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1.
Food Chem ; 339: 127985, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32920305

RESUMO

There is limited research focusing on the effects of human gut microbiota on the oral bioaccessibility and intestinal absorption of pesticide residues in food. In the present study, we use a modified setup of the Simulator of the Human Intestinal Microbial Ecosystem for the determination of pesticide residue bioaccessibility in Chaenomeles speciosa, and a Caco-2 cell model of human intestinal absorption. Results showed that gut microbiota played a dual role based their effects on contaminant release and metabolism in the bioaccessibility assay, and Lactobacillus plantarum was one of key bacterial species in the gut microbiota that influenced pesticide stability significantly. The addition of L. plantarum to the system reduced the relative amounts (by 11.40-86.51%) of six pesticides. The interaction between the food matrix and human gut microbiota led to different absorption rates, and the barrier effects increased with an increase in incubation time.


Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Praguicidas/farmacologia , Rosaceae/química , Bactérias/metabolismo , Células CACO-2 , Humanos , Mucosa Intestinal/citologia , Mucosa Intestinal/microbiologia , Lactobacillus plantarum/efeitos dos fármacos , Lactobacillus plantarum/isolamento & purificação , Neonicotinoides/metabolismo , Neonicotinoides/farmacologia , Nitrocompostos/metabolismo , Nitrocompostos/farmacologia , Compostos Organotiofosforados/metabolismo , Compostos Organotiofosforados/farmacologia , Praguicidas/química , Praguicidas/metabolismo , Rosaceae/metabolismo , Tiametoxam/metabolismo , Tiametoxam/farmacologia
2.
Mol Biol (Mosk) ; 54(6): 1018-1028, 2020.
Artigo em Russo | MEDLINE | ID: mdl-33276365

RESUMO

The effects of exogenous recombinant human heat shock protein Hsp70 and hydrogen sulfide donor GYY4137 on the mechanisms of endocytosis of lipopolysaccharide (LPS) by human neuroblastoma cells SH-SY5Ywas studied. Hsp70 and GYY4137 have been shown to significantly reduce LPS-induced production of inflammatory mediators by SH-SY5Y cells, including reactive oxygen species, nitric oxide, TNFα, IL-1ß, and IL-6. Both the recombinant protein Hsp70 and the hydrogen sulfide donor GYY4137 exhibited significant protective effects; however, the combined use of these agents did not lead to a cumulative effect. It has been shown that pinocytosis, as well as clathrin-, caveolin-, tubulin- and receptor-dependent endocytosis were involved in protecting the cells by both the hydrogen sulfide donor and Hsp70 from LPS-induced production of reactive oxygen species and NO.


Assuntos
Proteínas de Choque Térmico HSP70/metabolismo , Sulfeto de Hidrogênio , Morfolinas/farmacologia , Compostos Organotiofosforados/farmacologia , Linhagem Celular Tumoral , Citocinas , Humanos , Sulfeto de Hidrogênio/farmacologia , Lipopolissacarídeos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Proteínas Recombinantes/metabolismo
3.
Sci Rep ; 10(1): 6508, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32300246

RESUMO

Hydrogen sulphide (H2S) is involved in the physiology and pathophysiology of different cell types, but little is known about its role in sperm cells. Because of its reducing properties, we hypothesise that H2S protects spermatozoa against the deleterious effects of oxidative stress, a condition that is common to several male fertility disorders. This study aimed i) to determine the total antioxidant capacities of Na2S and GYY4137, which are fast- and slow-releasing H2S donors, respectively, and ii) to test whether H2S donors are able to protect spermatozoa against oxidative stress. We found that Na2S and GYY4137 show different antioxidant properties, with the total antioxidant capacity of Na2S being mostly unstable and even undetectable at 150 µM. Moreover, both H2S donors preserve sperm motility and reduce acrosome loss, although the effects were both dose and donor dependent. Within the range of concentrations tested (3-300 µM), GYY4137 showed positive effects on sperm motility, whereas Na2S was beneficial at the lowest concentration but detrimental at the highest. Our findings show that Na2S and GYY4137 have different antioxidant properties and suggest that both H2S donors might be used as in vitro therapeutic agents against oxidative stress in sperm cells, although the optimal therapeutic range differs between the compounds.


