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1.
Int J Mol Sci ; 20(15)2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31390813

RESUMO

Nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome P450 reductases (CPRs) function as redox partners of cytochrome P450 monooxygenases (P450s). CPRs and P450s in insects have been found to participate in insecticide resistance. However, the CPR of the moth Spodoptera litura has not been well characterized yet. Based on previously obtained transcriptome information, a full-length CPR cDNA of S. litura (SlCPR) was PCR-cloned. The deduced amino acid sequence contains domains and residues predicted to be essential for CPR function. Phylogenetic analysis with insect CPR amino acid sequences showed that SlCPR is closely related to CPRs of Lepidoptera. Quantitative reverse transcriptase PCR (RT-qPCR) was used to determine expression levels of SlCPR in different developmental stages and tissues of S. litura. SlCPR expression was strongest at the sixth-instar larvae stage and fifth-instar larvae showed highest expression in the midgut. Expression of SlCPR in the midgut and fat body was strongly upregulated when fifth-instar larvae were exposed to phoxim at LC15 (4 µg/mL) and LC50 (20 µg/mL) doses. RNA interference (RNAi) mediated silencing of SlCPR increased larval mortality by 34.6% (LC15 dose) and 53.5% (LC50 dose). Our results provide key information on the SlCPR gene and indicate that SlCPR expression levels in S. litura larvae influence their susceptibility to phoxim and possibly other insecticides.


Assuntos
Inativação Gênica , Resistência a Inseticidas/genética , Inseticidas/farmacologia , NADPH-Ferri-Hemoproteína Redutase/genética , Compostos Organotiofosforados/farmacologia , Spodoptera/efeitos dos fármacos , Spodoptera/genética , Sequência de Aminoácidos , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Larva , NADPH-Ferri-Hemoproteína Redutase/metabolismo , Filogenia , Interferência de RNA , Spodoptera/classificação , Spodoptera/metabolismo
2.
Food Chem Toxicol ; 131: 110543, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31154084

RESUMO

A dual role of hydrogen sulfide (H2S) in inflammation is well-reported and recent studies demonstrated adipogenic effects of H2S in 3T3-L1 cells. Here, we aimed to investigate the effects of H2S on adipocyte differentiation and inflammation. H2S concentration in 3T3-L1 culture media was increased during adipocyte differentiation in parallel to adipogenic and Cth gene expression, and its inhibition using DL-Propargyl Glycine (PPG) impaired 3T3-L1 differentiation. GYY4137 and Na2S administration only in the first or in the last stage of adipocyte differentiation resulted in a significant increased expression of adipogenic genes. However, when GYY4137 or Na2S were administrated during all process no significant effects on adipogenic gene expression were found, suggesting that excessive H2S administration might exert negative effects on adipogenesis. In fact, continuous addition of Na2S, which resulted in Na2S excess, inhibited adipogenesis, whereas time-expired Na2S had no effect. In inflammatory conditions, GYY4137, but not Na2S, administration attenuated the negative effects of inflammation on adipogenesis and insulin signaling-related gene expression during adipocyte differentiation. In inflamed adipocytes, Na2S administration enhanced the negative effects of inflammatory process. Altogether these data showed that slow-releasing H2S improved adipocyte differentiation in inflammatory conditions, and that H2S proadipogenic effects depend on dose, donor and exposure time.


Assuntos
Adipócitos/efeitos dos fármacos , Sulfeto de Hidrogênio/metabolismo , Morfolinas/farmacologia , Compostos Organotiofosforados/farmacologia , Sulfetos/farmacologia , Células 3T3-L1 , Adipogenia/efeitos dos fármacos , Adipogenia/fisiologia , Alquinos/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Glicina/análogos & derivados , Glicina/farmacologia , Inflamação/fisiopatologia , Camundongos
3.
J Enzyme Inhib Med Chem ; 34(1): 1018-1029, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31074292

RESUMO

7-methoxytacrine-4-pyridinealdoxime (7-MEOTA-4-PA, named hybrid 5C) is a compound formerly synthesized and evaluated in vitro, together with 4-pyridine aldoxime (4-PA) and commercial reactivators of acetylcholinesterase (AChE). This compound was designed with the purpose of being a prophylactic reactivator, capable of interacting with different subdomains of the active site of AChE. To investigate these interactions, theoretical results from docking were first compared with experimental data of hybrid 5C, 4-PA, and two commercial oximes, on the reactivation of human AChE (HssAChE) inhibited by VX. Then, further docking studies, molecular dynamics simulations, and molecular mechanics Poisson-Boltzmann surface area calculations, were carried out to investigate reactivation performances, considering the near attack conformation (NAC) approach, prior to the nucleophilic substitution mechanism. Our results helped to elucidate the interactions of such molecules with the different subdomains of the active site of HssAChE. Additionally, NAC poses of each oxime were suggested for further theoretical studies on the reactivation reaction.


