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1.
PLoS Genet ; 17(10): e1009888, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34710088

RESUMO

The evolution of resistance to insecticides is well known to be closely associated with the overexpression of detoxifying enzymes. Although the role of glutathione S-transferase (GST) genes in insecticide resistance has been widely reported, the underlying regulatory mechanisms are poorly understood. Here, one GST gene (GSTu1) and its antisense transcript (lnc-GSTu1-AS) were identified and cloned, and both of them were upregulated in several chlorantraniliprole-resistant Plutella xylostella populations. GSTu1 was confirmed to be involved in chlorantraniliprole resistance by direct degradation of this insecticide. Furthermore, we demonstrated that lnc-GSTu1-AS interacted with GSTu1 by forming an RNA duplex, which masked the binding site of miR-8525-5p at the GSTu1-3'UTR. In summary, we revealed that lnc-GSTu1-AS maintained the mRNA stability of GSTu1 by preventing its degradation that could have been induced by miR-8525-5p and thus increased the resistance of P. xylostella to chlorantraniliprole. Our findings reveal a new noncoding RNA-mediated pathway that regulates the expression of detoxifying enzymes in insecticide-resistant insects and offer opportunities for the further understanding of the mechanisms of insecticide and drug resistance.


Assuntos
Resistência a Medicamentos/genética , Resistência a Inseticidas/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Animais , Glutationa Transferase/genética , Inseticidas/farmacologia , Larva/efeitos dos fármacos , Larva/genética , Mariposas/efeitos dos fármacos , Mariposas/genética , ortoaminobenzoatos/farmacologia
2.
Int J Mol Sci ; 22(15)2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34360580

RESUMO

Melanin causes melasma, freckles, age spots, and chloasma. Anti-melanogenic agents can prevent disease-related hyperpigmentation. In the present study, the dose-dependent tyrosinase inhibitory activity of Avenanthramide (Avn)-A-B-C was demonstrated, and 100 µM Avn-A-B-C produced the strongest competitive inhibition against inter-cellular tyrosinase and melanin synthesis. Avn-A-B-C inhibits the expression of melanogenesis-related proteins, such as TRP1 and 2. Molecular docking simulation revealed that AvnC (-7.6 kcal/mol) had a higher binding affinity for tyrosinase than AvnA (-7.3 kcal/mol) and AvnB (-6.8 kcal/mol). AvnC was predicted to interact with tyrosinase through two hydrogen bonds at Ser360 (distance: 2.7 Å) and Asn364 (distance: 2.6 Å). In addition, AvnB and AvnC were predicted to be skin non-sensitizers in mammals by the Derek Nexus Quantitative Structure-Activity Relationship system.


Assuntos
Simulação por Computador , Melaninas/biossíntese , Melanoma/tratamento farmacológico , Monofenol Mono-Oxigenase/antagonistas & inibidores , Pele/efeitos dos fármacos , alfa-MSH/farmacologia , ortoaminobenzoatos/farmacologia , Hormônios/farmacologia , Humanos , Técnicas In Vitro , Melanoma/metabolismo , Melanoma/patologia , Simulação de Acoplamento Molecular , Células Tumorais Cultivadas
3.
Eur J Med Chem ; 224: 113680, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34245947

RESUMO

The viral infectivity factor (Vif)-apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G (APOBEC3G) axis has been recognized as a valid target for developing novel small-molecule therapies for acquired immune deficiency syndrome (AIDS) or for enhancing innate immunity against viruses. Our previous work reported the novel Vif antagonist 2-amino-N-(2-methoxyphenyl)-6-((4-nitrophenyl)sulfonyl)benzamide (2) with strong antiviral activity. In this work, through optimizations of ring C of 2, we discovered the more potent compound 6m with an EC50 of 0.07 µM in non-permissive H9 cells, reflecting an approximately 5-fold enhancement of antiviral activity compared to that of 2. Western blotting indicated that 6m more strongly suppressed the defensive protein Vif than 2 at the same concentration. Furthermore, 6m suppressed the replication of various clinical drug-resistant HIV strains (FI, NRTI, NNRTI, IN and PI) with relatively high efficacy. These results suggested that compound 6m is a more potent candidate for treating AIDS.