Assuntos
Sulfeto de Hidrogênio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Motilidade Espermática/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Humanos , Masculino , Morfolinas/farmacologia , Compostos Organotiofosforados/farmacologia , Sulfetos/farmacologia , Suínos
4.
Parasit Vectors ; 13(1): 152, 2020 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-32209131

RESUMO

BACKGROUND: Progress made in the control of malaria vectors globally is largely due to the use of insecticides. However, success in the fight against malaria has slowed down or even stalled due to a host of factors including insecticide resistance. The greatest burden of the disease is felt in Africa, particularly Nigeria. Unfortunately, adequate information on insecticide resistance is lacking in many parts of the country, particularly the South-East Zone. Hence, this study aims to bridge the information gap in the Zone. METHODS: The study was conducted from April to December 2016. Anopheles gambiae (s.l.) larvae and pupae were collected from one community each, in the five states of the South-East Zone and reared to the adult stage. The adults were subjected to bioassays for insecticide resistance in accordance with the World Health Organization test procedures, across the four classes of insecticides used in public health. The mosquitoes were also subjected to molecular identification to the species level, and genotyped for West African knockdown resistance mutation (L1014F) and insensitive acetylcholinesterase-1 resistance mutation (G119S). RESULTS: The mosquitoes were susceptible (100%) to bendiocarb but resistant to pirimiphos-methyl (39.6%), deltamethrin (57%) and dichlorodiphenyltrichloroethane (DDT) (13%). Molecular analysis revealed that only An. gambiae (sensu stricto) was found in all the states except for Ebonyi, where only Anopheles coluzzii was present. High frequencies (0.6-0.9) of the L1014F mutation were found across the zone. The L1014F mutation was significantly higher in An. gambiae (s.s.) than in An. coluzzii (P < 0.0001). A relatively low frequency (0.2) of the G119S mutation was found in An. coluzzii, and only in Ebonyi State. CONCLUSION: The results show that mosquitoes collected from the South-East Zone of Nigeria were resistant to all insecticides used, except for bendiocarb. The presence of L1014F and G119S resistance mutations reported in this study calls for urgent attention to stop the growing threat of insecticide resistance in the country.


Assuntos
Anopheles/efeitos dos fármacos , Anopheles/genética , Resistência a Inseticidas/efeitos dos fármacos , Resistência a Inseticidas/genética , Inseticidas/farmacologia , Controle de Mosquitos/métodos , Mosquitos Vetores/efeitos dos fármacos , Acetilcolinesterase/genética , Animais , DDT , Feminino , Técnicas de Silenciamento de Genes , Larva/efeitos dos fármacos , Malária , Mosquitos Vetores/genética , Mutação , Nigéria , Nitrilos , Compostos Organotiofosforados/farmacologia , Fenilcarbamatos/farmacologia , Pupa/efeitos dos fármacos , Piretrinas , Organização Mundial da Saúde
5.
Inflamm Res ; 69(5): 481-495, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32157318

RESUMO

BACKGROUND: Hydrogen sulfide donors reduce inflammatory signaling in vitro and in vivo. The biological effect mediated by H2S donors depends on the kinetics of the gas release from the donor molecule. However, the molecular mechanisms of H2S-induced immunomodulation were poorly addressed. Here, we studied the effect of two different hydrogen sulfide (H2S)-producing agents on the generation of the LPS-induced inflammatory mediators. Importantly, we investigated the transcriptomic changes that take place in human cells after the LPS challenge, combined with the pretreatment with a slow-releasing H2S donor-GYY4137. METHODS: We investigated the effects of GYY4137 and sodium hydrosulfide on the release of proinflammatory molecules such as ROS, NO and TNF-α from LPS-treated human SH-SY5Y neuroblastoma and the THP-1 promonocytic cell lines. Transcriptomic and RT-qPCR studies using THP-1 cells were performed to monitor the effects of the GYY4137 on multiple signaling pathways, including various immune-related and proinflammatory genes after combined action of LPS and GYY4137. RESULTS: The GYY4137 and sodium hydrosulfide differed in the ability to reduce the production of the LPS-evoked proinflammatory mediators. The pre-treatment with GYY4137 resulted in a drastic down-regulation of many TNF-α effectors that are induced by LPS treatment in THP-1 cells. Furthermore, GYY4137 pretreatment of LPS-exposed cells ameliorates the LPS-mediated induction of multiple pro-inflammatory genes and decreases expression of immunoproteasome genes. Besides, in these experiments we detected the up-regulation of several important pathways that are inhibited by LPS. CONCLUSION: Based on the obtained results we believe that our transcriptomic analysis significantly contributes to the understanding of the molecular mechanisms of anti-inflammatory and cytoprotective activity of hydrogen sulfide donors, and highlights their potential against LPS challenges and other forms of inflammation.


