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1.
J Agric Food Chem ; 69(45): 13373-13385, 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34735146

RESUMO

Succinate dehydrogenase (SDH) is known as an ideal target for the investigations of fungicides. To develop novel SDH inhibitors, 30 novel thiophene/furan-1,3,4-oxadiazole carboxamide derivatives were designed and synthesized. In the in vitro antifungal assay, a majority of the target compounds demonstrated fair to potent antifungal activity against seven tested phytopathogenic fungi. Compounds 4b, 4g, 4h, 4i, and 5j showed remarkable antifungal activity against Sclerotinia sclerotiorum, affording EC50 values ranging from 0.1∼1.1 mg/L. In particular, compound 4i displayed the most potent activity against S. sclerotiorum (EC50 = 0.140 ± 0.034 mg/L), which was superior to that of boscalid (EC50 = 0.645 ± 0.023 mg/L). A further morphological investigation revealed the abnormal mycelia and damaged cell structures of compound 4i-treated S. sclerotiorum by scanning electron microscopy. Furthermore, the in vivo antifungal assay against S. sclerotiorum revealed that compounds 4g and 4i were effective for suppressing rape Sclerotinia rot at a dosage of 200 mg/L. In the SDH inhibition assay, compounds 4g and 4i also presented significant inhibitory activity with IC50 values of 1.01 ± 0.21 and 4.53 ± 0.19 µM, respectively, which were superior or equivalent to that of boscalid (3.51 ± 2.02 µM). Molecular docking and molecular dynamics simulation of compound 4g with SDH revealed that compound 4g could form strong interactions with the key residues of the SDH. These results indicated that this class of derivatives could be a promising scaffold for the discovery and development of novel SDH inhibitors.


Assuntos
Fungicidas Industriais , Succinato Desidrogenase , Antifúngicos/farmacologia , Ascomicetos , Inibidores Enzimáticos/farmacologia , Fungicidas Industriais/farmacologia , Furanos/farmacologia , Simulação de Acoplamento Molecular , Oxidiazóis , Relação Estrutura-Atividade , Succinato Desidrogenase/metabolismo , Ácido Succínico , Tiofenos/farmacologia
2.
J Agric Food Chem ; 69(45): 13448-13459, 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34748325

RESUMO

Diversity of pesticide discovery provided a solution to resistance. Here, we presented a strategy of azo-incorporating to promote the diverse developments of fungicide. A series of novel fungicides were synthesized by incorporating azobenzene derivatives into fluxapyroxad. Much better in vitro fungicidal activity increases for compound 9d were observed compared to the positive control, fluxapyroxad against Botrytis cinerea and Rhizoctonia solani. Compound 9d (IC50 = 0.03 µM) also had a great enzyme-inhibiting activity increase toward succinate dehydrogenase in comparison with fluxapyroxad (IC50 = 4.40 µM). A comparatively equivalent biological activity was observed between compounds 8a and 9d. SEM analysis helped us to observe clearly the morphology of the fungi before and after active ingredient delivery. Our results of molecular docking analysis, fluorescence quenching analysis, and enzymatic assays demonstrated that compound 8a and 9d act on SDH. An increase in inhibitory activity could be occurring after incorporation of azobenzene, which provided a new strategy for molecular design in pesticide discovery.


Assuntos
Ascomicetos , Fungicidas Industriais , Ascomicetos/metabolismo , Botrytis , Fungicidas Industriais/farmacologia , Simulação de Acoplamento Molecular , Rhizoctonia/metabolismo , Relação Estrutura-Atividade , Succinato Desidrogenase/metabolismo
3.
J Agric Food Chem ; 69(44): 13227-13234, 2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34709809

RESUMO

Succinate dehydrogenase (SDH, EC 1.3.5.1) has proven to be an important fungicidal target, and the inhibition of SDH is useful in the treatment of plant pathogens. The discovery of a novel active SDH inhibitor is of high value. Herein, we disclose the discovery of a potent, highly active inhibitor as a fungicide candidate by using a computational substitution optimization method, a fast drug design method developed in our laboratory. The greenhouse experiments showed that compound 17c exhibited high protective activity against south corn rust, soybean rust (SBR), and rice sheath blight at a very low dosage of 0.781 mg/L. Moreover, the field trials indicated that compound 17c is comparable to and even better than commercial fungicides against SBR and cucumber powdery mildew at 50 mg/L concentration. Most surprisingly, compound 17c resulted to be strictly better in curative activity than the commercial fungicide benzovindiflupyr. The computation results indicated that 17c could form another hydrogen bond with C_S42 and then lead to strong van der Waals and electronic interactions with SDH. Our results suggested that 17c is a potential fungicide candidate for SDH.