Assuntos
Desaminase APOBEC-3G/metabolismo , Fármacos Anti-HIV/química , HIV-1/metabolismo , ortoaminobenzoatos/química , Produtos do Gene vif do Vírus da Imunodeficiência Humana/antagonistas & inibidores , Fármacos Anti-HIV/metabolismo , Fármacos Anti-HIV/farmacologia , Sítios de Ligação , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Farmacorresistência Viral/efeitos dos fármacos , HIV-1/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , ortoaminobenzoatos/metabolismo , ortoaminobenzoatos/farmacologia , Produtos do Gene vif do Vírus da Imunodeficiência Humana/metabolismo
4.
Nutrients ; 13(6)2021 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-34204635

RESUMO

Wholegrain oats contain a variety of phenolic compounds thought to help maintain healthy vascular function, through the maintenance of local levels of the vasodilator nitric oxide (NO). Thus, the full molecular mechanisms involved are not yet clear. With this work we aim to understand the possible cellular mechanisms by which avenanthramides and ferulic acid derivatives, present in oats, may help maintain a healthy vascular function through the modulation of the NO pathway. Primary Human Umbilical Vein Endothelial Cells (HUVEC) were exposed to ferulic acid, isoferulic acid, hydroferulic acid, ferulic acid 4-O-glucuronide, isoferulic acid 3-O-sulfate, dihydroferulic acid 4-O-glucuronide, avenanthramide A, avenanthramide B and avenanthramide C (1 µM) or vehicle (methanol) for 24 h. Apocynin and Nω-Nitro-L-arginine (L-NNA) were additionally included as controls. NO and cyclic GMP (cGMP) levels, superoxide production and the activation of the Akt1/eNOS pathway were assessed. The statistical analysis was performed using one-way ANOVA followed by a Tukey post-hoc t-test. Apocynin and all phenolic compounds increased NO levels in HUVEC cells (increased DAF2-DA fluorescence and cGMP), and significantly reduced superoxide levels. Protein expression results highlighted an increase in the Akt1 activation state, and increased eNOS expression. Overall, our results indicated that the glucuronide metabolites do not enhance NO production through the Akt1/eNOS pathway, thus all compounds tested are able to reduce NO degradation through reduced superoxide formation.


Assuntos
Ácidos Cumáricos/farmacologia , Endotélio Vascular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Óxido Nítrico/metabolismo , ortoaminobenzoatos/farmacologia , Humanos , Transdução de Sinais/efeitos dos fármacos , Vasodilatadores/metabolismo
5.
Pest Manag Sci ; 77(11): 4874-4883, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34176224

RESUMO

BACKGROUND: Although decoding the molecular mechanisms underlying insecticide resistance has often proven difficult, recent progress has revealed that specific mutations in the ryanodine receptor (RyR) of the diamondback moth, Plutella xylostella, can confer resistance to diamide insecticides. The extent to which specific RyR mutations contribute to the diamide resistance phenotype, the associated genetic traits and fitness costs remain limited. RESULTS: Three field-evolved PxRyR mutations (G4946E, I4790 M, and I4790 K) were respectively introgressed into a common susceptible background strain (IPP-S) of P. xylostella with marker-assisted backcrossing. The mutations alone can result in moderate to high levels of resistance to five commercial diamides (flubendiamide, chlorantraniliprole, cyantraniliprole, tetraniliprole, and cyclaniliprole), and the resistance intensity mediated by the three mutations was hierarchical in order of I4790 K (1199- to >2778-fold) > G4946E (39- to 739-fold) > I4790 M (16- to 57-fold). Flubendiamide resistance was autosomal and incompletely recessive, and was significantly linked with the introgressed mutations in the three constructed strains. In addition, the resistance levels to flubendiamide of hybrid progeny from any two resistant strains fell in between the status of their parents. Furthermore, by comparing the net replacement rate, the fitness of 4946E, 4790 M and 4790 K strains were 0.77, 0.93 and 0.92 relative to the IPP-S strain, respectively. CONCLUSION: Three independent PxRyR mutations confer varying degrees of resistance to diamides in P. xylostella. Among the three mutations, I4790 K confers highest levels of resistance (> 1000-fold) to all five commercial diamides. The findings can guide resistance management practices for diamides in P. xylostella and other arthropods.


Assuntos
Inseticidas , Mariposas , Animais , Diamida/farmacologia , Resistência a Inseticidas/genética , Inseticidas/farmacologia , Mariposas/genética , Mutação Puntual , Pirazóis , Piridinas , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Tetrazóis , ortoaminobenzoatos/farmacologia
6.
Int J Mol Sci ; 22(9)2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-34068540