Assuntos
Anti-Inflamatórios/farmacologia , Sulfeto de Hidrogênio/metabolismo , Inflamação/metabolismo , Morfolinas/farmacologia , Compostos Organotiofosforados/farmacologia , Sulfetos/farmacologia , Linhagem Celular , Citocinas/metabolismo , Humanos , Inflamação/induzido quimicamente , Inflamação/genética , Lipopolissacarídeos , Óxido Nítrico/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos
6.
Mol Med Rep ; 21(3): 1633-1639, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32016475

RESUMO

The present study aimed to clarify the protective effects of p­methoxyphenyl morpholino­phosphinodithioic acid (GYY4137), a water­soluble hydrogen sulfide­releasing molecule, on a rat model of intestinal ischemia­reperfusion (IIR). A total of 40 healthy male Sprague Dawley (SD) rats were randomly divided into four groups (n=10/group): Group A, a sham­surgery group; Group B, the IIR group; group C, rats with IIR that were administered an abdominal injection of low­dose GYY4137 (40 mg/kg); and group D, rats with IIR that were administered high­dose GYY4137 (80 mg/kg). Intestinal histomorphology was observed using hematoxylin and eosin staining, and the concentrations of malondialdehyde (MDA) and superoxide dismutase (SOD) were measured. Apoptotic index (AI) was determined by terminal deoxynucleotidyl­transferase­mediated dUTP nick end labeling. Reverse transcription­quantitative PCR analysis was performed to assess the expression levels of intestinal caspase­3, Bax and Bcl­2. Notably, disordered arrangement of intestinal villi and mucosal necrosis were detected in group B, which was substantially improved by GYY4137 treatment (groups C and D). MDA content (nmol/mg) was 2.83±0.36, 9.23±0.78, 4.97±0.45 and 3.51±1.05 nmol/mg in groups A, B, C and D, respectively. In addition, SOD concentration (U/mg) was 135.37±3.34, 76.45±1.39, 95.13±1.64 and 115.13±2.54 in groups A, B, C and D, respectively. Furthermore, AI in group B (21.73±1.17%) was markedly higher than that in group A (4.53±0.28%) and in the GYY4137 intervention groups (9.53±0.96 and 6.53±0.76% in groups C and D, respectively). Compared with in group A, the mRNA expression levels of Bax and caspase­3 were markedly higher in group B (P<0.05), whereas the expression of Bcl­2 was significantly lower (P<0.05). Furthermore, compared with in group B, Bcl­2 expression was higher, and Bax and caspase­3 expression was lower in groups C and D (P<0.05). In conclusion, GYY4137 may alleviate IIR­induced damage in SD rats.


