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1.
J Photochem Photobiol B ; 235: 112553, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36084362

RESUMO

This work reports on the reactive oxygen species (ROS) generation and the therapeutic activities of new triphenyl-phosphonium-labelled phthalocyanines (Pcs), the 2,9,16,23-tetrakis(N-(N-butyl-4-triphenyl-phosphonium)- pyridine-4-yloxy) Zn(II) Pc (3) and 2,9,16,23-tetrakis-(N-(N-butyl-4-triphenyl-phosphonium)-morpholino) Zn(II) Pc (4) upon exposure to light, ultrasound and the combination of light and ultrasound. Two types of ROS were detected: the singlet oxygen (1O2) and hydroxyl radicals. For light irradiations, only the 1O2 was detected. An increase in the ROS generation was observed for samples treated with the combination of light and ultrasound compared to the light and ultrasound mono-treatments. The in vitro anticancer activity through photodynamic (PDT) and sonodynamic (SDT) therapy for the Pcs were also determined and compared to the photo-sonodynamic combination therapy (PSDT). The two cancer cell lines used for the in vitro studies included the Michigan Cancer Foundation-7 (MCF-7) breast cancer and Henrietta Lacks (HeLa) cervical cancer cell lines. The SDT treatments showed improved therapeutic efficacy on the cancer cells for both the Pcs compared to PDT. PSDT showed better therapeutic efficacy compared to both the PDT and SDT mono-treatments.


Assuntos
Neoplasias da Mama , Fotoquimioterapia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Feminino , Células HeLa , Humanos , Indóis/metabolismo , Indóis/farmacologia , Células MCF-7 , Michigan , Mitocôndrias/metabolismo , Morfolinos/metabolismo , Piridinas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Oxigênio Singlete/metabolismo , Triazenos
2.
Int J Mol Sci ; 23(18)2022 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-36142812

RESUMO

Pinellia ternata (Thunb.) Druce is a traditional medicinal plant containing a variety of alkaloids, which are important active ingredients. Brassinolide (BR) is a plant hormone that regulates plant response to environmental stress and promotes the accumulation of secondary metabolites in plants. However, the regulatory mechanism of BR-induced alkaloid accumulation in P. ternata is not clear. In this study, we investigated the effects of BR and BR biosynthesis inhibitor (propiconazole, Pcz) treatments on alkaloid biosynthesis in the bulbil of P. ternata. The results showed that total alkaloid content and bulbil yield was enhanced by 90.87% and 29.67% under BR treatment, respectively, compared to the control. We identified 818 (476 up-regulated and 342 down-regulated) and 697 (389 up-regulated and 308 down-regulated) DEGs in the BR-treated and Pcz-treated groups, respectively. Through this annotated data and the Kyoto encyclopedia of genes and genomes (KEGG), the expression patterns of unigenes involved in the ephedrine alkaloid, tropane, piperidine, pyridine alkaloid, indole alkaloid, and isoquinoline alkaloid biosynthesis were observed under BR and Pcz treatments. We identified 11, 8, 2, and 13 unigenes in the ephedrine alkaloid, tropane, piperidine, and pyridine alkaloid, indole alkaloid, and isoquinoline alkaloid biosynthesis, respectively. The expression levels of these unigenes were increased by BR treatment and were decreased by Pcz treatment, compared to the control. The results provided molecular insight into the study of the molecular mechanism of BR-promoted alkaloid biosynthesis.


Assuntos
Alcaloides , Pinellia , Alcaloides/metabolismo , Brassinosteroides , Efedrina , Perfilação da Expressão Gênica , Isoquinolinas/metabolismo , Pinellia/genética , Piperidinas/metabolismo , Reguladores de Crescimento de Plantas/metabolismo , Reguladores de Crescimento de Plantas/farmacologia , Piridinas/metabolismo , Esteroides Heterocíclicos , Transcriptoma , Tropanos
3.
Int J Mol Sci ; 23(16)2022 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-36012366

