RESUMO
Necrotic enteritis causes economic losses estimated to be up to 6 billion US dollars per year. Clinical and subclinical infections in poultry are also both correlated with decreased growth and feed efficiency. Moreover, in a context of increased antibiotic resistance, feed additives with enhanced antimicrobial properties are a useful and increasingly needed strategy. In this study, the protective effects of a blend of thymol and organic acids against the effects of Clostridium perfringens type A (CP) on chicken intestinal epithelial cells were investigated and compared to bacitracin, a widely used antibiotic in poultry production. Primary chicken intestinal epithelial cells were challenged with CP for a total time of 3 h to assess the beneficial effect of 2 doses of citric acid, dodecanoic acid, and thymol-containing blend, and compare them with bacitracin. During the challenge, different parameters were recorded, such as transepithelial electrical resistance, cell viability, mRNA expression, and reactive oxygen species production. CP induced inflammation with cytokine production and loss of epithelial barrier integrity. It was also able to induce reactive oxygen species production and increase the caspase expression leading to cellular death. The high dose of the blend acted similarly to bacitracin, preventing the disruptive effects of CP and inducing also an increase in zonula occludens-1 mRNA expression. The low dose only partially prevented the disruptive effects of CP but successfully reduced the associated inflammation. This study shows that the usage of thymol combined with 2 organic acids can protect primary chicken intestinal epithelial cells from CP-induced damages creating a valid candidate to substitute or adjuvate the antibiotic treatment against necrotic enteritis.
Assuntos
Anti-Infecciosos , Infecções por Clostridium , Enterite , Doenças das Aves Domésticas , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Anti-Infecciosos/farmacologia , Bacitracina/farmacologia , Caspases , Galinhas , Ácido Cítrico/farmacologia , Infecções por Clostridium/tratamento farmacológico , Infecções por Clostridium/prevenção & controle , Infecções por Clostridium/veterinária , Clostridium perfringens , Citocinas , Enterite/veterinária , Células Epiteliais , Inflamação/veterinária , Ácidos Láuricos/farmacologia , Ácidos Láuricos/uso terapêutico , Aves Domésticas , Doenças das Aves Domésticas/tratamento farmacológico , Doenças das Aves Domésticas/prevenção & controle , RNA Mensageiro , Espécies Reativas de Oxigênio/uso terapêutico , Timol/farmacologiaRESUMO
BACKGROUND: Streptococcus mutans and Streptococcus sanguinis are Gram-positive bacteria that cause dental caries. MurA enzyme acts as a catalyst in the formation of peptidoglycan in bacterial cell walls, making it ideal as an antibacterial target. Basil (Ocimum americanum) is an edible plant that is diverse and has been used as a herbal medicine for a long time. It has been reported that basil has a pharmacological effect as well as antibacterial activity. The purpose of this study was to identify antibacterial compounds in O. americanum and analyze their inhibition activity on MurA enzyme. METHODS: Fresh leaves from O. americanum were extracted with n-hexane and purified by a combination of column chromatography on normal and reverse phases together with in vitro bioactivity assay against S. mutans ATCC 25175 and S. sanguinis ATCC 10556, respectively, while in silico molecular docking simulation of lauric acid (1) was conducted using PyRx 0.8. RESULTS: The structure determination of antibacterial compound by spectroscopic methods resulted in an active compound lauric acid (1). The in vitro evaluation of antibacterial activity in compound 1 showed Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) values of 78.13 and 156.3 ppm and 1250 and 2500 ppm against S. sanguinis and S. mutans, respectively. Further analysis and in silico evaluation determined lauric acid (1) as MurA Enzyme inhibitor. Lauric acid (1) showed a binding affinity of -5.2 Kcal/mol, which was higher than fosfomycin. CONCLUSION: Lauric acid showed the potential as a new natural antibacterial agent through MurA inhibition in bacterial cell wall biosynthesis.
Assuntos
Antibacterianos/farmacologia , Cárie Dentária/tratamento farmacológico , Ácidos Láuricos/farmacologia , Ocimum basilicum/química , Alquil e Aril Transferases/antagonistas & inibidores , Alquil e Aril Transferases/metabolismo , Antibacterianos/isolamento & purificação , Antibacterianos/uso terapêutico , Cárie Dentária/microbiologia , Humanos , Ácidos Láuricos/isolamento & purificação , Ácidos Láuricos/uso terapêutico , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Folhas de Planta/química , Streptococcus mutans/efeitos dos fármacos , Streptococcus mutans/enzimologia , Streptococcus sanguis/efeitos dos fármacos , Streptococcus sanguis/enzimologiaRESUMO
Airway remodeling in asthma is difficult to treat because of its complex pathophysiology that involves proinflammatory cytokines, as well as the arachidonic acid cytochrome P-450 (CYP) pathway; however, it has received little attention. In this study, we assessed the efficacy of a soluble epoxide hydrolase (sEH) on airway remodeling in a mouse model of chronic asthma. The expression of sEH and CYP2J2 and the level of 14,15-epoxyeicosatrienoic acid (14,15-EET), airway remodeling and hyperresponsiveness (AHR) were analyzed to determine the level of sEH inhibition. AUDA, a sEH inhibitor, was given daily for 9 weeks orally, which significantly increased the level of 14,15-EET by inhibiting the expression of sEH and increasing the expression of CYP2J2 in lung tissues. The inhibition of sEH reduced the expression of remodeling-related molecular markers, such as interleukin (IL)-13, IL-17, matrix metalloproteinase 9, N-cadherin, α-smooth muscle actin (α-SMA), S100A4, Twist, epithelial goblet cell metaplasia, and collagen deposition in bronchoalveolar lavage fluid (BAL fluid) and lung tissues. Moreover, remodeling-related eosinophil accumulation in the BAL fluid and infiltration into the lung tissue were improved by AUDA. Finally, AUDA alleviated AHR, which is a functional indicator of airway remodeling. The effect of AUDA on airway remodeling was related to the downregulation of extracellular-regulated protein kinases (Erk1/2), c-Jun N-terminal kinases (JNK) and signal transducer and activator of transcription 3 (STAT3). To our knowledge, this is the first report to demonstrate that inhibition of sEH exerts significant protective effects on airway remodeling in asthma.