Assuntos
Inibidores da Colinesterase/farmacologia , Cloreto de Obidoxima/farmacologia , Compostos Organotiofosforados/farmacologia , Oximas/farmacologia , Compostos de Pralidoxima/farmacologia , Piridinas/farmacologia , Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Cloreto de Obidoxima/química , Compostos Organotiofosforados/química , Oximas/química , Compostos de Pralidoxima/química , Piridinas/química , Relação Estrutura-Atividade
4.
Food Chem Toxicol ; 127: 218-227, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30910686

RESUMO

Edifenphos (EDF) is an Organophosphorus pesticide and used in agriculture for pest control. However, EDF has been shown to accumulate in agricultural products and causes hazards to human health. Although reports are available regarding environmental impact of EDF, toxic effects of EDF on human cellular system especially immune cells have not been elucidated. In this study, genotoxicity and cytotoxicity of EDF on human peripheral blood lymphocytes and its amelioration by apigenin (dietary flavonoid) was investigated. We demonstrated that EDF inhibited cell viability, and induced oxidative stress and DNA damage in lymphocytes. In addition, results indicate that EDF induced apoptosis in lymphocytes concurrent with ROS generation, loss of mitochondrial membrane potential, up-regulation of Bax and caspase-9/-3 activation. Mechanistically, incubation of lymphocytes with N-acetylcysteine (ROS scavenger) abrogated the ROS generation and apoptosis caused by EDF. These findings suggest that ROS generation by EDF acts as an upstream signal leading to DNA damage and apoptosis in lymphocytes. This study also showed that apigenin could potentially attenuate EDF-induced oxidative stress, DNA damage and apoptosis in lymphocytes. Collectively, these results suggest that EDF exerts cytotoxicity and DNA damage in lymphocytes, and apigenin could be a potent dietary anti-oxidant regimen against EDF-induced toxicity on human health.


Assuntos
Apigenina/farmacologia , Dano ao DNA , Linfócitos/efeitos dos fármacos , Compostos Organotiofosforados/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Acetilcisteína/farmacologia , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 9/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Linfócitos/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Carbonilação Proteica , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteína X Associada a bcl-2/metabolismo
5.
Surgery ; 165(5): 1014-1026, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30824287

RESUMO

BACKGROUND: Lung ischemia-reperfusion injury is a complex pathophysiologic process associated with high morbidity and mortality. We have demonstrated elsewhere that diabetes mellitus aggravated ischemia-induced lung injury. Oxidative stress and mitochondrial dysfunction are drivers of diabetic lung ischemia-reperfusion injury; however, the pathways that mediate these events are unexplored. In this study using a high-fat diet-fed model of streptozotocin-induced type 2 diabetes in rats, we determined the effect of hydrogen sulfide on lung ischemia-reperfusion injury with a focus on Sirtuin3 signaling. METHODS: Rats with type 2 diabetes were exposed to GYY4137, a slow release donor of hydrogen sulfide with or without administration of the Sirtuin3 short hairpin ribonucleic acid plasmid, and then subjected to a surgical model of ischemia-reperfusion injury of the lung (n = 8). Lung function, oxidative stress, inflammation, cell apoptosis, and mitochondrial function were measured. RESULTS: Compared with nondiabetic rats, animals with type 2 diabetes at baseline exhibited significantly decreased Sirtuin3 signaling in lung tissue and increased oxidative stress, apoptosis, inflammation, and mitochondrial dysfunction (P < .05 each). In addition, further impairment in Sirtuin3 signaling was found in diabetic rats subjected to this model of lung ischemia-reperfusion. Simultaneously, the indexes showed further aggravation. Treatment with hydrogen sulfide restored Sirtuin3 expression and decreased lung ischemia-reperfusion injury in animals with type 2 diabetes mellitus by improving lung functional recovery, decreasing oxidative damage, suppressing inflammation, ameliorating cell apoptosis, and preserving mitochondrial function (P < .05). Conversely, these protective effects were largely reversed in Sirtuin3 knockdown rats. CONCLUSION: Impaired lung Sirtuin3 signaling associated with type 2 diabetic conditions was further attenuated by an ischemia-reperfusion insult. Hydrogen sulfide ameliorated reperfusion-induced oxidative stress and mitochondrial dysfunction via activation of Sirtuin3 signaling, thereby decreasing lung ischemia-reperfusion damage in rats with a model of type II diabetes.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Sulfeto de Hidrogênio/farmacologia , Lesão Pulmonar/prevenção & controle , Mitocôndrias/efeitos dos fármacos , Sirtuínas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/patologia , Dieta Hiperlipídica/efeitos adversos , Avaliação Pré-Clínica de Medicamentos , Humanos , Sulfeto de Hidrogênio/uso terapêutico , Pulmão/efeitos dos fármacos , Pulmão/patologia , Lesão Pulmonar/etiologia , Lesão Pulmonar/patologia , Masculino , Mitocôndrias/metabolismo , Morfolinas/farmacologia , Compostos Organotiofosforados/farmacologia , Estresse Oxidativo/efeitos dos fármacos , RNA Interferente Pequeno/metabolismo , Ratos , Traumatismo por Reperfusão/complicações , Transdução de Sinais/efeitos dos fármacos , Sirtuínas/genética , Estreptozocina/toxicidade
6.
Mol Biol (Mosk) ; 53(1): 101-108, 2019.
Artigo em Russo | MEDLINE | ID: mdl-30895957

RESUMO

Lipopolysaccharides (LPS), components of the cell wall of gram-negative bacteria, activate neutrophils that trigger pathological processes, including gram-negative sepsis. LPS inhibit spontaneous apoptosis of neutrophils that leads to inflammation. In this work we tested the action of H2S donor (GYY4137) on the activation of human neutrophils by E. coli LPS. We estimated the changes in redox status (ROS level, intracellularglutathione, NO), apoptosis and mitochondrial potential of neutrophils under the LPS action in the presence and absence of GYY4137. GYY4137 reduces the ROS level, slightly reduces GSH, does not influence the NO level and has no apoptogenic effect. LPS induce the increasing of ROS level and inhibit spontaneous apoptosis of neutrophils. We found that GYY4137 prevents the growth of ROS caused by LPS and leads to a reduction of LPS-induced inhibition of neutrophil apoptosis. Thus the mechanism of GYY4137 protection against inflammation, triggered by bacterial infection, is concerned with the neutralization of LPS effect on neutrophils.