RESUMO

Human microbiota produces metabolites that may enter the bloodstream and exert systemic influence on various functions including mitochondrial. Mitochondria are not only a target for microbial metabolites, but also themselves, due to the inhibition of several enzymes, produce metabolites involved in infectious processes and immune response. The influence of indolic acids, microbial derivatives of tryptophan, as well as itaconic acid, formed in the tricarboxylic acid cycle under the action of bacterial lipopolysaccharides, on the activity of mitochondrial enzymes was studied by methyl thiazolyl tetrazolium (MTT), dichlorophenolindophenol (DCPIP) and pyridine nucleotide fluorescence assays. Thus, it was found that indolic acids suppressed succinate and glutamate oxidation, shifting the redox potential of pyridine nucleotides to a more oxidized state. Itaconic acid, in addition to the well-known inhibition of succinate oxidation, also decreased NAD reduction in reactions with glutamate as a substrate. Unlike itaconic acid, indolic acids are not direct inhibitors of succinate dehydrogenase and glutamate dehydrogenase as their effects could be partially eliminated by the thiol antioxidant dithiothreitol (DTT) and the scavenger of lipid radicals butyl-hydroxytoluene (BHT). Alkalization turned out to be the most effective means to decrease the action of these metabolites, including itaconic acid, which is due to the protective influence on redox-dependent processes. Thus, among mitochondrial oxidative enzymes, the most accessible targets of these microbial-related metabolites are succinate dehydrogenase and glutamate dehydrogenase. These are important in the context of the shifting of metabolic pathways involved in bacterial inflammation and sepsis as well as the detection of new markers of these pathologies.


Assuntos
Glutamato Desidrogenase , Succinato Desidrogenase , Glutamato Desidrogenase/metabolismo , Ácido Glutâmico/metabolismo , Humanos , Inflamação/metabolismo , Mitocôndrias/metabolismo , Oxirredução , Piridinas/metabolismo , Succinato Desidrogenase/metabolismo , Succinatos/metabolismo , Succinatos/farmacologia , Ácido Succínico/metabolismo
4.
J Hazard Mater ; 440: 129703, 2022 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-35963088

RESUMO

The removal of environmental pollutants is important for a sustainable ecosystem and human health. Shewanella oneidensis (S. oneidensis) has diverse electron transfer pathways and can use a variety of contaminants as electron acceptors or electron donors. This paper reviews S. oneidensis's function in removing environmental pollutants, including heavy metals, inorganic non-metallic ions (INMIs), and toxic organic pollutants. S. oneidensis can mineralize o-xylene (OX), phenanthrene (PHE), and pyridine (Py) as electron donors, and also reduce azo dyes, nitro aromatic compounds (NACs), heavy metals, and iodate by extracellular electron transfer (EET). For azo dyes, NACs, Cr(VI), nitrite, nitrate, thiosulfate, and sulfite that can cross the membrane, S. oneidensis transfers electrons to intracellular reductases to catalyze their reduction. However, most organic pollutants cannot be directly degraded by S. oneidensis, but S. oneidensis can remove these pollutants by self-synthesizing catalysts or photocatalysts, constructing bio-photocatalytic systems, driving Fenton reactions, forming microbial consortia, and genetic engineering. However, the industrial-scale application of S. oneidensis is insufficient. Future research on the metabolism of S. oneidensis and interfacial reactions with other materials needs to be deepened, and large-scale reactors should be developed that can be used for practical engineering applications.


Assuntos
Poluentes Ambientais , Fenantrenos , Shewanella , Compostos Azo/metabolismo , Ecossistema , Transporte de Elétrons , Poluentes Ambientais/metabolismo , Iodatos/metabolismo , Nitratos/metabolismo , Nitritos/metabolismo , Oxirredução , Oxirredutases/metabolismo , Fenantrenos/metabolismo , Piridinas/metabolismo , Shewanella/metabolismo , Sulfitos/metabolismo , Tiossulfatos/metabolismo
5.
Eur J Pharmacol ; 931: 175183, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-35940239

RESUMO

Tumor-specific growth signal inhibition is a major anticancer strategy. Receptor tyrosine kinases (RTKs) are the most upstream receptors for growth signaling in cancer. Therefore, inhibition of RTKs has been proposed as an efficient therapeutic target. Masitinib, a c-kit inhibitor of the c-kit RTK, was developed to treat mastocytoma in dogs. In humans, however, the antitumor efficacy of masitinib was found to be attenuated against tumor cells with mutations of the c-kit gene. Here, we report that masitinib induced cell death via the intrinsic apoptotic pathway in HepG2, a c-kit-negative hepatocellular carcinoma cell line. In masitinib-treated HepG2 cells, increases in intracellular reactive oxygen species levels, loss of mitochondrial membrane potential, and cleavage of caspase-9 were observed, activating the intrinsic apoptotic pathway. Moreover, the cytotoxicity of masitinib to HepG2 cells was suppressed by treatment with the antioxidant N-acetyl-L-cysteine or a c-Jun N-terminal kinase/stress-activated protein kinase (JNKs) inhibitor. Thus, we demonstrated that the anticancer effects of masitinib are not due to its targeting c-kit, but rather to its targeting the redox balance via the JNK pathway in HepG2 cells. These results suggest that masitinib has the potential to provide a robust antitumor effect in tumor lesions and could also be applied to a broad range of other anticancer therapies.