Assuntos
Basidiomycota , Cucumis sativus , Fungicidas Industriais , Basidiomycota/metabolismo , Cucumis sativus/metabolismo , Desenho de Fármacos , Fungicidas Industriais/farmacologia , Doenças das Plantas , Succinato Desidrogenase/genética , Succinato Desidrogenase/metabolismo
4.
Int J Mol Sci ; 22(18)2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34576241

RESUMO

Although it had been reported that Israeli acute paralysis virus (IAPV) can cause systemic infection in honey bees, little is known about how it establishes this infection and results in the typical symptoms, paralysis and trembling. Here, we used our previously constructed IAPV infectious clone to investigate viral loads in different tissues of honey bees and further identify the relation between tissue tropism and paralytic symptoms. Our results showed that tracheae showed a greater concentration of viral abundance than other tissues. The abundance of viral protein in the tracheae was positively associated with viral titers, and was further confirmed by immunological and ultrastructural evidence. Furthermore, higher viral loads in tracheae induced remarkable down-regulation of succinate dehydrogenase and cytochrome c oxidase genes, and progressed to causing respiratory failure of honey bees, resulting in the appearance of typical symptoms, paralysis and body trembling. Our results showed that paralysis symptoms or trembling was actually to mitigate tachypnea induced by IAPV infection due to the impairment of honey bee tracheae, and revealed a direct causal link between paralysis symptoms and tissue tropism. These findings provide new insights into the understanding of the underlying mechanism of paralysis symptoms of honey bees after viral infection and have implications for viral disease prevention and specific therapeutics in practice.


Assuntos
Dicistroviridae , Paralisia/fisiopatologia , Taquipneia/fisiopatologia , Viroses/fisiopatologia , Animais , Abelhas/virologia , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Paralisia/virologia , Succinato Desidrogenase/metabolismo , Taquipneia/virologia , Traqueia/virologia , Carga Viral , Proteínas Virais , Viroses/virologia
5.
J Agric Food Chem ; 69(38): 11470-11484, 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34543010

RESUMO

The development of new green fungicides based on the structural optimization of natural products can effectively solve the problems of low safety and high pathogen resistance of traditional fungicides. In this paper, based on pyrazole amide compound h-I-9 with excellent fungicidal activity discovered in the previous work, a series of l-serine-derived pyrazole amide and waltherione alkaloid-derived pyrazole ester derivatives were synthesized. The structures were successively identified by 1H NMR, 13C NMR, high-resolution mass spectrometry, and X-ray single-crystal diffraction. The in vitro and in vivo fungicidal activity screening demonstrated that compound II-5 showed a good inhibition rate against Physalospora piricola. A transmission electron microscope and fluorescence microscope observation further revealed that compound II-5 may cause damage to the cell membranes and vacuoles, and the hyphae treated with II-5 could produce obvious and easily observed blue fluorescence. The succinate dehydrogenase (SDH) enzymatic activity and molecular docking simulation indicated that compounds I-3 and I-4 may be potential SDH inhibitors against Alternaria sp.


