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3.
Toxicon ; 218: 19-24, 2022 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-36057394

RESUMO

Venoms are evolutionary novelties that have real-world implications due to their impact upon human health. However, relative to the abundant studies of elapid and viperid snake venoms, fewer investigations have been undertaken on those of rear-fanged snakes as they are more problematic for obtaining venom. While most rear-fanged venomous snakes are not considered to be of great medical importance, several species are capable of producing fatalities. Most notable among these are snakes from the genus Rhabdophis, the Asian "keelback" snakes. Prior work have described potent procoagulant toxicity suggesting Factor X and prothrombin activation, but did not investigate the ability to activate other clotting factors. Here we show that in addition to activating both Factor X and prothrombin (with prothrombin twice that of FX), the venom of Rhabdophis subminiatus is able to more potently activate Factor VII (ten times that of prothrombin), while also activating FXII and FIX equipotently to prothrombin, and with FXI also activated but at a much lower level. The ability to activate FVII represents a third convergent evolution of this trait. The Australian elapid clade of [Oxyuranus (taipans) + Pseudonaja (brown snakes)] was the first identified to have evolved this trait. and only recently was it shown to be independently present in another lineage (the Central American viperid species Porthidium volcanicum). In addition, the abilities to activate FXI and FXII are also convergent between R. subminiatus and P. volcanicum, but with R. subminiatus being much more potent. By testing across amphibian, avian, and mammalian plasmas we demonstrate that the venom is potently procoagulant across diverse plasma types. However, consistent with dietary preference, R. subminiatus venom was most potent upon amphibian plasma. While a Rhabdophis antivenom is produced in Japan to treat R. tigrinus envenomings, it is scarce even within Japan and is not exported. As this genus is very wide-ranging in Asia, alternate treatment options are in need of development. Hence we tested the ability of candidate, broad-spectrum enzyme inhibitors to neutralize R. subminiatus venom: marimastat was more effective than prinomastat but both marimastat and prinomastat were significantly more effective than DMPS (2,3-Dimercapto-1-propanesulfonic acid). The findings of this study shed light on the evolution of these fascinating rear-fanged snakes as well as explored their systemic effects upon blood coagulation and point to potential treatment options for the rare, but potentially lethal encounters.


Assuntos
Antivenenos , Colubridae , Animais , Antivenenos/farmacologia , Austrália , Coagulação Sanguínea , Fatores de Coagulação Sanguínea/metabolismo , Fatores de Coagulação Sanguínea/farmacologia , Elapidae/metabolismo , Fator VII/metabolismo , Fator VII/farmacologia , Fator X/metabolismo , Fator X/farmacologia , Humanos , Ácidos Hidroxâmicos , Mamíferos , Compostos Orgânicos , Protrombina , Venenos de Serpentes/farmacologia , Unitiol/metabolismo , Unitiol/farmacologia
4.
Neurotox Res ; 40(5): 1526-1536, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35922689

RESUMO

Ferroptosis is a necrotic cell death caused by lipid oxidation that may be responsible for neural degeneration in Parkinson's disease. We assessed whether three neuronal cell lines are sensitive to killing by ferroptosis. Ferroptosis inducer erastin killed LUHMES neurons at sub-micromolar concentrations, whereas neuronal cells derived from SH-SY5Y cells or neural stem cells were at least 50-fold less sensitive. LUHMES differentiated neurons were likewise sensitive to killing by RSL3 or ML210, inhibitors of the glutathione peroxidase 4 enzyme (GPX4) that consumes GSH to detoxify lipid peroxides. Additional assays showed that erastin, RSL3, and ML210 increased lipid peroxide levels, and that LUHMES neurons were protected from both peroxide accumulation and cell death by ferrostatin-1. A possible role of iron was assessed by evaluating the effects of five metal chelators on cytotoxicity of erastin and RSL3. LUHMES neurons were protected from RSL3 by three of the chelators, 2,3-dimercapto-1-propanesulfonic acid (DMPS), deferoxiprone (DFX), and deferiprone (DFP). Collectively, these results demonstrate the vulnerability of LUHMES neurons to ferroptosis by chemical treatments that disrupt glutathione synthesis, lipid peroxide detoxification, or iron metabolism. The same vulnerabilities may occur in CNS neurons, which reportedly generate low levels of GSH and metallothioneins, limiting their ability to neutralize oxidative stresses and toxic metals. These results suggest a rationale and methods to search for environmental toxicants that may exploit these vulnerabilities and promote neurodegenerative diseases.


