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1.
Molecules ; 27(8)2022 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-35458668

RESUMO

The synthesis of new insecticidal gem-dimethyspiro-cyclopropanes derived from pyrrolidine-2,3-dione have been described, and their biological effect against different insect species has been evaluated. The presented results demonstrate the excellent insecticidal activity of cyclopropane 5c against Aedes aegypti and Musca domestica. Cyclopropane 5c showed the quickest knockdown and the best killing against Aedes aegypti and Musca domestica compared to trans-chrysanthemic acid and pyrethrin. The biological results of the high insecticidal activity were confirmed by the results of docking. This is evident in the binding affinity obtained for cyclopropane 5c, indicating good binding with an important active amino acid residue of the 5FT3 protein.


Assuntos
Aedes , Moscas Domésticas , Inseticidas , Animais , Ciclopropanos/farmacologia , Inseticidas/química
2.
Molecules ; 27(4)2022 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-35209221

RESUMO

Copper oxide nanoparticles (CuO NPs) were synthesized through the coprecipitation method and used as nanocarriers for etoricoxib (selective COX-2 inhibitor drug) and montelukast (leukotriene product inhibitor drug) in combination therapy. The CuO NPs, free drugs, and nanoformulations were investigated through UV/Vis spectroscopy, FTIR spectroscopy, XRD, SEM, and DLS. SEM imaging showed agglomerated nanorods of CuO NPs of about 87 nm size. The CE1, CE2, and CE6 nanoformulations were investigated through DLS, and their particle sizes were 271, 258, and 254 nm, respectively. The nanoformulations were evaluated through in vitro anti-inflammatory activity, in vivo anti-inflammatory activity, in vivo analgesic activity, in vivo anti-pyretic activity, and in vivo acute toxicity activity. In vivo activities were performed on albino mice. BSA denaturation was highly inhibited by CE1, CE2, and CE6 as compared to other nanoformulations in the in vitro anti-inflammatory activity. The in vivo bioactivities showed that low doses (5 mg/kg) of nanoformulations were more potent than high doses (10 and 20 mg/kg) of free drugs in the inhibition of pain, fever, and inflammation. Lastly, CE2 was more potent than that of other nanoformulations.


Assuntos
Acetatos/síntese química , Acetatos/farmacologia , Cobre/química , Ciclopropanos/síntese química , Ciclopropanos/farmacologia , Etoricoxib/síntese química , Etoricoxib/farmacologia , Nanopartículas Metálicas , Quinolinas/síntese química , Quinolinas/farmacologia , Sulfetos/síntese química , Sulfetos/farmacologia , Acetatos/química , Analgésicos/síntese química , Analgésicos/química , Analgésicos/farmacologia , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Técnicas de Química Sintética , Ciclopropanos/química , Composição de Medicamentos , Etoricoxib/química , Nanopartículas Metálicas/química , Nanopartículas Metálicas/ultraestrutura , Quinolinas/química , Análise Espectral , Relação Estrutura-Atividade , Sulfetos/química
3.
Life Sci ; 296: 120432, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35219697

RESUMO

AIMS: Nitric oxide (NO) and hydrogen sulfide (H2S) are involved in nerve-mediated corpus cavernosum (CC) relaxation. Expression of phosphodiesterase type 5 (PDE5) and type 4 (PDE4), cyclic guanosine monophosphate (cGMP)- and cyclic adenosine monophosphate (cAMP)-specific, respectively, has been described and PDE5- and PDE4-inhibitors induce cavernous smooth muscle relaxation. Whereas the NO/cGMP signaling pathway is well established in penile erection, the cAMP-mediated mechanism is not fully elucidated. The aim of this study is to investigate the localization and the functional significance of PDE4 in rat CC tone regulation. MAIN METHODS: We performed immunohistochemistry for the detection of the PDE4A isoenzyme. Isometric tension recordings for roflumilast and tadalafil, PDE4 and PDE5 inhibitors, respectively, electrical field stimulation (EFS) and ß-adrenoceptor agonist isoproterenol and endogenous H2S production measurement. KEY FINDINGS: A marked PDE4A expression was detected mainly localized in the nerve cells of the cavernous smooth muscle. Furthermore, roflumilast and tadalafil exhibited strong corpus cavernous relaxations. Endogenous H2S production was decreased by NO and H2S synthase inhibitors and increased by roflumilast. Isoproterenol- and EFS-induced relaxations were increased by roflumilast. SIGNIFICANCE: These results indicate that PDE4A is mainly expressed within the nerves cells of the rat CC, where roflumilast induces a potent corpus cavernous relaxation per se and potentiates the response induced by ß-adrenoceptor activation. The fact that roflumilast enhances H2S production, as well as EFS-elicited responses suggests that PDE4 inhibitors modulate, in a positive feedback fashion, nerve-mediated relaxation induced by gasotransmitters, thus indicating a key role for neuronal PDE4 in penile erection.