Assuntos
Apoptose , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , Piridinas , Animais , Benzamidas , Linhagem Celular Tumoral , Cães , Células Hep G2 , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Piperidinas , Proteínas Proto-Oncogênicas c-kit/metabolismo , Piridinas/metabolismo , Piridinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Tiazóis
6.
Bioorg Chem ; 128: 106074, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35987188

RESUMO

The imidazo[1,2-a]pyridine-3-carboxyamides (IAPs) are a unique class of compounds endowed with impressive nanomolar in vitro potency against Mycobacterium tuberculosis (Mtb) as exemplified by clinical candidate Telacebec (Q203). These compounds target mycobacterial respiration through inhibition of the QcrB subunit of cytochrome bc1:aa3 super complex resulting in bacteriostatic efficacy in vivo. Our labs have had a long-standing interest in the design and development of IAPs. However, some of these compounds suffer from short in vivo half-lives, requiring multiple daily dosing or the addition of a cytochrome P450 inhibitor for murine efficacy evaluations. Deuteration has been shown to decrease metabolism as the C-D bond is stronger than the CH bond. Herein we describe our efforts on design and synthesis of potent deuterated IAPs and the effect that deuteration has upon metabolism through microsomal stability studies.


Assuntos
Mycobacterium tuberculosis , Tuberculose , Animais , Antituberculosos/química , Humanos , Camundongos , Piridinas/metabolismo , Piridinas/farmacologia , Tuberculose/microbiologia
7.
Eur J Med Chem ; 240: 114612, 2022 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-35863274

RESUMO

Cholesterol 24-hydroxylase (CH24H, CYP46A1) is a cytochrome P450 family enzyme that maintains the homeostasis of brain cholesterol. Soticlestat, a potent and selective CH24H inhibitor, is in development as a therapeutic agent for Dravet syndrome and Lennox-Gastaut syndrome. Herein, we report the discovery of aryl-piperidine derivatives as potent and selective CH24H positron emission tomography (PET) tracers which can be used for dose guidance of a clinical CH24H inhibitor and as a diagnostic tool for CH24H-related pathology. Starting from compound 1 (IC50 = 16 nM, logD = 1.7), which was reported as a CH24H inhibitor with lower lipophilicity, a18F-labeling site (3-fluoroazetidine) was incorporated by structure-based drug design (SBDD) utilizing the co-crystal structure of a compound 1 analog. Subsequent optimization to adjust key parameters for PET tracers, such as potency, lipophilicity, brain penetration, and unbound plasma protein binding, enabled compounds 3f (IC50 = 8.8 nM) and 3g (IC50 = 8.7 nM) as PET imaging candidates. Selectivity of these compounds for CH24H was validated by a brain distribution study using CH24H-WT and KO mice. In non-human primate PET imaging, [18F]3f and [18F]3g showed similar regional uptake in the brain, indicating that these tracers were specific to the CH24H-expressed regions and validated the expression of CH24H in the living brain by different tracers.


Assuntos
Tomografia por Emissão de Pósitrons , Piridinas , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Colesterol 24-Hidroxilase/metabolismo , Camundongos , Piperidinas/metabolismo , Piperidinas/farmacologia , Tomografia por Emissão de Pósitrons/métodos , Piridinas/metabolismo
8.
Appl Environ Microbiol ; 88(14): e0036022, 2022 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-35766505