Assuntos
Ferroptose , Neuroblastoma , Humanos , Carbolinas/toxicidade , Quelantes , Deferiprona , Neurônios Dopaminérgicos/metabolismo , Glutationa/metabolismo , Ferro/metabolismo , Ferro/toxicidade , Peróxidos Lipídicos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Unitiol
5.
Artigo em Chinês | MEDLINE | ID: mdl-35545590

RESUMO

Objective: To explore the expulsion effect of sodium dimercaptopropanesulfonate (DMPS) on mercury in different organs of mercury poisoning and the therapeutic effect of glutathione (GSH) combined with antioxidant therapy on mercury poisoning. Methods: In February 2019, 50 SPF male SD rats were randomly divided into 5 groups, 10 rats in each group: A (saline negative control group) , B (HgCL2 positive control group) , treatment group (C: intramuscular injection of DMPS 15 mg/kg treatment, D: intramuscular injection of DMPS30 mg/kg treatment, E: intramuscular injection of DMPS 15 mg/kg and intraperitoneal injection of GSH200 mg/kg treatment) . Rats in group B, C, D and E were subcutaneously injected with mercury chloride solution (1 mg/kg) to establish a rat model of subacute mercury poisoning kidney injury. Rats in group A were subcutaneously injected with normal saline. After the establishment of the model, rats in the treatment group were injected with DMPS and GSH. Rats in group A and group B were injected with normal saline. At 21 d (treatment 7 d) and 28 d (treatment 14 d) after exposure, urine and blood samples of 5 rats in each group were collected. Blood biochemistry, urine mercury, urine microalbumin and mercury content in renal cortex, cerebral cortex and cerebellum were detected. Results: After exposure to mercury, the contents of mercury in renal cortex, cerebrum and cerebellum of rats in group B, C, D and E increased, and urine microalbumin increased. Pathology showed renal tubular injury and renal interstitial inflammation. Compared with group B, urinary mercury and renal cortex mercury in group C, D and E decreased rapidly after DMPS treatment, and there was no significant decrease in mercury levels in cerebellum and cerebral cortex of rats, accompanied by transient increase in urinary albumin after DMPS treatment (P<0.05) ; the renal interstitial inflammation in group E was improved after GSH treatment. There was a positive correlation between urinary mercury and the contents of mercury in renal cortex, cerebral cortex and cerebellum (r=0.61, 0.47, 0.48, P<0.05) . Conclusion: DMPS mercury expulsion treatment can significantly reduce the level of metal mercury in the kidney, and there is no significant change in the level of metal mercury in the cortex and cerebellum.


Assuntos
Nefropatias , Intoxicação por Mercúrio , Mercúrio , Animais , Encéfalo/efeitos dos fármacos , Glutationa , Inflamação , Rim/efeitos dos fármacos , Nefropatias/induzido quimicamente , Masculino , Cloreto de Mercúrio/farmacologia , Cloreto de Mercúrio/uso terapêutico , Mercúrio/urina , Intoxicação por Mercúrio/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Solução Salina/farmacologia , Solução Salina/uso terapêutico , Unitiol/farmacologia , Unitiol/uso terapêutico
6.
Environ Toxicol Pharmacol ; 92: 103837, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35248761

RESUMO

The reaction between 2,3-dimercaptopropane-1-sulfonate (DMPS, unithiol) and four phenylarsonic(V) acids, i.e. phenylarsonic acid (PAA), 4-hydroxy-3-nitrophenylarsonic acid (HNPAA), 2-aminophenylarsonic acid (o-APAA) and 4-aminophenylarsonic acid (p-APAA), is investigated in aqueous solution. The pentavalent arsenic compounds are reduced by DMPS to their trivalent analogs and instantly chelated by the vicinal dithiol, forming covalent As-S bonds within a five-membered chelate ring. The different types and positions of polar substituents at the aromatic ring of the arsonic acids influence the reaction rates in the same way as observed for reaction with glutathione (GSH), as well as the syn/anti molar ratio of the diastereomeric products, which was analyzed using time- and temperature-dependent nuclear magnetic resonance (NMR) spectroscopy. Addition of DMPS to the conjugate formed by a phenylarsonic(V) acid and the biologically relevant tripeptide GSH showed the immediate replacement of GSH by chelating DMPS, underlining the importance of dithiols as detoxifying agent.


Assuntos
Arsenicais , Unitiol , Arsenicais/química , Quelantes , Glutationa , Espectroscopia de Ressonância Magnética , Oxirredução , Difração de Raios X
7.
Int J Mol Sci ; 23(3)2022 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-35163756