Assuntos
Sulfeto de Hidrogênio/farmacologia , Intestinos/irrigação sanguínea , Intestinos/efeitos dos fármacos , Morfolinas/farmacologia , Compostos Organotiofosforados/farmacologia , Substâncias Protetoras/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Biomarcadores , Modelos Animais de Doenças , Expressão Gênica , Sulfeto de Hidrogênio/química , Imuno-Histoquímica , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Intestinos/patologia , Masculino , Malondialdeído/metabolismo , Morfolinas/química , Compostos Organotiofosforados/química , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/química , Ratos , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/patologia , Superóxido Dismutase/metabolismo
7.
Int J Mol Sci ; 21(2)2020 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-31963875

RESUMO

The existence of a temperature effect of insecticides frustrated the control of the green plant bug Apolygus lucorum (Meyer-Dür). Previous studies mostly focused on the application of insecticides, but the underlying mechanism remains incompletely understood. Here, we report a transcriptome profiling of A. lucorum treated by three kinds of temperature coefficient insecticides (TCIs) (positive TCI: imidacloprid, negative TCI: b-cypermethrin and non-effect TCI: phoxim) at 15 °C, 25 °C and 35 °C by using next- and third-generation RNA-Seq methods. A total of 34,739 transcripts were annotated from 277.74 Gb of clean data. There were more up-regulated transcripts than down-regulated transcripts in all three kinds of TCI treatments. Further Venn diagrams indicate the regulatory transcripts and regulatory modes were different at the three temperatures. The responses to imidacloprid involved more detox and stress response transcripts such as cytochrome P450 (CYP450), carboxylesterase (CarE) and catalase (CAT) at 35 °C, which was the case for beta-cypermethrin at 15 °C. UDP-glucuronyltransferase (UGT) and heat shock protein (HSP) transcripts were heavily involved, and thus deserve particular note in the temperature effect of insecticides. This high-confidence transcriptome atlas provides improved gene information for further study on the insecticide temperature effect related physiological and biochemical processes of A. lucorum.


Assuntos
Perfilação da Expressão Gênica/métodos , Heterópteros/crescimento & desenvolvimento , Proteínas de Insetos/genética , Inseticidas/farmacologia , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Heterópteros/efeitos dos fármacos , Heterópteros/genética , Sequenciamento de Nucleotídeos em Larga Escala , Anotação de Sequência Molecular , Neonicotinoides/farmacologia , Nitrocompostos/farmacologia , Compostos Organotiofosforados/farmacologia , Piretrinas/farmacologia , Análise de Sequência de RNA , Temperatura
8.
Clin Hemorheol Microcirc ; 75(4): 409-417, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31929150

RESUMO

INTRODUCTION: Neointima formation is closely linked to vascular stenosis and occurs after endothelial damage. Hydrogen sulfide is an endogenous pleiotropic mediator with numerous positive effects on the cardio vascular system. OBJECTIVE: This study evaluates the effect of the slow releasing hydrogen sulfide donor GYY4137 (GYY) on neointimal formation in vivo. METHODS: The effect of GYY on neointimal formation in the carotid artery was studied in the FeCl3 injury model in GYY- or vehicle-treated mice. The carotid arteries were studied at days 7 and 21 after treatment by means of histology and immunohistochemistry for proliferating cell nuclear antigen (PCNA) and alpha smooth muscle actin (α-SMA). RESULTS: GYY treatment significantly reduced the maximal diameter and the area of the newly formed neointima on both days 7 and 21 when compared to vehicle treatment. GYY additionally reduced the number of PCNA- and α-SMA-positive cells within the neointima on day 21 after FeCl3 injury of the carotid artery. CONCLUSIONS: Summarizing, single treatment with the slow releasing hydrogen sulfide donor GYY reduced the extent of the newly formed neointima by affecting the cellular proliferation at the site of vascular injury.


Assuntos
Artéria Carótida Primitiva/fisiopatologia , Morfolinas/uso terapêutico , Neointima/tratamento farmacológico , Compostos Organotiofosforados/uso terapêutico , Animais , Artérias Carótidas/efeitos dos fármacos , Modelos Animais de Doenças , Sulfeto de Hidrogênio/farmacologia , Masculino , Camundongos , Morfolinas/farmacologia , Neointima/patologia , Compostos Organotiofosforados/farmacologia
9.
Chemosphere ; 245: 125597, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31864041