Assuntos
Alcaloides , Produtos Biológicos , Fungicidas Industriais , Alcaloides/farmacologia , Amidas/farmacologia , Produtos Biológicos/farmacologia , Ésteres , Fungicidas Industriais/farmacologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirazóis/farmacologia , Serina , Relação Estrutura-Atividade , Succinato Desidrogenase/metabolismo
6.
Proc Natl Acad Sci U S A ; 118(39)2021 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-34551979

RESUMO

Reduced succinate dehydrogenase (SDH) activity resulting in adverse succinate accumulation was previously considered relevant only in 0.05 to 0.5% of kidney cancers associated with germline SDH mutations. Here, we sought to examine a broader role for SDH loss in kidney cancer pathogenesis/progression. We report that underexpression of SDH subunits resulting in accumulation of oncogenic succinate is a common feature in clear cell renal cell carcinoma (ccRCC) (∼80% of all kidney cancers), with a marked adverse impact on survival in ccRCC patients (n = 516). We show that SDH down-regulation is a critical brake in the TCA cycle during ccRCC pathogenesis and progression. In exploring mechanisms of SDH down-regulation in ccRCC, we report that Von Hippel-Lindau loss-induced hypoxia-inducible factor-dependent up-regulation of miR-210 causes direct inhibition of the SDHD transcript. Moreover, shallow deletion of SDHB occurs in ∼20% of ccRCC. We then demonstrate that SDH loss-induced succinate accumulation contributes to adverse loss of 5-hydroxymethylcytosine, gain of 5-methylcytosine, and enhanced invasiveness in ccRCC via inhibition of ten-eleven translocation (TET)-2 activity. Intriguingly, binding affinity between the catalytic domain of recombinant TET-2 and succinate was found to be very low, suggesting that the mechanism of succinate-induced attenuation of TET-2 activity is likely via product inhibition rather than competitive inhibition. Finally, exogenous ascorbic acid, a TET-activating demethylating agent, led to reversal of the above oncogenic effects of succinate in ccRCC cells. Collectively, our study demonstrates that functional SDH deficiency is a common adverse feature of ccRCC and not just limited to the kidney cancers associated with germline SDH mutations.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/patologia , Metilação de DNA , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais/patologia , Succinato Desidrogenase/metabolismo , 5-Metilcitosina/química , Apoptose , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Ciclo Celular , Movimento Celular , Proliferação de Células , Humanos , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Mutação , Invasividade Neoplásica , Prognóstico , Succinato Desidrogenase/genética , Taxa de Sobrevida , Células Tumorais Cultivadas
7.
J Agric Food Chem ; 69(36): 10709-10721, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34476938

RESUMO

Thirty-one new 4H-chromene derivatives were designed and synthesized. Their structures were identified with IR, 1H NMR, 13C NMR, and HRMS. The crystal structure of compound 2a was determined by single-crystal X-ray diffraction. Their antifungal activities were evaluated against Pyricularia oryzae, Erysiphe graminis, Coniella diplodiella, Pseudoperonospora cubensis, and Sclerotinia sclerotiorum. These results demonstrated that most compounds exhibited remarkable inhibitory activities at 20 µg/mL. Compounds 4b and 4c displayed excellent antifungal activity against S. sclerotiorum and possessed better efficacy than fluopyram. At the same time, the inhibitory activity of the bioactive compounds was evaluated against succinate dehydrogenase (SDH). The results showed that these compounds possessed outstanding activity. Compounds 4b and 4c displayed better inhibitory activity than fluopyram. The molecular modeling results revealed that compound 4c had stronger affinity to SDH than fluopyram. It is the first time that the inhibitory activity of 4H-chromene analogs against SDH has been reported.


Assuntos
Benzopiranos , Succinato Desidrogenase , Antifúngicos/farmacologia , Ascomicetos , Benzopiranos/farmacologia , Estrutura Molecular , Relação Estrutura-Atividade , Succinato Desidrogenase/metabolismo
8.
J Agric Food Chem ; 69(33): 9557-9570, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34382800