RESUMO

Spodopteraexigua, a multifeeding insect pest, has developed a high level of resistance to chlorantraniliprole, which is a benzoylurea insecticide that targets the ryanodine receptors (RyRs). Herein, the resistant strain (SE-Sel) and sensitive strain (SE-Sus) were obtained by bidirectional screening for six generations. The potential oviposited eggs and oviposition rate of the SE-Sel strain were dramatically lower than those of the SE-Sus strain; on the contrary, the weights of prepupae and preadult were significantly increased. As a post-mating response, the higher number of non-oviposited eggs in the SE-Sel strain was caused by a lower mating rate. In addition, the expression levels of vitellogenin (SeVg) and its receptor (SeVgR) in the SE-Sel strain were consistently lower than those in the SE-Sus strain. An RyRI4743M mutation, contributing to the resistance to chlorantraniliprole, was located in the S3 transmembrane segments and might have affected the release of calcium ions; it led to the upregulated expression of the neuropeptide SeNPF and its receptor SeNPFR, and the mating and oviposition rate were significantly recovered when the SeNPF was knocked down though RNA interference (RNAi) in the male adult of the SE-Sel strain. Moreover, the expression of the juvenile hormone-binding proteins SeJHBWDS3 and SeJHBAN in the male adult of the SE-Sel strain was significantly decreased, which proved the existence of a fitness cost from another angle. Therefore, these results indicate that the fitness cost accompanied by chlorantraniliprole resistance in S. exigua may be related to the decrease in mating desire due to SeNPF overexpression.


Assuntos
Proteínas de Insetos/genética , Resistência a Inseticidas/genética , Spodoptera/genética , ortoaminobenzoatos/farmacologia , Animais , Proteínas de Transporte/genética , Resistência à Doença/efeitos dos fármacos , Resistência à Doença/genética , Proteínas do Ovo/genética , Aptidão Genética/genética , Inseticidas/farmacologia , Mutação/genética , Neuropeptídeos/genética , Interferência de RNA , Receptores de Superfície Celular/genética , Receptores de Neuropeptídeos/genética , Spodoptera/efeitos dos fármacos , Vitelogeninas/genética , ortoaminobenzoatos/efeitos adversos
7.
Chem Biol Interact ; 345: 109537, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34062171

RESUMO

The Breast Cancer Resistance Protein (BCRP/ABCG2) is an ATP-binding cassette efflux transporter that is expressed in the apical membrane of cells from relevant tissues involved in drug pharmacokinetics such as liver, intestine, kidney, testis, brain and mammary gland, among others. Tolfenamic acid is an anti-inflammatory drug used as an analgesic and antipyretic in humans and animals. Recently, tolfenamic acid has been repurposed as an antitumoral drug and for use in chronic human diseases such as Alzheimer. The aim of this work was to study whether tolfenamic acid is an in vitro Abcg2 substrate, and to investigate the potential role of Abcg2 in plasma exposure, secretion into milk and tissue accumulation of this drug. Using in vitro transepithelial assays with cells transduced with Abcg2, we showed that tolfenamic acid is an in vitro substrate of Abcg2. The in vivo effect of this transporter was tested using wild-type and Abcg2-/- mice, showing that after oral and intravenous administration of tolfenamic acid, its area under the plasma concentration-time curve in Abcg2-/- mice was between 1.7 and 1.8-fold higher compared to wild-type mice. Abcg2-/- mice also showed higher liver and testis accumulation of tolfenamic acid after intravenous administration. In this study, we demonstrate that tolfenamic acid is transported in vitro by Abcg2 and that its plasma levels as well as its tissue distribution are affected by Abcg2, with potential pharmacological and toxicological consequences.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Vacinas Bacterianas/sangue , Vacinas Bacterianas/farmacocinética , ortoaminobenzoatos/sangue , ortoaminobenzoatos/farmacocinética , Animais , Vacinas Bacterianas/farmacologia , Transporte Biológico , Camundongos , Distribuição Tecidual , ortoaminobenzoatos/farmacologia
8.
J Biochem Mol Toxicol ; 35(8): e22817, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34047436

RESUMO

Cisplatin is a chemotherapeutic agent whose therapeutic use is greatly limited by the associated organs' toxicity and particularly, testicular toxicity. Cisplatin-induced testicular damage reported being mediated through mitochondria-mediated apoptosis, inflammation, and oxidative stress. Evidence showed that tranilast (TRN) has the ability to restore the oxidative status and modulate TRAIL/caspase-8 signaling. This led us to hypothesize that TRN could abrogate cisplatin-induced testicular and epididymal injuries via inhibiting oxidative stress and modulating proliferation and TRAIL/caspase-8/cJNK signaling. Cisplatin injection induced oligospermia and abnormalities in testicular and epididymal structure along with impaired oxidative status. TRN administration (100 or 300 mg/kg) for 7 days post-cisplatin injection preserved spermatogenesis and restored testicular and epididymal architecture, but restoration was more so in TRN300 than TRN100. This was in line with the restoration of balanced oxidative status as indicated by the increased total antioxidant capacity, glutathione and superoxide dismutase activity, and the decreased malondialdehyde content in testes (p < 0.05 vs. cisplatin). TRN increased the cell proliferation revealed by the increased expression of proliferating cell nuclear antigen in a dose-dependent manner (p < 0.05 vs. cisplatin) whereas only TRN300 decreased testicular cJNK, TRAIL, and caspase-8 expression (p < 0.05 vs. cisplatin). Moreover, TRN dose-dependently inhibited the pro-inflammatory transcription factor NF-kB and the cytokine TNF-α expressions in testes. In conclusion, TRN300 was more effective than TRN100 in alleviating cisplatin-induced testicular and epididymal injuries and in enhancing spermatogenesis. This curative effect of TRN might be mediated through its antioxidant and anti-inflammatory impacts along with its modulatory impact on cJNK/TRAIL/caspase-8 signaling favoring proliferation rather than apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cisplatino/efeitos adversos , Oligospermia , ortoaminobenzoatos/farmacologia , Animais , Cisplatino/farmacologia , Epididimo/lesões , Epididimo/metabolismo , Masculino , Oligospermia/induzido quimicamente , Oligospermia/metabolismo , Oligospermia/prevenção & controle , Ratos , Ratos Sprague-Dawley , Testículo/lesões , Testículo/metabolismo
9.
J Pharmacol Sci ; 146(3): 125-135, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34030795