Assuntos
Aminopiridinas/farmacologia , Benzamidas/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Gasotransmissores/metabolismo , Pênis/fisiologia , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Aminopiridinas/administração & dosagem , Animais , Benzamidas/administração & dosagem , Ciclopropanos/administração & dosagem , Ciclopropanos/farmacologia , Relação Dose-Resposta a Droga , Sulfeto de Hidrogênio/metabolismo , Masculino , Relaxamento Muscular/efeitos dos fármacos , Nitroarginina/farmacologia , Pênis/efeitos dos fármacos , Nervos Periféricos/efeitos dos fármacos , Nervos Periféricos/fisiologia , Ratos Wistar , Tadalafila/farmacologia
4.
Biochem Biophys Res Commun ; 594: 31-37, 2022 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-35066377

RESUMO

The main pathological characteristics of demyelinating diseases are central nervous system (CNS) myelin damage, and the differentiation of oligodendrocyte precursor cells is the therapeutic target of myelin repair. Previous studies have found that a large number of platelet-derived growth factor receptor α(PDGFRα) positive oligodendrocyte progenitor cells (OPCs) accumulate in the lesion area of myelin injury, and differentiation is blocked. However, the therapeutic effects of drugs currently used clinically on OPCs differentiation and myelin repair are limited. The main reason is that it is difficult to reach the effective concentration of the drug in the lesion area. Therefore, efficiently delivering into the CNS lesion area is of great significance for the treatment of MS. Natural exosomes have good biocompatibility and are ideal drug carriers. The delivery of drugs to lesion areas can be achieved by giving the exosomes armed targeting ligand. Therefore, in this study, combining exosomes with PDGFA helps them accumulate in OPCs in vitro and in vivo. Further, load montelukast into exosomes to achieve targeted therapy for cuprizone-induced demyelination animal model. The implementation of this research will help provide effective treatments for demyelinating diseases and lay a theoretical foundation for its application in the clinical treatment of different demyelinating diseases.


Assuntos
Acetatos/farmacologia , Ciclopropanos/farmacologia , Doenças Desmielinizantes/metabolismo , Vesículas Extracelulares/metabolismo , Quinolinas/farmacologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Sulfetos/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem da Célula , Cuprizona , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Exossomos/metabolismo , Técnicas In Vitro , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína Básica da Mielina/metabolismo , Bainha de Mielina/metabolismo , Neurônios/metabolismo , Células Precursoras de Oligodendrócitos/metabolismo , Oligodendroglia/metabolismo , Fagocitose , Regeneração , Células-Tronco/metabolismo
5.
Life Sci ; 294: 120329, 2022 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-35090905

RESUMO

Antiretroviral therapy (ART), a life-saving treatment strategy in HIV/AIDS, has been implicated in increasing the risk of type 2 diabetes mellitus (T2DM). Direct damaging effects on beta-cell function and survival by either non-nucleoside reverse transcriptase inhibitors (NNRTIs) or nucleoside/tide reverse transcriptase inhibitors (NRTIs) may predispose individuals to developing T2DM or if already type 2 diabetic, to insulin dependency. The aim of this study was to investigate the effects of the NNRTIs efavirenz, rilpivirine and doravirine, and the NRTIs tenofovir disoproxil fumarate and emtricitabine, on beta-cell function and survival while suggesting potential cellular and molecular mechanism(s). Our results show contrasting effects within the NNRTI class as doravirine did not cause damaging effects in the rat insulinoma INS-1E cells while efavirenz and rilpivirine reduced insulin release and cell viability, and induced apoptosis in INS-1E cells. Additionally, efavirenz and rilpivirine increased ROS generation, disrupted Δψm and upregulated the mRNA and protein expression of CHOP and GRP78, key markers of endoplasmic reticulum stress. In silico docking studies predict a possible inhibition of the mitochondrial ATP synthase by rilpivirine. On the contrary, both the NRTIs tenofovir disoproxil fumarate and emtricitabine did not affect GSIS, cell viability and apoptosis/necrosis levels in INS-1E cells. The deleterious effects observed in beta-cells exposed to efavirenz or rilpivirine may be, at least partially, mediated by oxidative stress and mitochondrial toxicity. These findings provide potential mechanism(s) by which efavirenz and rilpivirine may contribute to the pathogenesis of T2DM and the progression of T2DM to insulin dependency in HIV-infected type 2 diabetics.