RESUMO

Succinate dehydrogenase inhibitors (SDHIs) have emerged in fungicide markets as one of the fastest-growing categories that are widely applied in agricultural production for crop protection. Currently, the structural modification focusing on the flexible amide link of SDHI molecules is being gradually identified as one of the innovative strategies for developing novel highly efficient and broad-spectrum fungicides. Based on the above structural features, a series of pyrazole-4-acetohydrazide derivatives potentially targeting fungal SDH were constructed and evaluated for their antifungal effects against Rhizoctonia solani, Fusarium graminearum, and Botrytis cinerea. Strikingly, the in vitro EC50 values of constructed pyrazole-4-acetohydrazides 6w against R. solani, 6c against F. graminearum, and 6f against B. cinerea were, respectively, determined as 0.27, 1.94, and 1.93 µg/mL, which were obviously superior to that of boscalid against R. solani (0.94 µg/mL), fluopyram against F. graminearum (9.37 µg/mL), and B. cinerea (1.94 µg/mL). Concurrently, the effects of the substituent steric, electrostatic, hydrophobic, and hydrogen-bond fields on structure-activity relationships were elaborated by the reliable comparative molecular field analysis and comparative molecular similarity index analysis models. Subsequently, the practical value of pyrazole-4-acetohydrazide derivative 6w as a potential SDHI was ascertained by the relative surveys on the in vivo anti-R. solani preventative efficacy, inhibitory effects against fungal SDH, and molecular docking studies. The present results provide an indispensable complement for the structural optimization of antifungal leads potentially targeting SDH.


Assuntos
Fungicidas Industriais , Succinato Desidrogenase , Botrytis , Fungicidas Industriais/farmacologia , Fusarium , Hidrazinas , Simulação de Acoplamento Molecular , Doenças das Plantas , Pirazóis/farmacologia , Relação Quantitativa Estrutura-Atividade , Rhizoctonia , Relação Estrutura-Atividade , Succinato Desidrogenase/metabolismo
9.
Mult Scler Relat Disord ; 54: 103132, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34289436

RESUMO

Succinate dehydrogenase (SDH), or respiratory complex II, consists of four nuclear-encoded subunits. The chaperone protein succinate dehydrogenase assembly factor 1 (SDHAF1) plays an essential role in the assembly of SDH, and in the incorporation of iron-sulfur clusters into the SDHB subunit. SDHB couples the oxidation of succinate to fumarate with the reduction of ubiquinone (coenzyme Q) to ubiquinol. Previously reported mutations in SDHAF1 have been associated with infantile leukoencephalopathy. We report an adult case with a homozygous variant of uncertain significance (VUS) mutation in SDHAF1, presenting with dementia, spastic paraparesis, and cardiomyopathy, initially diagnosed as multiple sclerosis.


Assuntos
Leucoencefalopatias , Paraparesia Espástica , Adulto , Humanos , Leucoencefalopatias/complicações , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/genética , Chaperonas Moleculares , Mutação , Proteínas/genética , Succinato Desidrogenase/genética , Succinato Desidrogenase/metabolismo
10.
Int J Mol Sci ; 22(13)2021 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-34199098

RESUMO

Mitochondria play an essential role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Previously, we found that succinate-activated respiration was the most affected mitochondrial parameter in mice with mild NAFLD. In this study, we focused on the role of succinate dehydrogenase (SDH) in NAFLD pathogenesis. To induce the progression of NAFLD to nonalcoholic steatohepatitis (NASH), C57BL/6J mice were fed a Western-style diet (WD) or control diet for 30 weeks. NAFLD severity was evaluated histologically and the expression of selected proteins and genes was assessed. Mitochondrial respiration was measured by high-resolution respirometry. Liver redox status was assessed using glutathione, malondialdehyde, and mitochondrial production of reactive oxygen species (ROS). Metabolomic analysis was performed by GC/MS. WD consumption for 30 weeks led to reduced succinate-activated respiration. We also observed decreased SDH activity, decreased expression of the SDH activator sirtuin 3, decreased gene expression of SDH subunits, and increased levels of hepatic succinate, an important signaling molecule. Succinate receptor 1 (SUCNR1) gene and protein expression were reduced in the livers of WD-fed mice. We did not observe signs of oxidative damage compared to the control group. The changes observed in WD-fed mice appear to be adaptive to prevent mitochondrial respiratory chain overload and massive ROS production.