RESUMO

The increasing antibiotic resistance is a clinical problem worldwide. Numerous Gram-negative bacteria have already become resistant to the most widely used class of antibacterial drugs, ß-lactams. One of the main mechanisms is inactivation of ß-lactam antibiotics by bacterial ß-lactamases. Appearance and spread of these enzymes represent a continuous challenge for the clinical treatment of infections and for the design of new antibiotics and inhibitors. Drug repurposing is a prospective approach for finding new targets for drugs already approved for use. We describe here the inhibitory potency of known detoxifying antidote 2,3-dimercaptopropane-1-sulfonate (unithiol) against metallo-ß-lactamases. Unithiol acts as a competitive inhibitor of meropenem hydrolysis by recombinant metallo-ß-lactamase NDM-1 with the KI of 16.7 µM. It is an order of magnitude lower than the KI for l-captopril, the inhibitor of angiotensin-converting enzyme approved as a drug for the treatment of hypertension. Phenotypic methods demonstrate that the unithiol inhibits natural metallo-ß-lactamases NDM-1 and VIM-2 produced by carbapenem-resistant K. pneumoniae and P. aeruginosa bacterial strains. The 3D full atom structures of unithiol complexes with NDM-1 and VIM-2 are obtained using QM/MM modeling. The thiol group is located between zinc cations of the active site occupying the same place as the catalytic hydroxide anion in the enzyme-substrate complex. The sulfate group forms both a coordination bond with a zinc cation and hydrogen bonds with the positively charged residue, lysine or arginine, responsible for proper orientation of antibiotics upon binding to the active site prior to hydrolysis. Thus, we demonstrate both experimentally and theoretically that the unithiol is a prospective competitive inhibitor of metallo-ß-lactamases and it can be utilized in complex therapy together with the known ß-lactam antibiotics.


Assuntos
Klebsiella pneumoniae/enzimologia , Pseudomonas aeruginosa/enzimologia , Unitiol/farmacologia , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/metabolismo , Carbapenêmicos/farmacologia , Reposicionamento de Medicamentos , Farmacorresistência Bacteriana/efeitos dos fármacos , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Klebsiella pneumoniae/efeitos dos fármacos , Modelos Moleculares , Conformação Proteica , Pseudomonas aeruginosa/efeitos dos fármacos , Relação Quantitativa Estrutura-Atividade , beta-Lactamases/química
8.
Langmuir ; 37(45): 13430-13443, 2021 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-34732050

RESUMO

Dopamine (DA), a naturally occurring neurotransmitter, plays a crucial role in the function of the mammalian nervous system. DA-lipid-membrane interaction is inevitable during the neurotransmission process. In this report, we have studied the interaction of DA with anionic 1,2-dimyristoyl-sn-glycero-3-phospho-l-serine (DMPS), neutral (zwitterionic) 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), and synaptic membrane-mimicking mixed DMPC/DMPS (3:1 molar ratio) model multilamellar vesicle (MLV) membranes. Differential scanning calorimetry (DSC) studies suggest a strong specific interaction of DA with the anionic DMPS membrane, a weak interaction with the zwitterionic DMPC membrane, and a moderate interaction with the mixed DMPC/DMPS (3:1) membrane. The intrinsic fluorescence of DA was used as a new approach to gain a molecular-level understanding of DA-lipid-membrane interaction. Toward this end, a detailed photophysical study of DA, including its steady-state fluorescence anisotropy and fluorescence lifetime, was undertaken for the first time. The partition coefficient, location, and distribution of DA in the DMPS and DMPC model membranes were studied by employing intrinsic fluorescence. The effect of DA on the phase transition of the model membranes was also examined using the intrinsic fluorescence of DA. Zeta potential studies suggest a strong electrostatic interaction of DA with the anionic DMPS membrane and a nonspecific, relatively weak interaction of DA with the zwitterionic DMPC membrane. In addition, we observed cholesterol-induced DA expulsion from both DMPS and DMPC membranes. We believe that this work will provide a more in-depth understanding of DA-membrane interaction at a molecular level.


Assuntos
Dimiristoilfosfatidilcolina , Bicamadas Lipídicas , Ânions , Dopamina , Unitiol
9.
Front Immunol ; 12: 688802, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34177943

RESUMO

Palearctic vipers are medically significant snakes in the genera Daboia, Macrovipera, Montivipera, and Vipera which occur throughout Europe, Central Asia, Near and Middle East. While the ancestral condition is that of a small-bodied, lowland species, extensive diversification has occurred in body size, and niche specialization. Using 27 venom samples and a panel of in vitro coagulation assays, we evaluated the relative coagulotoxic potency of Palearctic viper venoms and compared their neutralization by three antivenoms (Insoserp Europe, VIPERFAV and ViperaTAb) and two metalloprotease inhibitors (prinomastat and DMPS). We show that variation in morphology parallels variation in the Factor X activating procoagulant toxicity, with the three convergent evolutions of larger body sizes (Daboia genus, Macrovipera genus, and Vipera ammodytes uniquely within the Vipera genus) were each accompanied by a significant increase in procoagulant potency. In contrast, the two convergent evolutions of high altitude specialization (the Montivipera genus and Vipera latastei uniquely within the Vipera genus) were each accompanied by a shift away from procoagulant action, with the Montivipera species being particularly potently anticoagulant. Inoserp Europe and VIPERFAV antivenoms were both effective against a broad range of Vipera species, with Inoserp able to neutralize additional species relative to VIPERFAV, reflective of its more complex antivenom immunization mixture. In contrast, ViperaTAb was extremely potent in neutralizing V. berus but, reflective of this being a monovalent antivenom, it was not effective against other Vipera species. The enzyme inhibitor prinomastat efficiently neutralized the metalloprotease-driven Factor X activation of the procoagulant venoms. In contrast, DMPS (2,3-dimercapto-1-propanesulfonic acid), which as been suggested as another potential treatment option in the absence of antivenom, DMPS failed against all venoms tested. Overall, our results highlight the evolutionary variations within Palearctic vipers and help to inform clinical management of viper envenomation.


