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1.
Expert Opin Investig Drugs ; 29(2): 117-123, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31523999

RESUMO

Introduction: Nonalcoholic fatty liver disease (NAFLD) encompasses a progressive disease phenotype starting from simple steatosis, which can progress to nonalcoholic steatohepatitis (NASH). It is component of the metabolic syndrome with a large impact on mortality in these patients. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate lipid and insulin metabolism, two key components in pathophysiology of NAFLD and NASH. Elafibranor acts as an agonist of PPAR-α and PPAR-δ and is currently under development for the treatment of NAFLD.Areas covered: This review summarizes the pharmacological aspects, the preclinical and clinical effectivity, and safety data of elafibranor for the treatment of nonalcoholic steatohepatitis and fibrosis.Expert opinion: Current data support an effect of elafibranor on the resolution on NASH and the improvement of two key drivers of NASH progression - insulin resistance and serum lipid normalization. The safety profile is favorable, though reversible serum creatinine elevations occur with use, potentially limiting its use in patients with concurrent renal disease. The modest effect sizes in different NAFLD disease stages of elafibranor and other drugs in development for NASH, will likely lead to pursuing of drug combinations personalized to each stage of the NAFLD disease spectrum.


Assuntos
Chalconas/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Propionatos/uso terapêutico , Animais , Chalconas/efeitos adversos , Chalconas/farmacologia , Progressão da Doença , Humanos , Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , PPAR alfa/agonistas , PPAR delta/agonistas , Propionatos/efeitos adversos , Propionatos/farmacologia
2.
Chem Biol Interact ; 316: 108916, 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31870843

RESUMO

Oxidized low-density lipoprotein (ox-LDL)-induced endothelial inflammation plays an important role in the development of cardiovascular diseases. G protein-coupled receptors (GPCR) are gaining traction as potential treatment targets due to their roles in mediating a wide range of physiological processes. GPR120 is a recently identified omega-3 fatty acid receptor. We hypothesized that agonism of GPR120 might attenuate ox-LDL-induced endothelial dysfunction. In the present study, we tested the effects of two GPR120 agonists-GW9508 and TUG-891-in mitigating endothelial insult induced by ox-LDL in human aortic endothelial cells (HAECs). Real-time PCR, western blot, and ELISA analyses were used in our experiments. Our findings demonstrate that GPR120 is downregulated by exposure to ox-LDL, suggesting a role for GPR120 in mediating ox-LDL insult. Furthermore, we found that agonism of GPR120 could suppress oxidative stress and inflammation by inhibiting the production of reactive oxygen species and the expression of proinflammatory cytokines. Importantly, we show that agonism of GPR120 prevents the attachment of monocytes to endothelial cells by suppressing the expression of VCAM-1 and E-selectin. Finally, we show that agonism of GPR120 exerts a remarkable atheroprotective effect by elevating the expression level of Krüppel-like factor 2 (KLF2). Together, our results demonstrate a potential role for specific agonism of GPR120 in the prevention of endothelial damages induced by ox-LDL.


Assuntos
Adesão Celular/efeitos dos fármacos , Lipoproteínas LDL/farmacologia , Metilaminas/farmacologia , Propionatos/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Selectina E/genética , Selectina E/metabolismo , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Humanos , Inflamação/metabolismo , Inflamação/prevenção & controle , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Monócitos/citologia , Monócitos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/metabolismo
3.
Fitoterapia ; 139: 104410, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31707127

RESUMO

Phytochemical studies of the air-dried pericarp of Citrus grandis led to the isolation of four new compounds including three prenylated benzenepropanoic acids (2, 3 and 5) and one alkamidic glycoside (6), together with ten known compounds (1, 4 and 7-14). The structures of these compounds were determined by the NMR spectroscopy, optical rotation data and modified Mosher's method. Meanwhile, the anti-neuroinflammatory activities of all isolated compounds were evaluated by detecting the production of nitric oxide (NO) in LPS-stimulated BV2 cells. The results showed that compounds 1, 2, 5 and 13 exhibited strong inhibition effects on NO production in LPS-stimulated BV2 cells. Mechanistically, compounds 1, 2 and 5 could suppress the expressions of iNOS. In addition, compounds 1, 2 and 5 also showed obvious inhibition effects on COX-2 expression, another vital enzyme in the inflammation process, in LPS-treated BV2 cells. These findings shed light on the potent anti-neuroinflammatory effects of Citrus grandis.