RESUMO

Acephate is an organophosphate pesticide. It is widely used. However, whether it inhibits androgen synthesis and metabolism remains unclear. In the current study, we investigated the effect of acephate on the inhibition of androgen synthetic and metabolic pathways in rat immature Leydig cells after 3-h culture. Acephate inhibited basal androgen output in a dose-dependent manner with the inhibition starting at 0.5 µM. It significantly inhibited luteinizing hormone and 8-Br-cAMP stimulated androgen output at 50 µM. It significantly inhibited progesterone-mediated androgen output at 50 µM. Further study demonstrated that acephate down-regulated the expression of Hsd3b1 and its protein at ≥ 0.5 µM, Lhcgr at 5 µM and Star at 50 µM. Acephate directly blocked rat testicular HSD3B1 activity at 50 µM. Acephate did not affect other androgen synthetic and metabolic enzyme activities as well as ROS production, proliferation, and apoptosis of immature Leydig cells. In conclusion, acephate targets LHCGR, STAR, and HSD3B1, thus blocking androgen synthesis in rat immature Leydig cells and HSD3B1 is being the most sensitive target of acephate.


Assuntos
Androgênios/metabolismo , Células Intersticiais do Testículo/efeitos dos fármacos , Compostos Organotiofosforados/farmacologia , Fosforamidas/farmacologia , 8-Bromo Monofosfato de Adenosina Cíclica/análogos & derivados , 8-Bromo Monofosfato de Adenosina Cíclica/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Células Intersticiais do Testículo/metabolismo , Hormônio Luteinizante/antagonistas & inibidores , Hormônio Luteinizante/metabolismo , Masculino , Complexos Multienzimáticos/antagonistas & inibidores , Progesterona/farmacologia , Progesterona Redutase/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Receptores do LH/antagonistas & inibidores , Esteroide Isomerases/antagonistas & inibidores , Testículo/efeitos dos fármacos , Testículo/metabolismo
10.
Arch Biochem Biophys ; 680: 108237, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31881188

RESUMO

BACKGROUND AND PURPOSE: Several members of the core clock mechanism are equipped with a Per-Arnt-Sim (PAS) domain through which they can bind haem [Fe(II)]. Haem is a ligand for the orphan receptors REV-ERBα/ß (NR1D1/2), which regulate circadian rhythm and metabolism. The ability to bind haem sensitises these clock components to the action of small molecule gases, including NO, CO and H2S. Studies conducted with European hamsters revealed that during winter sleep, key clock genes stop oscillating. At the same time, H2S, when administered at subtoxic concentrations, can induce a hypometabolic state in the cell. We suppose that core clock components, including the nuclear receptors REV-ERBs, neuronal PAS domain protein 2 (nPAS2) and PER2, can be H2S targets. The general objective of this study was to investigate the effect of the H2S system on the expression profile of the core clock genes in cells in vitro. EXPERIMENTAL APPROACH: We analysed the expression of Per1, Per2, Per3, Bmal1, Cry1, Cry2, Nr1d1, Nfil-3 and Dbp messenger RNA (mRNA) in serum-shocked NIH-3T3 cells treated with a slow-releasing H2S donor (GYY4137) or the cystathionine beta-synthase (CBS) inhibitor (AOAA) cultured under constant darkness and collected during 3 days in 3 h interval. KEY RESULTS AND CONCLUSIONS AND IMPLICATIONS: We found that pharmacological CBS inhibition increased the general expression and dynamics of several clock genes. On the other hand, increased H2S decreased Per2 expression. These data suggest that CBS can affect circadian clock and effect on clock-controlled transcription output.


Assuntos
Ácido Amino-Oxiacético/farmacologia , Relógios Circadianos/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/genética , Morfolinas/farmacologia , Compostos Organotiofosforados/farmacologia , Animais , Ciclo Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , Células NIH 3T3
11.
Antioxid Redox Signal ; 32(2): 145-158, 2020 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-31642346