Assuntos
Antivenenos/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Fragmentos Fab das Imunoglobulinas/farmacologia , Inibidores de Metaloproteinases de Matriz/farmacologia , Compostos Orgânicos/farmacologia , Mordeduras de Serpentes/tratamento farmacológico , Unitiol/farmacologia , Venenos de Víboras/antagonistas & inibidores , Viperidae , Animais , Testes de Coagulação Sanguínea , Evolução Molecular , Humanos , Mordeduras de Serpentes/sangue , Mordeduras de Serpentes/enzimologia , Especificidade da Espécie , Fatores de Tempo , Venenos de Víboras/enzimologia
10.
BMC Pharmacol Toxicol ; 22(1): 25, 2021 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-33941274

RESUMO

BACKGROUND: There are no reports on the incidence of chronic mercury poisoning in a large population in China. This study investigated the epidemiology, clinical manifestations, treatment, and follow-up of Chinese patients with chronic mercury poisoning. METHODS: Data for 288 mercury poisoning patients were collected at our hospital from July 2014 to September 2019, including sex, age, admission time, blood mercury content, urine mercury content, creatinine, urinary mercury/creatinine ratio, 24-h urinary protein levels, electromyography (EMG) findings, renal biopsy, and follow-up. Patient characteristics were evaluated by statistical and correlation analyses. RESULTS: First, mercury poisoning in China mainly occurred through occupational exposure and the inappropriate use of mercury-containing cosmetics and Chinese folk remedies (CFRs). Second, the most common symptoms were nervous system (50.3 %), kidney (16.4 %) and breathing (8.0 %). Mercury poisoning-induced Nephrotic syndrome (NS) and peripheral neuropathy are common long-term complications. The complications of occupational and cosmetics-induced mercury poisoning are consistent with international belief. However, the NS caused by CFRs is mainly membranous nephropathy and the probability of peripheral neuropathy caused by CFRs is higher than other pathogens. Third, follow-up data shows that 13 patients with EMG-confirmed neurological injury, 10 showed full recovery after 38.50 ± 8.03 months. Furthermore, among 18 patients with NS, 15 had normal urine protein and serum albumin levels after 22.67 ± 10.26 months. CONCLUSIONS: Regulation of skin-lightening cosmetic products, safety surveillance of CFRs, and prevention and control of occupational exposure must be improved to decrease the incidence of mercury poisoning in China.


Assuntos
Intoxicação por Mercúrio , Doenças Profissionais , Adolescente , Adulto , Idoso , Anti-Inflamatórios/uso terapêutico , Quelantes/uso terapêutico , Criança , Pré-Escolar , China/epidemiologia , Doença Crônica , Cosméticos/toxicidade , Medicamentos de Ervas Chinesas/toxicidade , Feminino , Seguimentos , Humanos , Masculino , Mercúrio/sangue , Mercúrio/urina , Intoxicação por Mercúrio/sangue , Intoxicação por Mercúrio/tratamento farmacológico , Intoxicação por Mercúrio/epidemiologia , Intoxicação por Mercúrio/urina , Pessoa de Meia-Idade , Doenças Profissionais/sangue , Doenças Profissionais/tratamento farmacológico , Doenças Profissionais/epidemiologia , Doenças Profissionais/urina , Exposição Ocupacional/efeitos adversos , Prednisona/uso terapêutico , Estudos Retrospectivos , Unitiol/uso terapêutico , Adulto Jovem
11.
BMC Neurol ; 20(1): 255, 2020 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-32593295

RESUMO

BACKGROUND: Even though recent research has achieved significant advancement in the development of therapeutic approaches for Wilson's diseases (WD), the current treatment options available for WD are still limited, especially for WD patients with neurological symptoms. This study is intended to compare the therapeutic approaches for WD patients with neurological symptoms receiving either combined sodium 2, 3-dimercapto-1-propane sulfonate (DMPS) and zinc treatment or D-penicillamine (DPA) monotherapy as first-line therapy, and identify the more effective therapeutic approach. METHODS: The case records of 158 patients diagnosed with neurological WD were retrospectively analyzed. These patients treated with intravenous DMPS + Zinc and in combination with oral zinc as a maintenance therapy (Group 1) or DPA alone (Group 2) for 1 year. During the period of treatment, the neurological symptoms of the patients were assessed using the Global Assessment Scale (GAS) and Barthel index. The key hematological and biochemical parameters of the patients (such as the levels of aminotransferase, serum ceruloplasmin, 24-h urine copper excretion), as well as adverse effects were recorded and analyzed. RESULTS: Ninety-three patients in Group 1, displayed decreased GAS scores and increased Barthel indexes consistently in comparison with the baseline (P < 0.01). Among them, 82 patients (88.2%) exhibited significant neurological improvement after 1 year, while 8 patients (8.6%) experienced neurological deterioration. Among the 65 patients in Group 2, 37 patients (58.5%) exhibited neurological improvements, while 17 patients (26.2%) experienced neurological deterioration after 1-year follow up. Six patients discontinued their treatment midway due to their exacerbating neurological symptoms. A comprehensive comparison of the effectiveness of the two courses of treatment revealed that patients in group 1 demonstrated a higher improvement ratio (P < 0.01) and lower worsening ratio of the neurological symptoms for the patients (P < 0.01) in comparison to the patients in group 2. Meanwhile, renal function, liver enzyme and blood cell counts remained stabilized in group1. CONCLUSIONS: This study indicates that the combined therapeutic approach of DPMS and zinc may be a preferred first-line therapy in treating the neurological symptoms of WD, in comparison to the treatment with DPA.