Assuntos
Estresse do Retículo Endoplasmático , Células Secretoras de Insulina/patologia , Insulinoma/patologia , Mitocôndrias/patologia , Estresse Oxidativo , Inibidores da Transcriptase Reversa/farmacologia , Alcinos/farmacologia , Animais , Benzoxazinas/farmacologia , Ciclopropanos/farmacologia , Insulina/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Insulinoma/metabolismo , Mitocôndrias/efeitos dos fármacos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Ratos , Espécies Reativas de Oxigênio/metabolismo , Rilpivirina/farmacologia , Células Tumorais Cultivadas
6.
Mol Ther ; 30(2): 963-974, 2022 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-34678509

RESUMO

Small molecule inhibitors have previously been investigated in different studies as possible therapeutics in the treatment of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). In the current drug repurposing study, we identified the leukotriene (D4) receptor antagonist montelukast as a novel agent that simultaneously targets two important drug targets of SARS-CoV-2. We initially demonstrated the dual inhibition profile of montelukast through multiscale molecular modeling studies. Next, we characterized its effect on both targets by different in vitro experiments including the enzyme (main protease) inhibition-based assay, surface plasmon resonance (SPR) spectroscopy, pseudovirus neutralization on HEK293T/hACE2+TMPRSS2, and virus neutralization assay using xCELLigence MP real-time cell analyzer. Our integrated in silico and in vitro results confirmed the dual potential effect of montelukast both on the main protease enzyme inhibition and virus entry into the host cell (spike/ACE2). The virus neutralization assay results showed that SARS-CoV-2 virus activity was delayed with montelukast for 20 h on the infected cells. The rapid use of new small molecules in the pandemic is very important today. Montelukast, whose pharmacokinetic and pharmacodynamic properties are very well characterized and has been widely used in the treatment of asthma since 1998, should urgently be completed in clinical phase studies and, if its effect is proved in clinical phase studies, it should be used against coronavirus disease 2019 (COVID-19).


Assuntos
Acetatos/farmacologia , Enzima de Conversão de Angiotensina 2/metabolismo , Ciclopropanos/farmacologia , Quinolinas/farmacologia , SARS-CoV-2/fisiologia , Serina Endopeptidases/metabolismo , Sulfetos/farmacologia , Células A549 , Acetatos/química , Enzima de Conversão de Angiotensina 2/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Ciclopropanos/química , Reposicionamento de Medicamentos , Células HEK293 , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Testes de Neutralização , Conformação Proteica , Quinolinas/química , SARS-CoV-2/efeitos dos fármacos , Serina Endopeptidases/química , Sulfetos/química , Células Vero , Internalização do Vírus/efeitos dos fármacos
7.
Pharmacol Res ; 175: 106004, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34826603

RESUMO

Emerging evidence has shown that nonalcoholic fatty liver disease (NAFLD) may be both a consequence and a cause of hypertension. Recent studies have demonstrated that phosphodiesterase 4 (PDE4)-cAMP signaling represents a pathway relevant to the pathophysiology of metabolic disorders. This study aims to investigate the impact and the underlying mechanism of PDE4 in the pathogenesis of NAFLD and its associated hypertension. Here we demonstrated that high-fat-diet (HFD) fed mice developed NAFLD and hypertension, with an associated increase in hepatic PDE4D expression, which can be prevented and even reversed by PDE4 inhibitor roflumilast. Furthermore, we demonstrated that hepatic overexpression of PDE4D drove significant hepatic steatosis and elevation of blood pressure. Mechanistically, PDE4D activated fatty acid translocase CD36 signaling which facilitates hepatic lipid deposition, resulting in TGF-ß1 production by hepatocytes and excessive TGF-ß1 signaling in vessels and consequent hypertension. Specific silencing of TGF-ß1 in hepatocytes by siRNA using poly (ß-amino ester) nanoparticles significantly normalized hepatic PDE4D overexpression-activated TGF-ß1 signaling in vessels and hypertension. Together, the conclusions indicated that PDE4D plays an important role in the pathogenesis of NAFLD and associated hypertension via activation of CD36-TGF-ß1 signaling in the liver. PDE4 inhibitor such as roflumilast, which is clinically approved for chronic obstructive pulmonary disease (COPD) treatment, has the potential to be used as a preventive or therapeutic drug against NAFLD and associated hypertension in the future.


Assuntos
Aminopiridinas/uso terapêutico , Benzamidas/uso terapêutico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Hipertensão/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Inibidores da Fosfodiesterase 4/uso terapêutico , Aminopiridinas/farmacologia , Animais , Aorta/citologia , Becaplermina/farmacologia , Benzamidas/farmacologia , Antígenos CD36/genética , Antígenos CD36/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Ciclopropanos/farmacologia , Ciclopropanos/uso terapêutico , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hipertensão/genética , Hipertensão/metabolismo , Insulina/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Miócitos de Músculo Liso/fisiologia , Nanopartículas/administração & dosagem , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Inibidores da Fosfodiesterase 4/farmacologia , Polímeros/administração & dosagem , RNA Interferente Pequeno/administração & dosagem , Sirtuína 1/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
8.
Infect Immun ; 90(1): e0047921, 2022 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-34662213