Assuntos
Apoptose , Sulfeto de Hidrogênio/farmacologia , Morfolinas/farmacologia , Neutrófilos/efeitos dos fármacos , Compostos Organotiofosforados/farmacologia , Células Cultivadas , Escherichia coli , Humanos , Inflamação , Lipopolissacarídeos , Óxido Nítrico/metabolismo , Espécies Reativas de Oxigênio/metabolismo
7.
Nitric Oxide ; 87: 1-9, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30849492

RESUMO

We explored possibility that sodium/calcium exchanger 1 (NCX1) is involved in pH modulation and apoptosis induction in GYY4137 treated cells. We have shown that although 10 days treatment with GYY4137 did not significantly decreased volume of tumors induced by colorectal cancer DLD1 cells in nude mice, it already induced apoptosis in these tumors. Treatment of DLD1 and ovarian cancer A2780 cells with GYY4137 resulted in intracellular acidification in a concentration-dependent manner. We observed increased mRNA and protein expression of both, NCX1 and sodium/hydrogen exchanger 1 (NHE1) in DLD1-induced tumors from GYY4137-treated mice. NCX1 was coupled with NHE1 in A2780 and DLD1 cells and this complex partially disintegrated after GYY4137 treatment. We proposed that intracellular acidification is due to uncoupling of NCX1/NHE1 complex rather than blocking of the reverse mode of NCX1, probably due to internalization of NHE1. Results might contribute to understanding molecular mechanism of H2S-induced apoptosis in tumor cells.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Sulfeto de Hidrogênio/metabolismo , Morfolinas/farmacologia , Compostos Organotiofosforados/farmacologia , Trocador de Sódio e Cálcio/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Camundongos Nus , Trocador 1 de Sódio-Hidrogênio/metabolismo
8.
Can J Physiol Pharmacol ; 97(7): 655-660, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30870598

RESUMO

The present study was undertaken to explore the therapeutic potential of hydrogen sulfide against bone loss induced by modeled microgravity. Hindlimb suspension (HLS) and rotary wall vessel bioreactor were applied to model microgravity in vivo and in vitro, respectively. Treatment of rats with GYY4137 (a water soluble donor of hydrogen sulfide, 25 mg/kg per day, i.p.) attenuated HLS-induced reduction of bone mineral density in tibiae, and preserved bone structure in tibiae and mechanical strength in femurs. In HLS group, GYY4137 treatment significantly increased levels of osteocalcin in sera. Interestingly, treatment of HLS rats with GYY4137 enhanced osteoblast surface, but had no significant effect on osteoclast surface of proximal tibiae. In MC3T3-E1 cells exposed to modeled microgravity, GYY4137 stimulated transcriptional levels of runt-related transcription factor 2 and enhanced osteoblastic differentiation, as evidenced by increased mRNA expression and activity of alkaline phosphatase. HLS in rats led to enhanced levels of interleukin 6 in sera, skeletal muscle, and tibiae, which could be attenuated by GYY4137 treatment. Our study showed that GYY4137 preserved bone structure in rats exposed to HLS and promoted osteoblastic differentiation in MC3T3-E1 cells under modeled microgravity.


Assuntos
Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/etiologia , Sulfeto de Hidrogênio/metabolismo , Simulação de Ausência de Peso/efeitos adversos , Células 3T3 , Animais , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Diferenciação Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Sulfeto de Hidrogênio/sangue , Interleucina-6/metabolismo , Masculino , Camundongos , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Compostos Organotiofosforados/farmacologia , Compostos Organotiofosforados/uso terapêutico , Osteoblastos/efeitos dos fármacos , Osteoblastos/patologia , Ratos , Ratos Sprague-Dawley
9.
Pulm Pharmacol Ther ; 54: 77-86, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30605726

RESUMO

GYY4137, a slow-releasing hydrogen sulfide (H2S) donor, has been reported to exert anti-inflammatory activity and protect against sepsis. Heme oxygenase-1 (HO-1) is an important anti-inflammatory heat shock protein and plays a similar effect on sepsis. This study investigated the role of GYY4137 in acute lung injury (ALI) via HO-1 regulation. Lung injury was assessed in mice challenged with intratracheal lipopolysaccharide (LPS) and the mechanism of anti-inflammatory effects of GYY4137 was investigated in mice and RAW264.7 cells. GYY4137 reduced the LPS-mediated pulmonary injury and neutrophil infiltration, and inhibited the LPS-induced production of proinflammatory cytokines, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression. Moreover, GYY4137 suppressed the LPS-evoked NF-κB activation in RAW264.7 cells. GYY4137, not time-expired GYY4137 significantly induced HO-1 expression compared with the LPS group. The beneficial effects of GYY4137 above were reversed by the HO-1 inhibitor tin protoporphyrin (SnPP). These results suggest an anti-inflammatory effect and a therapeutic role of GYY4137 in LPS-induced ALI via HO-1 regulation.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Heme Oxigenase-1/metabolismo , Morfolinas/farmacologia , Compostos Organotiofosforados/farmacologia , Lesão Pulmonar Aguda/patologia , Animais , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Inflamação/tratamento farmacológico , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Masculino , Metaloporfirinas/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo II/metabolismo , Protoporfirinas/farmacologia , Células RAW 264.7
10.
Peptides ; 111: 89-97, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29684589

