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1.
J Microbiol ; 57(11): 1019-1024, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31659687

RESUMO

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


Assuntos
Antibacterianos/farmacologia , Enterococcus/efeitos dos fármacos , Propionatos/farmacologia , Acetatos/farmacologia , Butiratos/farmacologia , Clorexidina/análogos & derivados , Ciprofloxacino/farmacologia , Combinação de Medicamentos , Enterococcus/crescimento & desenvolvimento , Enterococcus faecalis/efeitos dos fármacos , Enterococcus faecalis/crescimento & desenvolvimento , Enterococcus faecium/efeitos dos fármacos , Enterococcus faecium/crescimento & desenvolvimento , Ácidos Graxos Voláteis/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Metronidazol/farmacologia , Testes de Sensibilidade Microbiana , Minociclina/farmacologia
2.
J Dairy Sci ; 102(12): 11051-11056, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31629511

RESUMO

The objective of this study was to evaluate the effects of butyrate supplementation on the dry matter intake (DMI), milk production, and blood metabolites of lactating dairy cows fed diets differing in starch content. Eight Holstein cows after peak lactation (58.6 ± 9.96 d in milk; mean ± SD) were blocked by parity and assigned to 1 of 2 Latin squares (4 × 4) balanced for carryover effects with a 2 × 2 factorial arrangement of treatments. Treatments differed by dietary starch content (20.6 vs. 27.5%) and butyrate supplementation (butyrate vs. control) with 21-d periods. Experimental diets contained 36 and 30% corn silage, 18 and 15% grass silage, and 46 and 55% concentrates, respectively, for low starch and high starch diets, on a dry matter (DM) basis. Butyrate was provided as Gustor BP70 WS (Norel S.A., Madrid, Spain), containing 70% sodium butyrate and 30% fatty acid mixture, at 2% of dietary DM (providing butyrate at 1.1% of dietary DM), and control premix contained 70% wheat bran and 30% fatty acid mixture. Interaction effects between dietary starch content and butyrate supplementation were not observed for primary response variables, and milk yield was not affected by treatment. Butyrate supplementation increased serum ß-hydroxybutyrate concentration compared with control (0.706 vs. 0.930 mM), but did not exceed 1.2 mM, a commonly accepted value for subclinical ketosis, and DMI was not affected. Cows fed butyrate had increased milk fat content (4.58 vs. 4.37%) and milk fat yield (1.51 vs. 1.42 kg/d), tended to have increased 4% fat-corrected milk yield (35.9 vs. 34.3 kg/d) and feed efficiency (1.56 vs. 1.50; 4% fat-corrected milk yield/DMI), and had decreased milk urea nitrogen (MUN) concentration (10.8 vs. 11.7 mg/dL) compared with control. Cows fed high starch diets tended to have increased DMI (23.3 vs. 22.5 kg/d), increased milk protein yield (1.13 vs. 1.05 kg/d), and decreased MUN concentration (10.3 vs. 12.2 mg/dL). Inclusion of butyrate at 1.1% of dietary DM increased milk fat production and decreased MUN concentration without affecting DMI or increasing the risk of subclinical ketosis, regardless of dietary starch content.


Assuntos
Ração Animal , Butiratos/farmacologia , Suplementos Nutricionais , Amido/farmacologia , Ração Animal/análise , Animais , Bovinos , Indústria de Laticínios , Dieta/veterinária , Fibras na Dieta , Ácidos Graxos/metabolismo , Feminino , Lactação/fisiologia , Leite , Gravidez , Silagem , Espanha , Amido/administração & dosagem , Zea mays
3.
J Neuroinflammation ; 16(1): 165, 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31399117

RESUMO

BACKGROUND: The association of gut microbiota and diseases of the central nervous system (CNS), including multiple sclerosis (MS), has attracted much attention. Although a previous analysis of MS gut microbiota revealed a reduction in species producing short-chain fatty acids (SCFAs), the influence of these metabolites on demyelination and remyelination, the critical factors of MS pathogenesis, remains unclear. METHODS: To investigate the relationship between demyelination and gut microbiota, we administered a mixture of non-absorbing antibiotics or SCFAs to mice with cuprizone-induced demyelination and evaluated demyelination and the accumulation of microglia. To analyze the direct effect of SCFAs on demyelination or remyelination, we induced demyelination in an organotypic cerebellar slice culture using lysolecithin and analyzed the demyelination and maturation of oligodendrocyte precursor cells with or without SCFA treatment. RESULTS: The oral administration of antibiotics significantly enhanced cuprizone-induced demyelination. The oral administration of butyrate significantly ameliorated demyelination, even though the accumulation of microglia into demyelinated lesions was not affected. Furthermore, we showed that butyrate treatment significantly suppressed lysolecithin-induced demyelination and enhanced remyelination in an organotypic slice culture in the presence or absence of microglia, suggesting that butyrate may affect oligodendrocytes directly. Butyrate treatment facilitated the differentiation of immature oligodendrocytes. CONCLUSIONS: We revealed that treatment with butyrate suppressed demyelination and enhanced remyelination in an organotypic slice culture in association with facilitating oligodendrocyte differentiation. Our findings shed light on a novel mechanism of interaction between the metabolites of gut microbiota and the CNS and may provide a strategy to control demyelination and remyelination in MS.


