RESUMO
Elevated triglyceride levels are associated with an increased risk of cardiovascular events despite guideline-based statin treatment of low-density lipoprotein cholesterol. Peroxisome proliferator-activated receptor α (PPARα) agonists exert a significant triglyceride-lowering effect. However, combination therapy of PPARα agonists with statins poses an increased risk of rhabdomyolysis, which is rare but a major concern of the combination therapy. Pharmacokinetic interaction is suspected to be a contributing factor to the risk. To examine the potential for combination therapy with the selective PPARα modulator (SPPARMα) pemafibrate and statins, drug-drug interaction studies were conducted with open-label, randomized, 6-sequence, 3-period crossover designs for the combination of pemafibrate 0.2 mg twice daily and each of 6 statins once daily: pitavastatin 4 mg/day (n = 18), atorvastatin 20 mg/day (n = 18), rosuvastatin 20 mg/day (n = 29), pravastatin 20 mg/day (n = 18), simvastatin 20 mg/day (n = 20), and fluvastatin 60 mg/day (n = 19), involving healthy male volunteers. The pharmacokinetic parameters of pemafibrate and each of the statins were similar regardless of coadministration. There was neither an effect on the systemic exposure of pemafibrate nor a clinically important increase in the systemic exposure of any of the statins on the coadministration although the systemic exposure of simvastatin was reduced by about 15% and its open acid form by about 60%. The HMG-CoA reductase inhibitory activity in plasma samples from the simvastatin and pemafibrate combination group was about 70% of that in the simvastatin alone group. In conclusion, pemafibrate did not increase the systemic exposure of statins, and vice versa, in healthy male volunteers.
Assuntos
Benzoxazóis , Butiratos , Estudos Cross-Over , Interações Medicamentosas , Voluntários Saudáveis , Inibidores de Hidroximetilglutaril-CoA Redutases , Humanos , Masculino , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Adulto , Butiratos/farmacocinética , Butiratos/administração & dosagem , Benzoxazóis/farmacocinética , Benzoxazóis/administração & dosagem , Benzoxazóis/efeitos adversos , Benzoxazóis/farmacologia , Adulto Jovem , Pessoa de Meia-Idade , PPAR alfa/agonistas , PPAR alfa/metabolismoRESUMO
Short chain fatty acid (SCFAs), such as butyrate, have shown promising therapeutic potential due to their immunomodulatory effects, particularly in maintaining immune homeostasis. However, the clinical application of SCFAs is limited by the need for frequent and high oral dosages. Rheumatoid arthritis (RA) is characterized by aberrant activation of peripheral T cells and myeloid cells. In this study, we aimed to deliver butyrate directly to the lymphatics using a polymeric micelle-based butyrate prodrug to induce long-lasting immunomodulatory effects. Notably, negatively charged micelles (Neg-ButM) demonstrated superior efficacy in targeting the lymphatics following subcutaneous (s.c.) administration and were retained in the draining lymph nodes, spleen, and liver for over one month. In the collagen antibody-induced arthritis (CAIA) mouse model of RA, only two s.c. injections of Neg-ButM successfully prevented disease onset and promoted tolerogenic phenotypes in T cells and myeloid cells, both locally and systemically. These results underscore the potential of this strategy in managing inflammatory autoimmune diseases by directly modulating immune responses via lymphatic delivery.
Assuntos
Artrite Experimental , Artrite Reumatoide , Butiratos , Micelas , Pró-Fármacos , Animais , Artrite Experimental/imunologia , Artrite Experimental/tratamento farmacológico , Artrite Experimental/prevenção & controle , Butiratos/administração & dosagem , Butiratos/farmacologia , Butiratos/química , Pró-Fármacos/administração & dosagem , Pró-Fármacos/uso terapêutico , Artrite Reumatoide/imunologia , Artrite Reumatoide/tratamento farmacológico , Camundongos , Agentes de Imunomodulação/administração & dosagem , Agentes de Imunomodulação/farmacologia , Camundongos Endogâmicos DBA , Feminino , Masculino , Camundongos Endogâmicos C57BLRESUMO
Ligand-modified nanocarriers can promote oral or inhalative administration of macromolecular drugs across the intestinal or pulmonary mucosa. However, enhancing the unidirectional transport of the nanocarriers through "apical uptakeâintracellular transportâbasolateral exocytosis" route remains a hot topic and challenge in current research. Forskolin is a naturally occurring diterpenoid compound extracted from the roots of C. forskohlii. In our studies, we found that forskolin could increase the transcellular transport of butyrate-modified nanoparticles by 1.67-fold and 1.20-fold in Caco-2 intestinal epithelial cell models and Calu-3 lung epithelial cell models, respectively. Further mechanistic studies revealed that forskolin, on the one hand, promoted the cellular uptake of butyrate-modified nanoparticles by upregulating the expression of monocarboxylic acid transporter-1 (MCT-1) on the apical membrane. On the other hand, forskolin facilitated the binding of MCT-1 to caveolae, thereby mediating butyrate-modified nanoparticles hijacking caveolae to promote the basolateral exocytosis of butyrate-modified nanoparticles. Studies in normal mice model showed that forskolin could promote the transmucosal absorption of butyrate-modified nanoparticles by >2-fold, regardless of oral or inhalative administration. Using semaglutide as the model drug, both oral and inhalation delivery approaches demonstrated significant hypoglycemic effects in type 2 diabetes mice model, in which inhalative administration was more effective than oral administration. This study optimized the strategies aimed at enhancing the transmucosal absorption of ligand-modified nanocarriers in the intestinal or pulmonary mucosa.