RESUMO

Hydrogen sulfide (H2S) is normally produced from l-cysteine in mammalian tissues and related to the pathogenesis of cardiovascular diseases. The aim of this study is to investigate the effects of H2S donor on atrial natriuretic peptide (ANP) secretion and define its mechanism using normal and isoproterenol (ISP)-treated rats. Several H2S donors were perfused into isolated beating rat atria, and atrial pressure (AP) and ANP secretion were measured. NaHS augmented high stretch-induced ANP secretion and decreased AP in a dose-dependent manner. The high stretch-induced ANP secretion was stimulated by Na2S but was not changed by GYY4137 and sodium thiosulfate. NaHS and Na2S produced very high amount of H2S rapidly whereas GYY4137 produced very low amount of H2S slowly. NaHS-stimulated ANP secretion was blocked by the pretreatment with inhibitor for KATP channel, nitric oxide synthase (NOS), soluble guanylyl cyclase (sGC), phosphoinositol 3 kinase (PI3K) or protein kinase B. H2S synthesis enzyme inhibitor (DL-propargylglycine) did not show any significant changes in atrial parameters. However, the response of ANP secretion to NaHS markedly attenuated and DL-propargylglycine suppressed ANP secretion in ISP-treated rat atria. The expression of eNOS protein was decreased but the expression of cardiomyocyte-specific H2S producing enzyme, cystathione γ-lyase, was not changed in ISP-treated rat atria. The attenuation of NaHS-induced ANP secretion in ISP-treated rat atria may be due to the low expression of eNOS protein. These findings clarify that NaHS stimulates ANP secretion via the KATP channel and the PI3K/Akt/NOS/sGC pathway in rat atria.


Assuntos
Fator Natriurético Atrial/metabolismo , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/metabolismo , Sulfeto de Hidrogênio/farmacologia , Canais KATP/metabolismo , Óxido Nítrico Sintase/metabolismo , Guanilil Ciclase Solúvel/metabolismo , Animais , Técnicas In Vitro , Masculino , Morfolinas/farmacologia , Compostos Organotiofosforados/farmacologia , Radioimunoensaio , Ratos , Ratos Sprague-Dawley , Sulfetos/farmacologia , Tiossulfatos/farmacologia
11.
J Surg Res ; 234: 294-302, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30527488

RESUMO

BACKGROUND: Necrotizing enterocolitis (NEC) in premature infants is often a devastating surgical condition with poor outcomes. GYY4137 is a long-acting donor of hydrogen sulfide, a gasotransmitter that is protective against intestinal injury in experimental NEC, likely through protection against injury secondary to ischemia. We hypothesized that administration of GYY4137 would improve mesenteric perfusion, reduce intestinal injury, and reduce inflammatory responses in experimental NEC and ischemia-reperfusion injury, and that these benefits would be mediated through endothelial nitric oxide synthase-dependent pathways. METHODS: NEC was induced in C57BL/6 wild-type (WT) and endothelial nitric oxide synthase (eNOS) knockout (eNOSKO) pups via maternal separation, formula feeding, enteral lipopolysaccharide, and intermittent hypoxic and hypothermic stress. Pups received daily intraperitoneal injections of 50 mg/kg GYY4137 or phosphate buffered saline vehicle. In separate groups, adult male WT and eNOSKO mice underwent superior mesenteric artery occlusion for 60 min. Before abdominal closure, 50 mg/kg GYY4137 or phosphate buffered saline vehicle was administered into the peritoneal cavity. Laser doppler imaging was used to assess mesenteric perfusion of pups at baseline and on postnatal day 9, and the adult mice at baseline and 24 h after ischemic insult. After euthanasia, the terminal ileum of each animal was fixed, paraffin embedded, sectioned, and stained with hematoxylin and eosin. Sections were blindly graded using published injury scores. Intestinal tissue was homogenized and cytokines measured by ELISA. Data were compared using Mann-Whitney U test, and P-values <0.05 were significant. RESULTS: After NEC and ischemia reperfusion (I/R) injury, GYY4137 improved perfusion in WT mice compared to vehicle, but this effect was lost in the eNOSKO animals. Histologic injury followed a similar pattern with reduced intestinal injury in WT mice treated with GYY4137, and no significant improvement in the eNOSKO group. Cytokine expression after GYY4137 administration was altered by the ablation of eNOS in both NEC and I/R injury groups, with significant differences noted in Interleukin 6 and vascular endothelial growth factor. CONCLUSIONS: GYY4137, a long-acting donor of hydrogen sulfide, has potential as a therapeutic compound for NEC. It improves mesenteric perfusion and intestinal injury in experimental NEC and intestinal I/R injury, and these benefits appear to be mediated through eNOS-dependent pathways.