Assuntos
Adamantano/análogos & derivados , Remodelação das Vias Aéreas/efeitos dos fármacos , Asma/tratamento farmacológico , Epóxido Hidrolases/antagonistas & inibidores , Ácidos Láuricos/farmacologia , Pulmão/efeitos dos fármacos , Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Ácido 8,11,14-Eicosatrienoico/sangue , Adamantano/farmacologia , Adamantano/uso terapêutico , Remodelação das Vias Aéreas/imunologia , Animais , Asma/imunologia , Asma/patologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocromo P-450 CYP2J2 , Sistema Enzimático do Citocromo P-450/metabolismo , Modelos Animais de Doenças , Epóxido Hidrolases/metabolismo , Feminino , Humanos , Ácidos Láuricos/uso terapêutico , Pulmão/imunologia , Pulmão/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/imunologia , Camundongos , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologiaRESUMO
Typically, antimicrobial peptides (AMPs) are short positive charged peptides serving a key role in innate immunity as well as antimicrobial activity. Discovering novel therapeutic agents is considered as an undeniable demand due to increasing microbial species with antibiotic resistance. In this direction, the unique ability of AMPs to modulate immune responses highlighted them as novel drug candidates in the field of microbiology. Patients affected by leishmaniasis; a neglected tropical disease, confront serious problems for their treatment including resistance to common drugs as well as toxicity and high cost of therapy. So, there is a need for development of new drug candidates to control the diseases. Jellein, a peptide derived from royal jelly of honeybee has been shown to have promising effect against several bacterial and fungal species. In current study, anti-leishmanial effect of Jellein and its lauric acid conjugated form was investigated against two forms of Leishmania major (L. major) parasite. Moreover, cytotoxic effect of these peptides was studied in THP1 cell line and human Red Blood Cells (RBCs). Furthermore, the mechanism of action of peptides on L. major promastigotes was assessed through different methods. The results demonstrated that, conjugation of lauric acid to Jellein not only had no effect on the elevation of antimicrobial activity but also halted it completely. Moreover, Jellein caused a limitation in the number of L. major promastigotes by pore formation as well as changing the membrane potential rather than induction of apoptosis or activation of caspases.
Assuntos
Peptídeos Catiônicos Antimicrobianos/farmacologia , Antiprotozoários/farmacologia , Leishmania major/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Oligopeptídeos/química , Antígenos de Diferenciação de Linfócitos B/farmacologia , Peptídeos Catiônicos Antimicrobianos/uso terapêutico , Peptídeos Catiônicos Antimicrobianos/toxicidade , Antiprotozoários/uso terapêutico , Antiprotozoários/toxicidade , Caspases/efeitos dos fármacos , Caspases/metabolismo , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Ácidos Graxos/química , Citometria de Fluxo , Hemólise , Antígenos de Histocompatibilidade Classe II/farmacologia , Humanos , Ácidos Láuricos/farmacologia , Ácidos Láuricos/uso terapêutico , Ácidos Láuricos/toxicidade , Leishmania major/ultraestrutura , Potenciais da Membrana/efeitos dos fármacos , Microscopia Eletrônica de Varredura , Doenças Negligenciadas/tratamento farmacológico , Doenças Negligenciadas/parasitologia , Oligopeptídeos/farmacologia , Oligopeptídeos/uso terapêutico , Oligopeptídeos/toxicidadeRESUMO
Gut microbiota has been demonstrated to be involved in intestinal nutrition, defense, and immunity, as well as participating in disease progression. This study was to investigate gut microbiota changes in chickens challenged with netB-positive Clostridium perfringens strain (CP1) and/or the predisposing Eimeria species (Eimeria) and fed diets with fishmeal supplementation. In addition, the effects of lauric acid, a medium-chain fatty acid (MCFA), on necrotic enteritis (NE) reduction and modulation of microbiota were evaluated. The results demonstrated that microbial communities in the jejunum were distinct from those in the cecum, and the microbial community change was more significant in jejunum. Challenge of CP1 in conjunction with Eimeria significantly reduced species diversity in jejunal microbiota, but cecal microbiota remained stable. In the jejunum, CP1 challenge increased the abundance of the genera of Clostridium sensu stricto 1, Escherichia Shigella, and Weissella, but significantly decreased the population of Lactobacillus. Eimeria infection on its own was unable to promote NE, demonstrating decrements of Clostridium sensu stricto 1 and Lactobacillus. Co-infection with CP1 and Eimeria reproduced the majority of NE lesions with significant increment of Clostridium sensu stricto 1 and reduction in Lactobacillus. The advance of changes on these two taxa increased the severity of NE lesions. Further analyses of metagenomeSeq, STAMP, and LEfSe consistently showed significant overgrowth of Clostridium sensu stricto 1 was associated with NE. The supplementation of lauric acid did not reduce NE incidence and severity but decreased the relative abundance of Escherichia Shigella. In conclusion, significant overgrowth of C. perfringens as well as other Clostridium species in Clostridium sensu stricto 1 with the decrement of Lactobacillus in the jejunum is the featured microbiota correlated with NE. Controlling proliferation of Clostridium sensu stricto 1 and manipulation of Lactobacillus in the jejunum should be the strategy to prevent NE.