Assuntos
Colforsina , Nanopartículas , Animais , Humanos , Colforsina/administração & dosagem , Administração Oral , Nanopartículas/administração & dosagem , Pulmão/metabolismo , Butiratos/administração & dosagem , Butiratos/farmacocinética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Células CACO-2 , Masculino , Simportadores/metabolismo , Camundongos , Administração por Inalação , Sistemas de Liberação de MedicamentosRESUMO
Butyrate-a metabolite produced by commensal bacteria-has been extensively studied for its immunomodulatory effects on immune cells, including regulatory T cells, macrophages and dendritic cells. However, the development of butyrate as a drug has been hindered by butyrate's poor oral bioavailability, owing to its rapid metabolism in the gut, its low potency (hence, necessitating high dosing), and its foul smell and taste. Here we report that the oral bioavailability of butyrate can be increased by esterifying it to serine, an amino acid transporter that aids the escape of the resulting odourless and tasteless prodrug (O-butyryl-L-serine, which we named SerBut) from the gut, enhancing its systemic uptake. In mice with collagen-antibody-induced arthritis (a model of rheumatoid arthritis) and with experimental autoimmune encephalomyelitis (a model of multiple sclerosis), we show that SerBut substantially ameliorated disease severity, modulated key immune cell populations systemically and in disease-associated tissues, and reduced inflammatory responses without compromising the global immune response to vaccination. SerBut may become a promising therapeutic for autoimmune and inflammatory diseases.
Assuntos
Artrite Experimental , Disponibilidade Biológica , Butiratos , Pró-Fármacos , Serina , Animais , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Pró-Fármacos/farmacocinética , Pró-Fármacos/química , Camundongos , Serina/metabolismo , Butiratos/farmacologia , Butiratos/uso terapêutico , Butiratos/química , Butiratos/administração & dosagem , Administração Oral , Artrite Experimental/tratamento farmacológico , Artrite Experimental/imunologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/imunologia , Camundongos Endogâmicos C57BL , Doenças Neuroinflamatórias/tratamento farmacológico , FemininoRESUMO
Although patients with nonalcoholic fatty liver disease have been reported to have cardiac dysfunction, and appropriate model has not been reported. We established a novel mouse model of diet-induced steatohepatitis-related cardiomyopathy and evaluated the effect of pemafibrate. C57Bl/6 male mice were fed a (1) chow diet (C), (2) high-fat, high-cholesterol, high-sucrose, bile acid diet (NASH diet; N), or (3) N with pemafibrate 0.1 mg/kg (NP) for 8 weeks. In the liver, macrophage infiltration and fibrosis in the liver was observed in the N group compared to the C group, suggesting steatohepatitis. Free cholesterol accumulated, and cholesterol crystals were observed. In the heart, free cholesterol similarly accumulated and concentric hypertrophy was observed. Ultrahigh magnetic field magnetic resonance imaging revealed that the left ventricular (LV) ejection fraction (EF) was attenuated and LV strain was focally impaired. RNA sequencing demonstrated that the NOD-like receptor and PI3 kinase-Akt pathways were enhanced. mRNA and protein expression of inflammasome-related genes, such as Caspase-1, NLRP3, and IL-1ß, were upregulated in both the liver and heart. In the NP compared to the N group, steatohepatitis, hepatic steatosis, and cardiac dysfunction were suppressed. Sequential administration of pemafibrate after the development of steatohepatitis-related cardiomyopathy recovered hepatic fibrosis and cardiac dysfunction.