RESUMO

Dipicolinic acid (DPA), an essential pyridine derivative biosynthesized in Bacillus spores, constitutes a major proportion of global biomass carbon pool. Alcaligenes faecalis strain JQ135 could catabolize DPA through the "3HDPA (3-hydroxydipicolinic acid) pathway." However, the genes involved in this 3HDPA pathway are still unknown. In this study, a dip gene cluster responsible for DPA degradation was cloned from strain JQ135. The expression of dip genes was induced by DPA and negatively regulated by DipR. A novel monooxygenase gene, dipD, was crucial for the initial hydroxylation of DPA into 3HDPA and proposed to encode the key catalytic component of the multicomponent DPA monooxygenase. The heme binding protein gene dipF, ferredoxin reductase gene dipG, and ferredoxin genes dipJ/dipK/dipL were also involved in the DPA hydroxylation and proposed to encode other components of the multicomponent DPA monooxygenase. The 18O2 stable isotope labeling experiments confirmed that the oxygen atom in the hydroxyl group of 3HDPA came from dioxygen molecule rather than water. The protein sequence of DipD exhibits no significant sequence similarities with known oxygenases, suggesting that DipD was a new member of oxygenase family. Moreover, bioinformatic survey suggested that the dip gene cluster was widely distributed in many Alpha-, Beta-, and Gammaproteobacteria, including soil bacteria, aquatic bacteria, and pathogens. This study provides new molecular insights into the catabolism of DPA in bacteria. IMPORTANCE Dipicolinic acid (DPA) is a natural pyridine derivative that serves as an essential component of the Bacillus spore. DPA accounts for 5 to 15% of the dry weight of spores. Due to the huge number of spores in the environment, DPA is also considered to be an important component of the global biomass carbon pool. DPA could be decomposed by microorganisms and enter the global carbon cycling; however, the underlying molecular mechanisms are rarely studied. In this study, a DPA catabolic gene cluster (dip) was cloned and found to be widespread in Alpha-, Beta-, and Gammaproteobacteria. The genes responsible for the initial hydroxylation of DPA to 3-hydroxyl-dipicolinic acid were investigated in Alcaligenes faecalis strain JQ135. The present study opens a door to elucidate the mechanism of DPA degradation and its possible role in DPA-based carbon biotransformation on earth.


Assuntos
Alcaligenes faecalis , Bacillus , Alcaligenes faecalis/química , Bacillus/genética , Bacillus/metabolismo , Carbono/metabolismo , Ferredoxinas/metabolismo , Oxigenases de Função Mista/genética , Oxigenases de Função Mista/metabolismo , Família Multigênica , Oxigenases/metabolismo , Ácidos Picolínicos/metabolismo , Piridinas/metabolismo , Esporos Bacterianos/metabolismo
9.
Anal Chem ; 94(23): 8373-8381, 2022 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-35647787

RESUMO

Various suborganelles are delimited by lipid bilayers, in which high spatial and temporal morphological changes are essential to many physiological and pathological processes of cells. However, almost all the amphiphilic fluorescent molecules reported until now are not available for in situ precise tracking of membrane dynamics in cell apoptosis. Here, the MO (coumarin pyridine derivatives) was devised by engineering lipophilic coumarin and cationic pyridine salt, which not only lastingly anchored onto the plasma membrane in dark due to appropriate amphipathicity and electrostatic interactions but also in situ reflected the membrane damage and heterogeneity with secretion of extracellular vesicles (EVs) under reactive oxygen species regulation and was investigated by two-photon fluorescence lifetime imaging microscopy. This work opens up a new avenue for the development of plasma membrane staining and EV-based medicines for the early diagnosis and treatment of disease.


Assuntos
Corantes Fluorescentes , Neoplasias , Membrana Celular/metabolismo , Cumarínicos/metabolismo , Corantes Fluorescentes/metabolismo , Humanos , Microscopia de Fluorescência , Neoplasias/metabolismo , Imagem Óptica , Piridinas/metabolismo
10.
Appl Environ Microbiol ; 88(11): e0017222, 2022 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-35604228