RESUMO

Gastroesophageal reflux disease (GERD) is a common gastrointestinal disorder. In the present study, we investigated TRP vanilloid subfamily member 2 (TRPV2) expression in lower oesophageal sphincter (LES) and its involvement in acid reflux oesophagitis in rats. Expression of TRPV2 and nerve growth factor mRNAs was significantly enhanced in LES of rats with reflux oesophagitis compared with normal rats. TRPV2 was mainly expressed in inhibitory motor neurons, and partly in intrinsic and extrinsic primary afferent neurons, and macrophages in LES of normal and reflux oesophagitis rats. Number of TRPV2-immunopositive nerve fibres was significantly increased, but that of nNOS-, CGRP-, and PGP9.5-nerve fibres was not changed in reflux oesophagitis compared with normal group. Probenecid produced nitric oxide production and relaxation in LES and this response was significantly enhanced in oesophagitis compared with normal group. Probenecid-induced relaxant effect was blocked by a TRPV2 inhibitor, tranilast, and a NOS inhibitor, NG-nitro-l-arginine methyl ester, in reflux oesophagitis rats. Oral administration of tranilast significantly improved body weight loss, oesophageal lesions, and epithelial thickness in oesophagitis model. These results suggest that up-regulation of TRPV2 in inhibitory motor neurons is involved in LES relaxation in oesophagitis model. TRPV2 inhibition might be beneficial for treatment of GERD.


Assuntos
Esfíncter Esofágico Inferior/metabolismo , Refluxo Gastroesofágico/tratamento farmacológico , Refluxo Gastroesofágico/genética , Expressão Gênica/genética , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo , Animais , Modelos Animais de Doenças , Esfíncter Esofágico Inferior/efeitos dos fármacos , Masculino , Relaxamento Muscular/efeitos dos fármacos , Óxido Nítrico/metabolismo , Probenecid/antagonistas & inibidores , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Canais de Cátion TRPV/antagonistas & inibidores , ortoaminobenzoatos/farmacologia , ortoaminobenzoatos/uso terapêutico
10.
Toxins (Basel) ; 13(3)2021 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-33809820

RESUMO

Concerns about resistance development to conventional insecticides in diamondback moth (DBM) Plutella xylostella (L.), the most destructive pest of Brassica vegetables, have stimulated interest in alternative pest management strategies. The toxicity of Bacillus thuringiensis subsp. aizawai (Bt GO33A) combined with chlorantraniliprole (Chl) has not been documented. Here, we examined single and combined toxicity of chlorantraniliprole and Bt to assess the levels of resistance in four DBM strains. Additionally, enzyme activities were tested in field-original highly resistant (FOH-DBM), Bt-resistant (Bt-DBM), chlorantraniliprole-resistant (CL-DBM), and Bt + chlorantraniliprole-resistant (BtC-DBM) strains. The Bt product had the highest toxicity to all four DBM strains followed by the mixture of insecticides (Bt + Chl) and chlorantraniliprole. Synergism between Bt and chlorantraniliprole was observed; the combination of Bt + (Bt + Chl) (1:1, LC50:LC50) was the most toxic, showing a synergistic effect against all four DBM strains with a poison ratio of 1.35, 1.29, 1.27, and 1.25. Glutathione S-transferase (GST) and carboxyl-esterase (CarE) activities showed positive correlations with chlorantraniliprole resistance, but no correlation was observed with resistance to Bt and Bt + Chl insecticides. Expression of genes coding for PxGST, CarE, AChE, and MFO using qRT-PCR showed that the PxGST and MFO were significantly overexpressed in Bt-DBM. However, AChE and CarE showed no difference in the four DBM strains. Mixtures of Bt with chlorantraniliprole exhibited synergistic effects and may aid the design of new combinations of pesticides to delay resistance in DBM strains substantially.