Assuntos
Galinhas , Clostridium perfringens , Eimeria , Enterocolite Necrosante/veterinária , Microbioma Gastrointestinal , Ácidos Láuricos/uso terapêutico , Doenças das Aves Domésticas/microbiologia , Ração Animal , Animais , Infecções por Clostridium/complicações , Infecções por Clostridium/microbiologia , Infecções por Clostridium/veterinária , Coccidiose/complicações , Coccidiose/microbiologia , Coccidiose/veterinária , Dieta/veterinária , Suplementos Nutricionais , Enterocolite Necrosante/microbiologia , Enterocolite Necrosante/prevenção & controle , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Ácidos Láuricos/farmacologia , Masculino , Doenças das Aves Domésticas/parasitologia , Doenças das Aves Domésticas/prevenção & controleRESUMO
Lauric acid is a green derivate that is abundant in some seeds such as coconut oil where it represents the most relevant fatty acid. Some studies have emphasized its anticancer effect due to apoptosis induction. In addition, the lauric acid is a Phase Change Material having a melting temperature of about 43.2 °C: this property makes it a powerful tool in cancer treatment by hyperthermal stress, generally induced at 43 °C. However, the direct use of lauric acid can have some controversial effects, and it can undergo degradation phenomena in the extracellular environment. For this reason, we have encapsulated lauric acid in a silica shell with a one-step and reproducible synthetic route in order to obtain a monodispersed SiO2@LA NPs with a good encapsulation efficiency. We have used these NPs to expose breast cancer cell lines (MCF-7) at different concentrations in combination with hyperthermal treatment. Uptake, viability, oxidative stress induction, caspases levels, and morphometric parameters were analyzed. These nanovectors showed double action in anticancer treatments thanks to the synergic effect of temperature and lauric acid activity.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Composição de Medicamentos , Ácidos Láuricos/uso terapêutico , Dióxido de Silício/química , Temperatura , Actinas/metabolismo , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Varredura Diferencial de Calorimetria , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Difusão Dinâmica da Luz , Feminino , Humanos , Ácidos Láuricos/farmacologia , Células MCF-7 , Nanopartículas/química , Nanopartículas/ultraestrutura , Espécies Reativas de Oxigênio/metabolismo , Espectrometria por Raios XRESUMO
OBJECTIVE: To analyze specific spectroscopic (FT-Raman) and thermal (limiting oxygen index) aspects of skin samples exposed to electrical injury compared with thermal injury. METHODS: An observational case-control study was conducted at the Dr Stanislaw Sakiel Center for Burns Treatment in Siemianowice, Silesia, Poland. A scanning electron microscope was used to diagnose and illustrate the topography of skin samples from electrical and thermal burns and the morphologic effects on damaged versus undamaged skin surfaces. In particular, researchers attempted to detect spectroscopic and thermal changes at the molecular level, namely, specific biomarkers of tissue degeneration and their regeneration under the influence of the applied modifiers (antioxidants and orthosilicic acid solutions). RESULTS: Modification with L-ascorbic acid and hydrogel of orthosilicic acid caused an increase in the intensity of the amide I Raman peaks, whereas modification with sodium ascorbate and orthosilicic acid resulted in the separation of the band protein side chains (1,440-1,448 cm), which is a part of tissue regeneration. The best result was obtained when the skin was treated with 7% orthosilicic acid (limiting oxygen index, 26%). CONCLUSIONS: Antioxidant treatment may be advantageous in minimizing injury in patients with thermal burns but not always in electrical burns.