RESUMO

Picolinic acid (PA) is a natural toxic pyridine derivative as well as an important intermediate used in the chemical industry. In a previous study, we identified a gene cluster, pic, that responsible for the catabolism of PA in Alcaligenes faecalis JQ135. However, the transcriptional regulation of the pic cluster remains known. This study showed that the entire pic cluster was composed of 17 genes and transcribed as four operons: picR, picCDEF, picB4B3B2B1, and picT1A1A2A3T2T3MN. Deletion of picR, encoding a putative MarR-type regulator, greatly shortened the lag phase of PA degradation. An electrophoretic mobility shift assay and DNase I footprinting showed that PicR has one binding site in the picR-picC intergenic region and two binding sites in the picB-picT1 intergenic region. The DNA sequences of the three binding sites have the palindromic characteristics of TCAG-N4-CTNN: the space consists of four nonspecific bases, and the four palindromic bases on the left and the first two palindromic bases on the right are strictly conserved, while the last two bases on the right vary among the three binding sites. An in vivo ß-galactosidase activity reporter assay indicated that 6-hydroxypicolinic acid but not PA acted as a ligand of PicR, preventing PicR from binding to promoter regions and thus derepressing the transcription of the pic cluster. This study revealed the negative transcriptional regulation mechanism of PA degradation by PicR in A. faecalis JQ135 and provides new insights into the structure and function of the MarR-type regulator. IMPORTANCE The pic gene cluster was found to be responsible for PA degradation and widely distributed in Alpha-, Beta-, and Gammaproteobacteria. Thus, it is very necessary to understand the regulation mechanism of the pic cluster in these strains. This study revealed that PicR binds to three sites of the promoter regions of the pic cluster to multiply regulate the transcription of the pic cluster, which enables A. faecalis JQ135 to efficiently utilize PA. Furthermore, the study also found a unique palindrome sequence for binding of the MarR-type regulator. This study enhanced our understanding of microbial catabolism of environmental toxic pyridine derivatives.


Assuntos
Alcaligenes faecalis , Alcaligenes faecalis/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Sítios de Ligação , DNA Intergênico , Regulação Bacteriana da Expressão Gênica , Família Multigênica , Ácidos Picolínicos , Ligação Proteica , Piridinas/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
11.
Ecotoxicol Environ Saf ; 238: 113575, 2022 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-35500402

RESUMO

Sogatella furcifera is one of the main agricultural pests in many Asian countries, bringing about enormous injury. A triflumezopyrim-resistant (Tri) strain of S. furcifera was established through continuous screening in laboratory. The determination of synergist and enzyme activity indicated that P450s, especially for the upregulation expression of CYPSF01, played a key role in the increased resistance, confirmed by RNAi, and the recombinant protein of CYPSF01 and NADPH-P450 reductase was able to degrade triflumezopyrim. CYPSF01 had an obviously co-expression relationship with nuclear receptor ultraspiracle (USP), which were all significantly up-regulated when exposed to triflumezopyrim. Further, a USP-binding motif MA0534.1 was enriched from the upregulated peaks by Assay for Transposase Accessible Chromatin (ATAC-seq) analysis, which exited in the peaks located on the promoter of CYPSF01; the yeast one-hybrid experiments confirmed that USP could bind to the CYPSF01 promoter. And the USP interference significantly down-regulated CYPSF01 expression, and resulted in the significantly increasing sensitivity to triflumezopyrim, its mortality rate increased 28.37%. Therefore, the overexpression of USP could cause to the overexpression of CYPSF01, ultimately resulting in the resistance to triflumezopyrim in S. furcifera.


Assuntos
Hemípteros , Inseticidas , Animais , Hemípteros/metabolismo , Inseticidas/metabolismo , Piridinas/metabolismo , Pirimidinonas , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo
12.
Xenobiotica ; 52(3): 219-228, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35379057

RESUMO

1. GDC-0575 is an ATP-competitive small-molecule inhibitor of ChK1 that is being developed by Genentech for the treatment of various human malignancies.2. In a radiolabeled mass balance study of GDC-0575 in rats, two novel metabolites, named M12 (-71 Da,) and M17 (+288 Da), were detected as abundant circulating metabolites.3. Subsequent mass spectrometry and nuclear magnetic resonance analysis showed that M12 was a cyclized metabolite of GDC-0575, whereas M17 was its heterodimer to the parent. We further determined that M12 was mainly generated by cytochrome P450 (Cyp) 2d2.4. We proposed the potential mechanism was initiated by the oxidation on the pyrrole ring and subsequent cyclisation of the free primary amine onto C-3 of the pyrrole ring. This was followed by expulsion of cyclopropylcarboxamide and a loss of water to form intermediate I, which can be further oxidised to form M12, or dimerise with another molecule of GDC-0575 as nucleophile to form M17.5. To verify this hypothesis, we attempted to trap the intermediate I with glutathione (GSH) trapping assay and the GSH conjugate on the pyrrole ring was identified. This suggests the oxidation on the pyrrole led to reactive metabolite formation and supported this proposed mechanism.