Assuntos
Benzoxazóis/farmacologia , Butiratos/farmacologia , Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Inflamassomos/metabolismo , Fígado/metabolismo , Miocárdio/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Benzoxazóis/administração & dosagem , Butiratos/administração & dosagem , Cardiomiopatias/tratamento farmacológico , Dieta Hiperlipídica/efeitos adversos , Carboidratos da Dieta/efeitos adversos , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Inflamassomos/genética , Masculino , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológicoRESUMO
Short-chain fatty acids (SCFAs) play a pivotal role in maintaining intestinal homeostasis. We aimed to investigate the effects of SCFA supplementation on gut inflammation and microbiota composition in a murine colitis model. Mice were fed with sodium butyrate or a mixture of SCFAs in the drinking water for 2 weeks, followed by 2% dextran sulfate sodium (DSS) for 7 d. After euthanasia, mouse colons were extracted to examine histological findings. Flow cytometry of the mouse colon tissues was performed to assess T cell differentiation. Changes in gut microbiota were assessed by high-throughput sequencing of the mouse feces. There were no significant differences in weight change, colonic length, or histologic inflammation score between the DSS, butyrate, and SCFA mix groups. However, flow cytometry revealed that both the expression of CD4+Foxp3+ regulatory T cells and of IL-17-producing T cells were increased in the butyrate and SCFA mix groups. Microbial compositions of the butyrate and SCFA mix groups were significantly different from those of the control and DSS groups in principal coordinate analysis. Relative abundances of the phyla Verrucomicrobia and Proteobacteria, species Akkermansia muciniphila and Escherichia fergusonii were increased in the butyrate and SCFA mix groups. Genera Roseburia and Lactobacillus showed a negative correlation with the degree of colitis, whereas genera Escherichia and Mucispirillum showed a positive correlation. SCFA supplementation did not result in a significant reduction in colon inflammation, but it promoted both regulatory T cell and IL-17-producing T cell expression, and increased both protective and aggressive gut microbiota.
Assuntos
Butiratos/administração & dosagem , Suplementos Nutricionais , Ácidos Graxos Voláteis/administração & dosagem , Microbioma Gastrointestinal , Trato Gastrointestinal/microbiologia , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/patologia , Animais , Diferenciação Celular , Colite/imunologia , Colite/microbiologia , Colite/patologia , Colo/patologia , Modelos Animais de Doenças , Fezes/microbiologia , Feminino , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/patologia , Doenças Inflamatórias Intestinais/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/imunologiaRESUMO
BACKGROUND: Recent studies suggest that lipids, including free fatty acids (FFAs), are necessary for proper µ opioid receptor (MOR) binding and that activation of opioid receptors (ORs) improves intestinal inflammation. The objective of the study was to investigate a possible interaction between the ORs and FFA receptors (FFARs) ligands in the colitis. METHODS: The potential synergistic effect of ORs and FFARs ligands was evaluated using mouse model of acute colitis induced by dextran sulfate sodium (DSS, 4%). Compounds were injected intraperitoneally (i.p.) once or twice daily at the doses of 0.01 or 0.02 mg/kg body weight (BW) (DAMGO-an MOR agonist), 0.3 mg/kg BW (DPDPE-a δ OR (DOR) agonist) and 1 mg/kg BW (naloxone-a non-selective OR antagonist, GLPG 0974-a FFAR2 antagonist, GSK 137647-a FFAR4 agonist and AH 7614-a FFAR4 antagonist) for 4 days. RESULTS: Myeloperoxidase (MPO) activity was significantly decreased after DAMGO (0.02 mg/kg BW) and GSK 137647 (1 mg/kg BW) administration and co-administration as compared to DSS group. CONCLUSIONS: Treatment with ligands of ORs and FFARs may affect the immune cells in the inflammation; however, no significant influence on the severity of colitis and no synergistic effect were observed.
Assuntos
Colite/tratamento farmacológico , Colite/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Opioides/metabolismo , Compostos de Anilina/administração & dosagem , Animais , Butiratos/administração & dosagem , Colite/imunologia , Modelos Animais de Doenças , Sinergismo Farmacológico , Ala(2)-MePhe(4)-Gly(5)-Encefalina/administração & dosagem , D-Penicilina (2,5)-Encefalina/administração & dosagem , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Naloxona/administração & dosagem , Antagonistas de Entorpecentes/administração & dosagem , Peroxidase/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Opioides/agonistas , Receptores Opioides delta/agonistas , Receptores Opioides delta/metabolismo , Receptores Opioides mu/agonistas , Receptores Opioides mu/metabolismo , Sulfonamidas/administração & dosagem , Tiofenos/administração & dosagem , Xantenos/administração & dosagemRESUMO
Worldwide, â¼196 million are afflicted with endometriosis, a painful disease in which endometrial tissue implants and proliferates on abdominal peritoneal surfaces. Theories on the origin of endometriosis remained inconclusive. Whereas up to 90% of women experience retrograde menstruation, only 10% develop endometriosis, suggesting that factors that alter peritoneal environment might contribute to endometriosis. Herein, we report that whereas some gut bacteria promote endometriosis, others protect against endometriosis by fermenting fiber to produce short-chain fatty acids. Specifically, we found that altered gut microbiota drives endometriotic lesion growth and feces from mice with endometriosis contained less of short-chain fatty acid and n-butyrate than feces from mice without endometriosis. Treatment with n-butyrate reduced growth of both mouse endometriotic lesions and human endometriotic lesions in a pre-clinical mouse model. Mechanistic studies revealed that n-butyrate inhibited human endometriotic cell survival and lesion growth through G-protein-coupled receptors, histone deacetylases, and a GTPase activating protein, RAP1GAP. Our findings will enable future studies aimed at developing diagnostic tests, gut bacteria metabolites and treatment strategies, dietary supplements, n-butyrate analogs, or probiotics for endometriosis.