Assuntos
Antioxidantes/uso terapêutico , Queimaduras por Corrente Elétrica/tratamento farmacológico , Queimaduras por Corrente Elétrica/patologia , Dimetil Sulfóxido/uso terapêutico , Ácidos Láuricos/uso terapêutico , Ácido Silícico/uso terapêutico , Pele/lesões , Adulto , Biomarcadores , Biópsia , Queimaduras por Corrente Elétrica/diagnóstico por imagem , Queimaduras por Corrente Elétrica/mortalidade , Estudos de Casos e Controles , Humanos , Hidrogéis , Masculino , Microscopia Eletrônica de Transmissão por Filtração de Energia , Pessoa de Meia-Idade , Necrose/diagnóstico por imagem , Polônia , Pele/patologia , Estatísticas não Paramétricas , Cicatrização/efeitos dos fármacos , Adulto JovemRESUMO
Coconut oil (CO), the primary choice of cooking purposes in the south Asian countries, is rich in medium chain saturated fatty acids, especially lauric acid (50-52%). The oil has high medicinal use in Ayurvedic system and known to contain polyphenolic antioxidants. Studies have reported that CO improves insulin sensitivity and shows hypoglycemic effect. However, there is no information regarding its effect on chronic diabetic complications including retinopathy and nephropathy is available. The secondary diabetic complications are mediated by the activation of polyol pathway, where aldose reductase (AR) plays crucial role. In this study, in silico analysis has been used to screen the effect of CO as well as its constituents, MCFAs and phenolic compounds, for targeting the molecules in polyol pathway. The study revealed that lauric acid (LA) interacts with AR and DPP-IV of polyol pathway and inhibits the activity of these enzymes. Validation studies using animal models confirmed the inhibition of AR and SDH in wistar rats. Further, the LA dose dependently reduced the expression of AR in HCT-15 cells. Together, the study suggests the possible role of CO, particularly LA in reducing secondary diabetic complications.
Assuntos
Óleo de Coco/uso terapêutico , Nefropatias Diabéticas/dietoterapia , Retinopatia Diabética/dietoterapia , Ácidos Graxos/uso terapêutico , Aldeído Redutase/química , Aldeído Redutase/metabolismo , Animais , Antioxidantes/uso terapêutico , Óleo de Coco/química , Nefropatias Diabéticas/patologia , Retinopatia Diabética/patologia , Humanos , Ácidos Láuricos/química , Ácidos Láuricos/uso terapêutico , Ayurveda , Polímeros/química , Polifenóis/química , Polifenóis/uso terapêutico , RatosRESUMO
The effects of acute administration of lauric acid (LA), the most abundant medium-chain fatty acid of coconut oil, on blood pressure, heart rate and oxidative stress were investigated in spontaneously hypertensive rats (SHR). Intravenous doses of LA reduced blood pressure in a dose-dependent fashion (1, 3, 4, 8 and 10 mg/kg) in both SHR and Wistar Kyoto rats. LA (10-8 to 3 × 10-3 M) induced vasorelaxation in isolated superior mesenteric artery rings of SHR in the presence (n = 7) or absence (n = 8) of functional endothelium [maximum effect (ME) = 104 ± 3 versus 103 ± 4%]. After exposure to KCl (60 mM), LA also induced concentration-dependent vasorelaxation (n = 7) compared to that under Phe-induced contraction (ME = 113.5 + 5.1 versus 104.5 + 4.0%). Furthermore, LA-induced vasorelaxation in vessels contracted with S(-)-BayK8644 (200 nM), a L-type Ca2+ channel agonist (ME = 91.4 + 4.3 versus 104.5 + 4.0%, n = 7). Lastly, LA (10-3 M) reduced NADPH-dependent superoxide accumulation in the heart (18 ± 1 versus 25 ± 1 MLU/min/µg protein, n = 4, p < 0.05) and kidney (82 ± 3 versus 99 ± 4 MLU/min/µg protein, n = 4, p < 0.05). Our data show that LA reduces blood pressure in normotensive and hypertensive rats. In SHR, this effect might involve Ca+2 channels in the resistance vessels and by its capability of reducing oxidative stress in heart and kidneys.
Assuntos
Antioxidantes/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Ácidos Láuricos/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/administração & dosagem , Relação Dose-Resposta a Droga , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/metabolismo , Técnicas In Vitro , Injeções Intravenosas , Ácidos Láuricos/administração & dosagem , Artéria Mesentérica Superior/efeitos dos fármacos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Superóxidos/metabolismo , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacosRESUMO
Hypertension can be programmed in response to nutritional insults in early life. Maternal high-fructose (HF) intake induced programmed hypertension in adult male offspring, which is associated with renal programming and arachidonic acid metabolism pathway. We examined whether early treatment with a soluble epoxide hydrolase (SEH) inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA) or 15-Deoxy-Δ12,14-prostagandin J2 (15dPGJ2) can prevent HF-induced programmed hypertension. Pregnant Sprague Dawley rats received regular chow or chow supplemented with fructose (60% diet by weight) during the whole period of pregnancy and lactation. Four groups of male offspring were studied: control, HF, HF+AUDA and HF+15dPGJ2. In HF+AUDA group, mother rats received AUDA 25 mg/L in drinking water during lactation. In the HF+15dPGJ2 group, male offspring received 15dPGJ2 1.5 mg/kg body weight by subcutaneous injection once daily for 1 week after birth. Rats were sacrificed at 12 weeks of age. Maternal HF-induced programmed hypertension is associated with increased renal protein level of SEH and oxidative stress, which early AUDA therapy prevents. Comparison of AUDA and 15dPGJ2 treatments demonstrated that AUDA was more effective in preventing HF-induced programmed hypertension. AUDA therapy increases angiotensin converting enzyme-2 (ACE2) protein levels and PGE2 levels in adult offspring kidney exposed to maternal HF. 15dPGJ2 therapy increases plasma asymmetric dimethylarginine (ADMA) levels and decreases L-arginine-to-ADMA ratio. Better understanding of the impact of arachidonic acid pathway, especially inhibition of SEH, on renal programming may aid in developing reprogramming strategy to prevent programmed hypertension in children exposed to antenatal HF intake.