Assuntos
Dieta Ocidental , Mitocôndrias Hepáticas/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Oxirredução , Estresse Oxidativo , Ácido Succínico/metabolismo , Animais , Apoptose , Biomarcadores , Respiração Celular , Modelos Animais de Doenças , Suscetibilidade a Doenças , Fibrose , Metaboloma , Metabolômica/métodos , Camundongos , Hepatopatia Gordurosa não Alcoólica/patologia , Succinato Desidrogenase/metabolismo
11.
Int J Mol Sci ; 22(11)2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34199982

RESUMO

Lysine succinylation is a post-translational modification which alters protein function in both physiological and pathological processes. Mindful that it requires succinyl-CoA, a metabolite formed within the mitochondrial matrix that cannot permeate the inner mitochondrial membrane, the question arises as to how there can be succinylation of proteins outside mitochondria. The present mini-review examines pathways participating in peroxisomal fatty acid oxidation that lead to succinyl-CoA production, potentially supporting succinylation of extramitochondrial proteins. Furthermore, the influence of the mitochondrial status on cytosolic NAD+ availability affecting the activity of cytosolic SIRT5 iso1 and iso4-in turn regulating cytosolic protein lysine succinylations-is presented. Finally, the discovery that glia in the adult human brain lack subunits of both alpha-ketoglutarate dehydrogenase complex and succinate-CoA ligase-thus being unable to produce succinyl-CoA in the matrix-and yet exhibit robust pancellular lysine succinylation, is highlighted.


Assuntos
Lisina/química , Lisina/metabolismo , Processamento de Proteína Pós-Traducional , Proteínas/química , Proteínas/metabolismo , Humanos , Complexo Cetoglutarato Desidrogenase/metabolismo , Neuroglia/metabolismo , Sirtuínas/metabolismo , Succinato Desidrogenase/metabolismo
13.
Nat Commun ; 12(1): 3428, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34103526

RESUMO

Dysregulated extravillous trophoblast invasion and proliferation are known to increase the risk of recurrent spontaneous abortion (RSA); however, the underlying mechanism remains unclear. Herein, in our retrospective observational case-control study we show that villous samples from RSA patients, compared to healthy controls, display reduced succinate dehydrogenase complex iron sulfur subunit (SDHB) DNA methylation, elevated SDHB expression, and reduced succinate levels, indicating that low succinate levels correlate with RSA. Moreover, we find high succinate levels in early pregnant women are correlated with successful embryo implantation. SDHB promoter methylation recruited MBD1 and excluded c-Fos, inactivating SDHB expression and causing intracellular succinate accumulation which mimicked hypoxia in extravillous trophoblasts cell lines JEG3 and HTR8 via the PHD2-VHL-HIF-1α pathway; however, low succinate levels reversed this effect and increased the risk of abortion in mouse model. This study reveals that abnormal metabolite levels inhibit extravillous trophoblast function and highlights an approach for RSA intervention.


Assuntos
Aborto Habitual/metabolismo , Vilosidades Coriônicas/metabolismo , Ácido Succínico/metabolismo , Aborto Habitual/enzimologia , Aborto Habitual/genética , Animais , Estudos de Casos e Controles , Hipóxia Celular , Linhagem Celular Tumoral , Ilhas de CpG/genética , Metilação de DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Regulação da Expressão Gênica , Glicólise , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Metaboloma , Camundongos Endogâmicos C57BL , Gravidez , Regiões Promotoras Genéticas/genética , Ligação Proteica , Proteínas Proto-Oncogênicas c-fos/metabolismo , Fatores de Risco , Succinato Desidrogenase/genética , Succinato Desidrogenase/metabolismo , Fatores de Transcrição/metabolismo , Transcrição Genética , Trofoblastos/metabolismo , Trofoblastos/patologia
15.
Cell Death Dis ; 12(5): 444, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33947839