RESUMO

A variety of eubacteria, plants, and protozoa can modify membrane lipids by cyclopropanation, which is reported to modulate membrane permeability and fluidity. The ability to cyclopropanate membrane lipids has been associated with resistance to oxidative stress in Mycobacterium tuberculosis, organic solvent stress in Escherichia coli, and acid stress in E. coli and Salmonella. In bacteria, the cfa gene encoding cyclopropane fatty acid (CFA) synthase is induced during the stationary phase of growth. In the present study, we constructed a cfa mutant of Salmonella enterica serovar Typhimurium 14028s (S. Typhimurium) and determined the contribution of CFA-modified lipids to stress resistance and virulence in mice. Cyclopropane fatty acid content was quantified in wild-type and cfa mutant S. Typhimurium. CFA levels in the cfa mutant were greatly reduced compared to CFA levels in the wild type, indicating that CFA synthase is the major enzyme responsible for cyclopropane modification of lipids in Salmonella. S. Typhimurium cfa mutants were more sensitive to extreme acid pH, the protonophore CCCP, and hydrogen peroxide compared to the wild type. In addition, cfa mutants exhibited reduced viability in murine macrophages and could be rescued by the addition of the NADPH phagocyte oxidase inhibitor diphenyleneiodonium (DPI) chloride. S. Typhimurium lacking cfa was also attenuated for virulence in mice. These observations indicate that CFA modification of lipids makes an important contribution to Salmonella virulence.


Assuntos
Ciclopropanos/metabolismo , Ácidos Graxos/metabolismo , Infecções por Salmonella/microbiologia , Salmonella typhimurium/fisiologia , Animais , Fenômenos Fisiológicos Bacterianos , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Vias Biossintéticas , Ciclopropanos/química , Ciclopropanos/farmacologia , Modelos Animais de Doenças , Ácidos Graxos/química , Ácidos Graxos/farmacologia , Concentração de Íons de Hidrogênio , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/microbiologia , Camundongos , Viabilidade Microbiana/efeitos dos fármacos , Viabilidade Microbiana/imunologia , Mutação , Estresse Oxidativo , Infecções por Salmonella/imunologia , Infecções por Salmonella/mortalidade , Salmonella typhimurium/efeitos dos fármacos , Virulência
9.
Addict Biol ; 27(1): e13082, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34363284

RESUMO

Methamphetamine (METH) is a psychostimulant with high abuse potential. Currently, there are no pharmacological treatments specific for METH abuse or stimulant use disorder generally. Although phosphodiesterase inhibitors have shown some promise, current animal models have not examined their use in abstinence from stimulant abuse. We employed a METH self-administration model in the rat followed by a forced abstinence period during which roflumilast, a phosphodiesterase 4 inhibitor, was administered. A detailed behavioral analysis of chronic treatment with roflumilast during 7 days of forced abstinence showed that roflumilast reduced METH seeking and METH taking upon subsequent relapse test. Roflumilast treatment during 7 days of forced abstinence did not affect sucrose seeking and sucrose taking behaviors. These data suggest that roflumilast may be a treatment for METH use disorder that is effective when administered only during abstinence.


Assuntos
Aminopiridinas/farmacologia , Transtornos Relacionados ao Uso de Anfetaminas/tratamento farmacológico , Benzamidas/farmacologia , Inibidores da Fosfodiesterase 4/farmacologia , Animais , Estimulantes do Sistema Nervoso Central/administração & dosagem , Ciclopropanos/farmacologia , Comportamento de Procura de Droga/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Masculino , Metanfetamina/administração & dosagem , Ratos , Recidiva , Autoadministração
10.
Food Microbiol ; 102: 103922, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34809948

RESUMO

This study evaluated the impact of 1-methylcyclopropene (1-MCP), an ethylene synthesis inhibitor, followed by long-term commercial cold storage with low-dose gaseous ozone on the microbiological safety and quality of fresh apples. Granny Smith apples were inoculated with or without Listeria innocua, treated with or without 1.0 mg/L 1-MCP for 24 h, then subjected to commercial cold storage conditions including refrigerated air (RA, 0.6 °C, control), controlled atmosphere (CA, 2% O2, 1% CO2, 0.6 °C), and CA with 51-87 µg/L ozone gas for up to 36 weeks. RA storage reduced L. innocua on apples by up to 3.6 log10 CFU/apple. CA had no advantage over RA in controlling Listeria. Continuous ozone gas application resulted in an additional ∼2.0 log10 CFU/apple reduction of L. innocua (total reduction up to 5.7 log10 CFU/apple) and suppressed native bacteria and fungi. Treatment with 1-MCP had a minor impact on survival of L. innocua or background microbiota on apples, while it significantly delayed fruit ripening and reduced the incidence of superficial scald and internal browning. In summary, 1-MCP treatment followed by CA storage with low-dose continuous ozone gas can effectively control Listeria on fresh apples and delay fruit ripening.