Assuntos
Bactérias/metabolismo , Butiratos/administração & dosagem , Butiratos/metabolismo , Endometriose/metabolismo , Endometriose/microbiologia , Microbioma Gastrointestinal , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Linhagem Celular Transformada , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Endometriose/tratamento farmacológico , Endometriose/patologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Fezes/química , Fezes/microbiologia , Feminino , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Complexo Shelterina/metabolismo , Transdução de Sinais/genética , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Proteínas de Ligação a Telômeros/metabolismo , TransfecçãoRESUMO
Short chain fatty acids readily crosses the gut-blood and blood-brain barrier and acts centrally to influence neuronal signaling. We hypothesized that butyrate, a short-chain fatty acid produced by bacterial fermentation, in the central nervous system may play a role in the regulation of intestinal functions. Colonic permeability and visceral sensation was evaluated in rats. Septic lethality was evaluated in a sepsis model induced by subcutaneous administration of both lipopolysaccharide and colchicine. Intracisternal butyrate dose-dependently improved colonic hyperpermeability and visceral nociception. In contrast, subcutaneous injection of butyrate failed to change it. Intracisternal orexin 1 receptor antagonist or surgical vagotomy blocked the central butyrate-induced improvement of colonic hyperpermeability. The improvement of intestinal hyperpermeability by central butyrate or intracisternal orexin-A was blocked by cannabinoid 1 or 2 receptor antagonist. Intracisternal butyrate significantly improved survival period in septic rats. These results suggest that butyrate acts in the central nervous system to improve gut permeability and visceral nociception through cannabinoid signaling. Endogenous orexin in the brain may mediate the reduction of intestinal hyperpermeability by central butyrate through the vagus nerve. We would suggest that improvement of leaky gut by central butyrate may induce visceral antinociception and protection from septic lethality.
Assuntos
Butiratos/farmacologia , Colo/metabolismo , Ácidos Graxos Voláteis/farmacologia , Nociceptividade/efeitos dos fármacos , Choque Séptico/mortalidade , Vísceras/fisiologia , Animais , Encéfalo/metabolismo , Butiratos/administração & dosagem , Colchicina/efeitos adversos , Modelos Animais de Doenças , Ácidos Graxos Voláteis/administração & dosagem , Lipopolissacarídeos/efeitos adversos , Masculino , Orexinas/metabolismo , Orexinas/fisiologia , Permeabilidade , Ratos Sprague-Dawley , Choque Séptico/induzido quimicamente , Choque Séptico/prevenção & controle , Vísceras/efeitos dos fármacosRESUMO
Parkinson's disease (PD), an age-related progressive neurodegenerative condition, is associated with loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), which results in motor deficits characterized by the following: akinesia, rigidity, resting tremor, and postural instability, as well as nonmotor symptoms such as emotional changes, particularly depression, cognitive impairment, gastrointestinal, and autonomic dysfunction. The most common treatment for PD is focused on dopamine (DA) replacement (e.g., levodopa = L-Dopa), which unfortunately losses its efficacy over months or years and can induce severe dyskinesia. Hence, more efficacious interventions without such adverse effects are urgently needed. In this review, following a general description of PD, potential novel therapeutic interventions for this devastating disease are examined. Specifically, the focus is on nicotine and nicotinic cholinergic system, as well as butyrate, a short chain fatty acid (SCFA), and fatty acid receptors.
Assuntos
Antiparkinsonianos/administração & dosagem , Encéfalo/efeitos dos fármacos , Dopaminérgicos/administração & dosagem , Neurônios Dopaminérgicos/efeitos dos fármacos , Doença de Parkinson/tratamento farmacológico , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Butiratos/administração & dosagem , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Quimioterapia Combinada , Humanos , Levodopa/administração & dosagem , Nicotina/administração & dosagem , Doença de Parkinson/metabolismo , Doença de Parkinson/patologiaRESUMO
Gut microbiome studies in multiple sclerosis (MS) patients are unravelling some consistent but modest patterns of gut dysbiosis. Among these, a significant decrease of Clostridia cluster IV and XIVa has been reported. In the present study, we investigated the therapeutic effect of a previously selected mixture of human gut-derived 17 Clostridia strains, which belong to Clostridia clusters IV, XIVa, and XVIII, on the clinical outcome of experimental autoimmune encephalomyelitis (EAE). The observed clinical improvement was related to lower demyelination and astrocyte reactivity as well as a tendency to lower microglia reactivity/infiltrating macrophages and axonal damage in the central nervous system (CNS), and to an enhanced immunoregulatory response of regulatory T cells in the periphery. Transcriptome studies also highlighted increased antiinflammatory responses related to interferon beta in the periphery and lower immune responses in the CNS. Since Clostridia-treated mice were found to present higher levels of the immunomodulatory short-chain fatty acid (SCFA) butyrate in the serum, we studied if this clinical effect could be reproduced by butyrate administration alone. Further EAE experiments proved its preventive but slight therapeutic impact on CNS autoimmunity. Thus, this smaller therapeutic effect highlighted that the Clostridia-induced clinical effect was not exclusively related to the SCFA and could not be reproduced by butyrate administration alone. Although it is still unknown if these Clostridia strains will have the same effect on MS patients, gut dysbiosis in MS patients could be partially rebalanced by these commensal bacteria and their immunoregulatory properties could have a beneficial effect on MS clinical course.
