- mice compared to wt mice. Showing opposing features in overexpression and knock-out, we conclude that Mep1b plays a role in regulating brain endothelial TJ-proteins and therefore affecting BBB tightness in vitro and in vivo.


Assuntos
Barreira Hematoencefálica/fisiopatologia , Encéfalo/metabolismo , Células Endoteliais/metabolismo , Proteínas de Junções Íntimas/metabolismo , Tiopronina/metabolismo , Animais , Humanos , Camundongos
5.
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
6.
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
7.
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
9.
Minerva Urol Nefrol ; 72(4): 427-440, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32083421

RESUMO

INTRODUCTION: To systematically review the effect of additional drug therapy as metaphylaxis in patients with cystinuria. EVIDENCE ACQUISITION: A literature search of three databases (MEDLINE, Embase and the Cochrane Library) was performed according to the PRISMA-guidelines enclosing articles published up to May 2019. A total of 1117 articles were screened. Thirty-four publications met the inclusion criteria for this review. EVIDENCE SYNTHESIS: Male-female ratio in the studied cohorts was 49.9% - 50.1%. The majority of studies showed a positive effect in reducing stone events and/or urinary cystine excretion. D-Penicillamine showed success in 13/14 (92%) studies, whereas Tiopronin-treatment showed a reduction in all (8/8; 100%) studies. All studies on Captopril (4/4) showed a decrease, however not all significant. The same is true for studies on Thiols in combination with Captopril (2/2). Furthermore, Tiopronin showed less side effects compared to D-penicillamine, respectively 30% and 37%. Captopril showed the least adverse events, with one event in nine patients. CONCLUSIONS: The evidence on benefit of additional drug therapy in patients with cystinuria is scarce. All studied medications showed an effect on stone event and urinary cystine excretion, when used in addition to hyperhydration, alkalization and a diet low on methionine. Based on this systematic review, no drug can be preferred over another. An important aspect in the choice of drug is the risk of side effects. Therefore, the choice of additional drug should be personalized for every patient where the risk of side effects should be taken into consideration.


Assuntos
Cistinúria/tratamento farmacológico , Quimioterapia Combinada , Captopril/uso terapêutico , Cistina/uso terapêutico , Medicina Baseada em Evidências , Feminino , Humanos , Masculino , Penicilamina/uso terapêutico , Tiopronina/uso terapêutico
10.
Br J Pharmacol ; 177(12): 2872-2885, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32072633

RESUMO

BACKGROUND AND PURPOSE: Abdominal aorticaneurysm (AAA) rupture is mainly due to elastic lamina degradation. As a metalloendopeptidase, meprin-α (Mep1A) critically modulates the activity of proteins and inflammatory cytokines in various diseases. Here, we sought to investigate the functional role of Mep1A in AAA formation and rupture. EXPERIMENTAL APPROACH: AAA tissues were detected by using real-time PCR (RT-PCR), western blotting (WB), and immunohistochemistry. Further mechanistic studies used RT-PCR, WB, and enzyme-linked immunosorbent assays. KEY RESULTS: Mep1A mediated AAA formation by regulating the mast cell (MC) secretion of TNF-α, which promoted matrix metalloproteinase (MMP) expression and apoptosis in smooth muscle cells (SMCs). Importantly, increased Mep1A expression was found in human AAA tissues and in angiotensin II-induced mouse AAA tissues. Mep1A deficiency reduced AAA formation and increased the survival rate of AAA mice. Pathological analysis showed that Mep1A deletion decreased elastic lamina degradation and SMC apoptosis in AAA tissues. Furthermore, Mep1A was expressed mainly in MCs, wherein it mediated TNF-α expression. Mep1A inhibitor actinonin significantly inhibited TNF-α secretion in MCs. TNF-α secreted by MCs enhanced MMP2 expression in SMCs and promoted SMC apoptosis. CONCLUSION AND IMPLICATIONS: Taken together, these data suggest that Mep1A may be vital in AAA pathophysiology by regulating TNF-α production by MCs. Knocking out Mep1A significantly decreased AAA diameter and improved AAA stability in mice. Therefore, Mep1A is a potential new therapeutic target in the development of AAA.