Assuntos
Anti-Inflamatórios/farmacologia , Citrus/química , Glicosídeos/farmacologia , Propionatos/farmacologia , Animais , Anti-Inflamatórios/isolamento & purificação , Linhagem Celular Tumoral , China , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/isolamento & purificação , Inibidores de Ciclo-Oxigenase 2/farmacologia , Frutas/química , Glicosídeos/isolamento & purificação , Macrófagos , Camundongos , Estrutura Molecular , Neuroblastoma , Óxido Nítrico Sintase Tipo II/metabolismo , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Prenilação , Propionatos/isolamento & purificação
4.
J Microbiol ; 57(11): 1019-1024, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31659687

RESUMO

Enterococci are Gram-positive facultative anaerobic bacteria that colonize the oral cavity and gastrointestinal tract. Enterococcal infections, mainly caused by Enterococcus faecalis and Enterococcus faecium, include apical periodontitis, endocarditis, and bloodstream infections. Recently, vancomycinresistant Enterococci are considered major pathogens that are common but difficult to treat, especially in nosocomial settings. Moreover, E. faecalis is closely associated with recurrent endodontic infections and failed endodontic treatment. In this study, we investigated the effects of short-chain fatty acids (SCFAs), acetate, propionate, and butyrate, which are metabolites fermented by gut microbiota, on the growth of Enterococci. Enterococci were cultured in the presence or absence of acetate, propionate, or butyrate, and the optical density at 600 nm was measured to determine bacterial growth. The minimum inhibitory concentration/minimum bactericidal concentration test was conducted. Bacteria were treated with a SCFA, together with clinically used endodontic treatment methods such as triple antibiotics (metronidazole, minocycline, and ciprofloxacin) and chlorhexidine gluconate (CHX) to determine the effects of combination treatment. Of the SCFAs, propionate had a bacteriostatic effect, inhibiting the growth of E. faecalis in a dose-dependent manner and also that of clinical strains of E. faecalis isolated from dental plaques. Meanwhile, acetate and butyrate had minimal effects on E. faecalis growth. Moreover, propionate inhibited the growth of other Enterococci including E. faecium. In addition, combination treatment of propionate and triple antibiotics led to further growth inhibition, whereas no cooperative effect was observed at propionate plus CHX. These results indicate that propionate attenuates the growth of Enterococci, suggesting propionate as a potential agent to control Enterococcal infections, especially when combined with triple antibiotics.


Assuntos
Antibacterianos/farmacologia , Enterococcus/efeitos dos fármacos , Propionatos/farmacologia , Acetatos/farmacologia , Butiratos/farmacologia , Clorexidina/análogos & derivados , Ciprofloxacino/farmacologia , Combinação de Medicamentos , Enterococcus/crescimento & desenvolvimento , Enterococcus faecalis/efeitos dos fármacos , Enterococcus faecalis/crescimento & desenvolvimento , Enterococcus faecium/efeitos dos fármacos , Enterococcus faecium/crescimento & desenvolvimento , Ácidos Graxos Voláteis/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Metronidazol/farmacologia , Testes de Sensibilidade Microbiana , Minociclina/farmacologia
5.
Life Sci ; 238: 116965, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31629762

RESUMO

AIMS: Diabetic nephropathy (DN) is responsible for the occurrence of 30-47% of the incident cases of end-stage renal disease (ESRD) worldwide. DN is a chronic inflammatory disorder, which results from hyperglycemia-induced alterations and leads to renal fibrosis and ESRD. Toll like receptor-4 (TLR-4) participates in regulation of inflammatory response through controlling of innate immune system. P-Coumaric Acid (P-CA) is a natural hydroxycinnamic acid derivative and is widely present in vegetables, fruits, mushrooms and cereals. This study aimed to explore the renoprotective effect of P-CA, as anti-inflammatory and antioxidant natural compound, against experimental DN. METHODS: DN was induced by single intraperitoneal injection of streptozotocin (45 mg/kg) in rats. In kidney homogenate, levels of TLR-4, interleukin-6 (IL-6) and transforming growth factor ß1 (TGFß1) were measured using ELISA technique. Also, kidney collagen content was determined colorimetrically. KEY FINDINGS: Oral administration of P-CA (100 mg/kg) for 8 weeks significantly alleviated the DN. P-CA significantly reduced serum concentrations of glucose, creatinine, blood urea nitrogen (BUN) and reduced protein content in urine. Also, P-CA significantly increased superoxide dismutase (SOD) activity and significantly reduced kidney contents of malondialdehyde (MDA), TLR-4, IL-6, TGFß1 and collagen when compared with DN group. Moreover, P-CA significantly improved DN-induced histopathological abnormalities. SIGNIFICANCE: P-CA confers protection against the progression of DN. This renoprotective effect can be attributed to its ability to decrease the generation of inflammatory and fibrotic cytokines in addition to restoring oxidant/antioxidant balance through its ability to down-regulate TLR-4 activation.