Assuntos
Bacillus thuringiensis/metabolismo , Brassica/parasitologia , Resistência a Inseticidas , Inseticidas/farmacologia , Mariposas/efeitos dos fármacos , Mariposas/microbiologia , Controle Biológico de Vetores , ortoaminobenzoatos/farmacologia , Acetilcolinesterase/genética , Acetilcolinesterase/metabolismo , Animais , Bacillus thuringiensis/genética , Carboxilesterase/genética , Carboxilesterase/metabolismo , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Regulação Enzimológica da Expressão Gênica , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Resistência a Inseticidas/genética , Mariposas/enzimologia , Mariposas/genética
11.
Pest Manag Sci ; 77(7): 3491-3499, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33837648

RESUMO

BACKGROUND: Plutella xylostella (L.) is a serious worldwide pest that feeds on cruciferous plants and has evolved resistance to different classes of insecticides used for its control, including chlorantraniliprole. ATP-binding cassette (ABC) transporters, constituting the largest transport family in organisms, are involved in phase III of the detoxification process and may play important roles in insecticide resistance. RESULTS: A total of 15 ABC transporter transcripts from subfamily G were identified in P. xylostella based on the latest DBM genome. Synergism studies showed that treatment with verapamil, a potent inhibitor of ABC transporters, significantly increased the toxicity of chlorantraniliprole against larvae of two chlorantraniliprole-resistant P. xylostella populations (NIL and BL). ABCG2, ABCG5, ABCG6, ABCG9, ABCG11, ABCG14 and ABCG15 were significantly overexpressed in NIL and BL compared with the susceptible population (SS), and ABCG1, ABCG6, ABCG8, ABCG9, ABCG14 and ABCG15 were significantly upregulated after treatment with the LC50 of chlorantraniliprole in SS. Subsequently, ABCG6, ABCG9 and ABCG14, which were overexpressed in both NIL and BL and could be induced in SS, were chosen for functional study. RNAi-mediated knockdown of each of the three ABCGs significantly increased the sensitivity of larvae to chlorantraniliprole. These results confirmed that overexpression of ABCG6, ABCG9 and ABCG14 may contribute to chlorantraniliprole resistance in P. xylostella. CONCLUSION: Overexpression of some genes in the ABCG subfamily is involved in P. xylostella resistance to chlorantraniliprole. These results may help to establish a foundation for further studies investigating the role played by ABC transporters in chlorantraniliprole resistance in P. xylostella or other insect pests. © 2021 Society of Chemical Industry.


Assuntos
Inseticidas , Mariposas , Subfamília G de Transportadores de Cassetes de Ligação de ATP , Animais , Resistência a Inseticidas/genética , Inseticidas/farmacologia , Larva/genética , Mariposas/genética , ortoaminobenzoatos/farmacologia
12.
Arch Biochem Biophys ; 706: 108857, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-33781769

RESUMO

Accumulating evidence has demonstrated that cellular antioxidant systems play essential roles in retarding oxidative stress-related diseases, such as Parkinson's disease. Because nuclear factor erythroid 2-related factor 2 (Nrf2) is a chief regulator of cellular antioxidant systems, small molecules with Nrf2-activating ability may be promising neuroprotective agents. Avenanthramide-2c (Aven-2c), avenanthramide-2f (Aven-2f) and avenanthramide-2p (Aven-2p) are the most abundant avenanthramides in oats, and they have been documented to possess multiple pharmacological benefits. In this work, we synthesized these three compounds and evaluated their cytoprotective effect against oxidative stress-induced PC12 cell injuries. Aven-2c displayed the best protective potency among them. Aven-2c conferred protection on PC12 cells by scavenging free radicals and activating the Nrf2-ARE signaling pathway. Pretreatment of PC12 cells with Aven-2c efficiently enhanced Nrf2 nuclear accumulation and evoked the expression of a set of cytoprotective molecules. The mechanistic study also supports that Nrf2 activation is the molecular basis for the cellular action of Aven-2c. Collectively, this study demonstrates that Aven-2c is a potent Nrf2 agonist, shedding light on the potential usage of Aven-2c in the treatment of neuroprotective diseases.