Assuntos
Ciclopropanos/farmacologia , Armazenamento de Alimentos , Frutas/microbiologia , Listeria , Malus , Ozônio , Malus/microbiologia , Ozônio/farmacologia
11.
PLoS One ; 16(12): e0260706, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34871316

RESUMO

Airway epithelial barrier dysfunction is increasingly recognized as a key feature of asthma and other lung diseases. Respiratory viruses are responsible for a large fraction of asthma exacerbations, and are particularly potent at disrupting epithelial barrier function through pattern recognition receptor engagement leading to tight junction dysfunction. Although different mechanisms of barrier dysfunction have been described, relatively little is known about whether barrier integrity can be promoted to limit disease. Here, we tested three classes of drugs commonly prescribed to treat asthma for their ability to promote barrier function using a cell culture model of virus-induced airway epithelial barrier disruption. Specifically, we studied the corticosteroid budesonide, the long acting beta-agonist formoterol, and the leukotriene receptor antagonist montelukast for their ability to promote barrier integrity of a monolayer of human bronchial epithelial cells (16HBE) before exposure to the viral mimetic double-stranded RNA. Of the three, only budesonide treatment limited transepithelial electrical resistance and small molecule permeability (4 kDa FITC-dextran flux). Next, we used a mouse model of acute dsRNA challenge that induces transient epithelial barrier disruption in vivo, and studied the effects budesonide when administered prophylactically or therapeutically. We found that budesonide similarly protected against dsRNA-induced airway barrier disruption in the lung, independently of its effects on airway inflammation. Taken together, these data suggest that an under-appreciated effect of inhaled budesonide is to maintain or promote airway epithelial barrier integrity during respiratory viral infections.


Assuntos
Asma/tratamento farmacológico , Brônquios/efeitos dos fármacos , Broncodilatadores/farmacologia , Budesonida/farmacologia , Permeabilidade da Membrana Celular/efeitos dos fármacos , Poli I-C/antagonistas & inibidores , Acetatos/farmacologia , Administração por Inalação , Animais , Asma/induzido quimicamente , Asma/metabolismo , Asma/patologia , Brônquios/metabolismo , Brônquios/patologia , Linhagem Celular , Ciclopropanos/farmacologia , Dextranos/metabolismo , Impedância Elétrica , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Feminino , Fluoresceína-5-Isotiocianato/análogos & derivados , Fluoresceína-5-Isotiocianato/metabolismo , Fumarato de Formoterol/farmacologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Mimetismo Molecular , Poli I-C/farmacologia , Quinolinas/farmacologia , RNA de Cadeia Dupla/antagonistas & inibidores , RNA de Cadeia Dupla/farmacologia , RNA Viral/antagonistas & inibidores , RNA Viral/farmacologia , Sulfetos/farmacologia , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo
12.
J Agric Food Chem ; 69(49): 14906-14914, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34851114

RESUMO

Starch degradation with fruit ripening is closely related to the aging process and flavor formation in apples. In this study, ethylene, 1-methylcyclopropene (1-MCP), and apples treated at different temperatures were used to determine the key genes of starch-sugar metabolism during storage. Compared with 4 °C storage, 20 °C storage promoted starch degradation and sugar accumulation in apples. In addition, ethylene treatment promoted starch degradation and sugar accumulation in apples, while 1-MCP treatment showed the opposite effects. The expression of MdBams indicated the crucial role of MdBam5 in starch-sugar conversion. Transient overexpression of MdBam5 significantly reduced the starch content in apples. Furthermore, MdWRKY32 directly combined the MdBam5 promoter and activated the MdBam5 expression, which may promote the starch degradation in apples. Therefore, it was concluded that MdWRKY32 may be involved in the regulation of starch-sugar metabolism in postharvest apples by activating the MdBam5 expression.


Assuntos
Malus , Ciclopropanos/farmacologia , Frutas/genética , Malus/genética , Amido , Açúcares , Fatores de Transcrição/genética
13.
Aging (Albany NY) ; 13(24): 25670-25693, 2021 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-34919533

RESUMO

Autophagy is an important cellular mechanism for maintaining cellular homeostasis, and its impairment correlates highly with age and age-related diseases. Retinal pigment epithelial (RPE) cells of the eye represent a crucial model for studying autophagy, as RPE functions and integrity are highly dependent on an efficient autophagic process. Cysteinyl leukotriene receptor 1 (CysLTR1) acts in immunoregulation and cellular stress responses and is a potential regulator of basal and adaptive autophagy. As basal autophagy is a dynamic process, the aim of this study was to define the role of CysLTR1 in autophagy regulation in a chronobiologic context using the ARPE-19 human RPE cell line. Effects of CysLTR1 inhibition on basal autophagic activity were analyzed at inactive/low and high lysosomal degradation activity with the antagonists zafirlukast (ZTK) and montelukast (MTK) at a dosage of 100 nM for 3 hours. Abundances of the autophagy markers LC3-II and SQSTM1 and LC3B particles were analyzed in the absence and presence of lysosomal inhibitors using western blot analysis and immunofluorescence microscopy. CysLTR1 antagonization revealed a biphasic effect of CysLTR1 on autophagosome formation and lysosomal degradation that depended on the autophagic activity of cells at treatment initiation. ZTK and MTK affected lysosomal degradation, but only ZTK regulated autophagosome formation. In addition, dexamethasone treatment and serum shock induced autophagy, which was repressed by CysLTR1 antagonization. As a newly identified autophagy modulator, CysLTR1 appears to be a key player in the chronobiological regulation of basal autophagy and adaptive autophagy in RPE cells.