Assuntos
Endotélio Vascular/efeitos dos fármacos , Enterocolite Necrosante/prevenção & controle , Isquemia Mesentérica/prevenção & controle , Morfolinas/farmacologia , Óxido Nítrico/metabolismo , Compostos Organotiofosforados/farmacologia , Substâncias Protetoras/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Animais , Biomarcadores/metabolismo , Citocinas/metabolismo , Esquema de Medicação , Endotélio Vascular/metabolismo , Enterocolite Necrosante/metabolismo , Sulfeto de Hidrogênio/metabolismo , Injeções Intraperitoneais , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Masculino , Isquemia Mesentérica/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Morfolinas/uso terapêutico , Óxido Nítrico Sintase/metabolismo , Compostos Organotiofosforados/uso terapêutico , Substâncias Protetoras/uso terapêutico , Traumatismo por Reperfusão/metabolismo , Resultado do Tratamento
12.
Int J Impot Res ; 31(2): 111-118, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30302015

RESUMO

GYY4137 is a novel hydrogen sulfide (H2S) releasing molecule with vasodilator activity. The objectives of this study were to investigate: (1) the pharmacological effect of GYY4137 on the reactivity of the corpus cavernosum (CC) from normal and diabetic rats; (2) the contribution of ATP-sensitive potassium (K-ATP) channels and nitric oxide (NO) pathway; (3) the reactivity to vasoactive agonists following ex vivo incubation of the diabetic rat CC with GYY4137. Longitudinal strips of CC from control and diabetic male Sprague-Dawley (SD) rats (n = 5-6 animals per group) were suspended in organ-baths. Responses to GYY4137, carbachol, or phenylephrine (PE) were determined by measurement of changes in isometric tension. The effects of acute incubation of the CC strips with L-NAME (NO synthase inhibitor) or glibenclamide (K-ATP channel inhibitor) on the relaxant responses to GYY4137 were examined. The effect of ex vivo incubation with GYY4137 (10-5 M) on the responses of CC to carbachol or PE was evaluated. We found that GYY4137 provoked relaxation in the CC strips, which was significantly reduced in the presence of L-NAME or glibenclamide. Ex vivo incubation of diabetic CC with GYY4137 resulted in a significant improvement in the vascular responses to the added agonists. We conclude that GYY4137 is a relaxant agonist in SD rats CC, and the response is mediated, at least in part, by NO and K-ATP channels. Brief incubation of diabetic CC with GYY4137 markedly improved the impaired vascular reactivity, thus raising the question whether chronic in vivo treatment of diabetic animals with GYY4137 would have any protective effect, which is worth further investigation.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Morfolinas/farmacologia , Compostos Organotiofosforados/farmacologia , Pênis/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Canais KATP/metabolismo , Masculino , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , NG-Nitroarginina Metil Éster/metabolismo , Óxido Nítrico/metabolismo , Pênis/patologia , Ratos , Ratos Sprague-Dawley , Estreptozocina
13.
Parasit Vectors ; 11(1): 618, 2018 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-30509288

RESUMO

BACKGROUND: This study aims to provide baseline data on the resistance status to insecticides, the frequency of mechanisms involved and the impact of the association with the synergist piperonyl butoxide (PBO) on resistant Anopheles gambiae (s.l.) populations in two regions of northern Benin, prior to an indoor residual spraying campaign and introduction of next generation long-lasting insecticidal nets (LLINs) incorporating PBO. METHODS: Adult Anopheles gambiae (s.l.) originating from larvae collected in two study regions (Alibori within the Kandi-Gogounou-Segbana districts and Donga within the Djougou-Copargo-Ouake districts) were tested with impregnated papers (bendiocarb 0.1%, pirimiphos-methyl 0.25%, permethrin 0.75% and deltamethrin 0.05%). The synergist PBO was used to check for the involvement of detoxification enzymes in pyrethroid resistant populations. Molecular analyses were performed for the identification of species within the Anopheles gambiae (s.l.) complex and kdr L1014F and G119S Ace-1 mutations. Biochemical assays assessed the activity of detoxification enzymes. RESULTS: Anopheles gambiae (s.l.) was resistant to pyrethroids, with a mortality range of 25-83% with deltamethrin and 6-55% with permethrin. A significant increase in mortality was observed after pre-exposure to PBO for both deltamethrin (63-99%) and permethrin (56-99%). With bendiocarb, An. gambiae (s.l.) were susceptible in Kandi (99% mortality), with possible resistance (92-95%) recorded in Djougou, Copargo, Gogounou, Ouake and Segbana. All study populations were fully susceptible to pirimiphos-methyl. The frequencies of resistant mutations varied according to species and sites: 0.67-0.88 for L1014F kdr and 0-0.06 for G119S Ace-1. Three study locations (Djougou, Gogounou and Kandi) showed high oxidase activity and four sites (Djougou, Ouake, Copargo and Kandi) showed elevated esterase activity. CONCLUSIONS: This study confirms resistance to pyrethroids and suggests emerging bendiocarb resistance in An. gambiae (s.l.) populations in northern Benin. However, recovery of susceptibility to pyrethroids after PBO exposure, and susceptibility to organophosphates in the An. gambiae (s.l.) populations indicate that next generation LLINs incorporating PBO synergist combined with an indoor residual spraying (IRS) campaign with organophosphate insecticides may be regarded as alternative control tools.