Assuntos
Adamantano/análogos & derivados , Anti-Hipertensivos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Epóxido Hidrolases/antagonistas & inibidores , Hipertensão/prevenção & controle , Rim/efeitos dos fármacos , Ácidos Láuricos/uso terapêutico , Prostaglandina D2/análogos & derivados , Adamantano/uso terapêutico , Enzima de Conversão de Angiotensina 2 , Animais , Anti-Hipertensivos/administração & dosagem , Biomarcadores/sangue , Biomarcadores/metabolismo , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Dieta da Carga de Carboidratos/efeitos adversos , Repressão Enzimática/efeitos dos fármacos , Epóxido Hidrolases/metabolismo , Feminino , Desenvolvimento Fetal/efeitos dos fármacos , Frutose/efeitos adversos , Hipertensão/etiologia , Hipertensão/metabolismo , Hipertensão/patologia , Injeções Subcutâneas , Oxirredutases Intramoleculares/antagonistas & inibidores , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/metabolismo , Rim/metabolismo , Rim/patologia , Lactação , Lipocalinas/antagonistas & inibidores , Lipocalinas/genética , Lipocalinas/metabolismo , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Gravidez , Prostaglandina D2/administração & dosagem , Prostaglandina D2/metabolismo , Prostaglandina D2/uso terapêutico , Ratos , Ratos Sprague-DawleyRESUMO
Multiple players are involved in the highly complex pathophysiologic responses after stroke. Therefore, therapeutic approaches that target multiple cellular elements of the neurovascular unit in the damage cascade hold considerable promise for the treatment of stroke. Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid to biologically active eicosanoids called epoxyeicosatrienoic acids (EETs), which are further converted by soluble epoxide hydrolase (sEH) to less bioactive diols. EETs have been shown to exert direct cytoprotective effects upon several individual components of the neurovascular unit under simulated ischemic conditions in vitro. However, the cellular mechanism underlying EET-mediated neuroprotective effects after ischemia remains to be clarified. In this study, we investigated the effects of 14,15-EET and 12-(3-adamantan-1-yl-ureido)dodecanoic acid (AUDA), a selective inhibitor of sEH, on multiple elements of neurovascular unit of the rat brain after middle cerebral artery occlusion-induced focal ischemia. The results showed that exogenous administration of 14,15-EET or AUDA could suppress astrogliosis and glial scar formation, inhibit microglia activation and inflammatory response, promote angiogenesis, attenuate neuronal apoptosis and infarct volume, and further promote the behavioral function recovery after focal ischemia. The results suggest that epoxyeicosanoid signaling is a promising multi-mechanism therapeutic target for the treatment of stroke.
Assuntos
Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Infarto da Artéria Cerebral Média/tratamento farmacológico , Neovascularização Fisiológica/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Transdução de Sinais , Ácido 8,11,14-Eicosatrienoico/farmacologia , Ácido 8,11,14-Eicosatrienoico/uso terapêutico , Adamantano/análogos & derivados , Adamantano/farmacologia , Adamantano/uso terapêutico , Animais , Apoptose , Epóxido Hidrolases/antagonistas & inibidores , Infarto da Artéria Cerebral Média/metabolismo , Ácidos Láuricos/farmacologia , Ácidos Láuricos/uso terapêutico , Masculino , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Ratos , Ratos Sprague-DawleyRESUMO
The total and positional fatty acid composition in camphor tree (Cinnamomum camphora) seed kernel oil (CKO) were analyzed, and for the first time, the effect of CKO on body fat deposition and blood lipids in rats was studied. The major fatty acids in CKO were determined to be decanoic acid (C10:0, 51.49%) and dodecanoic acid (C12:0, 40.08%), and uniformly distributed at Sn-1, 3, and Sn-2 positions in triglyceride (TG). Rats were randomly divided into control, CKO, lard, and soybean oil groups. At the end of the experiment, levels of blood lipids and the fats of abdomen in the rats were measured. The main organ were weighted and used for the histological examination. The results showed that body weight and fat deposition in CKO group were significantly lower than the lard and soybean groups. Moderate consumption of CKO was found to improve the levels of blood TG and low density lipoprotein cholesterol.