Assuntos
Sistema Enzimático do Citocromo P-450 , Microssomos Hepáticos , Animais , Sistema Enzimático do Citocromo P-450/metabolismo , Glutationa/metabolismo , Microssomos Hepáticos/metabolismo , Piperidinas , Piridinas/metabolismo , Pirróis/metabolismo , Ratos
13.
Int J Oncol ; 60(4)2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35244188

RESUMO

Hypoxia promotes drug resistance and induces the expression of hypoxia inducible factor (HIF)­1α in liver cancer cells. However, to date, no selective HIF­1α inhibitor has been clinically approved. The aim of this study is to investigate a drug­targetable molecule that can regulate HIF­1α under hypoxia. The present study demonstrated that hyperactivation of dual­specificity tyrosine­phosphorylation­regulated kinase 1A (DYRK1A)/HIF­1α signaling was associated with an increased risk of liver cancer. In addition, DYRK1A knockdown using small interfering RNA transfection or treatment with harmine, a natural alkaloid, significantly reduced the protein expression levels of HIF­1α in liver cancer cells under hypoxic conditions in vitro. Conversely, DYRK1A overexpression­vector transfection in liver cancer cell lines notably induced HIF­1α expression under the same conditions. Furthermore, DYRK1A was shown to interact and activate STAT3 under hypoxia to regulate HIF­1α expression. These findings indicated that DYRK1A may be a potential upstream activator of HIF­1α and positively regulate HIF­1α via the STAT3 signaling pathway in liver cancer cells. Additionally, treatment with harmine attenuated the proliferative ability of liver cancer cells under hypoxic conditions using sulforhodamine B and colony formation assay. Furthermore, DYRK1A knockdown could significantly enhance the anti­liver cancer effects of regorafenib and sorafenib under hypoxia. Co­treatment with harmine and either regorafenib or sorafenib also promoted cell death via the STAT3/HIF­1α/AKT signaling pathway under hypoxia using PI staining and western blotting. Overall, the results from the present study suggested that DYRK1A/HIF­1α signaling may be considered a novel pathway involved in chemoresistance, thus providing a potentially effective therapeutic regimen for treating liver cancer.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Hipóxia/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Compostos de Fenilureia/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Piridinas/farmacologia , Sorafenibe/farmacocinética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Hepáticas/fisiopatologia , Compostos de Fenilureia/metabolismo , Fatores de Proteção , /metabolismo , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Piridinas/metabolismo , Sorafenibe/metabolismo
14.
Pest Manag Sci ; 78(6): 2657-2666, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35355395

RESUMO

BACKGROUND: Fenpicoxamid and florylpicoxamid are picolinamide fungicides targeting the Qi site of the cytochrome bc1 complex, via their primary metabolites UK-2A and CAS-649, respectively. We explore binding interactions and resistance mechanisms for picolinamides, antimycin A and ilicicolin H in yeast by testing effects of cytochrome b amino acid changes on fungicide sensitivity and interpreting results using molecular docking. RESULTS: Effects of amino acid changes on sensitivity to UK-2A and CAS-649 were similar, with highest resistance associated with exchanges involving G37 and substitutions N31K and L198F. These changes, as well as K228M, also affected antimycin A, while ilicicolin H was affected by changes at G37 and L198, as well as Q22E. N31 substitution patterns suggest that a lysine at position 31 introduces an electrostatic interaction with neighbouring D229, causing disruption of a key salt-bridge interaction with picolinamides. Changes involving G37 and L198 imply resistance primarily through steric interference. G37 changes also showed differences between CAS-649 and UK-2A or antimycin A with respect to branched versus unbranched amino acids. N31K and substitution of G37 by large amino acids reduced growth rate substantially while L198 substitutions showed little effect on growth. CONCLUSION: Binding of UK-2A and CAS-649 at the Qi site involves similar interactions such that general cross-resistance between fenpicoxamid and florylpicoxamid is anticipated in target pathogens. Some resistance mutations reduced growth rate and could carry a fitness penalty in pathogens. However, certain changes involving G37 and L198 carry little or no growth penalty and may pose the greatest risk for resistance development in the field. © 2022 Society of Chemical Industry.