Assuntos
Anopheles/efeitos dos fármacos , Anopheles/genética , Resistência a Inseticidas/genética , Inseticidas/farmacologia , Controle de Mosquitos/métodos , Animais , Anopheles/classificação , Benin , Esterases/análise , Feminino , Genes de Insetos/genética , Glutationa Transferase/análise , Proteínas de Insetos/genética , Larva/classificação , Larva/efeitos dos fármacos , Larva/genética , Oxigenases de Função Mista/análise , Mutação , Compostos Organotiofosforados/farmacologia , Sinergistas de Praguicidas/farmacologia , Fenilcarbamatos/farmacologia , Butóxido de Piperonila/farmacologia , Piretrinas/farmacologia
14.
Molecules ; 23(11)2018 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-30441775

RESUMO

GYY4137 is a hydrogen sulfide (H2S) donor that has been shown to act in an anti-inflammatory manner in vitro and in vivo. Microglial cells are among the major players in immunoinflammatory, degenerative, and neoplastic disorders of the central nervous system, including multiple sclerosis, Parkinson's disease, Alzheimer's disease, and glioblastoma multiforme. So far, the effects of GYY4137 on microglial cells have not been thoroughly investigated. In this study, BV2 microglial cells were stimulated with interferon-gamma and lipopolysaccharide and treated with GYY4137. The agent did not influence the viability of BV2 cells in concentrations up to 200 µM. It inhibited tumor necrosis factor but not interleukin-6 production. Expression of CD40 and CD86 were reduced under the influence of the donor. The phagocytic ability of BV2 cells and nitric oxide production were also affected by the agent. Surprisingly, GYY4137 upregulated generation of reactive oxygen species (ROS) by BV2 cells. The effect was mimicked by another H2S donor, Na2S, and it was not reproduced in macrophages. Our results demonstrate that GYY4137 downregulates inflammatory properties of BV2 cells but increases their ability to generate ROS. Further investigation of this unexpected phenomenon is warranted.


Assuntos
Microglia/efeitos dos fármacos , Microglia/metabolismo , Morfolinas/farmacologia , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico/metabolismo , Compostos Organotiofosforados/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Animais , Linhagem Celular , Citocinas/metabolismo , Fagocitose , Fenótipo
15.
J Vector Borne Dis ; 55(2): 122-129, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30280710

RESUMO

Background & objectives: There is an urgent need of introducing new insecticide molecules with novel modes of action to counter the ever growing insecticide-resistance in mosquito vectors. In the present study, a new insecticide molecule, SumiShield 50 WG (clothianidin 50%, w/w) was investigated for its efficacy as an indoor residual spray along with its residual action in comparison to deltamethrin, pirimiphos-methyl and bendiocarb. Methods: The study area included three villages in Almatti Dam catchment area in Bagalkot district, Karnataka, India. Spraying was done using Hudson sprayers with the following dosages-Clothianidin, 300 mg AI/m2; deltamethrin, 25 mg AI/m2; bendiocarb, 400 mg AI/m2; and pirimiphos-methyl, 1 g AI/m2. Cone bioassays were conducted on cement and mud plastered surfaces at fortnightly intervals to assess the bioefficacy and residual activity. Mosquito densities in the sprayed houses were recorded at regular intervals for assessment of the insecticidal efficacy. Filter paper samples collected from the sprayed houses were analyzed for insecticide content sprayed on different wall surfaces at the Walloon Agricultural Research Institute, Gembloux, Belgium. Results: Chemical content analysis of filter paper samples revealed that the applied to target ratios were in the acceptable range (1 + 0.5) for all the treatment types. Duration of persistence of effectiveness of bendiocarb (≥80% mortality in cone bioassays) was 19 to 21 wk on cement plastered surfaces and 15 to 19 wk on mud plastered surfaces. Duration of persistence of effectiveness of deltamethrin was 17 to 21 wk on both mud and cement plastered surfaces and that of pirimiphos-methyl was 15 to 19 wk. For SumiShield, it was 17 to 25 wk on both types of surfaces, indicating slow action of SumiShield. The densities of Anopheles culicifacies were lower in bendiocarb sprayed houses throughout the observation period, followed by pirimiphos methyl, deltamethrin and clothianidin sprayed houses. In case of other mosquitoes also, similar trend was observed. Interpretation & conclusion: Considering the persistence of effectiveness of SumiShield on sprayed surfaces, effectiveness in reducing the density of mosquitoes, operational feasibility, safety and community acceptance, the formulation of clothianidin is a better option for IRS for the control of insecticide-resistant mosquito vectors.


Assuntos
Anopheles/efeitos dos fármacos , Inseticidas/farmacologia , Mosquitos Vetores/efeitos dos fármacos , Nitrilos/farmacologia , Compostos Organotiofosforados/farmacologia , Fenilcarbamatos/farmacologia , Piretrinas/farmacologia , Animais , Anopheles/fisiologia , Feminino , Guanidinas/farmacologia , Índia , Malária/transmissão , Controle de Mosquitos , Mosquitos Vetores/fisiologia , Neonicotinoides/farmacologia , Tiazóis/farmacologia
16.
Parasitol Res ; 117(12): 4027-4032, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30324257