Assuntos
Gordura Abdominal/metabolismo , Peso Corporal/efeitos dos fármacos , Cinnamomum camphora/química , Ácidos Decanoicos/farmacologia , Ácidos Láuricos/farmacologia , Lipídeos/sangue , Óleos de Plantas/farmacologia , Animais , LDL-Colesterol/sangue , Ácidos Decanoicos/uso terapêutico , Gorduras na Dieta/farmacologia , Hiperlipidemias/metabolismo , Hiperlipidemias/prevenção & controle , Hipolipemiantes/farmacologia , Hipolipemiantes/uso terapêutico , Ácidos Láuricos/uso terapêutico , Masculino , Obesidade/metabolismo , Obesidade/prevenção & controle , Óleos de Plantas/química , Óleos de Plantas/uso terapêutico , Ratos Sprague-Dawley , Sementes/química , Óleo de Soja/farmacologia , Óleo de Soja/uso terapêutico , Árvores , Triglicerídeos/sangueRESUMO
In this study, we aimed to detect the effects of the soluble epoxide hydrolase (sEH) inhibitor 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA) on atherosclerotic diseases and to explore its mechanism. The atherosclerosis animal model was constructed by ApoE-/- mice. To determine the optimal therapeutic concentration of AUDA, different concentrations of AUDA were infused into ApoE-/- mice, with controls receiving infusions of normal saline alone. Mouse body weight and serum total cholesterol, triglyceride, LDL and HDL levels were measured. The western blotting (WB) method was used to detect the expression of TLR4 and NFKB in the aortic wall of the AUDA-treated and control mice. After the animals were sacrificed, we performed Oil Red O staining of the aortic sinus atherosclerotic plaque area followed by quantitative analysis of the aortic atherosclerotic plaque size and the percentage of lumen area in the two groups of mice. The expression levels of inflammatory cytokines, adhesion molecules and chemokines in the AUDA group were significantly decreased compared to the saline-treatment group (P < 0.05). The optimal AUDA concentration was found to be 0.35 ml/mg. AUDA significantly inhibited the expression of TLR4 and NFκB in ApoE-/- mouse aortas and reduced the aortic sinus plaque area of the ApoE-/- mouse group (P < 0.05). In conclusion, AUDA can regulate blood lipid balance, which may be one of the mechanisms for its protective effects on the cardiovascular system.
Assuntos
Adamantano/análogos & derivados , Aterosclerose/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Epóxido Hidrolases/antagonistas & inibidores , Ácidos Láuricos/uso terapêutico , Adamantano/uso terapêutico , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Citocinas/biossíntese , Técnicas In Vitro , Camundongos , Camundongos Knockout , NF-kappa B/metabolismo , Placa Aterosclerótica/tratamento farmacológico , Placa Aterosclerótica/metabolismo , Receptor 4 Toll-Like/metabolismoRESUMO
Soluble epoxide hydrolase (sEH) inhibition has been demonstrated to have beneficial effects on various diseases, such as hypertension, diabetes, and brain ischemia. However, whether sEH inhibition has therapeutic potential in Parkinson's disease is still unknown. In this paper, we found that sEH expression is increased in 1-methyl-4-phenyl-1,2,3,6-tetrahydro pyridine (MPTP)-treated mice, and sEH deficiency and inhibition significantly attenuated tyrosine hydroxylase (TH)-positive cell loss and improved rotarod performance. The substrate of sEH, 14,15-epoxyeicosatrienoic acid (14,15-EET), protected TH-positive cells and alleviated the rotarod performance deficits of wild-type mice but not sEH-knockout mice. Moreover, the 14,15-EET antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE) abolished the neuronal protective effects of sEH deficiency. In primary cultured cortical neurons, MPP(+) induced significant Akt inactivation in neurons from sEH wild-type mice, and this effect was not observed in neurons from knockout mice. Our data indicate that sEH deficiency and inhibition increased 14,15-EET in MPTP-treated mice, which activated the Akt-mediated protection of TH-positive neurons and behavioral functioning. We also found that sEH deficiency attenuated TH-positive cell loss in a paraquat-induced mouse model of Parkinson's. Our data suggest that sEH inhibition might be a powerful tool to protect dopaminergic neurons in Parkinson's disease.