Assuntos
Elementos de Resposta Antioxidante , Antioxidantes/farmacologia , Fator 2 Relacionado a NF-E2/genética , Fármacos Neuroprotetores/farmacologia , Transdução de Sinais/genética , ortoaminobenzoatos/farmacologia , Animais , Avena/química , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica , Glutamato-Cisteína Ligase/genética , Glutamato-Cisteína Ligase/metabolismo , Heme Oxigenase (Desciclizante)/genética , Heme Oxigenase (Desciclizante)/metabolismo , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/farmacologia , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Oxidopamina/antagonistas & inibidores , Oxidopamina/farmacologia , Células PC12 , Extratos Vegetais/química , Ratos , Tiorredoxina Redutase 1/genética , Tiorredoxina Redutase 1/metabolismo , Tiorredoxinas/genética , Tiorredoxinas/metabolismo
13.
J Physiol Sci ; 71(1): 7, 2021 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-33618673

RESUMO

BACKGROUND: Currently available tocolytic agents are not effective treatment for preterm labor beyond 48 h. A major reason is the development of maternal side effects which preclude the maintenance of an effective steady-state drug concentration. One strategy that can mitigate these side effects is utilizing synergistic drug combinations to reduce the drug concentrations necessary to elicit a clinical effect. We have previously shown that three anoctamin 1 (ANO1) antagonists mediate potent relaxation of precontracted human uterine smooth muscle (USM). In this study, we aimed to determine whether a combination of sub-relaxatory doses of tocolytic drugs in current clinical use [the L-type voltage-gated calcium channel (VGCC) blocker, nifedipine (NIF); and the ß2-adrenergic (ß2AR) agonist, terbutaline (TRB)] will potentiate USM relaxation with two ANO1 antagonists [benzbromarone (BB) and MONNA (MN)]. OBJECTIVE: This study sought to examine the synergistic potency and mechanistic basis of two ANO1 antagonists with currently available tocolytic drugs. Functional endpoints assessed included relaxation of pre-contracting pregnant human USM tissue, inhibition of intracellular calcium release, and reduction of spontaneous transient inward current (STIC) recordings in human uterine smooth muscle cells. METHODS: Human myometrial strips and primary human USM cells were used in organ bath and calcium flux experiments with different combinations of sub-threshold doses of ANO1 antagonists and terbutaline or nifedipine to determine if ANO1 antagonists potentiate tocolytic drugs. RESULTS: The combination of sub-threshold doses of two ANO1 antagonists and current tocolytic drugs demonstrate a significant degree of synergy to relax human pregnant USM compared to the effects achieved when these drugs are administered individually. CONCLUSION: A combination of sub-threshold doses of VGCC blocker and ß2AR agonist with ANO1 antagonists potentiates relaxation of oxytocin-induced contractility and calcium flux in human USM ex vivo. Our findings may serve as a foundation for novel tocolytic drug combinations.


Assuntos
Anoctamina-1/antagonistas & inibidores , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Nifedipino/farmacologia , Terbutalina/farmacologia , Útero/fisiologia , Benzobromarona/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Gravidez , Técnicas de Cultura de Tecidos , Tocolíticos/farmacologia , Uricosúricos/farmacologia , ortoaminobenzoatos/farmacologia
14.
Insect Sci ; 28(3): 639-648, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33386702

RESUMO

Spodoptera frugiperda (Lepidoptera: Noctuidae) is a widely distributed pest of corn. Since it invaded China in 2018, it has caused serious damage to local corn production. Chlorantraniliprole, an anthranilic diamide insecticide, has been widely used to control lepidopteran pests. Tetrachloropyramid is a new allosteric modulator insecticide developed based on chlorantraniliprole, so it has a similar mechanism and insecticidal effect. In this study, we investigated resistance levels to chlorantraniliprole and tetrachloropyramid in S. frugiperda from 13 populations in China. Among the populations tested, the relative highest resistance to chlorantraniliprole occurred in the Guangzhou population, and the most susceptible to chlorantraniliprole was found in the Wuhan population. The lethal dosage LD50 value of the Guangzhou population against chlorantraniliprole was 27.8-fold higher than that of the Wuhan population. Minimal differences were observed among S. frugiperda populations in terms of sensitivity to tetrachloropyramid. Heterozygous mutations at the I4734 site of the ryanodine receptor (RyR) were found, while no mutations were found in the G4891 site. The mutations were detected in only two of the 786 individuals analyzed, one from the Qinzhou population and other from the Anshun population (frequency below 2% in both cases). There were no significant differences in the expression levels of RyR between Guangzhou and Wuhan populations. In summary, our results indicate that: (i) S. frugiperda has low resistance levels to diamide insecticides in China; and (ii) the differences in relative resistance among the 13 populations analyzed are not caused by the mutations in RyR or the expression of RyR.