Assuntos
Quelantes/administração & dosagem , Degeneração Hepatolenticular/tratamento farmacológico , Penicilamina/uso terapêutico , Unitiol/administração & dosagem , Zinco/administração & dosagem , Adulto , Quimioterapia Combinada/métodos , Feminino , Humanos , Masculino , Estudos Retrospectivos , Resultado do Tratamento
12.
J Neurol ; 267(6): 1643-1650, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32060651

RESUMO

OBJECTIVE: A randomized-controlled trial comparing study of the changes in brain sensitive-weighted imaging (SWI) of Wilson disease (WD) patients during the treatment with metal chelator was done. METHODS: 100 untreated WD patients (80 cases of cerebral type, 20 cases of hepatic type, age 20.13 ± 9.12 years old) and 20 normal controls were selected. Neurological symptoms were scored using the modified Young scale. Liver function tests and copper indices were collected. All study objects received SWI test of the brain. The values of corrected phase (CP) were calculated on SWI. Cerebral-type WD patients were treated with D-penicillamine (DPA) (group 1) or Dimercaptopropane Sulfonate (DMPS) + Dimercaptosuccinic Acid (DMSA) (group 2). Hepatic-type WD patients were treated with DPA (group 3). All patients received annual neurological symptom score, liver function, copper indices, and SWI examination. RESULTS: At the first year of treatment, score of the modified Young scale in group 2 was lower than that in group 1 (P = 0.023) and lower than that before treatment (P = 0.040). After 2 years of treatment, the score of the modified Young scale in group 1 was lower than that before treatment (P = 0.012). At the second year after treatment, the urinary copper in group 2 was higher than that in group 1 (P = 0.014). Urinary copper was maintained at 200 µg/day in group 1 and 300 µg/day in group 2 after 3 years of treatment. At the first year of treatment, serum copper in group 1 was lower than that in group 2 (P = 0.032). At the first year of treatment, CP values of the pallidum and substantia nigra in group 2 were higher than those in group 1 (P = 0.026, 0.040). At the second year of treatment, CP value of substantia nigra in group 2 was higher than that in group 1 (P = 0.037). After 3 years of treatment, there was no difference in CP values between WD patients and normal controls. CONCLUSIONS: Therapy with DMPS and DMSA improves neurological symptoms of WD patients more quickly and leads to less aggravation, compared with therapy with DPA. The metal content in the brain of WD patients was at a low level after 3 years of treatment. DMPS and DMSA can remove metal from brain tissue faster than DPA.


Assuntos
Quelantes/farmacologia , Globo Pálido/diagnóstico por imagem , Degeneração Hepatolenticular/diagnóstico por imagem , Degeneração Hepatolenticular/tratamento farmacológico , Penicilamina/farmacologia , Substância Negra/diagnóstico por imagem , Unitiol/farmacologia , Adolescente , Adulto , Cobre/sangue , Cobre/urina , Feminino , Degeneração Hepatolenticular/sangue , Degeneração Hepatolenticular/urina , Humanos , Imageamento por Ressonância Magnética , Masculino , Avaliação de Resultados em Cuidados de Saúde , Adulto Jovem
13.
Protein Pept Lett ; 27(8): 801-807, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32003653

RESUMO

BACKGROUND: Ionic complementary peptide EAK-16 has been studies for anticancer drug delivery application. This is a 16 residues, short sequence peptide has ability to trosnform into micro/nanoparticle via self-assembly. However, it is still not clear that how this can bind with cell membrane to induce membrane leakage or delivering their cargo inside cell membrane. OBJECTIVE: The main objective of this work was to understand behaviour of secondary structure conformation of peptide in solution and at lipid membrane interfaces and membrane permeability of synthetic ionic complementary peptide EAK-16. The corresponding secondary structure conformation was evaluated. METHODS: We performed biophysical investigation to probe the interaction of synthesised ionic complementary peptide (EAK-16) with dimyristoylphospholcholine (DMPC) and dimyristoylphosphoserine (DMPS) membrane interfaces. The folding behaviours of EAK-16 were studied with Circular Dichroism (CD) spectroscopy. Membrane leakage with peptide was confirmed with calcein leakage assay. RESULTS: Our finding of this study showed that in aqueous phase EAK-16 was predominantly folded into ß-sheets. The temperature could alter the ß-sheets. However, in DMPC and DMPS membrane interfaces, EAK-16 adopted helical conformation. EAK-16 has preference in perturbing anionic compared Zwitterionic lipid vesicles. This study proposed that hydrophobic grooves of EAK-16 might be a key in the association with lipid bilayers. Secondly, a charge distribution of ionic residues would also support the orientation at lipid bilayers. This peptide membrane association would facilitate the membrane destabilisation. CONCLUSION: This study demonstrated the supporting evidence that EAK-16 could interact with lipid membranes and conforming to helical structure, while the helical conformation induced the lipid membrane leakage. Overall, this study provides a physical rationale that ionic complementary peptide can be a useful tool for designing and development of novel antibiotics and anticancer agents along its previous drug delivery applications.