Assuntos
Antioxidantes/farmacologia , Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/prevenção & controle , Regulação da Expressão Gênica/efeitos dos fármacos , Propionatos/farmacologia , Receptor 4 Toll-Like/metabolismo , Animais , Glicemia/metabolismo , Creatinina/sangue , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptor 4 Toll-Like/genética
6.
Yakugaku Zasshi ; 139(9): 1155-1162, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31474631

RESUMO

Nonalcoholic steatohepatitis (NASH) is a lifestyle-related disease characterized by hepatic fibrosis with the accumulation of fat and inflammation and can progress to cirrhosis or hepatocellular carcinoma. However, effective pharmacotherapeutic strategies for hepatic fibrosis in NASH remain to be established. Among the initiators of inflammation, we have been investigating the possible involvement of group IVA phospholipase A2 (IVA-PLA2), which catalyzes the initial step in the generation of lipid mediators, including eicosanoids and lysophospholipids, in the progression of hepatic fibrosis. We have recently demonstrated that a lack of IVA-PLA2 alleviates hepatic fibrosis in NASH model mice fed a high-fat and high-cholesterol diet and in CCl4-treated mice. CCl4-induced hepatic fibrosis was also prevented by the administration of an orally active, specific IVA-PLA2 inhibitor even after hepatic fibrosis had developed. Based on these findings suggesting that IVA-PLA2 mediates the cellular responses contributing to the progression of hepatic fibrosis, we have been exploring which types of cells in the liver are involved in IVA-PLA2-mediated hepatic fibrosis using cell-specific IVA-PLA2 knockout mice. The preliminary experimental results suggest that IVA-PLA2 in endothelial cells, but not monocyte-derived cells, plays a role, in part, in the hepatic stellate cell-mediated progression of hepatic fibrosis. In this paper, we discuss the possibility that IVA-PLA2 and/or its related molecules are candidate pharmacotherapeutic targets for NASH treatment.


Assuntos
Fosfolipases A2 do Grupo IV/antagonistas & inibidores , Indóis/uso terapêutico , Terapia de Alvo Molecular , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Propionatos/uso terapêutico , Animais , Modelos Animais de Doenças , Fosfolipases A2 do Grupo IV/fisiologia , Humanos , Indóis/administração & dosagem , Indóis/farmacologia , Camundongos , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/enzimologia , Propionatos/administração & dosagem , Propionatos/farmacologia
7.
Int J Nanomedicine ; 14: 4931-4947, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31371941

RESUMO

Background: Phototherapy, including photothermal therapy (PTT) and photodynamic therapy (PDT), is a promising noninvasive strategy in the treatment of cancers due to its highly localized specificity to tumors and minimal side effects to normal tissues. However, single phototherapy often causes tumor recurrence which hinders its clinical applications. Therefore, developing a NIR-guided dendritic nanoplatform for improving the phototherapy effect and reducing the recurrence of tumors by synergistic chemotherapy and phototherapy is essential. Methods: A fluorescent targeting ligand, insisting of ICG derivative cypate and a tumor penetration peptide iRGD (CRGDKGPDC), was covalently combined with PAMAM dendrimer to prepare a single agent-based dendritic theranostic nanoplatform iRGD-cypate-PAMAM-DTX (RCPD). Results: Compared with free cypate, the resulted RCPD could generate enhanced singlet oxygen species while maintaining its fluorescence intensity and heat generation ability when subjected to NIR irradiation. Furthermore, our in vitro and in vivo therapeutic studies demonstrated that compared with phototherapy or chemotherapy alone, the combinatorial chemo-photo treatment of RCPD with the local exposure of NIR light can significantly improve anti-tumor efficiency and reduce the risk of recurrence of tumors. Conclusion: The multifunctional theranostic platform (RCPD) could be used as a promising method for NIR fluorescence image-guided combinatorial treatment of tumor cancers.


Assuntos
Antineoplásicos/farmacologia , Dendrímeros/química , Raios Infravermelhos , Nanopartículas/química , Fototerapia , Animais , Proliferação de Células/efeitos dos fármacos , Terapia Combinada , Docetaxel/farmacologia , Endocitose/efeitos dos fármacos , Fluorescência , Células Hep G2 , Temperatura Alta , Humanos , Indóis/farmacologia , Camundongos Nus , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Oligopeptídeos/química , Fotoquimioterapia , Propionatos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Nanomedicina Teranóstica
8.
Chem Biodivers ; 16(10): e1900362, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31400187

RESUMO

A series of novel esters and amides was synthesized on the basis of para-coumaric acid containing isobornyl groups in ortho-positions relative to the phenolic hydroxy group. Antioxidant properties of the obtained compounds were evaluated and compared on in vitro models: radical-scavenging ability, antioxidant activity on a substrate containing the lipids of animal brain, cytotoxicity of red blood cells, antioxidant and membrane-protective properties on the model of oxidative red blood cells hemolysis. Statistically significant relationship was established between the antioxidant activity of the studied compounds in model system containing animal lipids and the parameters reflecting their antioxidant properties on the model of H2 O2 -induced hemolysis of red blood cells. It was determined that an amide with a morpholine fragment has the highest antioxidant activity. The specified derivative significantly surpassed the reference substances (parent acid, BHT) and was not inferior to the effective antioxidant 2,6-diisobornyl-4-methylphenol in terms of its properties.