Assuntos
Autofagia/efeitos dos fármacos , Células Epiteliais/metabolismo , Receptores de Leucotrienos/efeitos dos fármacos , Epitélio Pigmentado da Retina/efeitos dos fármacos , Acetatos/farmacologia , Western Blotting , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Fenômenos Cronobiológicos , Ciclopropanos/farmacologia , Humanos , Indóis/farmacologia , Antagonistas de Leucotrienos/farmacologia , Estresse Oxidativo/fisiologia , Fenilcarbamatos/farmacologia , Quinolinas/farmacologia , Epitélio Pigmentado da Retina/citologia , Epitélio Pigmentado da Retina/metabolismo , Sulfetos/farmacologia , Sulfonamidas/farmacologia
14.
Int J Mol Sci ; 22(21)2021 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-34769111

RESUMO

Characterization of new pharmacological targets is a promising approach in research of neurorepair mechanisms. The G protein-coupled receptor 17 (GPR17) has recently been proposed as an interesting pharmacological target, e.g., in neuroregenerative processes. Using the well-established ex vivo model of organotypic slice co-cultures of the mesocortical dopaminergic system (prefrontal cortex (PFC) and substantia nigra/ventral tegmental area (SN/VTA) complex), the influence of GPR17 ligands on neurite outgrowth from SN/VTA to the PFC was investigated. The growth-promoting effects of Montelukast (MTK; GPR17- and cysteinyl-leukotriene receptor antagonist), the glial cell line-derived neurotrophic factor (GDNF) and of two potent, selective GPR17 agonists (PSB-16484 and PSB-16282) were characterized. Treatment with MTK resulted in a significant increase in mean neurite density, comparable with the effects of GDNF. The combination of MTK and GPR17 agonist PSB-16484 significantly inhibited neuronal growth. qPCR studies revealed an MTK-induced elevated mRNA-expression of genes relevant for neuronal growth. Immunofluorescence labelling showed a marked expression of GPR17 on NG2-positive glia. Western blot and RT-qPCR analysis of untreated cultures suggest a time-dependent, injury-induced stimulation of GPR17. In conclusion, MTK was identified as a stimulator of neurite fibre outgrowth, mediating its effects through GPR17, highlighting GPR17 as an interesting therapeutic target in neuronal regeneration.


Assuntos
Acetatos/farmacologia , Ciclopropanos/farmacologia , Antagonistas de Leucotrienos/farmacologia , Crescimento Neuronal/efeitos dos fármacos , Quinolinas/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Sulfetos/farmacologia , Animais , Animais Recém-Nascidos , Técnicas de Cocultura , Avaliação Pré-Clínica de Medicamentos , Feminino , Masculino , Regeneração Nervosa/efeitos dos fármacos , Crescimento Neuronal/genética , Ratos
15.
Drugs ; 81(16): 1821-1830, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34731461

RESUMO

Phosphodiesterase (PDE) 4 inhibitors prevent the metabolism of cyclic adenosine monophosphate, thereby reducing inflammation. Inhaled PDE4 inhibitors aim to restrict systemic drug exposure to enhance the potential for clinical benefits (in the lungs) versus adverse events (systemically). The orally administered PDE4 inhibitor roflumilast reduces exacerbation rates in the subgroup of chronic obstructive pulmonary disease patients with a history of exacerbations and the presence of chronic bronchitis, but can cause PDE4 related adverse effects due to systemic exposure. CHF6001 is an inhaled PDE4 inhibitor, while inhaled ensifentrine is an inhibitor of both PDE3 and PDE4; antagonism of PDE3 facilitates smooth muscle relaxation and hence bronchodilation. These inhaled PDE inhibitors have both reported positive findings from early phase clinical trials, and have been well tolerated. Longer term trials are needed to firmly establish the clinical benefits of these drugs.


Assuntos
Inibidores da Fosfodiesterase 4/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Administração por Inalação , Aminopiridinas/administração & dosagem , Aminopiridinas/efeitos adversos , Aminopiridinas/farmacologia , Animais , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Benzamidas/farmacologia , AMP Cíclico/metabolismo , Ciclopropanos/administração & dosagem , Ciclopropanos/efeitos adversos , Ciclopropanos/farmacologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/patologia , Isoquinolinas/administração & dosagem , Isoquinolinas/efeitos adversos , Isoquinolinas/farmacologia , Inibidores da Fosfodiesterase 4/efeitos adversos , Inibidores da Fosfodiesterase 4/farmacologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Pirimidinonas/administração & dosagem , Pirimidinonas/efeitos adversos , Pirimidinonas/farmacologia , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacologia , para-Aminobenzoatos/administração & dosagem , para-Aminobenzoatos/efeitos adversos , para-Aminobenzoatos/farmacologia
16.
Respir Res ; 22(1): 266, 2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34666750