Assuntos
Butiratos/administração & dosagem , Clostridiaceae/imunologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/terapia , Microbioma Gastrointestinal/fisiologia , Animais , Disbiose/imunologia , Disbiose/patologia , Disbiose/terapia , Encefalomielite Autoimune Experimental/patologia , Ácidos Graxos Voláteis/administração & dosagem , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologiaRESUMO
This study was designed to determine adequate levels for sodium butyrate inclusion in pre-hatching and pre-starter feed in order to minimize the negative effects of post-hatch delayed placement on broiler chicks. Newly-hatched chicks were allotted in a completely randomized design, with five treatments, each comprising five replicates of ten birds each. Five dietetic levels of sodium butyrate (control, 0.050, 0.075, 0.100 and 0.200%) were used in the pre-starter feed offered to the chicks in the transporting box and during the pre-starter phase. Performance, yolk sac retraction, plasma glucose concentration, weight and histomorphometry of the small intestine were evaluated after 24 hours of feed access and at 7 days of age. A metabolic trial was performed when the chicks were seven to ten days of age. Supplementation of 0.1% sodium butyrate increased the development of broiler chicks' intestinal villi at seven days of age but was not able to improve performance in the pre-starter phase. Supplementation with sodium butyrate in a diet offered in the transportation box does not improve broiler performance in the pre-starter phase. Supplementation of up to 0.16% is recommended, in order to improve the metabolizability of the ether extract for broilers at seven days of age.(AU)
Objetivou-se, com este estudo, encontrar níveis adequados de inclusão de butirato de sódio em ração pós-eclosão e pré-inicial, buscando minimizar os efeitos negativos do jejum de pintos de corte. Os animais foram distribuídos em delineamento inteiramente ao acaso, com cinco tratamentos e cinco repetições de 10 aves cada. Foram utilizadas cinco suplementações de butirato de sódio (controle; 0,05; 0,075; 0,100 e 0,200%) na ração pré-inicial, fornecidas aos pintos na caixa de transporte e durante a fase pré-inicial. Após 24 horas de acesso ao alimento e aos sete dias de idade, foram avaliados desempenho, retração do saco vitelino, concentração de glicose plasmática, peso e histomorfometria do intestino delgado. De sete a 10 dias de idade, realizou-se ensaio de metabolizabilidade. A suplementação de 0,10% de butirato de sódio aumentou o desenvolvimento das vilosidades intestinais dos pintos de corte aos sete dias de idade, mas não foi capaz de melhorar o desempenho na fase pré-inicial. A suplementação com butirato de sódio em dieta oferecida na caixa de transporte não melhora o desempenho dos frangos na fase pré-inicial. Recomenda-se suplementação de até 0,16%, a fim de melhorar a metabolizabilidade do extrato etéreo para frangos de corte aos sete dias de idade.(AU)
Assuntos
Animais , Butiratos/administração & dosagem , Galinhas/crescimento & desenvolvimento , Ração Animal/análise , Saco Vitelino , Jejum/fisiologia , Ácidos OrgânicosRESUMO
BACKGROUND: Pemafibrate, a selective PPARα modulator, has the beneficial effects on serum triglycerides (TGs) and very low density lipoprotein (VLDL), especially in patients with diabetes mellitus or metabolic syndrome. However, its effect on the low density lipoprotein cholesterol (LDL-C) levels is still undefined. LDL-C increased in some cases together with a decrease in TGs, and the profile of lipids, especially LDL-C, during pemafibrate administration was evaluated. METHODS: Pemafibrate was administered to type 2 diabetes patients with hypertriglyceridemia. Fifty-one type 2 diabetes patients (mean age 62 ± 13 years) with a high rate of hypertension and no renal insufficiency were analyzed. Pemafibrate 0.2 mg (0.1 mg twice daily) was administered, and serum lipids were monitored every 4-8 weeks from 8 weeks before administration to 24 weeks after administration. LDL-C was measured by the direct method. Lipoprotein fractions were measured by electrophoresis (polyacrylamide gel, PAG), and LDL-migration index (LDL-MI) was calculated to estimate small, dense LDL. RESULTS: Pemafibrate reduced serum TGs, midband and VLDL fractions by PAG. Pemafibrate increased LDL-C levels from baseline by 5.3% (- 3.8-19.1, IQR). Patients were divided into 2 groups: LDL-C increase of > 5.3% (group I, n = 25) and < 5.3% (group NI, n = 26) after pemafibrate. Compared to group NI, group I had lower LDL-C (2.53 [1.96-3.26] vs. 3.36 [3.05-3.72] mmol/L, P = 0.0009), higher TGs (3.71 [2.62-6.69] vs. 3.25 [2.64-3.80] mmol/L), lower LDL by PAG (34.2 [14.5, SD] vs. 46.4% [6.5], P = 0.0011), higher VLDL by PAG (28.2 [10.8] vs. 22.0% [5.2], P = 0.0234), and higher LDL-MI (0.421 [0.391-0.450] vs. 0.354 [0.341-0.396], P < 0.0001) at baseline. Pemafibrate decreased LDL-MI in group I, and the differences between the groups disappeared. These results showed contradictory effects of pemafibrate on LDL-C levels, and these effects were dependent on the baseline levels of LDL-C and TGs. CONCLUSIONS: Pemafibrate significantly reduced TGs, VLDL, midband, and small, dense LDL, but increased LDL-C in diabetes patients with higher baseline TGs and lower baseline LDL-C. Even if pre-dose LDL-C remains in the normal range, pemafibrate improves LDL composition and may reduce cardiovascular disease risk.