Assuntos
Antioxidantes/farmacologia , Encéfalo/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Propionatos/farmacologia , Animais , Antioxidantes/síntese química , Antioxidantes/química , Hidroxitolueno Butilado/química , Hemólise/efeitos dos fármacos , Peróxido de Hidrogênio/farmacologia , Camundongos , Estrutura Molecular , Propionatos/síntese química , Propionatos/química
9.
Cell Host Microbe ; 26(2): 273-282.e7, 2019 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-31378678

RESUMO

Despite evidence linking the human microbiome to health and disease, how the microbiota affects human physiology remains largely unknown. Microbiota-encoded metabolites are expected to play an integral role in human health. Therefore, assigning function to these metabolites is critical to understanding these complex interactions and developing microbiota-inspired therapies. Here, we use large-scale functional screening of molecules produced by individual members of a simplified human microbiota to identify bacterial metabolites that agonize G-protein-coupled receptors (GPCRs). Multiple metabolites, including phenylpropanoic acid, cadaverine, 9-10-methylenehexadecanoic acid, and 12-methyltetradecanoic acid, were found to interact with GPCRs associated with diverse functions within the nervous and immune systems, among others. Collectively, these metabolite-receptor pairs indicate that diverse aspects of human health are potentially modulated by structurally simple metabolites arising from primary bacterial metabolism.


Assuntos
Bactérias/metabolismo , Interações entre Hospedeiro e Microrganismos/imunologia , Interações entre Hospedeiro e Microrganismos/fisiologia , Microbiota/imunologia , Microbiota/fisiologia , Receptores Acoplados a Proteínas-G/agonistas , Proteínas Angiogênicas/agonistas , Animais , Cadaverina/metabolismo , Cadaverina/farmacologia , Ácidos Graxos/metabolismo , Ácidos Graxos/farmacologia , Fermentação , Vida Livre de Germes , Agonistas dos Receptores Histamínicos , Humanos , Sistema Imunitário , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Propionatos/metabolismo , Propionatos/farmacologia , Receptores Acoplados a Proteínas-G/metabolismo , Receptores Histamínicos/efeitos dos fármacos , Receptores de Neurotransmissores/agonistas
10.
Insect Biochem Mol Biol ; 113: 103224, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31446031

RESUMO

In addition to its primary function as an insect repellent, DEET has many "off-label" properties, including a deterrent effect on the attraction of gravid female mosquitoes. DEET negatively affects oviposition sites. While deorphanizing odorant receptors (ORs) using the Xenopus oocyte recording system, we have previously observed that DEET generated outward (inhibitory) currents on ORs sensitive to oviposition attractants. Here, we systematically investigated these inhibitory currents. We recorded dose-dependent outward currents elicited by DEET and other repellents on ORs from Culex quinquefasciatus, Aedes aegypti, and Anopheles gambiae. Similar responses were observed with other plant-derived and plant-inspired compounds, including methyl jasmonate and methyl dihydrojasmolate. Inward (regular) currents elicited by skatole upon activation of CquiOR21 were modulated when this oviposition attractant was coapplied with a repellent. Compounds that generate outward currents in ORs sensitive to oviposition attractants elicited inward currents in a DEET-sensitive receptor, CquiOR136. The best ligand for this receptor, methyl dihydrojasmolate, showed repellency activity but was not as strong as DEET in our test protocol.


Assuntos
Aedes/efeitos dos fármacos , Anopheles/efeitos dos fármacos , Culex/efeitos dos fármacos , Proteínas de Insetos/antagonistas & inibidores , Repelentes de Insetos/farmacologia , Oviposição/efeitos dos fármacos , Receptores Odorantes/antagonistas & inibidores , Aedes/fisiologia , Animais , Anopheles/fisiologia , Quimiotaxia/efeitos dos fármacos , Culex/fisiologia , DEET/farmacologia , Mentol/análogos & derivados , Mentol/farmacologia , Piperidinas/farmacologia , Propionatos/farmacologia
11.
Artigo em Inglês | MEDLINE | ID: mdl-31405165

RESUMO

This study evaluated the antifungal effects of various volatile organic compounds (VOCs) against two common pathogens: Fusarium culmorum and Cochliobolus sativus. Among the various VOCs, methyl propanoate (MP) and methyl prop-2-enoate (MA) exhibited remarkable antifungal effects under different experimental conditions (direct or indirect contact) and at different concentrations (500-1000 µM). In addition, the type of antifungal effect (fungistatic or fungicidal) appeared to be strongly correlated with the VOC concentrations. Additional tests revealed that both molecules increased membrane permeability of pathogenic spores, which resulted in a decreased efflux of K+ ions into the intracellular medium.