RESUMO

INTRODUCTION: Over 300 million people in the world live with asthma, resulting in 500,000 annual global deaths with future increases expected. It is estimated that around 50-80% of asthma exacerbations are due to viral infections. Currently, a combination of long-acting beta agonists (LABA) for bronchodilation and glucocorticoids (GCS) to control lung inflammation represent the dominant strategy for the management of asthma, however, it is still sub-optimal in 35-50% of moderate-severe asthmatics resulting in persistent lung inflammation, impairment of lung function, and risk of mortality. Mechanistically, LABA/GCS combination therapy results in synergistic efficacy mediated by intracellular cyclic adenosine monophosphate (cAMP). HYPOTHESIS: Increasing intracellular cAMP during LABA/GCS combination therapy via inhibiting phosphodiesterase 4 (PDE4) and/or blocking the export of cAMP by ATP Binding Cassette Transporter C4 (ABCC4), will potentiate anti-inflammatory responses of mainstay LABA/GCS therapy. METHODS: Expression and localization experiments were performed using in situ hybridization and immunohistochemistry in human lung tissue from healthy subjects, while confirmatory transcript and protein expression analyses were performed in primary human airway epithelial cells and cell lines. Intervention experiments were performed on the human airway epithelial cell line, HBEC-6KT, by pre-treatment with combinations of LABA/GCS with PDE4 and/or ABCC4 inhibitors followed by Poly I:C or imiquimod challenge as a model for viral stimuli. Cytokine readouts for IL-6, IL-8, CXCL10/IP-10, and CCL5/RANTES were quantified by ELISA. RESULTS: Using archived human lung and human airway epithelial cells, ABCC4 gene and protein expression were confirmed in vitro and in situ. LABA/GCS attenuation of Poly I:C or imiquimod-induced IL-6 and IL-8 were potentiated with ABCC4 and PDE4 inhibition, which was greater when ABCC4 and PDE4 inhibition was combined. Modulation of cAMP levels had no impact on LABA/GCS modulation of Poly I:C-induced CXCL10/IP-10 or CCL5/RANTES. CONCLUSION: Modulation of intracellular cAMP levels by PDE4 or ABCC4 inhibition potentiates LABA/GCS efficacy in human airway epithelial cells challenged with viral stimuli. The data suggest further exploration of the value of adding cAMP modulators to mainstay LABA/GCS therapy in asthma for potentiated anti-inflammatory efficacy.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Budesonida/farmacologia , AMP Cíclico/metabolismo , Células Epiteliais/efeitos dos fármacos , Fumarato de Formoterol/farmacologia , Glucocorticoides/farmacologia , Pulmão/efeitos dos fármacos , Aminopiridinas/farmacologia , Benzamidas/farmacologia , Benzotiazóis/farmacologia , Linhagem Celular , Quimiocinas/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Ácidos Cicloexanocarboxílicos/farmacologia , Ciclopropanos/farmacologia , Sinergismo Farmacológico , Quimioterapia Combinada , Células Epiteliais/metabolismo , Humanos , Pulmão/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Nitrilas/farmacologia , Inibidores da Fosfodiesterase 4/farmacologia , Rolipram/farmacologia , Sistemas do Segundo Mensageiro , Triazóis/farmacologia
17.
J Med Microbiol ; 70(10)2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34668851

RESUMO

Introduction. Biofilm formation and hemolysis are closely related to the pathogenicity of Staphylococcus aureus.Hypothesis/Gap Statement. Strategies that reduce the mortality of S. aureus infections may involve novel antimicrobials and/or drugs that decrease S. aureus virulence, such as biofilm formation. The antiviral drug efavirenz is a non-nucleoside reverse transcriptase inhibitor, which also has shown antibacterial effect on Bacillus subtilis and Escherichia coli. Its effect on pathogen virulence has not yet been explored.Aim. This study investigates the antimicrobial and anti-virulence effect of efavirenz on S. aureus.Methodology. Biofilm biomasses were detected by crystal violet staining. Hemolysis activities of S. aureus were determined by rabbit erythrocytes lysis assay. RNA levels of transcriptional regulatory genes, biofilm-related genes, and virulence-related genes of S. aureus were determined by RT-qPCR.Results. Efavirenz showed an inhibitory effect on the growth of S. aureus, Enterococcus faecalis and Streptococcus agalactiae at 50 µM. Efavirenz significantly inhibited biofilm formation of both methicillin-sensitive S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) at 25 µM, but did not affect the growth of planktonic S. aureus cells. Moreover, hemolysis by S. aureus was inhibited by efavirenz at 25 µM. The expression levels of RNA transcriptional regulatory genes (agrA, agrC, sigB, saeR and saeS), biofilm-related genes (cidA, clfA, clfB, fnbA, fnbB), and virulence-related genes (hla, hld, staphopain B, alpha-3 PSM, beta PSM, delta PSM) of S. aureus decreased significantly at 25 µM efavirenz.Conclusion. Efavirenz inhibits S. aureus biofilm formation and virulence in vitro.