Assuntos
Dimiristoilfosfatidilcolina/química , Bicamadas Lipídicas/química , Peptídeos/química , Unitiol/química , Conformação Proteica em Folha beta
14.
Biomolecules ; 10(2)2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-32033229

RESUMO

: High arsenic (As) levels in food and drinking water, or under some occupational conditions, can precipitate chronic toxicity and in some cases cancer. Millions of people are exposed to unacceptable amounts of As through drinking water and food. Highly exposed individuals may develop acute, subacute, or chronic signs of poisoning, characterized by skin lesions, cardiovascular symptoms, and in some cases, multi-organ failure. Inorganic arsenite(III) and organic arsenicals with the general formula R-As2+ are bound tightly to thiol groups, particularly to vicinal dithiols such as dihydrolipoic acid (DHLA), which together with some seleno-enzymes constitute vulnerable targets for the toxic action of As. In addition, R-As2+-compounds have even higher affinity to selenol groups, e.g., in thioredoxin reductase that also possesses a thiol group vicinal to the selenol. Inhibition of this and other ROS scavenging seleno-enzymes explain the oxidative stress associated with arsenic poisoning. The development of chelating agents, such as the dithiols BAL (dimercaptopropanol), DMPS (dimercapto-propanesulfonate) and DMSA (dimercaptosuccinic acid), took advantage of the fact that As had high affinity towards vicinal dithiols. Primary prevention by reducing exposure of the millions of people exposed to unacceptable As levels should be the prioritized strategy. However, in acute and subacute and even some cases with chronic As poisonings chelation treatment with therapeutic dithiols, in particular DMPS appears promising as regards alleviation of symptoms. In acute cases, initial treatment with BAL combined with DMPS should be considered.


Assuntos
Antídotos/uso terapêutico , Intoxicação por Arsênico/tratamento farmacológico , Arsênio/toxicidade , Quelantes/uso terapêutico , Animais , Antídotos/química , Antídotos/farmacologia , Arsênio/efeitos adversos , Intoxicação por Arsênico/etiologia , Intoxicação por Arsênico/metabolismo , Arsenicais/efeitos adversos , Quelantes/química , Quelantes/farmacologia , Dimercaprol/análogos & derivados , Dimercaprol/farmacologia , Dimercaprol/uso terapêutico , Água Potável/efeitos adversos , Humanos , Modelos Moleculares , Exposição Ocupacional/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , Succímero/química , Succímero/farmacologia , Succímero/uso terapêutico , Unitiol/química , Unitiol/farmacologia , Unitiol/uso terapêutico , Poluentes Químicos da Água/efeitos adversos , Poluentes Químicos da Água/toxicidade
15.
BMC Nephrol ; 20(1): 374, 2019 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-31623560

RESUMO

BACKGROUND: Heavy metal poisoning can cause debilitating illness if left untreated, and its management in anuric patients poses challenges. Literature with which to guide clinical practice in this area is rather scattered. CASE PRESENTATION: We present a case of symptomatic lead and arsenic poisoning from use of Ayurvedic medicine in a 28-year-old man with end-stage kidney disease on chronic hemodialysis. We describe his treatment course with chelating agents and extracorporeal blood purification, and review the relevant literature to provide general guidance. CONCLUSION: Cumulative clinical experience assists in identifying preferred chelators and modalities of extracorporeal blood purification when managing such patients. However, a larger body of real-world or clinical trial evidence is necessary to inform evidence-based guidelines for the management of heavy metal poisoning in anuric patients.