Assuntos
Epóxido Hidrolases/antagonistas & inibidores , Epóxido Hidrolases/deficiência , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/enzimologia , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Ácido 8,11,14-Eicosatrienoico/farmacologia , Ácido 8,11,14-Eicosatrienoico/uso terapêutico , Adamantano/análogos & derivados , Adamantano/farmacologia , Adamantano/uso terapêutico , Animais , Comportamento Animal , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Epóxido Hidrolases/metabolismo , Ácidos Láuricos/farmacologia , Ácidos Láuricos/uso terapêutico , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Paraquat , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/patologia , Teste de Desempenho do Rota-Rod , Solubilidade , Substância Negra/efeitos dos fármacos , Substância Negra/enzimologia , Substância Negra/patologia , Tirosina 3-Mono-Oxigenase/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
AIMS/HYPOTHESES: Glucagon-like peptide-1 (GLP-1), an important mediator of postprandial glycaemia, could potentially be stimulated by delivering small quantities of nutrient to a long length of distal gut. We aimed to determine whether enteric-coated pellets, releasing small amounts of lauric acid throughout the ileum and colon, could reduce glycaemic responses to meals in type 2 diabetes, associated with stimulation of GLP-1. METHODS: Eligible patients, who had type 2 diabetes controlled by diet or metformin, were each studied on two occasions in a hospital setting. After an overnight fast, patients consumed 5 g active pellets (47% lauric acid by weight) or placebo with breakfast (T = 0 min) and lunch (T = 240 min), in a crossover design with order randomised by the hospital pharmacy and allocation concealed by numbered containers. Patients and investigators making measurements were blinded to the intervention. Blood was sampled frequently for blood glucose (the primary outcome) and hormone assays. RESULTS: Eight patients were randomised (four to receive either intervention first), and all completed the study without adverse effects. Blood glucose was lower after breakfast (T = 0-240 min, area under the curve (AUC) 2,075 ± 368 vs 2,216 ± 163 mmol/l × min) and lunch (T = 240-480 min, AUC 1,916 ± 115 vs 2,088 ± 151 mmol/l × min) (p = 0.02 for each) after active pellets than after placebo. Plasma GLP-1 concentrations were higher after breakfast (p = 0.08) and lunch (p = 0.04) for active pellets. While there were no differences in insulin or glucose-dependent insulinotropic polypeptide concentrations, glucagon concentrations were higher after breakfast and lunch (p = 0.002 for each) for active pellets. CONCLUSIONS/INTERPRETATION: Delivering small amounts of nutrient to the ileum and colon can stimulate substantial endogenous GLP-1 release and attenuate postprandial glycaemia. This novel approach has therapeutic potential in type 2 diabetes. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12612000600842. FUNDING: The study was funded by Meyer Nutriceuticals.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Hiperglicemia/complicações , Comprimidos com Revestimento Entérico/uso terapêutico , Área Sob a Curva , Glicemia/metabolismo , Colo/metabolismo , Estudos Cross-Over , Feminino , Glucagon/metabolismo , Humanos , Íleo/metabolismo , Insulina/metabolismo , Ácidos Láuricos/uso terapêutico , Masculino , Metformina/uso terapêutico , Pessoa de Meia-Idade , Fatores de TempoRESUMO
We assessed anti-C. albicans activities of the 4 fatty acids : caproic acid, caprylic acid, capric acid and lauric acid in vitro. All four inhibited not only the mycelial but also the yeast-form growth of Candida albicans. In particular, capric acid and caprylic acid inhibited Candida mycelia growth at very low concentrations. The effects of treatment of these two fatty acids on oral candidiasis were examined using a murine model. When 50 µl of capric acid (more than 48.8 µM) was administered three times into the oral cavity of Candida-infected mice, symptom scores of tongues of the mice were significantly improved. Histological studies of the capric acid-treated animals indicated that the fatty acid suppressed mycelial growth of the fungus on the tongue surface. These results suggest that all four fatty acids, and especially capric acid, have potential as substances supporting anti-Candida treatment.
Assuntos
Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candida albicans/efeitos dos fármacos , Candidíase Bucal/tratamento farmacológico , Caproatos/farmacologia , Caprilatos/farmacologia , Ácidos Decanoicos/farmacologia , Ácidos Láuricos/farmacologia , Animais , Caproatos/uso terapêutico , Caprilatos/uso terapêutico , Quimioterapia Adjuvante , Ácidos Decanoicos/uso terapêutico , Ácidos Láuricos/uso terapêutico , Masculino , Camundongos , Micélio/efeitos dos fármacosRESUMO
The strong bactericidal properties of lauric acid (C12:0), a middle chain-free fatty acid commonly found in natural products, have been shown in a number of studies. However, it has not been demonstrated whether lauric acid can be used for acne treatment as a natural antibiotic against Propionibacterium acnes (P. acnes), which promotes follicular inflammation (inflammatory acne). This study evaluated the antimicrobial property of lauric acid against P. acnes both in vitro and in vivo. Incubation of the skin bacteria P. acnes, Staphylococcus aureus (S. aureus), and Staphylococcus epidermidis (S. epidermidis) with lauric acid yielded minimal inhibitory concentration (MIC) values against the bacterial growth over 15 times lower than those of benzoyl peroxide (BPO). The lower MIC values of lauric acid indicate stronger antimicrobial properties than that of BPO. The detected values of half maximal effective concentration (EC(50)) of lauric acid on P. acnes, S. aureus, and S. epidermidis growth indicate that P. acnes is the most sensitive to lauric acid among these bacteria. In addition, lauric acid did not induce cytotoxicity to human sebocytes. Notably, both intradermal injection and epicutaneous application of lauric acid effectively decreased the number of P. acnes colonized with mouse ears, thereby relieving P. acnes-induced ear swelling and granulomatous inflammation. The obtained data highlight the potential of using lauric acid as an alternative treatment for antibiotic therapy of acne vulgaris.