Assuntos
Aneurisma da Aorta Abdominal , Animais , Mastócitos , Metaloproteinase 2 da Matriz , Camundongos , Tiopronina , Fator de Necrose Tumoral alfa
11.
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
12.
J Biomol Struct Dyn ; 38(7): 2080-2092, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31184526

RESUMO

Human meprin-ß, a zinc metalloprotease belonging to the astacin family, have been found to be associated with many pathological conditions like inflammatory bowel disease, fibrosis and neurodegenerative disease. The inhibition of meprin-ß by various inhibitors, both macromolecular and small molecules, is crucial in the control of several diseases. Human fetuin-A, a negative acute phase protein involved in inflammatory disease, has recently been identified as an endogenous inhibitor for meprin-ß. In this computational study, an integrated in silico approach was performed using existing structural information of meprin-ß coupled with ab initio modelling of human fetuin-A to predict a rational model of the complex through protein-protein docking. Further, the models were optimized and validated to generate an ensemble of conformations through extensive molecular dynamics simulation. Virtual alanine scanning mutagenesis was explored to identify hotspot residues on both proteins significant for protein-protein interaction (PPI). The results of the study provide structural insight into PPI between meprin-ß and fetuin-A which can be useful in designing molecules to modulate meprin-ß activity. Communicated by Ramaswamy H. Sarma.


Assuntos
Doenças Neurodegenerativas , Tiopronina , Humanos , Metaloproteases , Simulação de Dinâmica Molecular , alfa-2-Glicoproteína-HS
13.
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
14.
Urolithiasis ; 48(4): 313-320, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31834425

RESUMO

Cystinuria comprises less than 1% of kidney stones and is associated with impaired health-related quality of life (HRQOL). Limited evidence is available regarding HRQOL of patients with cystinuria treated with tiopronin (Thiola®). The objective of this study was to assess the HRQOL of patients with or without tiopronin treatment. For this cross-sectional survey, patients on tiopronin treatment were recruited through the "Thiola® Total Care Hub," a specialty pharmacy used to dispense tiopronin, and compared with patients not taking tiopronin (non-tiopronin group) who were identified from the Cystinuria Contact Registry at New York University School of Medicine. Consented patients responded to a survey that included questions about their experiences with kidney stones, the Wisconsin stone quality of life (WISQOL) (disease-specific) questionnaire, and the short form-36 version 2 (SF-36v2) (generic) HRQOL questionnaire. Statistical analyses included independent-sample t tests, one-way analysis of variance (ANOVA), and correlations. The survey was completed by 312 patients: 267 in the tiopronin group (144 male, 123 female; mean 49 years) and 45 in the non-tiopronin group (10 male, 35 female; mean 48 years). Both groups utilized pain medications similarly (24% overall). Patients on tiopronin had a significantly better HRQOL than patients not on tiopronin for all WISQOL domains (p < 0.001) and all but the physical functioning SF-36v2 domain (p < 0.001), where both groups approached the US normative mean, when controlling for the last stone event. Compared with patients in the non-tiopronin group, patients taking tiopronin reported better HRQOL on both the WISQOL and SF-36v2.


Assuntos
Cistinúria/tratamento farmacológico , Qualidade de Vida , Tiopronina/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Cistinúria/complicações , Feminino , Humanos , Cálculos Renais/complicações , Masculino , Pessoa de Meia-Idade , Adulto Jovem
15.
Sci Adv ; 5(10): eaaw6264, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31616782

RESUMO

The development of an efficient delivery system for enhanced and controlled gene interference-based therapeutics is still facing great challenges. Fortunately, the flourishing field of nanotechnology provides more effective strategies for nucleic acid delivery. Here, the triplex-forming oligonucleotide sequence and its complementary strand were used to mediate self-assembly of ultrasmall gold nanoparticles. The obtained sunflower-like nanostructures exhibited strong near-infrared (NIR) absorption and photothermal conversion ability. Upon NIR irradiation, the large-sized nanostructure could disassemble and generate ultrasmall nanoparticles modified with c-myc oncogene silencing sequence, which could directly target the cell nucleus. Moreover, the controlled gene silencing effect could be realized by synergistically controlling the preincubation time with the self-assembled nanostructure (in vitro and in vivo) and NIR irradiation time point. This study provides a new approach for constructing more efficient and tailorable nanocarriers for gene interference applications.


Assuntos
Inativação Gênica , Ouro/química , Nanopartículas Metálicas/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Núcleo Celular/genética , Feminino , Humanos , Células MCF-7 , Nanopartículas Metálicas/uso terapêutico , Camundongos Endogâmicos BALB C , Nanoestruturas/química , Oligonucleotídeos , Regiões Promotoras Genéticas , Ressonância de Plasmônio de Superfície , Fatores de Tempo , Tiopronina/química , Transformação Genética
16.
J Agric Food Chem ; 67(41): 11508-11517, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31538478