RESUMO

Significance: Hydrogen sulfide (H2S) is regarded as the third gasotransmitter along with nitric oxide and carbon monoxide. Extensive studies have demonstrated a variety of biological roles for H2S in neurophysiology, cardiovascular disease, endocrine regulation, and other physiological and pathological processes. Recent Advances: Novel H2S donors have proved useful in understanding the biological functions of H2S, with morpholin-4-ium 4 methoxyphenyl (morpholino) phosphinodithioate (GYY4137) being one of the most common pharmacological tools used. One advantage of GYY4137 over sulfide salts is its ability to release H2S in a slow and sustained manner akin to endogenous H2S production, rather than the delivery of H2S as a single concentrated burst. Critical Issues: Here, we summarize recent progress made in the characterization of the biological activities and pharmacological effects of GYY4137 in a range of in vitro and in vivo systems. Recent developments in the structural modification of GYY4137 to generate new compounds and their biological effects are also discussed. Future Directions: Slow-releasing H2S donor, GYY4137, and other phosphorothioate-based H2S donors are potent tools to study the biological functions of H2S. Despite recent progress, more work needs to be performed on these new compounds to unravel the mechanisms behind H2S release and pace of its discharge, as well as to define the effects of by-products of donors after H2S liberation. This will not only lead to better in-depth understanding of the biological effects of H2S but will also shed light on the future development of a new class of therapeutic agents with potential to treat a wide range of human diseases.


Assuntos
Sulfeto de Hidrogênio/química , Morfolinas/farmacologia , Compostos Organotiofosforados/farmacologia , Oligonucleotídeos Fosforotioatos/farmacologia , Animais , Humanos , Estrutura Molecular , Morfolinas/química , Compostos Organotiofosforados/química , Oligonucleotídeos Fosforotioatos/química , Relação Estrutura-Atividade
12.
Biomed Res Int ; 2019: 5752323, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31737669

RESUMO

Objectives: Substantial studies have demonstrated that an elevated concentration of deoxycholic acid (DCA) in the colonic lumen may play a critical role in the pathogenesis of intestinal barrier dysfunction and inflammatory bowel disease (IBD). The purpose of this study was to investigate the protective effects of GYY4137, as a novel and synthetic H2S donor, on the injury of intestinal barrier induced by sodium deoxycholate (SDC) both in vivo and in vitro. Methods: In this study, Caco-2 monolayers and mouse models with high SDC concentration in the lumen were used to study the effect of GYY4137 on intestinal barrier dysfunction induced by SDC and its underlying mechanisms. Results: In Caco-2 monolayers, a short period of addition of SDC increased the permeability of monolayers obviously, changed distribution of tight junctions (TJs), and improved the phosphorylation level of myosin light chain kinase (MLCK) and myosin light chain (MLC). However, pretreatment with GYY4137 markedly ameliorated the SDC-induced barrier dysfunction. Being injected with GYY4137 could enable mice to resist the SDC-induced injury of the intestinal barrier. Besides, GYY4137 promoted the recovery of the body weight and intestinal barrier histological score of mice with the gavage of SDC. GYY4137 also attenuated the decreased expression level of TJs in mice treated with SDC. Conclusion: Taken together, this research suggests that GYY4137 preserves the intestinal barrier from SDC-induced injury via suppressing the activation of P-MLCK-P-MLC2 signaling pathway and increasing the expression level of tight junctions.


Assuntos
Ácido Desoxicólico/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Intestinos/efeitos dos fármacos , Morfolinas/farmacologia , Compostos Organotiofosforados/farmacologia , Animais , Células CACO-2 , Linhagem Celular Tumoral , Colo/efeitos dos fármacos , Colo/metabolismo , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/metabolismo , Mucosa Intestinal/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Cadeias Leves de Miosina/metabolismo , Quinase de Cadeia Leve de Miosina/metabolismo , Permeabilidade/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo
13.
Pestic Biochem Physiol ; 161: 61-67, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31685198