Assuntos
Anuria/complicações , Intoxicação por Arsênico/terapia , Quelantes/uso terapêutico , Terapia de Substituição Renal Contínua , Falência Renal Crônica/complicações , Intoxicação por Chumbo/terapia , Adulto , Animais , Intoxicação por Arsênico/complicações , Dimercaprol/uso terapêutico , Ácido Edético/uso terapêutico , Humanos , Falência Renal Crônica/terapia , Intoxicação por Chumbo/complicações , Masculino , Diálise Renal , Succímero/uso terapêutico , Unitiol/uso terapêutico
16.
Pediatr Emerg Care ; 35(10): 696-699, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27977534

RESUMO

OBJECTIVE: Elemental mercury is a toxic liquid element that is used widely in the home, medicine, agriculture, and industry. It is readily vaporized and inhaled at room temperature. Thereby, inhalation can cause acute or chronic poisoning. Mercury can be found in environmental naturally find but some dangers sources give rise to contaminations. It can be very dangerous to all living organisms, especially children. METHODS: This study presents the features of mercury poisoning in a group of pediatric cases. Data were obtained for 29 pediatric cases exposed to elemental mercury in a high school chemistry laboratory in Turkey. Patients with a blood mercury level exceeding 10 µg/L or a urine mercury level exceeding 15 µg/L were considered to have mercury poisoning. The patients were treated with 2,3-dimercaptopropane sulfonic acid or D-penicillamine. RESULTS: Twenty-nine children with mercury poisoning were admitted to the hospital. The median duration of exposure was 58 (range, 15-120) minutes. Ten (29%) children were asymptomatic. Physical and neurological examinations were normal in 19 (65.5%) children. The most common presenting complaint was headache. The most common neurological abnormality, partly dilated/dilated pupils, was present in 9 (31%) children. Mercury levels were measured in blood samples every 5 days, and the median blood mercury level was 51.98 (range, 24.9-86.4) µg/L. There was a positive correlation between the duration of exposure and maximum blood/urine mercury levels (P = 0.001). CONCLUSIONS: Elemental mercury exposure is potentially toxic; its symptomatology varies, especially in children. Secure storage of mercury and other toxic substances and provision of information about this subject to individuals who might be exposed to mercury and their families might help to prevent mercury poisoning.


Assuntos
Exposição Ambiental/efeitos adversos , Intoxicação por Mercúrio/diagnóstico , Mercúrio/sangue , Instituições Acadêmicas/estatística & dados numéricos , Doença Aguda , Adolescente , Quelantes/uso terapêutico , Criança , Feminino , Humanos , Masculino , Mercúrio/urina , Intoxicação por Mercúrio/tratamento farmacológico , Intoxicação por Mercúrio/patologia , Medicina de Emergência Pediátrica , Penicilamina/uso terapêutico , Turquia/epidemiologia , Unitiol/uso terapêutico
17.
Acta Clin Belg ; 74(3): 200-202, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29912651

RESUMO

BACKGROUND: Fixed drug eruptions (FDE) are characterized by recurrent, usually solitary erythematous or dark red macular, plaque or bullous lesions, all at the same site. Among the first choices for antidotal treatment in mercury exposure, 2,3-dimercapto-1-propanesulfonic acid (DMPS) is generally a drug with a low incidence of side effects. FDE due to DMPS was not detected in our literature research and so we aimed to present this rare case. CASE REPORT: Forty-eight-year-old male patient, gunpowder and explosives factory worker, was admitted to our hospital because of mercury exposure and we started DMPS treatment. On the second day of chelation treatment, swelling and felting on lips and complaints of wound formation in genital areas started. Annular, purple color plaque on penis with no angioedema was observed. Case was regarded as FDE. Systemic and topical steroid therapy was started after termination of chelation therapy and lesions regressed with steroids. DISCUSSION: Drug eruptions are substantially common dermatological problems and can be seen in about 2.2% of inpatients. The most common unexpected effects of DMPS are allergic skin reactions. The clinical state regress rapidly after the cessation of chelation therapy.


Assuntos
Quelantes/efeitos adversos , Erupção por Droga/tratamento farmacológico , Intoxicação por Mercúrio/tratamento farmacológico , Unitiol/efeitos adversos , Quelantes/uso terapêutico , Erupção por Droga/etiologia , Glucocorticoides/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Doenças do Pênis/induzido quimicamente , Doenças do Pênis/tratamento farmacológico , Unitiol/uso terapêutico
18.
Medicine (Baltimore) ; 97(50): e13744, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30558096

RESUMO

RATIONALE: Both Wilson disease (WD) and Oculocutaneous Albinism (OCA) are rare autosomal recessive disorders that are caused by mutations on chromosome 13 and chromosome 11, respectively. Here, we report on a patient with coexisting WD and OCA, initially presenting episodes of tremors. PATIENT CONCERNS: WD is a disorder of copper metabolism. The main sites of copper accumulation are the liver and the brain, resulting in hepatic symptoms. OCA is a disorder of melanin biosynthesis, characterized by a generalized reduction in pigmentation of the eyes (oculo-), skin (-cutaneous), and hair. DIAGNOSIS: The diagnosis of WD was confirmed by neurological symptoms, metabolism tests, and MRI scans. Interestingly, the patient also had very light skin color, blond hair and eyebrows, and dark brown eyelashes and irises. Because the association of dermatologic signs in WD has rarely been reported, OCA was highly suspected based on these clinical findings. Genetic analysis was subsequently conducted, and the results revealed the p. (Arg778Leu) mutation in 1 allele and the p. (Asn1270Ser) mutation in the other allele of the ATP7B gene, confirming the diagnosis of WD; the p. (D456fs) mutation in 1 allele and the p. (R299H) mutation in the other allele of the TYR gene, confirming the diagnosis of OCA. The family history was positive for WD with a 14-year-old younger brother also being diagnosed with it. Her parents are negative for OCA and WD. INTERVENTIONS: Sodium dimercaptopropanesulfonate (DMPS) was given during hospitalization. D-penicillamine and zinc sulfate treatment was initiated after discharge for long-term control. OUTCOMES: Postural and intention tremor disappeared, and other symptoms and signs markedly improved after treatment. LESSONS: In this study, we reported on the first case of a child who simultaneously presented WD and OCA, bringing up the possibility of a presumable link between these 2 rare diseases.