RESUMO

Tiopronin, as a novel thiol-containing nucleophile, was introduced for depolymerizing polymeric proanthocyanidins from grape seed into catechins and three new proanthocyanidin-tiopronin degradation products: (+)-catechin-4ß-S-tiopronin methyl ester (CT), (-)-epicatechin-4ß-S-tiopronin methyl ester (ECT), and (-)-epicatechin gallate-4ß-S-tiopronin methyl ester (ECGT). A Box-Behnken design was employed to optimize degradation conditions based on single-factor experiments to obtain target products. Each of the new degradation compounds was isolated by the high-speed counter-current chromatography combined with semipreparative high performance liquid chromatography in large amounts, and then, their structures were identified by 1H NMR, 13C NMR, 2D-NMR, as well as mass spectrometry analysis. The absolute configurations were further confirmed by comparison between the calculated electronic circular dichroism and experimental spectra. Further evaluation of antibacterial activities of these compounds showed that CT and ECT possessed more inhibiting capacity against Staphylococcus aureus and Escherichia coli than parent compound catechin and epicatechin. However, ECGT has no bacteriostatic capacity against these two bacteria.


Assuntos
Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Catequina/química , Distribuição Contracorrente/métodos , Extrato de Sementes de Uva/isolamento & purificação , Extrato de Sementes de Uva/farmacologia , Proantocianidinas/isolamento & purificação , Proantocianidinas/farmacologia , Tiopronina/química , Antibacterianos/química , Cromatografia Líquida de Alta Pressão , Escherichia coli/efeitos dos fármacos , Extrato de Sementes de Uva/química , Proantocianidinas/química , Sementes/química , Espectrometria de Massas por Ionização por Electrospray , Staphylococcus aureus/efeitos dos fármacos , Vitis/química
17.
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
18.
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
19.
Mikrochim Acta ; 186(9): 609, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31392427

RESUMO

Tiopronin is a widely used drug for treatment of cystinuria, rheumatoid arthritis and hepatic disorders. It is also an antidote to heavy metal poisoning and a radioprotective agent. A method is described for rapid and sensitive determination of tiopronin using DNA-stabilized silver nanoclusters (DNA-AgNCs) as a fluorescent probe. Tiopronin can selectively bind to DNA-AgNCs to form a stable Ag-S bond upon which the red photoluminescence (best measured at excitation/emission wavelengths of 590/640 nm) is quenched. The finding is used to design an assay that has a linear response in the 1-150 nM tiopronin concentration range and a 270 pM limit of detection. Compared with previously reported methods, the present approach is more rapid, highly sensitive and selective. It has been successfully applied in the detection of tiopronin in spiked urine and serum, and in pharmaceutical products (tablets and injections). Graphical abstract An ultrasensitive and reliable method for tiopronin assay is developed using red-emissive silver nanoclusters as a fluorescent probe. It has been successfully applied in the determination of tiopronin in biological fluids and pharmaceutical products.


Assuntos
Técnicas Biossensoriais/métodos , DNA/química , Corantes Fluorescentes/química , Limite de Detecção , Nanoestruturas/química , Prata/química , Tiopronina/análise , Sequência de Bases , DNA/genética , Humanos , Tiopronina/sangue , Tiopronina/urina
20.
Int J Mol Sci ; 20(15)2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31357561

RESUMO

Interleukin-11 (IL-11) has been associated with inflammatory conditions, bone homeostasis, hematopoiesis, and fertility. So far, these functions have been linked to classical IL-11 signaling via the membrane bound receptor (IL-11R). However, a signaling cascade via the soluble IL-11R (sIL-11R), generated by proteolytic cleavage, can also be induced. This process is called IL-11 trans-signaling. A disintegrin and metalloprotease 10 (ADAM10) and neutrophil elastase were described as ectodomain sheddases of the IL-11R, thereby inducing trans-signaling. Furthermore, previous studies employing approaches for the stimulation and inhibition of endogenous ADAM-proteases indicated that ADAM10, but not ADAM17, can cleave the IL-11R. Herein, we show that several metalloproteases, namely ADAM9, ADAM10, ADAM17, meprin ß, and membrane-type 1 matrix metalloprotease/matrix metalloprotease-14 (MT1-MMP/MMP-14) when overexpressed are able to shed the IL-11R. All sIL-11R ectodomains were biologically active and capable of inducing signal transducer and activator of transcription 3 (STAT3) phosphorylation in target cells. The difference observed for ADAM10/17 specificity compared to previous studies can be explained by the different approaches used, such as stimulation of protease activity or making use of cells with genetically deleted enzymes.


Assuntos
Proteínas ADAM/metabolismo , Metaloproteinase 14 da Matriz/metabolismo , Receptores de Interleucina-11/metabolismo , Tiopronina/metabolismo , Proteínas ADAM/química , Humanos , Metaloproteinase 14 da Matriz/química , Fosforilação , Proteólise , Receptores de Interleucina-11/química , Receptores de Interleucina-6/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Relação Estrutura-Atividade
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