RESUMO

Extensive use of pyrethroids for malaria control in Africa has led to widespread pyrethroid resistance in the two major African vectors of malaria An. gambiae and An. funestus. This is often associated with constitutively elevated levels of cytochrome P450s involved with pyrethroid metabolism and detoxification. P450s have the capacity to metabolise diverse substrates, which raises concerns about their potential to cause cross-resistance. A bank of seven recombinant P450s from An. gambiae (CYPs 6M2, 6P2, 6P3, 6P4, 6P5, 9J5) and An. funestus (CYP6P9a) commonly associated with pyrethroid resistance were screened against twelve insecticides representing the five major classes of insecticides recommended by WHO for malaria control; permethrin, etofenprox and bifenthrin (type I pyrethroids), deltamethrin, lambda cyhalothrin and cypermethrin (type II pyrethroids), DDT (organochlorine), bendiocarb (carbamate), malathion, pirimiphos methyl and fenitrothion (organophosphates) and pyriproxyfen (juvenile hormone analogue). DDT was not metabolised by the P450 panel, while bendiocarb was only metabolised by CYP6P3. Pyrethroids and pyriproxyfen were largely susceptible to metabolism by the P450 panel, as were organophosphates, which are activated by P450s. Primiphos-methyl is increasingly used for malaria control. Examination of the pirimiphos-methyl metabolites generated by CYP6P3 revealed both the active pirimiphos-methyl-oxon form and the inactive oxidative cleavage product 2-diethylamino-6-hydroxy-4-methylpyrimidine. The inhibition profile of CYPs 6M2, 6P2, 6P3, 6P9a and 9J5 was also examined using diethoxyfluorescein (DEF) as the probe substrate. Bendiocarb was the weakest inhibitor with IC50 > 100 µM across the P450 panel, while CYP6M2 showed strongest inhibition by malathion (IC50 0.7 µM). The results suggest that P450s present at elevated levels in two major Anopheline vectors of malaria in Africa have the capacity to metabolise a diverse range of pyrethroid and organophosphate insecticides as well as pyriproxyfen that could impact vector control.


Assuntos
Anopheles/efeitos dos fármacos , Anopheles/enzimologia , Sistema Enzimático do Citocromo P-450/metabolismo , Resistência a Inseticidas , Malária/transmissão , Mosquitos Vetores/efeitos dos fármacos , Piretrinas/farmacologia , Animais , Anopheles/classificação , Controle de Mosquitos/métodos , Mosquitos Vetores/parasitologia , Compostos Organotiofosforados/farmacologia , Especificidade da Espécie
14.
Endocr J ; 66(11): 1029-1037, 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31366822

RESUMO

In the present study, we investigate the effect of reduced cystathionine-γ-lyase (CSE) expression in high glucose induced metalloproteinases14 (MMP14) expression in adipocytes and visceral adipose tissues. Diabetic mice were prepared by injections of STZ and the expression of CSE, MMP14 in visceral adipose tissues were determined. Adipocytes were differentiated from 3T3-L1 cells and treated with high glucose (HG), H2S slow-releasing compound GYY4137 or transfected with CSE siRNA. Then the expression of CSE, MMP14 were determined by western blotting. CSE knockout mice were generated by crossing CSE+/- heterozygous mice and given intraperitoneally (i.p.) injections of GYY4137, and then the expression of CSE and MMP14 in visceral adipose tissues were determined by quantitative real-time PCR and western blotting. The following results were obtained from the study. In adipose tissues of diabetic mice, the mRNA and protein expression of MMP14 increased while the mRNA and protein expression of CSE decreased. In 3T3-L1 adipocytes, both HG DMEM and CSE siRNA transfection increased the mRNA and protein of MMP14. The addition of GYY4137 inhibited HG-induced upregulation of MMP14 expression. In CSE knockout mice, the mRNA and protein expression of MMP14 in adipose tissues increased, which could be inhibited by i.p. injections of GYY4137. In conclusion, high glucose increased the expression of MMP14 in adipocytes and visceral adipose tissues through inhibiting the expression of CSE.


Assuntos
Adipócitos/metabolismo , Cistationina gama-Liase/genética , Diabetes Mellitus Experimental/genética , Gordura Intra-Abdominal/metabolismo , Metaloproteinase 14 da Matriz/genética , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Animais , Western Blotting , Cistationina gama-Liase/efeitos dos fármacos , Cistationina gama-Liase/metabolismo , Diabetes Mellitus Experimental/metabolismo , Glucose/farmacologia , Metaloproteinase 14 da Matriz/efeitos dos fármacos , Metaloproteinase 14 da Matriz/metabolismo , Camundongos , Camundongos Knockout , Morfolinas/farmacologia , Compostos Organotiofosforados/farmacologia , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , RNA Interferente Pequeno , Reação em Cadeia da Polimerase em Tempo Real
15.
Avian Pathol ; 48(sup1): S35-S43, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31362523