Assuntos
Albinismo Oculocutâneo/complicações , Albinismo Oculocutâneo/metabolismo , Degeneração Hepatolenticular/complicações , Degeneração Hepatolenticular/metabolismo , Albinismo Oculocutâneo/diagnóstico , Albinismo Oculocutâneo/genética , Povo Asiático/genética , Adstringentes/uso terapêutico , Quelantes/uso terapêutico , Feminino , Degeneração Hepatolenticular/diagnóstico por imagem , Degeneração Hepatolenticular/tratamento farmacológico , Humanos , Imageamento por Ressonância Magnética/métodos , Mutação , Penicilamina/administração & dosagem , Penicilamina/uso terapêutico , Resultado do Tratamento , Unitiol/administração & dosagem , Unitiol/uso terapêutico , Adulto Jovem , Sulfato de Zinco/administração & dosagem , Sulfato de Zinco/uso terapêutico
19.
Retina ; 38(9): 1688-1698, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28723845

RESUMO

PURPOSE: Ophthalmologists serve an increasing volume of a growing elderly population undergoing increasingly complex outpatient medical care, including extensive diagnostic testing and treatment. The resulting prolonged patient visit times ("patient flow times") limit quality, patient and employee satisfaction, and represent waste. Lean Six Sigma process improvement was used in a vitreoretinal practice to decrease patient flow time, demonstrating that this approach can yield significant improvement in health care. METHODS: Process flow maps were created to determine the most common care pathways within clinic. Three months' visits from the electronic medical record system, which tracks patient task times at each process step in the office were collected. Care tasks and care pathways consuming the greatest time and variation were identified and modified. Follow-up analysis from 6 weeks' visits was conducted to assess improvement. RESULTS: Nearly all patients took one of five paths through the office. Patient flow was redesigned to reduce waiting room time by having staff members immediately start patients into one of those five paths; staffing was adjusted to address high demand tasks, and scheduling was optimized around derived predictors of patient flow times. Follow-up analysis revealed a statistically significant decline in mean patient flow time by 18% and inpatient flow time SD by 4.6%. Patient and employee satisfaction scores improved. CONCLUSION: Manufacturing industry techniques, such as Lean and Six Sigma, can be used to improve patient care, minimize waste, and enhance patient and staff satisfaction in outpatient clinics.


Assuntos
Instituições de Assistência Ambulatorial/normas , Eficiência Organizacional , Oftalmopatias/terapia , Oftalmologia , Satisfação do Paciente , Gestão da Qualidade Total , Fluxo de Trabalho , Humanos , Unitiol
20.
J Tradit Chin Med ; 38(5): 781-786, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-32185997

RESUMO

OBJECTIVE: To evaluate the efficacy and safety of gandouling plus sodium dimercaptosulphonate (DMPS) on neurological Wilson's disease (WD) in patients. METHODS: We retrospectively evaluated the clinical records of 125 WD patients with neurological syndromes who were treated with gandouling plus sodium DMPS or DMPS used alone. All patients had a history of neurological deterioration during their diseases courses. The clinical efficacies, adverse reactions, and results of the various hematological and biochemical investigations were recorded for statistical analysis. RESULTS: 92.30% (60 patients) of the WD patients treated with the combined therapy experienced an improved or stable neurological condition paralleled by a significantly improved GAS score. Meanwhile, the WBC and PLT counts stabilized, liver function and renal function were improved or remained stable. The combined therapy also obviously promoted the 24-h urinary copper excretion. In particular, only 30.76% of the WD patients experienced mild adverse reactions, including neurological deterioration in 5 patients (7.69%), hepatic worsening in 1 subject (1.89%), which was less frequently than those in the control group treated with DMPS only. CONCLUSION: Our findings indicate that the safety and efficacy of gandou-ling plus DMPS is superior to those of DMPS used alone in the WD patients with neurological symptoms.


Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , Degeneração Hepatolenticular/tratamento farmacológico , Unitiol/administração & dosagem , Adolescente , Adulto , China , Quimioterapia Combinada/efeitos adversos , Medicamentos de Ervas Chinesas/efeitos adversos , Feminino , Degeneração Hepatolenticular/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Unitiol/efeitos adversos , Adulto Jovem
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