RESUMO

Pheochromocytoma/paraganglioma (PPGL) is an endocrine tumor of the chromaffin cells in the adrenal medulla or the paraganglia. Currently, about 70% of PPGLs can be explained by germline or somatic mutations in several broadly expressed susceptibility genes including RET, VHL, and SDHB, while for the remaining, mainly sporadic cases, the pathogenesis is still unclear. Even for known susceptible genes, how mutations in these mostly ubiquitous genes result in tissue-specific pathogenesis remains unanswered, and why RET-mutated tumors almost always occur in the adrenal while SDHB-mutated tumors mostly occur extra-adrenal remains a mystery. By analyzing 22 sporadic PPGLs using SNP 6.0 genotyping arrays combined with expression profiling of 4 normal and 4 tumor tissues, we identified GIPC2, a gene located at 1p31.1 with preferential expression in adrenal and inducible by adrenal glucocorticoid, as a novel putative tumor suppressor gene for PPGLs. Copy number deletion and GIPC2 promoter hypermethylation but not GIPC2 mutation, accompanied with reduced GIPC2 expression, were observed in 39 of 55 PPGLs in our cohort. Examination of a published expression database consisting of 188 PPGLs found little GIPC2 expression in Cluster 1A (SDHx-associated) and Cluster 2A (NF1/RET-associated) tumors, but less pronounced reduction of GIPC2 expression in Cluster 1B (VHL-associated) and Cluster 2B/2C tumors. GIPC2 induced p27, suppressed MAPK/ERK and HIF-1ɑ pathways as well as cancer cell proliferation. Overexpressing GIPC2 in PC12 cells inhibited tumor growth in nude mice. We found GIPC2 interacted with the nucleoprotein NONO and both proteins regulated p27 transcription through the same GGCC box on p27 promoter. Significantly, low expression of both GIPC2 and p27 was associated with shorter disease-free survival time of PPGLs patients in the TCGA database. We found that PPGL-causing mutations in RET and in SDHB could lead to primary rat adrenal chromaffin cell proliferation, ERK activation, and p27 downregulation, all requiring downregulating GIPC2. Notably, the RET-mutant effect required the presence of dexamethasone while the SDHB-mutant effect required its absence, providing a plausible explanation for the tumor location preference. In contrast, the PPGL-predisposing VHL mutations had no effect on proliferation and GIPC2 expression but caused p53 downregulation and reduced apoptosis in chromaffin cells compared with wild-type VHL. Thus, our study raises the importance of cortical hormone in PPGL development, and GIPC2 as a novel tumor suppressor provides a unified molecular mechanism for the tumorigenesis of both sporadic and hereditary tumors of Clusters 1A and 2A concerning SDHB and RET, but not tumors of Cluster 1B concerning VHL and other clusters.


Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Proteínas de Transporte/metabolismo , Genes Supressores de Tumor/fisiologia , Feocromocitoma/genética , Proteínas Proto-Oncogênicas c-ret/metabolismo , Succinato Desidrogenase/metabolismo , Neoplasias das Glândulas Suprarrenais/patologia , Humanos , Feocromocitoma/patologia , Transfecção
16.
J Agric Food Chem ; 69(20): 5746-5754, 2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-33988994

RESUMO

To promote the discovery and development of new fungicides, a series of novel pyrazol-5-yl-benzamide derivatives were designed, synthesized by hopping and inversion of amide groups of pyrazole-4-carboxamides, and evaluated for their antifungal activities. The bioassay data revealed that compound 5IIc exhibited an excellent in vitro activity against Sclerotinia sclerotiorum with an EC50 value of 0.20 mg/L, close to that of commercial fungicide Fluxapyroxad (EC50 = 0.12 mg/L) and Boscalid (EC50 = 0.11 mg/L). For Valsa mali, compound 5IIc (EC50 = 3.68 mg/L) showed a significantly higher activity than Fluxapyroxad (EC50 = 12.67 mg/L) and Boscalid (EC50 = 14.83 mg/L). In addition, in vivo experiments proved that compound 5IIc has an excellent protective fungicidal activity with an inhibitory rate of 97.1% against S. sclerotiorum at 50 mg/L, while the positive control Fluxapyroxad showed a 98.6% inhibitory effect. The molecular docking simulation revealed that compound 5IIc interact with TRP173, SER39, and ARG43 of succinate dehydrogenase (SDH) through a hydrogen bond and p-π interaction, which could explain the probable mechanism of the action between compound 5IIc and target protein. Also, the SDH enzymatic inhibition assay was carried out to further validate its mode of action. These results demonstrate that compound 5IIc could be a promising fungicide candidate and provide a valuable reference for further investigation.