Assuntos
Benzoxazóis/administração & dosagem , Butiratos/administração & dosagem , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipertrigliceridemia/tratamento farmacológico , Lipídeos/sangue , Idoso , LDL-Colesterol/sangue , VLDL-Colesterol/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Feminino , Humanos , Hipertrigliceridemia/sangue , Hipertrigliceridemia/complicações , Hipertrigliceridemia/patologia , Masculino , Pessoa de Meia-Idade , Triglicerídeos/sangueRESUMO
OBJECTIVE: The combination therapy of HMG-CoA reductase inhibitors (statins), which are anti-hyperlipidemic agents, and fibrates may increase the risk of hepatic dysfunction and myopathy, therefore, this combination required careful administration for patients. In the present study, the effects of combination therapy of pemafibrate, a novel fibrate, and statins, was evaluated. METHODS: Pemafibrate was administered for 6 months as an add-on to statin therapy in 27 type 2 diabetes patients with dyslipidemia already receiving statins for 6 months (combination group), and the efficacy and safety of the combination therapy in comparison with a pemafibrate monotherapy group was examined. RESULTS: In the combination group, a decrease in serum total cholesterol levels was observed after 6 months of pemafibrate treatment compared to baseline, along with an increase in HDL-cholesterol. While serum triglyceride level was reduced, HbA1c level was elevated in both the groups. Serum creatinine kinase level, which is an indicator of myopathy, was lowered in the combination group. In addition, a decrease in γ-glutamyl transpeptidase, a parameter of hepatic dysfunction, was observed in the combination group. CONCLUSION: The statin-pemafibrate combination therapy in type 2 diabetes patients with dyslipidemia improved lipid metabolism safely without increasing the risk of hepatic dysfunction and myopathy.
Assuntos
Benzoxazóis/administração & dosagem , Butiratos/administração & dosagem , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hipolipemiantes/administração & dosagem , Adulto , Idoso , HDL-Colesterol/sangue , Quimioterapia Combinada , Feminino , Humanos , Hiperlipidemias/sangue , Hiperlipidemias/tratamento farmacológico , Japão , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Triglicerídeos/sangueRESUMO
This study aims to evaluate the neuroprotective effect of sodium butyrate against the pentylenetetrazol (PTZ)-induced kindling epilepsy. Sodium butyrate (SB) (5, 10 and 20 mg/kg) and sodium valproate for 40 days and PTZ (37 mg/kg) injection every day were conducted for Kunming mice, to investigate seizure intensity and latency, oxidative stress parameters, mitochondrial structure and function, histopathology, and Keap1/Nrf2/HO-1 expressions. It is shown that seizure latency was effectively increased and the intensity of seizures decreased by treatment with sodium butyrate. It was also found to reverse the structural disruption of the mitochondria, reduce the ROS level and improve the levels of NAD + and ATP in the brains of epileptic mice. Furthermore, pretreatment with SB led to an increase in antioxidant enzyme activity (CAT, SOD and GSH-PX) in the brain as well as conferred a neuroprotective effect against neuron loss and apoptosis. The activation of Keap1/Nrf2/HO-1 signals was also identified, in which the antiepileptic effect of SB may be partially due to its anti-mitochondrial injury and neuroprotective activities. Accordingly, the results of a series of functional tests indicate a significant improvement of neurological function following SB treatment. In a mouse model of seizures, brain injury and neurological deficits can be attenuated by treatment with butyrate through the activation of Nrf2 pathway and the improvement of mitochondrial function.