RESUMO

Dermanyssus gallinae (De Geer, 1778) is a major problem for the poultry industry worldwide, as it negatively affects virtually all kinds of rearing systems. Therefore, the control of infestation has become a routine process, and its economic cost is constantly increasing. Until now, most of the control strategies have relied on the use of synthetic chemical drugs, but their efficacy is often questioned by the emergence and diffusion of resistant mite populations. With this in mind, the efficacy of λ-cyhalothrin, amitraz, and phoxim has been verified by testing them against 86 mite populations collected from the same number of poultry farms in Italy from 2008 to 2015. Assays were performed according to the filter paper method using the recommended, half, quarter, double and quadruple doses. The results showed that phoxim and amitraz were the most effective acaricides (median efficacies 80.35% and 80.83%, respectively), but amitraz exhibited a sharp fall in its efficacy during 2011 and 2012, while phoxim maintained its high effectiveness up to 2015, when it dropped. The overall median efficacy of λ-cyhalothrin was 58.33%. The data also highlighted the importance of the use of the right concentration, as an increase in dosage was not always useful against resistant populations, while its reduction also diminished efficacy, simultaneously increasing the risk for the development of resistance.


Assuntos
Acaricidas/farmacologia , Infestações por Ácaros/veterinária , Ácaros/efeitos dos fármacos , Doenças das Aves Domésticas/tratamento farmacológico , Animais , Itália , Infestações por Ácaros/tratamento farmacológico , Infestações por Ácaros/parasitologia , Nitrilos/farmacologia , Compostos Organotiofosforados/farmacologia , Aves Domésticas , Doenças das Aves Domésticas/parasitologia , Piretrinas/farmacologia , Inquéritos e Questionários , Toluidinas/farmacologia
16.
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
17.
Artigo em Inglês | MEDLINE | ID: mdl-31319266

RESUMO

Meteorus pulchricornis (Wesmael) (Hymenoptera: Braconidae) is a preponderant endoparasitoid wasp, attacking the larvae of many lepidopteran pests. We present the first body transcriptome dataset for M. pulchricornis. In total, 50,781,796 clean reads were obtained and 33,144 unigenes were assembled; 15,458 unigenes showed a significant similarity (E value < 10-5) to known proteins in the NCBI non-redundant protein database. Gene ontology and cluster of orthologous group analyses were performed to classify the functions of genes. To better understand the role of glutathione-S-transferases (GSTs) in detoxification mechanism in M. pulchricornis, we identified seventeen GST genes (MpulGSTs) from the body transcriptome. Among these, fifteen MpulGSTs belonged to cytosolic GSTs and the other two belonged to microsomal classes. The cytosolic GSTs were classified into four different clades: four in delta, three in omega, seven in sigma, and one in zeta. The expression levels of these MpulGSTs after exposure to sub-lethal concentrations of phoxim and cypermethrin were determined using real-time quantitative polymerase chain reaction: seven MpulGSTs (MpulGSTD3, MpulGSTS1, MpulGSTS2, MpulGSTS4, MpulGSTS6 MpulGSTO3, and MpulGSTmic1) and 11 MpulGSTs (MpulGSTD1, MpulGSTD2, MpulGSTD3, MpulGSTO2, MpulGSTS1, MpulGSTS2, MpulGSTS3, MpulGSTS4, MpulGSTS5, MpulGSTS7, and MpulGSTmic1) were highly expressed, respectively. These results suggested that GST genes may play a pivotal role in detoxification process in M. pulchricornis. Our findings would provide a theoretical base for elucidating insecticide susceptibility and should promote functional research on specific GST genes in parasitoid wasps.


Assuntos
Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Glutationa Transferase/genética , Himenópteros/genética , Inseticidas/farmacologia , Compostos Organotiofosforados/farmacologia , Piretrinas/farmacologia , Animais
18.
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
19.
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
20.
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
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