Assuntos
Acne Vulgar/tratamento farmacológico , Anti-Infecciosos/farmacologia , Anti-Infecciosos/uso terapêutico , Ácidos Láuricos/farmacologia , Ácidos Láuricos/uso terapêutico , Propionibacterium acnes/efeitos dos fármacos , Animais , Peróxido de Benzoíla/farmacologia , Linhagem Celular , Fármacos Dermatológicos/farmacologia , Modelos Animais de Doenças , Orelha , Humanos , Camundongos , Camundongos Endogâmicos ICR , Glândulas Sebáceas/citologia , Glândulas Sebáceas/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/microbiologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus epidermidis/efeitos dos fármacosRESUMO
Hypertension and Type 2 diabetes are co-morbid diseases that lead to the development of nephropathy. sEH (soluble epoxide hydrolase) inhibitors are reported to provide protection from renal injury. We hypothesized that the sEH inhibitor AUDA [12-(3-adamantan-1-yl-ureido)-dodecanoic acid] protects the kidney from the development of nephropathy associated with hypertension and Type 2 diabetes. Hypertension was induced in spontaneously diabetic GK (Goto-Kakizaki) rats using AngII (angiotensin II) and a high-salt diet. Hypertensive GK rats were treated for 2 weeks with either AUDA or its vehicle added to drinking water. MAP (mean arterial pressure) increased from 118+/-2 mmHg to 182+/-20 and 187+/-6 mmHg for vehicle and AUDA-treated hypertensive GK rats respectively. AUDA treatment did not alter blood glucose. Hypertension in GK rats resulted in a 17-fold increase in urinary albumin excretion, which was decreased with AUDA treatment. Renal histological evaluation determined that AUDA treatment decreased glomerular and tubular damage. In addition, AUDA treatment attenuated macrophage infiltration and inhibited urinary excretion of MCP-1 (monocyte chemoattractant protein-1) and kidney cortex MCP-1 gene expression. Taken together, these results provide evidence that sEH inhibition with AUDA attenuates the progression of renal damage associated with hypertension and Type 2 diabetes.
Assuntos
Adamantano/análogos & derivados , Anti-Hipertensivos/uso terapêutico , Nefropatias Diabéticas/prevenção & controle , Epóxido Hidrolases/antagonistas & inibidores , Hipertensão/tratamento farmacológico , Ácidos Láuricos/uso terapêutico , Adamantano/uso terapêutico , Adamantano/urina , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/enzimologia , Nefropatias Diabéticas/enzimologia , Nefropatias Diabéticas/patologia , Progressão da Doença , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/uso terapêutico , Hipertensão/complicações , Hipertensão/enzimologia , Hipertensão/patologia , Insulina/sangue , Ácidos Láuricos/urina , Lipídeos/sangue , Masculino , NF-kappa B/metabolismo , Ratos , Ratos EndogâmicosRESUMO
In stroke-prone spontaneously hypertensive rats (SHRSP) end-organ damage is markedly accelerated by high-salt (HS) intake. Since epoxyeicosatrienoic acids (EETs) possess vasodepressor and natriuretic activities, we examined whether a soluble epoxide hydrolase (sEH) inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), to inhibit the metabolism of EETs, would protect against pathologic changes in SHRSP. Seven-week-old male SHRSP were treated as follows: normal salt (NS), NS + AUDA, HS and HS + AUDA. Systolic blood pressure (SBP) (205 +/- 4 v 187 +/- 7 mmHg) and proteinuria (3.7 +/- 0.2 v 2.6 +/- 0.2 mg/6 h), but not plasma EETs (11.0 +/- 0.9 v 9.7 +/- 1.1 ng/ml), were significantly increased at 9 weeks of age in HS v NS SHRSP. HS was associated with fibrinoid degeneration and hypertrophy of arterioles in the kidney and perivascular fibrosis and contraction band necrosis in the heart. AUDA ameliorated these early salt-dependent changes in saline-drinking SHRSP and increased plasma levels of EETs but did not affect water and electrolyte excretion. sEH inhibition may provide a therapeutic strategy for treating salt-sensitive hypertension and its sequelae.
Assuntos
Adamantano/análogos & derivados , Inibidores Enzimáticos/uso terapêutico , Epóxido Hidrolases/antagonistas & inibidores , Hipertensão/prevenção & controle , Ácidos Láuricos/uso terapêutico , Adamantano/uso terapêutico , Animais , Ácidos Eicosanoicos/metabolismo , Canais Epiteliais de Sódio/fisiologia , Masculino , Ratos , Ratos Endogâmicos SHR , Cloreto de Sódio/efeitos adversos , Acidente Vascular Cerebral/epidemiologiaRESUMO
Kozva Co Ltd, under license from Roche Holding AG, is developing K-111, an orally available peroxisome proliferator-activated receptor a ligand and insulin-potentiating agent, for the potential treatment of type 2 diabetes. Phase II clinical trials of K-111 are underway.