Assuntos
Resistência a Inseticidas/genética , Mutação , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Spodoptera , ortoaminobenzoatos/farmacologia , Animais , China , Diamida/farmacologia , Inseticidas/farmacologia , Larva/efeitos dos fármacos , Larva/genética , Larva/metabolismo , Spodoptera/efeitos dos fármacos , Spodoptera/genética , Spodoptera/metabolismo , ortoaminobenzoatos/análise
15.
Pest Manag Sci ; 77(4): 1739-1747, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33232550

RESUMO

BACKGROUND: The field population of Spodoptera exigua, an intermittently occurring polyphagous pest, has developed resistance to chlorantraniliprole, while whether or not such resistance carries fitness costs remains poorly understood. Here we selected six generations of the Leshan population (LS-P) by two-way selecting method, and obtained a highly resistant strain (CH-RE) and resistant degeneration strain (CH-SE) sharing a similar genetic background. After that fitness costs were evaluated by comparing the life history characteristics of CH-RE, CH-SE and the laboratory susceptible strain (SE-Lab) via the age-stage two-sex life table method. RESULTS: The resistance ratio of CH-RE and CH-SE were 226.69-fold and 3.72-fold, respectively, and the estimated realized heritability (h2 ) of CH-RE was 0.058. Compared with CH-SE, the duration of pre-adult, the longevity of adult, adult preoviposition period (APOP) and average generation time (T) of CH-RE had significantly increased, but the oviposition days, average fecundity, intrinsic growth rate (r), weekly growth rate (λ) and reproductive rate (R0 ) decreased significantly. Moreover, the relative fitness of CH-RE was 0.25, and showed fitness costs. Concurrently, the fecundity of CH-SE was slightly lower than SE-Lab, but there was no significant difference in r, λ and R0 , and the fitness (1) of CH-SE was similar to SE-Lab (1.02), which was no fitness cost. CONCLUSION: These findings represent that chlorantraniliprole resistance in S. exigua has a fitness cost, and the fitness cost will disappear with the recovery of sensitivity when the insecticide is stopped for field populations, supporting that such resistance would be managed by switching off the selection pressure with rotation with alternate insecticides. © 2020 Society of Chemical Industry.


Assuntos
Resistência a Inseticidas , Inseticidas , Animais , Feminino , Resistência a Inseticidas/genética , Inseticidas/farmacologia , Larva , Spodoptera/genética , ortoaminobenzoatos/farmacologia
16.
Food Chem ; 343: 128408, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33158678

RESUMO

From a mutagenized oat population, produced by ethyl methanesulfonate mutagenesis, hulled grains from 17 lines with elevated avenanthramide (AVN) content were selected and their AVN structures, concentrations and antioxidant potentials were determined by HPLC-MS2 and HPLC equipped with an on-line ABTS+ antioxidant detection system. The data obtained showed qualitative and quantitative differences in the synthesis of AVNs in the different lines, with a total AVN concentration up to 227.5 µg/g oat seed flour in the highest line, compared with 78.2 µg/g seed in the commercial line, SW Belinda. In total, 25 different AVNs were identified with avenanthramide B structures being among the most abundant, and AVN C structures having the highest antioxidant activity. The findings indicate the potential of oat mutagenesis in combination with a high precision biochemical selection method for the generation of stable mutagenized lines with a high concentration of total and/or individual AVNs in the oat seed grain.


Assuntos
Antioxidantes/química , Avena/química , Avena/genética , ortoaminobenzoatos/análise , ortoaminobenzoatos/química , Antioxidantes/análise , Cromatografia Líquida de Alta Pressão/métodos , Farinha , Espectrometria de Massas , Mutagênese , Extratos Vegetais/química , Sementes/química , ortoaminobenzoatos/farmacologia
17.
Neurotoxicology ; 82: 167-176, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33352273

RESUMO

Silver nanoparticles (AgNPs) are widely applied in various aspects of life. However, recent studies reported their potential toxicity both on environment and human health. The present study aimed to unravel the underlying molecular mechanisms involved in AgNPs-induced brain toxicity. Moreover, chemopreventive effect of tranilast, an analogue of tryptophan metabolite and a mast cell membrane stabilizer was evaluated. Thirty Sprague Dawley rats were enrolled equally into Normal control group, AgNPs-intoxicated group (50 mg/kg, 3 times/week) and tranilast (300 mg/kg, 3 times/week)+AgNPs group. AgNPs administration triggered brain oxidative stress as depicted by reduced Nrf-2 expression, decreased TAC and GSH as well as upregulated brain lipid peroxidation. The apparent brain oxidative damage was accompanied by elevated levels of inflammatory cytokines (IL-1ß, IL-6 and TNF-α). Moreover, brain levels of TLR4, NLRP3 and caspase-1 were up-regulated. Additionally, histological study indicated marked cellular injury in cerebrum and cerebellum specimens. This was concomitant with elevated serum CK activity and CK-BB level. On the other hand, tanilast administration remarkably alleviated AgNPs-induced brain toxicity. The present study shed the light on implication of TLR4/NLRP3 axis and NrF2 in AgNPs-induced brain toxicity. In addition, it explored the potential protective effect of tranilast on AgNPs-induced brain injury via antioxidant and anti-inflammatory efficacies.