Assuntos
Fungicidas Industriais , Succinato Desidrogenase , Ascomicetos , Benzamidas/farmacologia , Fungicidas Industriais/farmacologia , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Succinato Desidrogenase/metabolismo
17.
Pest Manag Sci ; 77(9): 3910-3920, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33871901

RESUMO

BACKGROUND: Succinate dehydrogenase inhibitors (SDHIs) play an increasingly important role in controlling plant diseases. However, the similar structures of SDHIs result in rapid development of cross-resistance development and a clear bottleneck of poor activity against oomycetes, therefore the need to seek new SDHI fungicides with novel structures is urgent. RESULTS: Innovative pyrazolyl oxime ethers were designed by replacing amide with oxime ether based on the succinate dehydrogenase (SDH) structure, and 19 pairs of Z- and E-isomers were efficiently prepared for the discovery of SDHI compounds with a novel bridge. Their biological activities against four fungi and two oomycetes were evaluated, and substantial differences were observed between the Z- and E- isomers of the title compounds. Furthermore, most of these compounds exhibited remarkable activities against Rhizoctonia solani with EC50 values of less than 10 mg L-1 in vitro, and bioassay in vivo further confirmed that E-I-6 exhibited good protective efficacy (76.12%) at 200 mg L-1 . In addition, Z-I-12 provided better activity against the oomycetes Pythium aphanidermatum and Phytophthora capsici (EC50  = 1.56 and 0.93 mg L-1 ) than those of boscalid. Moreover, E-I-12 exhibited excellent SDH inhibition (IC50  = 0.21 mg L-1 ) thanks to its good binding ability to the SDH by hydrogen-bonding interactions, π-cation interaction and hydrophobic interactions. CONCLUSION: Novel pyrazolyl oxime ethers have the potential as SDHI compounds for future development, and the strategy of replacing an amide bond with oxime ether may offer an alternative option in SDHI fungicide discovery.


Assuntos
Fungicidas Industriais , Oomicetos , Antifúngicos/farmacologia , Éteres/farmacologia , Fungicidas Industriais/farmacologia , Oximas/farmacologia , Rhizoctonia , Relação Estrutura-Atividade , Succinato Desidrogenase/metabolismo
18.
Pest Manag Sci ; 77(9): 3980-3989, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33882186

RESUMO

BACKGROUND: For Corynespora cassiicola (Berk. & M.A. Curtis) C.T. Wei, a necrotrophic pathogen with a broad host range and a worldwide distribution, resistance to fluopyram has been attributed to mutations in SdhB/C/D subunit of the succinate dehydrogenase (SDH) complex. In our previous study, two point mutations in SdhB from isoleucine to valine at position 280 (I280V) and histidine to tyrosine at position 278 (H278Y) showed different resistance phenotypes to fluopyram and boscalid. This research was conducted to explore the correlation between the mutation of SdhB-I280V or SdhB-H278Y and resistance to fluopyram or boscalid and its effect on the fitness characteristics of C. cassiicola. RESULTS: The sdhB gene in a succinate dehydrogenase inhibitor (SDHI)-sensitive C. cassiicola strain (wild type) was successfully replaced with the mutant sdhB gene (GTT at position 280, SdhB-I280V) or with the mutant sdhB gene (TAC at position 278, SdhB-H278Y,). Compared with the wild-type strain, the replacement mutants exhibited significantly different resistance phenotypes, with SdhB-V280 demonstrating moderate resistance to fluopyram and low resistance to boscalid, while SdhB-Y278 was supersensitive to fluopyram and very highly resistant to boscalid. Both of the mutants exhibited decreased sensitivity to salt stress and increased SDH activity. These two mutations had no effect on the mycelial growth rate, sporulation ability, pathogenicity in vivo, sensitivity to osmotic stress and oxidative stress, cell wall damaging agents, or SHAM. CONCLUSION: Two adjacent mutations in the SdhB gene conferred different resistance phenotypes to SDHIs in C. cassiicola, which is important for the development of alternative antifungal fungicides and fluopyram resistance management. © 2021 Society of Chemical Industry.