Assuntos
Antifúngicos/farmacologia , Ascomicetos/efeitos dos fármacos , Fusarium/efeitos dos fármacos , Propionatos/farmacologia , Compostos Orgânicos Voláteis/farmacologia , Hordeum/microbiologia
12.
Regul Toxicol Pharmacol ; 108: 104449, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31449916

RESUMO

Multidrug resistance associated protein 2 (MRP2) is an important efflux transporter involved in clinical drug disposition and drug-drug interactions. The study of MRP2-mediated drug transport has become an integral part of drug discovery and development. In particular, screening of specific MRP2 inhibitors will help overcome the multidrug resistance in cancer. In this report, a new method for rapid and sensitive detection of Mrp2 function was established via using mouse small intestinal organoids. Firstly, small intestinal crypts isolated from mouse intestine were induced by Noggin, R-spondin1 and EGF to develop three-dimensional (3D) organoids. Secondly, the 3D organoids were characterized by the physical and physiological structure of Mrp2-mediated drug transport. Finally, Mrp2 fluorescent substrate 5(6)-carboxyl- 2', 7'-dichlorofluorescein (CDF) and its inhibitor MK-571 and probenecid were used to demonstrate Mrp2-mediated CDF transport in 3D organoids. The results showed that the small intestinal organoids have a physiological structure for Mrp2-mediated compound transport. Moreover, MK-571 and probenecid, inhibitors of MRP2, significantly decreased the accumulation of CDF in 3D organoids. In summary, a novel intestinal organoid model has been successfully established for the rapid and effective study of Mrp2-mediated drug transport.


Assuntos
Intestino Delgado/metabolismo , Modelos Biológicos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Organoides/metabolismo , Animais , Fluoresceínas/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Probenecid/farmacologia , Propionatos/farmacologia , Quinolinas/farmacologia
13.
Pestic Biochem Physiol ; 159: 80-84, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31400787

RESUMO

The plastid acetyl coenzyme carboxylase (ACCase) Trp1999Leu mutation was identified in a Beckmannia syzigachne population resistant to fenoxaprop-p-ethyl. The pattern of cross-resistance for the Trp1999Leu mutation is still ambiguous. In this paper, mutant homozygote (1999Leu/Leu, RR) and wild type (1999Trp/Trp, SS) B. syzigachne plants with the same genetic background were purified from the JS-26 population using the dCAPS method. The activity of ACCase in RR and SS was determined. Then, the cross-resistance pattern to ACCase inhibiting herbicides of the Trp1999Leu mutation was determined using the whole-plant method. ACCase activity showed that the Trp1999Leu mutation decreased ACCase sensitivity to fenoxaprop-p-ethyl by 2.73-fold. A dose-response experiment indicated that the Trp1999Leu mutation conferred high resistance to quizalofop-p-ethyl (20.29-fold), metamifop (12.22-fold) and pinoxaden (18.60-fold), moderate resistance to fenoxaprop-p-ethyl (8.20-fold) and sethoxydim (6.38-fold), low resistance to cyhalofop-butyl (2.73-fold) and no resistance to clodinafop-propargyl (1.42 fold) and clethodim (1.59-fold). This is the first report of the role of Trp1999Leu in fenoxaprop-p-ethyl resistance and of the patterns of cross-resistance to ACCase-inhibiting herbicides in B. syzigachne.


Assuntos
Acetil-CoA Carboxilase/genética , Herbicidas/farmacologia , Poaceae/efeitos dos fármacos , Poaceae/genética , Anilidas/farmacologia , Benzoxazóis/farmacologia , Cicloexanonas/farmacologia , Resistência a Herbicidas/genética , Compostos Heterocíclicos com 2 Anéis/farmacologia , Mutação/genética , Propionatos/farmacologia , Piridinas/farmacologia , Quinoxalinas/farmacologia
14.
Mol Med Rep ; 20(2): 1569-1574, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31257531

RESUMO

Short­chain fatty acids (SCFAs; butyrate, propionate and acetate) are metabolites derived from the gut microbiota via dietary fiber fermentation. In colon cancer, treatment with SCFAs, mainly butyrate and propionate, suppresses cell proliferation, migration and invasion. Furthermore, although sodium butyrate is known to induce cell apoptosis in lung cancer, the anticancer effects of sodium propionate (SP) on lung cancer are not well understood. In the present study, SP treatment induced cell cycle arrest, especially in the G2/M phase, and cell apoptosis in the H1299 and H1703 lung cancer cell lines. As determined by reverse transcription­quantitative PCR and western blotting, Survivin and p21 expression levels were significantly affected by SP treatment, suggesting that SP treatment suppressed cell proliferation in these lung cancer cell lines. Thus, it was proposed that the SP­mediated regulation of Survivin and p21 in lung cancer may be applicable to lung cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Ácido Butírico/farmacologia , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Propionatos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p21/agonistas , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Pontos de Checagem da Fase G2 do Ciclo Celular/genética , Microbioma Gastrointestinal/fisiologia , Humanos , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Transdução de Sinais , Survivina/antagonistas & inibidores , Survivina/genética , Survivina/metabolismo
15.
PLoS One ; 14(7): e0206271, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31318884