Assuntos
Cérebro/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Fator 2 Relacionado a NF-E2/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fármacos Neuroprotetores/farmacologia , Compostos de Prata/toxicidade , Receptor 4 Toll-Like/metabolismo , ortoaminobenzoatos/farmacologia , Animais , Caspase 1/metabolismo , Cérebro/metabolismo , Cérebro/patologia , Creatina Quinase/sangue , Creatina Quinase Forma BB/sangue , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
18.
Life Sci ; 267: 118984, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33383049

RESUMO

An increase in oxidative stress is an important pathological mechanism of heart injury induced by doxorubicin (DOX). Tranilast is an anti-allergy drug that has been shown to possess good antioxidant activity in previous studies. The overexpression and secretion of chymase by mast cells (MCs) increase the pathological overexpression of angiotensin II (Ang II), which plays a crucial role in myocardial hypertrophy and the deterioration of heart disease. The MC stabilizer tranilast (N-(3,4-dimethoxycinnamoyl) anthranilic acid; tran) prevents mast cells from degranulating, which may reduce DOX-induced Ang II synthesis. Therefore, in the present study, we hypothesized that tranilast will protect rats from DOX-induced myocardial damage via its antioxidant activity, thereby inhibiting Ang II expression. Thirty male Wistar rats were divided into three groups (n = 10 in each group) that received DOX, a combination of DOX and tranilast or saline (the control group) to test this hypothesis. Tranilast suppressed chymase expression, reduced Ang II levels and prevented the myocardial hypertrophy and the deterioration of heart function induced by DOX. Based on the findings of the present study, the suppression of chymase-dependent Ang-II production and the direct effect of tranilast on the inhibition of apoptosis and fibrosis because of its antioxidant stress capacity may contribute to the protective effect of tranilast against DOX-induced myocardial hypertrophy.


Assuntos
Angiotensina II/efeitos dos fármacos , Cardiomegalia/metabolismo , Doxorrubicina/efeitos adversos , ortoaminobenzoatos/farmacologia , Angiotensina II/biossíntese , Angiotensina II/metabolismo , Animais , Antioxidantes/farmacologia , Cardiomegalia/tratamento farmacológico , Doxorrubicina/farmacologia , Fibrose , Cardiopatias/etiologia , Masculino , Mastócitos/efeitos dos fármacos , Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , ortoaminobenzoatos/metabolismo
20.
Bioorg Chem ; 105: 104368, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33091671

RESUMO

The discovery of the antiproliferative potential of tranilast prompted additional studies directed at understanding the mechanisms of tranilast action. Its inhibitory effect on cell proliferation depends principally on the capacity of tranilast to interfere with transforming growth factor beta (TGFßR1) signaling. This work summarizes design, synthesis and biological evaluation of sixteen novel tranilast analogs on different tumors such as PC-3, HepG-2 and MCF-7 cell lines. The in vitro cytotoxicity was evaluated using MTT assay showed that, twelve compounds out of sixteen showed higher cytotoxic activities (IC50's 1.1-6.29 µM), than that of the reference standard, 5-FU (IC50 7.53 µM). The promising cytotoxic hits (4b, 7a, b and 14c-e), proved to be selective to cancer cells when their cytotoxicity's are examined on human normal cell line (WI-38). Then they are investigated for their possible mode of action as TGFßR1 inhibitors; remarkable inhibition of TGFßR1 by these hits was observed at the range of IC50 0.087-3.276 µM. The cell cycle analysis of the most potent TGFßR1 inhibitor, 4b revealed cell cycle arrest at G2/M phase on prostate cancer cells. Additionally, it is clearly indicated apoptosis induction at Pre-G1 phase, this is substantiated by significant increase in the expression on the tumor suppressor gene, p53 and up regulation the level of apoptosis mediator, caspase-3. In addition, in silico study was performed for validating the physicochemical and ADME properties which revealed that, all compounds are orally bioavailable with no side effects complying with Lipinski rule. The proposed mode of action can be further explored on the light of molecular modeling simulation of the most potent compounds, 4b and 14e which were docked into the active sites of TGFßR1 to predict their affinities toward the receptor.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/farmacologia , Receptor do Fator de Crescimento Transformador beta Tipo I/antagonistas & inibidores , ortoaminobenzoatos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas , ortoaminobenzoatos/síntese química , ortoaminobenzoatos/química
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