RESUMEN
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.
Asunto(s)
Antiinfecciosos , Infecciones por Clostridium , Enteritis , Enfermedades de las Aves de Corral , Animales , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Antiinfecciosos/farmacología , Bacitracina/farmacología , Caspasas , Pollos , Ácido Cítrico/farmacología , Infecciones por Clostridium/tratamiento farmacológico , Infecciones por Clostridium/prevención & control , Infecciones por Clostridium/veterinaria , Clostridium perfringens , Citocinas , Enteritis/veterinaria , Células Epiteliales , Inflamación/veterinaria , Ácidos Láuricos/farmacología , Ácidos Láuricos/uso terapéutico , Aves de Corral , Enfermedades de las Aves de Corral/tratamiento farmacológico , Enfermedades de las Aves de Corral/prevención & control , ARN Mensajero , Especies Reactivas de Oxígeno/uso terapéutico , Timol/farmacologíaRESUMEN
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.
Asunto(s)
Antibacterianos/farmacología , Caries Dental/tratamiento farmacológico , Ácidos Láuricos/farmacología , Ocimum basilicum/química , Transferasas Alquil y Aril/antagonistas & inhibidores , Transferasas Alquil y Aril/metabolismo , Antibacterianos/aislamiento & purificación , Antibacterianos/uso terapéutico , Caries Dental/microbiología , Humanos , Ácidos Láuricos/aislamiento & purificación , Ácidos Láuricos/uso terapéutico , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Hojas de la Planta/química , Streptococcus mutans/efectos de los fármacos , Streptococcus mutans/enzimología , Streptococcus sanguis/efectos de los fármacos , Streptococcus sanguis/enzimologíaRESUMEN
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.
Asunto(s)
Pollos , Clostridium perfringens , Eimeria , Enterocolitis Necrotizante/veterinaria , Microbioma Gastrointestinal , Ácidos Láuricos/uso terapéutico , Enfermedades de las Aves de Corral/microbiología , Alimentación Animal , Animales , Infecciones por Clostridium/complicaciones , Infecciones por Clostridium/microbiología , Infecciones por Clostridium/veterinaria , Coccidiosis/complicaciones , Coccidiosis/microbiología , Coccidiosis/veterinaria , Dieta/veterinaria , Suplementos Dietéticos , Enterocolitis Necrotizante/microbiología , Enterocolitis Necrotizante/prevención & control , Femenino , Microbioma Gastrointestinal/efectos de los fármacos , Ácidos Láuricos/farmacología , Masculino , Enfermedades de las Aves de Corral/parasitología , Enfermedades de las Aves de Corral/prevención & controlRESUMEN
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.
Asunto(s)
Aceite de Coco/uso terapéutico , Nefropatías Diabéticas/dietoterapia , Retinopatía Diabética/dietoterapia , Ácidos Grasos/uso terapéutico , Aldehído Reductasa/química , Aldehído Reductasa/metabolismo , Animales , Antioxidantes/uso terapéutico , Aceite de Coco/química , Nefropatías Diabéticas/patología , Retinopatía Diabética/patología , Humanos , Ácidos Láuricos/química , Ácidos Láuricos/uso terapéutico , Medicina Ayurvédica , Polímeros/química , Polifenoles/química , Polifenoles/uso terapéutico , RatasRESUMEN
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.