Assuntos
Fungicidas Industriais , Succinato Desidrogenase , Ascomicetos , Benzamidas , Farmacorresistência Fúngica/genética , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Fungicidas Industriais/farmacologia , Mutação , Fenótipo , Doenças das Plantas , Piridinas , Succinato Desidrogenase/genética , Succinato Desidrogenase/metabolismo
19.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33805743

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a lethal age-related lung disease whose pathogenesis involves an aberrant response of alveolar epithelial cells (AEC). Activated epithelial cells secrete mediators that participate in the activation of fibroblasts and the excessive deposition of extracellular matrix proteins. Previous studies indicate that matrix metalloproteinase 14 (MMP14) is increased in the lung epithelium in patients with IPF, however, the role of this membrane-type matrix metalloproteinase has not been elucidated. In this study, the role of Mmp14 was explored in experimental lung fibrosis induced with bleomycin in a conditional mouse model of lung epithelial MMP14-specific genetic deletion. Our results show that epithelial Mmp14 deficiency in mice increases the severity and extension of fibrotic injury and affects the resolution of the lesions. Gain-and loss-of-function experiments with human epithelial cell line A549 demonstrated that cells with a deficiency of MMP14 exhibited increased senescence-associated markers. Moreover, conditioned medium from these cells increased fibroblast expression of fibrotic molecules. These findings suggest a new anti-fibrotic mechanism of MMP14 associated with anti-senescent activity, and consequently, its absence results in impaired lung repair. Increased MMP14 in IPF may represent an anti-fibrotic mechanism that is overwhelmed by the strong profibrotic microenvironment that characterizes this disease.


Assuntos
Células Epiteliais/patologia , Fibrose Pulmonar Idiopática/genética , Metaloproteinase 14 da Matriz/genética , Alvéolos Pulmonares/metabolismo , Células A549 , Actinas/genética , Actinas/metabolismo , Animais , Bleomicina/administração & dosagem , Senescência Celular/genética , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Fibronectinas/genética , Fibronectinas/metabolismo , Regulação da Expressão Gênica , Humanos , Hipoxantina Fosforribosiltransferase/genética , Hipoxantina Fosforribosiltransferase/metabolismo , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Metaloproteinase 14 da Matriz/deficiência , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Cultura Primária de Células , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/patologia , Succinato Desidrogenase/genética , Succinato Desidrogenase/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
20.
BMC Surg ; 21(1): 202, 2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33879132

RESUMO

BACKGROUND: Gastrointestinal stromal tumors rarely occur in children, but when they do, their biological behavior and histopathological patterns differ from those of adults. CASE PRESENTATION: A 13-year-old boy with a gastrointestinal stromal tumor was characterized by a rare genetic mutation. The patient complained of "fatigue with intermittent abdominal pain for 1 month". According to the preoperative imaging examination, gastroscopy, and gastroscopic biopsy, the patient was diagnosed with a gastric stromal tumor. Postoperative pathology showed that the tumor cells were fusiform and ovoid, and mitotic figures were easily seen. Immunohistochemistry revealed that the tumor was S-100(+), SOX10(-), CD34(+), SMA(partially+), DOG-1(+), CD117(+), KI-67 (positive for 20% + of the subjects and 40% + of the hotspots), and SDHB(-). Genetic tests showed missense mutations in ALK and TSC1. With surgical treatment, the tumor was completely removed. The patient recovered well and was discharged on the ninth day after the operation. He is currently under follow-up. CONCLUSIONS: In this case involving a patient with a gastrointestinal stromal tumor, immunohistochemistry indicated that the tumor was an "SDH-deficient type", and gene detection showed no KIT or PDGFRA mutation but rare ALK and TSC1 mutations, which adds to the knowledge of the types of gene mutations in children with gastrointestinal stromal tumors.


Assuntos
Quinase do Linfoma Anaplásico/genética , Tumores do Estroma Gastrointestinal , Neoplasias Gástricas , Proteína 1 do Complexo Esclerose Tuberosa/genética , Adolescente , Tumores do Estroma Gastrointestinal/diagnóstico , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/metabolismo , Tumores do Estroma Gastrointestinal/cirurgia , Humanos , Imuno-Histoquímica , Masculino , Mutação de Sentido Incorreto , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/cirurgia , Succinato Desidrogenase/metabolismo
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