RESUMO

Broiler breeders, the parent stock of meat chickens, are feed-restricted throughout the production cycle to avoid obesity-related problems in their health and reproductive performance. Broiler breeders often show signs of chronic hunger, lack of satiety and feeding frustration, and the development of alternative feeding strategies has investigated the inclusion of calcium propionate (CaP) as an appetite suppressant. The mechanisms involved in the reduction of voluntary feed intake are unknown, but are thought to be due to low palatability, gastrointestinal discomfort, or both. The objective of this experiment was to examine the effect of CaP as an appetite suppressant on the experience of a negative affective state, using a conditioned place preference test. Twenty four broiler breeders were trained to associate the consumption of CaP or a placebo pill with a red or blue place, depending on inherent colour preference. Pullets consumed two pills followed by 20 g feed allotment. The CaP pill contained 160 mg of CaP and the placebo pill had 160 mg of feed. Conditioning lasted for 90 min/pullet/day over 8 consecutive days at 7 and 9 weeks of age, and pullets' choice was tested in a T-maze twice on two consecutive days at both 8 and 10 weeks of age. Data were analysed using a linear mixed regression model, with pen nested in the model and age as a repeated measure. Pullets were less likely to choose the place conditioned with the consumption of CaP (P<0.05) and the preference of the placebo linearly increased with training sessions (P<0.05). These results suggest that calcium propionate as an appetite suppressant can induce a negative affective state, reducing feed intake in broiler breeders fed CaP diets by causing an avoidance response rather than satiety.


Assuntos
Ração Animal , Depressores do Apetite/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Propionatos/farmacologia , Animais , Galinhas , Feminino , Masculino
16.
Biomed Res Int ; 2019: 6740616, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31321239

RESUMO

Identification of new pharmacological approaches to inhibit the excessive fat intake-induced steatohepatitis and chronic kidney disease (CKD) is important. High-fat diet (HFD)-induced steatohepatitis and CKD share common pathogenesis involving peroxisome proliferator-activated receptor (PPAR)-α and -δ. Elafibranor, a dual PPARα/δ agonist, can ameliorate the HFD-induced steatohepatitis. Nonetheless, the effects of HFD-induced CKD had not yet explored. This study investigated the effects of elafibranor (elaf) on the progression of HFD-induced CKD in mice. In vivo and in vitro renal effects were evaluated in HFD-elaf mice receiving 12 weeks of elafibranor (from 13th to 24th week of HFD feeding) treatment. In elafibranor-treated HFD mice, increased insulin sensitivity, reduced obesity and body fat mass, decreased severity of steatohepatitis, increased renal expression of PPARα, PPARδ, SIRT1, and autophagy (Beclin-1 and LC3-II) as well as glomerular/renal tubular barrier markers [synaptopodin (podocyte marker), zona occludin-1, and cubulin], reduced renal oxidative stress and caspase-3, and less urinary 8-isoprostanes excretion were observed. Aforementioned benefits of elafibranor were associated with low renal tubular injury and tubulointerstitial fibrosis scores, less albuminuria, low urinary albumin-to-creatinine ratio, and preserved glomerular filtration rate. Acute incubation of podocytes and HK-2 cells with elafibranor or recombinant SIRT1 reversed the HFD-sera-induced oxidative stress, autophagy dysfunction, cell apoptosis, barrier marker loss, albumin endocytosis, and reuptake reduction. Besides hepatoprotective and metabolic beneficial effects, current study showed that elafibranor inhibited the progression of HFD-induced CKD through activation of renal PPARα, PPARδ, SIRT1, autophagy, reduction of oxidative stress, and apoptosis in mice with steatohepatitis.