Asunto(s)
Adamantano/análogos & derivados , Antihipertensivos/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Epóxido Hidrolasas/antagonistas & inhibidores , Hipertensión/prevención & control , Riñón/efectos de los fármacos , Ácidos Láuricos/uso terapéutico , Prostaglandina D2/análogos & derivados , Adamantano/uso terapéutico , Enzima Convertidora de Angiotensina 2 , Animales , Antihipertensivos/administración & dosificación , Biomarcadores/sangre , Biomarcadores/metabolismo , Ciclooxigenasa 2/química , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Dieta de Carga de Carbohidratos/efectos adversos , Represión Enzimática/efectos de los fármacos , Epóxido Hidrolasas/metabolismo , Femenino , Desarrollo Fetal/efectos de los fármacos , Fructosa/efectos adversos , Hipertensión/etiología , Hipertensión/metabolismo , Hipertensión/patología , Inyecciones Subcutáneas , Oxidorreductasas Intramoleculares/antagonistas & inhibidores , Oxidorreductasas Intramoleculares/genética , Oxidorreductasas Intramoleculares/metabolismo , Riñón/metabolismo , Riñón/patología , Lactancia , Lipocalinas/antagonistas & inhibidores , Lipocalinas/genética , Lipocalinas/metabolismo , Masculino , Fenómenos Fisiologicos Nutricionales Maternos , Peptidil-Dipeptidasa A/química , Peptidil-Dipeptidasa A/metabolismo , Embarazo , Prostaglandina D2/administración & dosificación , Prostaglandina D2/metabolismo , Prostaglandina D2/uso terapéutico , Ratas , Ratas Sprague-DawleyRESUMEN
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.
Asunto(s)
Grasa Abdominal/metabolismo , Peso Corporal/efectos de los fármacos , Cinnamomum camphora/química , Ácidos Decanoicos/farmacología , Ácidos Láuricos/farmacología , Lípidos/sangre , Aceites de Plantas/farmacología , Animales , LDL-Colesterol/sangre , Ácidos Decanoicos/uso terapéutico , Grasas de la Dieta/farmacología , Hiperlipidemias/metabolismo , Hiperlipidemias/prevención & control , Hipolipemiantes/farmacología , Hipolipemiantes/uso terapéutico , Ácidos Láuricos/uso terapéutico , Masculino , Obesidad/metabolismo , Obesidad/prevención & control , Aceites de Plantas/química , Aceites de Plantas/uso terapéutico , Ratas Sprague-Dawley , Semillas/química , Aceite de Soja/farmacología , Aceite de Soja/uso terapéutico , Árboles , Triglicéridos/sangreRESUMEN
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.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Péptido 1 Similar al Glucagón/metabolismo , Hiperglucemia/complicaciones , Comprimidos Recubiertos/uso terapéutico , Área Bajo la Curva , Glucemia/metabolismo , Colon/metabolismo , Estudios Cruzados , Femenino , Glucagón/metabolismo , Humanos , Íleon/metabolismo , Insulina/metabolismo , Ácidos Láuricos/uso terapéutico , Masculino , Metformina/uso terapéutico , Persona de Mediana Edad , Factores de TiempoRESUMEN
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.
Asunto(s)
Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Candida albicans/efectos de los fármacos , Candidiasis Bucal/tratamiento farmacológico , Caproatos/farmacología , Caprilatos/farmacología , Ácidos Decanoicos/farmacología , Ácidos Láuricos/farmacología , Animales , Caproatos/uso terapéutico , Caprilatos/uso terapéutico , Quimioterapia Adyuvante , Ácidos Decanoicos/uso terapéutico , Ácidos Láuricos/uso terapéutico , Masculino , Ratones , Micelio/efectos de los fármacosRESUMEN
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.
Asunto(s)
Adamantano/análogos & derivados , Antihipertensivos/uso terapéutico , Nefropatías Diabéticas/prevención & control , Epóxido Hidrolasas/antagonistas & inhibidores , Hipertensión/tratamiento farmacológico , Ácidos Láuricos/uso terapéutico , Adamantano/uso terapéutico , Adamantano/orina , Animales , Glucemia/metabolismo , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/enzimología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/enzimología , Nefropatías Diabéticas/enzimología , Nefropatías Diabéticas/patología , Progresión de la Enfermedad , Evaluación Preclínica de Medicamentos/métodos , Inhibidores Enzimáticos/uso terapéutico , Hipertensión/complicaciones , Hipertensión/enzimología , Hipertensión/patología , Insulina/sangre , Ácidos Láuricos/orina , Lípidos/sangre , Masculino , FN-kappa B/metabolismo , Ratas , Ratas EndogámicasRESUMEN
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.