Assuntos
Apoptose/efeitos dos fármacos , Butiratos/administração & dosagem , Epilepsia/metabolismo , Mitocôndrias/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Animais não Endogâmicos , Epilepsia/induzido quimicamente , Heme Oxigenase-1/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Mitocôndrias/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Neurônios/metabolismo , Pentilenotetrazol/administração & dosagemRESUMO
Many food, cosmetic and pharmaceutical industries have increased their interest in short-chain esters due to their flavor properties. From the industrial standpoint, enzyme reactions are the most economical strategy to reach green products with neither toxicity nor damage to human health. Isoamyl butyrate (pear flavor) was synthesized by isoamyl alcohol (a byproduct of alcohol production) and butyric acid with the use of the immobilized lipase Lipozyme TL IM and hexane as solvents. Reaction variables (temperature, butyric acid concentration, isoamyl alcohol:butyric acid molar ratio and enzyme concentration) were investigated in ester conversion (%), concentration (mol L-1) and productivity (mmol ester g-1 mixture . h), by applying a sequential strategy of the Fractional Factorial Design (FFD) and the Central Composite Rotatable Design (CCRD). High isoamyl butyrate conversion of 95.8% was achieved at 24 hours. At 3 hours, the highest isoamyl butyrate concentration (1.64 mol L-1) and productivity (0.19 mmol ester g-1 mixture . h) were obtained under different reaction conditions. Due to high specificity and selectivity of lipases, process parameters of this study and their interaction with the Lipozyme TL IM are fundamental to understand and optimize the system so as to achieve maximum yield to scale up. Results show that fusel oil may be recycled by the green chemistry process proposed by this study.
Assuntos
Ativação Enzimática , Butiratos/administração & dosagem , Butiratos/análise , Isoamilase , Otimização de Processos/análiseRESUMO
The gut microbiota and associated metabolites have emerged as potential modulators of pathophysiological changes in obesity and related metabolic disorders. Butyrate, a product of bacterial fermentation, has been shown to have beneficial effects in obesity and rodent models of diet-induced obesity. Here, we aimed to determine the beneficial effects of butyrate (as glycerol ester of butyrate monobutyrin, MB) supplementation on metabolic phenotype, intestinal permeability and inflammation, feeding behavior, and the gut microbiota in low-fat (LF)- and high-fat (HF)-fed mice. Two cohorts (separated by 2 weeks) of male C57BL/6J mice (n = 24 in each cohort, 6/group/cohort; 6 weeks old) were separated into four weight-matched groups and fed either a LF (10 % fat/kcal) or HF (45% fat/kcal) with or without supplementation of MB (LF/MB or HF/MB) at 0.25% (w/v) in drinking water for 6 weeks. Metabolic phenotypes (body weight and adiposity), intestinal inflammation, feeding behavior, and fecal microbiome and metabolites were measured. Despite identical genetic and experimental conditions, we found marked differences between cohorts in the response (body weight gain, adiposity, and intestinal permeability) to HF-diet and MB. Notably, the composition of the gut microbiota was significantly different between cohorts, characterized by lower species richness and differential abundance of a large number of taxa, including subtaxa from five phyla, including increased abundance of the genera Bacteroides, Proteobacteria, and Parasutterella in cohort 2 compared to cohort 1. These differences may have contributed to the differential response in intestinal permeability to the HF diet in cohort 2. MB supplementation had no significant effect on metabolic phenotype, but there was a trend to protect from HF-induced impairments in intestinal barrier function in cohort 1 and in sensitivity to cholecystokinin (CCK) in both cohorts. These data support the concept that microbiota composition may have a crucial effect on metabolic responses of a host to dietary interventions and highlight the importance of taking steps to ensure reproducibility in rodent studies.
Assuntos
Butiratos/administração & dosagem , Microbioma Gastrointestinal/efeitos dos fármacos , Inflamação/induzido quimicamente , Obesidade/induzido quimicamente , Ração Animal/análise , Animais , Peso Corporal , Dieta/veterinária , Dieta com Restrição de Gorduras , Dieta Hiperlipídica , Suplementos Nutricionais , Fezes/microbiologia , Inflamação/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológicoRESUMO
During weaning, methionine (Met) supply decreases as liquid feed intake is reduced and ruminal function is developing. During this transition, the calf starter should both promote ruminal development and provide adequate nutrients post-ruminally. In mature ruminants, rumen-protected Met (RPM) and the Met analogs, 2-hydroxy-4-(methylthio)-butanoic acid (HMTBa) and HMTBa isopropyl ester (HMBi), are used to increase Met supply, stimulate ruminal fermentation, or exert both effects, respectively. To evaluate the effects of these forms of Met on calf performance during development of ruminal function, 74 Holstein calves were raised until 91 d of age, in 2 enrollment periods. Calves were individually housed from birth and, at 14 d of age, balanced for sex and randomly assigned to receive a starter with no added Met (CTRL, n = 20) or one supplemented with RPM (Smartamine M, Adisseo USA Inc., Alpharetta, GA; n = 16), HMTBa (RumenSmart, Adisseo; n = 19), or HMBi (MetaSmart, Adisseo; n = 19). Milk replacer [28% crude protein (CP), 15% fat] was offered up to 1.6 kg of dry matter (DM)/d and fed 3 times daily. Weaning was facilitated from d 49 to 63. The 4 starters (25% CP, 2.5 Mcal of metabolizable energy/kg of DM) were offered ad libitum, and supplement inclusion was set to provide an additional 0.16% DM of Met equivalents, and equal amounts of HMTBa within the analogs. Body weight and stature were measured, and blood was collected and analyzed for plasma urea nitrogen, ß-hydroxybutyrate, and free AA on a weekly basis. Supplementation of RPM and HMBi increased free plasma Met, but no differences in growth or feed efficiency compared with calves fed the CTRL starter could be attributed to the additional Met supply alone. The addition of HMBi in the starter increased feed intake and body weight during the last weeks of the experiment. On the contrary, HMTBa failed to increase plasma Met and depressed intake and growth after weaning, likely because the level included in the diet was too high and intake was greater than previous studies, exacerbating the level of HMTBa ingested. No differences were observed in stature, feed efficiency, or non-AA plasma measurements among groups. These results demonstrate that RPM and HMBi are effective sources of metabolizable Met; however, Met was apparently not limiting calves fed the basal diet in this study. The increased feed intake observed with the inclusion of HMBi in the starter during the weaning and early postweaning period might be mediated by its metabolism in the rumen, and further research is needed to determine the mechanisms involved.