Assuntos
Complexo III da Cadeia de Transporte de Elétrons , Fungicidas Industriais , Ácidos Picolínicos , Aminoácidos , Antimicina A/farmacologia , Citocromos , Complexo III da Cadeia de Transporte de Elétrons/química , Complexo III da Cadeia de Transporte de Elétrons/genética , Fungicidas Industriais/química , Fungicidas Industriais/farmacologia , Lactonas/química , Lactonas/metabolismo , Simulação de Acoplamento Molecular , Mutação , Ácidos Picolínicos/metabolismo , Piridinas/química , Piridinas/metabolismo , Saccharomyces cerevisiae/genética
15.
Acta Crystallogr F Struct Biol Commun ; 78(Pt 2): 81-87, 2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-35102897

RESUMO

Peroxisome proliferator-activated receptor δ (PPARδ) is a member of the nuclear receptor family and regulates glucose and lipid homeostasis in a ligand-dependent manner. Numerous phenylpropanoic acid derivatives targeting three PPAR subtypes (PPARα, PPARγ and PPARδ) have been developed towards the treatment of serious diseases such as lipid-metabolism disorders. In spite of the increasing attraction of PPARδ as a pharmaceutical target, only a limited number of protein-ligand complex structures are available. Here, four crystal structures of the ligand-binding domain of PPARδ in complexes with phenylpropanoic acid derivatives and a pyridine carboxylic acid derivative are described, including an updated, higher resolution version of a previous studied structure and three novel structures. These structures showed that the ligands were bound in the ligand-binding pocket of the receptor in a similar manner but with minor variations. The results could provide variable structural information for the further design and development of ligands targeting PPARδ.


Assuntos
PPAR delta/química , PPAR delta/metabolismo , Sítios de Ligação , Ácidos Carboxílicos/química , Cristalografia por Raios X , Humanos , Ligantes , Modelos Moleculares , PPAR delta/agonistas , Conformação Proteica , Piridinas/química , Piridinas/metabolismo
16.
Sci Rep ; 12(1): 2827, 2022 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-35181691

RESUMO

Afidopyropen, a novel insecticide, is a derivative of pyripyropene A, which is produced by the filamentous fungus Penicillium coprobium. Afidopyropen has strong insecticidal activity against aphids and is currently used as a control agent of sucking pests worldwide. In this study, we summarized the biological properties and field efficacies of its derivatives against agricultural pests using official field trials conducted in Japan. Afidopyropen showed good residual efficacies against a variety of aphids, whiteflies and other sucking pests under field conditions. Furthermore, toxicological studies revealed its safety profiles against nontarget organisms, such as the honeybee, natural enemies and other beneficial insects, as well as mammals. Thus, afidopyropen is a next-generation agrochemical for crop protection that has a low environmental impact.


Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/química , Inseticidas/química , Lactonas/química , Penicillium/metabolismo , Piridinas/metabolismo , Sesquiterpenos/metabolismo , Animais , Afídeos/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Inseticidas/farmacologia , Japão , Lactonas/farmacologia , Penicillium/química , Piridinas/química , Sesquiterpenos/química
17.
Food Chem ; 382: 132273, 2022 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-35152013

RESUMO

Chilling injury occurs in banana fruit under cold storage, which decreases commercial value and limits the shelf-life. Here, exogenous epibrassinolide was applied to investigate its regulation on chilling tolerance. The results found 2.5 µmol/L epibrassinolide was the optimal concentration to reduce chilling injury, which showed 23% lower chilling injury index compared with the control. Epibrassinolide alleviated the symptoms of chilling injury, including maintaining total chlorophyll, as well as reducing browning index, electrolyte leakage, and MDA. Energy status assay showed 7% higher energy charge was observed in epibrassinolide-treated fruit, which was due to the increase of SDH, CCO, and NADH/NAD+ ratio. In addition, the activation of NADK and PPP pathway induced the increase of NADPH and NADPH/NADP+ ratio, which inhibited H2O2 accumulation and O2·- production rate, and thus alleviated chilling injury. This study clarified the potential regulation of epibrassinolide on the balance of energy metabolism and pyridine nucleotide homeostasis.