Assuntos
Chalconas/farmacologia , PPAR alfa/genética , PPAR delta/genética , Propionatos/farmacologia , Insuficiência Renal Crônica/tratamento farmacológico , Sirtuína 1/genética , Animais , Apoptose/efeitos dos fármacos , Proteína Beclina-1/genética , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Progressão da Doença , Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Rim/efeitos dos fármacos , Rim/patologia , Camundongos , Proteínas Associadas aos Microtúbulos/genética , Estresse Oxidativo/efeitos dos fármacos , Podócitos/efeitos dos fármacos , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia
17.
J Periodontal Res ; 54(6): 690-701, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31328274

RESUMO

OBJECTIVE: Dietary bioactive materials having anti-inflammatory and antioxidant potentials are able to inhibit diabetes-associated periodontal complications. Although numerous studies indicate that administration of p-coumaric acid (p-CA) ameliorates diabetes and diabetes-related complications, the roles of p-CA on periodontal tissue destruction in diabetic mice and the possible mechanisms therein are not completely understood. In this study, we evaluated whether supplementation with p-CA protects mice against diabetes-associated spontaneous periodontal destruction and also explored the associated mechanism therein using in vivo and in vitro experimental systems. MATERIALS AND METHODS: C57BL/6 male mice were divided into sham, streptozotocin (STZ), and STZ+CA groups (n = 5/group). Sham group was intraperitoneally injected with sodium buffer, whereas other two groups were injected with the buffer containing 160 mg/kg of STZ. STZ-induced diabetic mice received oral gavage with p-CA (50 mg/kg) (STZ+CA group) or with buffer only (STZ group) daily for 6 weeks. The effect of p-CA on diabetes-associated spontaneous periodontal destruction was evaluated using µCT analysis, hematoxylin and eosin staining, tartrate-resistant acid phosphatase staining, and immunohistochemical staining methods. The efficacies of p-CA on cell proliferation, osteoblast differentiation, reactive oxygen species (ROS) accumulation, and antioxidant-related marker expression were examined using human periodontal ligament fibroblasts (hPLFs) cultured under high glucose condition. RESULTS: Streptozotocin group exhibited periodontal tissue destruction along with increased inflammation, oxidative stress, and osteoclast formation, as well as with decreased osteogenesis. However, oral administration with p-CA protected mice against STZ-induced periodontal destruction by inhibiting inflammation and osteoclastic activation. STZ+CA group also showed higher expression of antioxidant and osteogenic markers in periodontal tissue than did STZ group. Treatment with high glucose concentration (30 mmol/L) impaired proliferation and osteoblast differentiation of hPLFs along with cellular ROS accumulation, whereas these impairments were almost completely disappeared by supplementation with p-CA. CONCLUSION: These findings demonstrate that supplementation with p-CA inhibits diabetes-associated spontaneous destruction of periodontal tissue by enhancing anti-inflammatory, anti-osteoclastogenic, and antioxidant defense systems in STZ-treated mice.


Assuntos
Diabetes Mellitus Experimental/complicações , Suplementos Nutricionais , Estresse Oxidativo , Doenças Periodontais/tratamento farmacológico , Propionatos/farmacologia , Administração Oral , Animais , Antioxidantes/metabolismo , Células Cultivadas , Fibroblastos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Doenças Periodontais/etiologia , Ligamento Periodontal/citologia , Estreptozocina
18.
Int J Food Microbiol ; 306: 108258, 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31362161

RESUMO

Propionic acid is widely used as a preservative in (poultry) feed. In this study we have isolated and identified fungal strains from nine samples poultry feed originating from different countries. The majority of the strains were Aspergilli with a eurotium-morph, such as Aspergillus proliferans and A. chevalieri. These and three other species were selected and tested for their sensitivity towards the feed preservative propionic acid, among them Penicillium lanosocoeruleum. The determined MIC values of 6.1-31 mM of these poultry feed specific fungi were well in the range as described in literature. Propionic acid (at 31 mM) damages conidia (spores) in a species dependent fashion after a 24-hour-treatment. The majority of the conidia (over 70%) of P. lanosocoeruleum germinated within 60 h on agar medium, while 50 and 80% of the A. chevalieri and A. proliferans conidia did not, respectively. Dependent on the species, cell damage was visible after incubation with propionic acid. Germ tubes of P. lanosocoeruleum in a biofilm showed extensive (85%) cell death after a 30 min treatment with propionic acid and slightly lower sensitivity was observed with A. proliferans (62% cell death). Microscopic analysis of these fungal biofilms revealed extensive damage to the cell membrane and showed distorted intracellular structures. Fluorescent life-dead staining of the germ tubes showed a clear dose response of propionic acid indicating a fungicidal effect on these growing cells. These results show that conidia can be inactivated by propionic acid, but that germ tubes show a much higher sensitivity. These observations shed new light on the mode of action of this important preservative to prevent fungal contamination of feed.