Assuntos
Bovinos/crescimento & desenvolvimento , Dieta/veterinária , Metionina/administração & dosagem , Rúmen/metabolismo , Ácido 3-Hidroxibutírico/sangue , Aminoácidos/sangue , Ração Animal/análise , Fenômenos Fisiológicos da Nutrição Animal , Animais , Nitrogênio da Ureia Sanguínea , Peso Corporal , Butiratos/administração & dosagem , Butiratos/metabolismo , Bovinos/sangue , Doenças dos Bovinos/metabolismo , Suplementos Nutricionais , Feminino , Fermentação/efeitos dos fármacos , Masculino , Metionina/metabolismo , Leite , DesmameRESUMO
The αvß6 integrin plays a key role in the activation of transforming growth factor-ß (TGFß), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule αvß6 RGD-mimetic, GSK3008348, and profiled it in a range of disease relevant pre-clinical systems. To understand the relationship between target engagement and inhibition of fibrosis, we measured pharmacodynamic and disease-related end points. Here, we report, GSK3008348 binds to αvß6 with high affinity in human IPF lung and reduces downstream pro-fibrotic TGFß signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the αvß6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages αvß6, induces prolonged inhibition of TGFß signaling and reduces lung collagen deposition and serum C3M, a marker of IPF disease progression. These studies highlight the potential of inhaled GSK3008348 as an anti-fibrotic therapy.
Assuntos
Butiratos/farmacologia , Fibrose Pulmonar Idiopática/tratamento farmacológico , Integrinas/antagonistas & inibidores , Naftiridinas/farmacologia , Pirazóis/farmacologia , Pirrolidinas/farmacologia , Administração por Inalação , Animais , Antígenos de Neoplasias/metabolismo , Bleomicina/toxicidade , Butiratos/administração & dosagem , Butiratos/metabolismo , Butiratos/farmacocinética , Colágeno/metabolismo , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Humanos , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/patologia , Integrinas/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Naftiridinas/administração & dosagem , Naftiridinas/metabolismo , Naftiridinas/farmacocinética , Pirazóis/administração & dosagem , Pirazóis/metabolismo , Pirazóis/farmacocinética , Pirrolidinas/administração & dosagem , Pirrolidinas/metabolismo , Pirrolidinas/farmacocinética , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Tomografia Computadorizada de Emissão de Fóton Único , Fator de Crescimento Transformador beta/metabolismo , Pesquisa Translacional BiomédicaRESUMO
Diabetic retinopathy (DR) is one of the leading causes of blindness globally. Retinal neuronal abnormalities occur in the early stage in DR. Therefore, maintaining retinal neuronal activity in DR may prevent vision loss. Previously, pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, was suggested as a promising drug in hypertriglyceridemia. However, the role of pemafibrate remains obscure in DR. Therefore, we aimed to unravel systemic and retinal changes by pemafibrate in diabetes. Adult mice were intraperitoneally injected with streptozotocin (STZ) to induce diabetes. After STZ injection, diet supplemented with pemafibrate was given to STZ-induced diabetic mice for 12 weeks. During the experiment period, body weight and blood glucose levels were examined. Electroretinography was performed to check the retinal neural function. After sacrifice, the retina, liver, and blood samples were subjected to molecular analyses. We found pemafibrate mildly improved blood glucose level as well as lipid metabolism, boosted liver function, increased serum fibroblast growth factor21 level, restored retinal functional deficits, and increased retinal synaptophysin protein expression in STZ-induced diabetic mice. Our present data suggest a promising pemafibrate therapy for the prevention of early DR by improving systemic metabolism and protecting retinal function.