Assuntos
Musa , Temperatura Baixa , Armazenamento de Alimentos , Frutas/metabolismo , Homeostase , Peróxido de Hidrogênio/metabolismo , Musa/metabolismo , Nucleotídeos/metabolismo , Piridinas/metabolismo
18.
Nat Commun ; 13(1): 569, 2022 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-35091547

RESUMO

Target residence time plays a crucial role in the pharmacological activity of small molecule inhibitors. Little is known, however, about the underlying causes of inhibitor residence time at the molecular level, which complicates drug optimization processes. Here, we employ all-atom molecular dynamics simulations (~400 µs in total) to gain insight into the binding modes of two structurally similar p38α MAPK inhibitors (type I and type I½) with short and long residence times that otherwise show nearly identical inhibitory activities in the low nanomolar IC50 range. Our results highlight the importance of protein conformational stability and solvent exposure, buried surface area of the ligand and binding site resolvation energy for residence time. These findings are further confirmed by simulations with a structurally diverse short residence time inhibitor SB203580. In summary, our data provide guidance in compound design when aiming for inhibitors with improved target residence time.


Assuntos
Inibidores Enzimáticos/química , Proteína Quinase 14 Ativada por Mitógeno/química , Simulação de Dinâmica Molecular , Conformação Proteica , Água/química , Sítios de Ligação , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Ligação de Hidrogênio , Imidazóis/química , Imidazóis/metabolismo , Imidazóis/farmacologia , Cinética , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Estrutura Molecular , Ligação Proteica , Estabilidade Proteica , Piridinas/química , Piridinas/metabolismo , Piridinas/farmacologia , Termodinâmica , Água/metabolismo
19.
J Med Chem ; 65(3): 2297-2312, 2022 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-34986308

RESUMO

The development of novel and safe insecticides remains an important need for a growing world population to protect crops and animal and human health. New chemotypes modulating the insect nicotinic acetylcholine receptors have been recently brought to the agricultural market, yet with limited understanding of their molecular interactions at their target receptor. Herein, we disclose the first crystal structures of these insecticides, namely, sulfoxaflor, flupyradifurone, triflumezopyrim, flupyrimin, and the experimental compound, dicloromezotiaz, in a double-mutated acetylcholine-binding protein which mimics the insect-ion-channel orthosteric site. Enabled by these findings, we discovered novel pharmacophores with a related mode of action, and we describe herein their design, synthesis, and biological evaluation.


Assuntos
Desenho de Fármacos , Proteínas de Insetos/metabolismo , Inseticidas/síntese química , Receptores Nicotínicos/metabolismo , 4-Butirolactona/análogos & derivados , 4-Butirolactona/química , 4-Butirolactona/metabolismo , Animais , Sítios de Ligação , Besouros/efeitos dos fármacos , Besouros/metabolismo , Cristalografia por Raios X , Humanos , Controle de Insetos/métodos , Proteínas de Insetos/química , Proteínas de Insetos/genética , Inseticidas/metabolismo , Inseticidas/farmacologia , Conformação Molecular , Simulação de Dinâmica Molecular , Mutagênese Sítio-Dirigida , Piridinas/química , Piridinas/metabolismo , Pirimidinonas/química , Pirimidinonas/metabolismo , Receptores Nicotínicos/química , Receptores Nicotínicos/genética , Compostos de Enxofre/química , Compostos de Enxofre/metabolismo
20.
PLoS One ; 17(1): e0262482, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35015795

RESUMO

Based on previous large-scale in silico screening several factor Xa inhibitors were proposed to potentially inhibit SARS-CoV-2 Mpro. In addition to their known anticoagulants activity this potential inhibition could have an additional therapeutic effect on patients with COVID-19 disease. In this study we examined the binding of the Apixaban, Betrixaban and Rivaroxaban to the SARS-CoV-2 Mpro with the use of the MicroScale Thermophoresis technique. Our results indicate that the experimentally measured binding affinity is weak and the therapeutic effect due to the SARS-CoV-2 Mpro inhibition is rather negligible.


Assuntos
Proteínas M de Coronavírus/antagonistas & inibidores , Inibidores do Fator Xa/química , SARS-CoV-2/metabolismo , Benzamidas/química , Benzamidas/metabolismo , Sítios de Ligação , COVID-19/tratamento farmacológico , COVID-19/virologia , Proteínas M de Coronavírus/metabolismo , Inibidores do Fator Xa/metabolismo , Humanos , Simulação de Dinâmica Molecular , Ligação Proteica , Estabilidade Proteica , Pirazóis/química , Pirazóis/metabolismo , Piridinas/química , Piridinas/metabolismo , Piridonas/química , Piridonas/metabolismo , Rivaroxabana/química , Rivaroxabana/metabolismo , SARS-CoV-2/isolamento & purificação
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