RESUMO

Stomoxys calcitrans (Diptera: Muscidae), is an important vector of lumpy skin disease and bovine besnoitiosis in Europe. Control of this biting fly could represent a keystone in the containment of this emerging disease. Reports of insecticide resistance in S. calcitrans are scarce in Europe. Therefore, the purpose of this study was to evaluate the phenotypic susceptibility to deltamethrin, cypermethrin and phoxim of five wild S. calcitrans populations from southwestern France, where transmission of bovine besnoitiosis is very prevalent. Adult S. calcitrans were caught at each study site and exposed to insecticide-impregnated filter papers under laboratory conditions. Quantities of active ingredients on filter papers corresponded to the recommended doses proposed by the manufacturers (37.5 mg a.i./m2 of cattle's skin, 125 mg a.i./m2 and 750 mg a.i./m2 for deltamethrin, cypermethrin and phoxim respectively) were tested. Knock-down effects (KD) (1 h after the onset of exposure) and mortality rates (24 h and 48 h after exposure) were evaluated. Phoxim showed a rapid and full efficacy in all populations. However, the KD effects (37.5 to 97.5%) and the mortality rates at 48 h (10 to 91.25%) induced by the exposure to pyrethroids varied greatly according to the study site but none of the populations showed full susceptibility. Therefore, the current recommended doses of these pyrethroids are probably less efficient than expected in the field and should be considered with caution in the control of bovine besnoitiosis in France.


Assuntos
Inseticidas/farmacologia , Muscidae/efeitos dos fármacos , Nitrilos/farmacologia , Organofosfatos/farmacologia , Compostos Organotiofosforados/farmacologia , Piretrinas/farmacologia , Animais , Bovinos , Doenças dos Bovinos/parasitologia , Doenças dos Bovinos/transmissão , Europa (Continente) , França , Insetos Vetores/efeitos dos fármacos , Resistência a Inseticidas , Muscidae/classificação
17.
Parasit Vectors ; 11(1): 544, 2018 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-30305147

RESUMO

BACKGROUND: Across most of sub-Saharan Africa, malaria is transmitted by mosquitoes from the Anopheles gambiae complex, comprising seven morphologically indistinguishable but behaviourally-diverse sibling species with ecologically-distinct environmental niches. Anopheles gambiae and An. arabiensis are the mostly widely distributed major malaria vectors within the complex, while An. quadriannulatus is sparsely distributed. METHODS: Indoor residual spraying (IRS) with the organophosphate pirimiphos-methyl (PM) was conducted four times between 2011 and 2017 in the Luangwa Valley, south-east Zambia. Anopheles mosquitoes were repeatedly collected indoors by several experiments with various objectives conducted in this study area from 2010 onwards. Indoor mosquito collection methods included human landing catches, Centres for Disease Control and Prevention miniature light traps and back pack aspirators. Anopheles gambiae complex mosquitoes were morphologically identified to species level using taxonomic keys, and to molecular level by polymerase chain reaction. These multi-study data were collated so that time trends in the species composition of this complex could be assessed. RESULTS: The proportion of indoor An. gambiae complex accounted for by An. quadriannulatus declined from 95.1% to 69.7% following two application PM-IRS rounds with an emulsifiable concentrate formulation from 2011 to 2013, while insecticidal net utilisation remained consistently high throughout that period. This trend continued after two further rounds of PM-IRS with a longer-lasting capsule suspension formulation in 2015 and 2016/2017, following which An. quadriannulatus accounted for only 4.5% of the complex. During the same time interval there was a correspondingly steady rise in the proportional contribution of An. arabiensis to the complex, from 3.9 to 95.1%, while the contribution of nominate An. gambiae remained stable at ≤ 0.9%. CONCLUSION: It seems likely that An. arabiensis is not only more behaviourally resilient against IRS than An. gambiae, but also than An. quadriannulatus populations exhibiting indoor-feeding, human-feeding and nocturnal behaviours that are unusual for this species. Routine, programmatic entomological monitoring of dynamic vector population guilds will be critical to guide effective selection and deployment of vector control interventions, including supplementary measures to tackle persisting vectors of residual malaria transmission like An. arabiensis.


Assuntos
Anopheles/efeitos dos fármacos , Habitação , Inseticidas/farmacologia , Controle de Mosquitos/instrumentação , Mosquitos Vetores/efeitos dos fármacos , Compostos Organotiofosforados/farmacologia , Vento , Animais , Anopheles/classificação , Meio Ambiente , Comportamento Alimentar/efeitos dos fármacos , Humanos , Malária/epidemiologia , Malária/prevenção & controle , Malária/transmissão , Controle de Mosquitos/métodos , Estudos Retrospectivos , Zâmbia/epidemiologia
18.
Cell Mol Biol Lett ; 23: 47, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30305826