Assuntos
Ração Animal/microbiologia , Aspergillus/efeitos dos fármacos , Fungicidas Industriais/farmacologia , Penicillium/efeitos dos fármacos , Propionatos/farmacologia , Esporos Fúngicos/efeitos dos fármacos , Animais , Aspergillus/classificação , Aspergillus/isolamento & purificação , Biofilmes/efeitos dos fármacos , Meios de Cultura/farmacologia , Eurotium , Microbiologia de Alimentos/métodos , Testes de Sensibilidade Microbiana , Penicillium/classificação , Penicillium/isolamento & purificação , Aves Domésticas
19.
J Pharmacol Exp Ther ; 370(2): 172-181, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31182471

RESUMO

The GPR40/FFA1 receptor is a G-protein-coupled receptor expressed in the pancreatic islets and enteroendocrine cells. Here, we report the pharmacological profiles of (3S)-3-cyclopropyl-3-{2-[(1-{2-[(2,2-dimethylpropyl)(6-methylpyridin-2-yl)carbamoyl]-5-methoxyphenyl}piperidin-4-yl)methoxy]pyridin-4-yl}propanoic acid (SCO-267), a novel full agonist of GPR40. Ca2+ signaling and insulin and glucagon-like peptide-1 (GLP-1) secretion were evaluated in GPR40-expressing CHO, MIN6, and GLUTag cells. Hormone secretions and effects on fasting glucose were tested in rats. Single or repeated dosing effects were evaluated in neonatally streptozotocin-induced diabetic rats (N-STZ-1.5 rats), diet-induced obese (DIO) rats, and GPR40-knockout (Ffar1-/- ) mice. Treatment with SCO-267 activated Gq signaling in both high- and low-FFAR1-expressing CHO cells, stimulated insulin secretion in MIN6 cells, and induced GLP-1 release in GLUTag cells. When administered to normal rats, SCO-267 increased insulin, glucagon, GLP-1, glucose-dependent insulinotropic peptide, and peptide YY (PYY) secretions under nonfasting conditions. These results show the full agonistic property of SCO-267 against GPR40. Hypoglycemia was not induced in SCO-267-treated rats during the fasting condition. In diabetic N-STZ-1.5 rats, SCO-267 was highly effective in improving glucose tolerance in single and 2-week dosing studies. DIO rats treated with SCO-267 for 2 weeks showed elevated plasma GLP-1 and PYY levels, reduced food intake, and decreased body weight. In wild-type mice, SCO-267 induced GLP-1 secretion, food intake inhibition, and body weight reduction; however, these effects were abolished in Ffar1-/- mice, indicating a GPR40-dependent mechanism. In conclusion, SCO-267 stimulated islet and gut hormone secretion, improved glycemic control in diabetic rats, and decreased body weight in obese rats. These data suggest the therapeutic potential of SCO-267 for the treatment of diabetes and obesity.


Assuntos
Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Ciclopropanos/farmacologia , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Obesidade/complicações , Piperidinas/farmacologia , Propionatos/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Animais , Células CHO , Cricetulus , Ciclopropanos/uso terapêutico , Diabetes Mellitus Experimental/complicações , Modelos Animais de Doenças , Cães , Ingestão de Alimentos/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Humanos , Secreção de Insulina/efeitos dos fármacos , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Masculino , Camundongos , Piperidinas/uso terapêutico , Propionatos/uso terapêutico , Ratos
20.
Mini Rev Med Chem ; 19(17): 1459-1471, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31218957

RESUMO

BACKGROUND: Cardiovascular diseases are the leading cause of global mortality with a tendency to increase due to population ageing as well as an increase in associated risk factors. Although current therapies improve survival rates, they are associated with several side effects, thus justifying the development of novel preventive and/or therapeutic approaches. In this way, plant metabolites such as essential oils have emerged as promising agents due to their biological effects. OBJECTIVE: Bearing in mind that several essential oils are characterized by high amounts of phenylpropanoids, which may play a crucial role in the activity of these volatile extracts, a comprehensive and systematic review focusing on the cardiovascular effects of phenylpropanoid-rich essential oils is presented. METHODS: Popular search engines including PubMed, Science Direct, Scopus and Google Scholar were consulted and papers from 2000 onwards were selected. Non-volatile phenylpropanoids were not considered in this review. RESULTS: A compilation of the current knowledge on this thematic pointed out beneficial effects for volatile phenylpropanoids namely hypotensive, vasorelaxant, antiplatelet aggregation, antidyslipidaemic and antidiabetic, as well as protective properties against ischemia/reperfusion injury and heart hypertrophy. CONCLUSION: A better understanding of the protective effects of phenylpropanoids on the cardiovascular system is presented, thus paving the way towards future research on plant-based therapies for cardiovascular diseases.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/prevenção & controle , Sistema Cardiovascular/efeitos dos fármacos , Óleos Voláteis/farmacologia , Propionatos/farmacologia , Substâncias Protetoras/farmacologia , Doenças Cardiovasculares/metabolismo , Sistema Cardiovascular/metabolismo , Humanos , Óleos Voláteis/química , Óleos Voláteis/isolamento & purificação , Propionatos/química , Propionatos/isolamento & purificação , Substâncias Protetoras/química , Substâncias Protetoras/isolamento & purificação
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