Assuntos
Alcinos/farmacologia , Antibacterianos/farmacologia , Benzoxazinas/farmacologia , Biofilmes/efeitos dos fármacos , Ciclopropanos/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Virulência/efeitos dos fármacos
18.
J Med Chem ; 64(21): 15582-15592, 2021 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-34623802

RESUMO

The "inverse drug discovery" strategy is a potent means of exploring the cellular targets of latent electrophiles not typically used in medicinal chemistry. Cyclopropenone, a powerful electrophile, is generally used in bio-orthogonal reactions mediated by triarylphosphine or in photo-triggered cycloaddition reactions. Here, we have studied, for the first time, the proteome reactivity of cyclopropenones in live cells and discovered that the cyclopropenone warhead can specifically and efficiently modify a triple-negative breast cancer driver, glutathione S-transferase pi-1 (GSTP1), by covalently binding at the catalytic active site. Further structure optimization and signaling pathway validation have led to the discovery of potent inhibitors of GSTP1.


Assuntos
Antineoplásicos/farmacologia , Ciclopropanos/farmacologia , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Glutationa S-Transferase pi/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ciclopropanos/síntese química , Ciclopropanos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Glutationa S-Transferase pi/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
19.
Bioengineered ; 12(1): 8476-8484, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34565285

RESUMO

Montelukast is a cysteinyl leukotriene receptor 1 (CysLTR1) antagonist widely used to suppress the inflammatory response in asthma and allergic rhinitis. This study aimed to investigate the potential impacts of montelukast on osteoarthritis (OA) progression. To determine the role of montelukast in OA, the expression of CysLTR1 was first examined by quantitative reverse transcription PCR (RT-qPCR) and western blot in IL-1ß-induced ATDC5 cells treated with or without montelukast. Subsequently, the impacts of montelukast on cell viability and oxidative stress were measured by Cell-Counting-Kit-8 (CCK-8), commercial kits and western blot. Oxidative stress-related protein expressions were determined by western blot analysis in Il-1ß-induced ATDC5 cells. Cell apoptosis and cartilage degradation were examined by TdT-mediated dUTP Nick-End Labeling (TUNEL) assay, western blot and RT-qPCR. KLF2 expression was measured in IL-1ß-induced ATDC5 cells treated with montelukast. After interference with small interfering RNA (siRNA)-KLF2 in ATDC5 cells, the loss-of-function assays were also performed in same ways. CysLTR1 expression was elevated in IL-1ß-induced ATDC5 cells but inhibited significantly by montelukast. Montelukast attenuated the oxidative stress and apoptosis, improved cell viability. Moreover, montelukast enhanced KLF2 expression. After transfected with siRNA-KLF2, montelukast attenuated cell injury, oxidative stress, apoptosis and cartilage degradation in IL-1ß-induced ATDC5 cells by activating KLF2.In summary, this work elaborates the evidence that montelukast could attenuate oxidative stress and apoptosis in IL-1ß-induced chondrocytes by inhibiting CysLTR1 and activating KLF2, which can guide the therapeutic strategies of montelukast for OA development in the future.


Assuntos
Acetatos/farmacologia , Condrócitos/efeitos dos fármacos , Ciclopropanos/farmacologia , Interleucina-1beta/efeitos adversos , Fatores de Transcrição Kruppel-Like/metabolismo , Quinolinas/farmacologia , Receptores de Leucotrienos/metabolismo , Sulfetos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Condrócitos/metabolismo , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
20.
Pharmacology ; 106(9-10): 469-476, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34350893

RESUMO

BACKGROUND: The coronavirus disease-19 (COVID-19) pandemic is a serious devastating disease and has posed a global health emergency. So far, there is not any specific therapy approved till date to control the clinical symptoms of the disease. Remdesivir has been approved by the FDA as an emergency clinical therapy. But it may not be effective alone to control the disease as it can only control the viral replication in the host. SUMMARY: This article summarizes the possible therapeutic potential and benefits of using montelukast, a cysteinyl leukotriene 1 (CysLT1) receptor antagonist, to control COVID-19 pathophysiology. Montelukast has shown anti-inflammatory effects, reduced cytokine production, improvement in post-infection cough production and other lung complications. Key Messages: Recent reports clearly indicate a distinct role of CysLT-regulated cytokines and immunological signaling in COVID-19. Thus, montelukast may have a clinical potential to control lung pathology during COVID-19.


Assuntos
Acetatos/farmacologia , COVID-19/tratamento farmacológico , Ciclopropanos/farmacologia , Antagonistas de Leucotrienos/farmacologia , Quinolinas/farmacologia , Sulfetos/farmacologia , Acetatos/uso terapêutico , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/farmacologia , Alanina/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , COVID-19/metabolismo , COVID-19/fisiopatologia , Ciclopropanos/uso terapêutico , Humanos , Antagonistas de Leucotrienos/uso terapêutico , Quinolinas/uso terapêutico , Receptores de Leucotrienos/metabolismo , Sulfetos/uso terapêutico
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