RESUMO

Background: Evidence has shown that endogenous H2S plays an important role in the physiological and pathophysiological processes of many organs. The study aimed to explore whether exogenous H2S has a potential therapeutic effect on a rat ovariectomy-induced model of osteoporosis. Methods: The OVX osteoporosis model was established in female Sprague-Dawley rats by full bilateral ovariectomy. The rats were randomly divided into four groups, with the two experimental groups receiving an intraperitoneal injection of GYY4137 or sodium alendronate. The level of H2S in the plasma was determined and common laboratory indicators to diagnose osteoporosis, such as alkaline phosphatase (ALP) activity and the levels of osteocalcin (OCN), calcitonin, parathyroid hormone and leptin were measured. The bone mineral density (BMD) of the 4th and 5th lumbar vertebrae was measured using dual-energy X-ray absorptiometry. The maximum stress of femoral fracture was obtained through a three-point bending test of the femur. Results: The OVX osteoporosis model was successfully established. GYY4137 was injected to increase the level of H2S in the plasma in one group, designated OVX-GYY during the observation period (p < 0.05). At 12 weeks, the BMD value of the fourth lumbar vertebra in the OVX-GYY group had increased (p < 0.05). The BMD femur value in the OVX-vehicle group had decreased (p < 0.05). Bilateral ovariectomy leads to biochemical disorders related to bone metabolism and hormone levels in rat plasma (all p < 0.05). Ovariectomy also reduced blood calcium, blood phosphate and calcitonin, and increased parathyroid hormone and leptin. The opposite results were obtained for the groups with alendronate sodium or GYY4137 treatment (all p < 0.05). Conclusions: Through the slow release of H2S, GYY4137 did an excellent job of simulating endogenous neuroendocrine gaseous signaling molecules. Exogenous H2S had a regulatory effect on osteoporosis in ovariectomized rats, showing potential value for the treatment of human postmenopausal osteoporosis.


Assuntos
Morfolinas/uso terapêutico , Compostos Organotiofosforados/uso terapêutico , Osteoporose/tratamento farmacológico , Osteoporose/etiologia , Ovariectomia/efeitos adversos , Animais , Fenômenos Biomecânicos , Densidade Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Cálcio/sangue , Modelos Animais de Doenças , Feminino , Hormônios/sangue , Morfolinas/farmacologia , Compostos Organotiofosforados/farmacologia , Osteoporose/sangue , Osteoporose/fisiopatologia , Fósforo/sangue , Ratos Sprague-Dawley
19.
Toxicol Appl Pharmacol ; 360: 257-272, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30291936

RESUMO

Methamidophos (MET) is an organophosphate (OP) pesticide widely used in agriculture in developing countries. MET causes adverse effects in male reproductive function in humans and experimental animals, but the underlying mechanisms remain largely unknown. We explored the effect of MET on mice testes (5 mg/kg/day/4 days), finding that this pesticide opens the blood-testis barrier and perturbs spermatogenesis, generating the appearance of immature germ cells in the epididymis. In the seminiferous tubules, MET treatment changed the level of expression or modified the stage-specific localization of tight junction (TJ) proteins ZO-1, ZO-2, occludin, and claudin-3. In contrast, claudin-11 was barely altered. MET also modified the shape of claudin-11, and ZO-2 at the cell border, from a zigzag to a more linear pattern. In addition, MET diminished the expression of ZO-2 in spermatids present in seminiferous tubules, induced the phosphorylation of ZO-2 and occludin in testes and reduced the interaction between these proteins assessed by co-immunoprecipitation. MET formed covalent bonds with ZO-2 in serine, tyrosine and lysine residues. The covalent modifications formed on ZO-2 at putative phosphorylation sites might interfere with ZO-2 interaction with regulatory molecules and other TJ proteins. MET bonds formed at ZO-2 ubiquitination sites likely interfere with ZO-2 degradation and TJ sealing, based on results obtained in cultured epithelial cells transfected with ZO-2 mutated at a MET target lysine residue. Our results shed light on MET male reproductive toxicity and are important to improve regulations regarding the use of OP pesticides and to protect the health of agricultural workers.


Assuntos
Barreira Hematotesticular/efeitos dos fármacos , Inseticidas/farmacologia , Organofosfatos/farmacologia , Compostos Organotiofosforados/farmacologia , Proteína da Zônula de Oclusão-2/metabolismo , Animais , Barreira Hematotesticular/metabolismo , Claudinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Ocludina/metabolismo , Fosfoproteínas/metabolismo , Fosforilação/efeitos dos fármacos , Túbulos Seminíferos/efeitos dos fármacos , Túbulos Seminíferos/metabolismo , Espermatogênese/efeitos dos fármacos , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Proteína da Zônula de Oclusão-1/metabolismo
20.
J Am Chem Soc ; 140(39): 12383-12387, 2018 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-30230336

RESUMO

Hydrogen sulfide (H2S) is a biological gasotransmitter that has been employed for the treatment of ischemia-reperfusion injury. Despite its therapeutic value, the implementation of this gaseous molecule for this purpose has required H2S-releasing prodrugs for effective intracellular delivery. The majority of these prodrugs, however, spontaneously release H2S via uncontrolled hydrolysis. Here, we describe a Ru(II)-based H2S-releasing agent that can be activated selectively by red light irradiation. This compound operates in living cells, increasing intracellular H2S concentration only upon irradiation with red light. Furthermore, the red light irradiation of this compound protects H9c2 cardiomyoblasts from an in vitro model of ischemia-reperfusion injury. These results validate the use of red light-activated H2S-releasing agents as valuable tools for studying the biology and therapeutic utility of this gasotransmitter.


Assuntos
Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Sulfeto de Hidrogênio/química , Sulfeto de Hidrogênio/farmacologia , Rutênio/química , Rutênio/farmacologia , Células A549 , Linhagem Celular , Cristalografia por Raios X , Humanos , Morfolinas/química , Morfolinas/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Compostos Organotiofosforados/química , Compostos Organotiofosforados/farmacologia , Processos Fotoquímicos , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/prevenção & controle
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