Assuntos
Butiratos/uso terapêutico , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/prevenção & controle , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/metabolismo , Remielinização/efeitos dos fármacos , Animais , Antibacterianos/toxicidade , Butiratos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Cuprizona/toxicidade , Doenças Desmielinizantes/induzido quimicamente , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Técnicas de Cultura de Órgãos , Remielinização/fisiologia
4.
BMB Rep ; 52(8): 508-513, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31383251

RESUMO

In this study, the anti-inflammatory effects of α-lipoic acid (LA) and decursinol (Dec) hybrid compound LA-Dec were evaluated and compared with its prodrugs, LA and Dec. LA-Dec dose-dependently inhibited lipopolysaccharide (LPS)-induced nitric oxide (NO) generation in BV2 mouse microglial cells. On the other hand, no or mild inhibitory effect was shown by the Dec and LA, respectively. LA-Dec demonstrated dose-dependent protection from activation-induced cell death in BV2 cells. LA-Dec, but not LA or Dec individually, inhibited LPS-induced increased expressions of induced NO synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins in a dosedependent manner in both BV2 and mouse macrophage, RAW264.7 cells. Furthermore, LA-Dec inhibited LPS-induced expressions of iNOS, COX-2, interleukin-6, tumor necrosis factor-α, and interleukin-1ß mRNA in BV2 cells, whereas the same concentration of LA or Dec was ineffective. Signaling studies demonstrated that LA-Dec inhibited LPS-activated signal transducer and activator of transcription 3 and protein kinase B activation, but not nuclear factor-kappa B or mitogen-activated protein kinase signaling. The data implicate LA-Dec hybrid compound as a potential therapeutic agent for inflammatory diseases of the peripheral and central nervous systems. [BMB Reports 2019; 52(8): 508-513].


Assuntos
Benzopiranos/farmacologia , Butiratos/farmacologia , Mediadores da Inflamação/farmacologia , Inflamação/tratamento farmacológico , Lipopolissacarídeos/antagonistas & inibidores , Ácido Tióctico/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Nitritos/análise , Células RAW 264.7 , Relação Estrutura-Atividade
5.
Anticancer Res ; 39(7): 3795-3801, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262906

RESUMO

BACKGROUND/AIM: Butyric acid, a short chain fatty acid, plays an important role in the prevention of colon cancer. The aim of this study was to analyze the growth inhibitory and apoptotic effect of butyric acid derivatives in colorectal cancer cells. MATERIALS AND METHODS: Human colorectal carcinoma HCT116 cells, were treated with the IC50 concentration of sodium butyrate, indole-3-butyric acid, tributyrin and 2-amino-n-butyric acid. Comet assay, caspase-3 assay and cell-cycle analysis were used to analyze apoptosis. RESULTS: Tributyrin and indole-3-butyric acid showed the least IC50 values at 24 h incubation. Butyric acid derivatives significantly activated caspase-3 activity compared with the control. Additionally, indole-3-butyric acid and tributyrin caused G0/G1 and G2/M phase arrest. CONCLUSION: Butyric acid derivatives effectively induced apoptosis in HCT116 cells.


Assuntos
Antineoplásicos/farmacologia , Butiratos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Dano ao DNA , Células HCT116 , Humanos
6.
Food Chem Toxicol ; 132: 110699, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31351099

RESUMO

Decursinol angelate (DA) is a pyranocoumarin purified from the roots of Angelica gigas. Here, we synthesized DA and determined its anti-inflammatory potential on TPA-induced mice ear inflammation. First, we evaluated the non-toxic behaviour of DA on HaCaT cells. Additionally, we observed the free radical scavenging potential of DA at 60 µM to be 50%. This finding was further supported by nitric oxide assay, malondialdehyde assay, H2DCFDA staining and western blotting analysis of antioxidant enzymes. DA also suppressed the activation and polarization of macrophage phagocytic activity on RAW 264.7 cells. We further evaluated the expression of ICAM-1, MCP-1, MIP-2 and MIP-1ß on in-vivo model system. Consequently, DA significantly reduced the production of NF-κB and COX-2 induced proinflammatory cytokine levels on TPA induced ear edema. Inhibition of MAPK and transcriptional factor NF-κB was also validated by western blotting analysis of p-ERK, p-p38, IKKα, IKKγ, IκBα, NF-κB-p65. Immunohistochemistry and immunofluorescence staining of NFκB-p65, TNF-α and IL-1ß were also performed to support the findings. Conclusively, these results suggest that topical administration of DA significantly inhibited the expression of pro-inflammatory cytokines by blocking the canonical NF-κB and MAPK pathway. Therefore, we suggest DA as a potent therapeutic compound against skin inflammation related diseases.


Assuntos
Benzopiranos/farmacologia , Butiratos/farmacologia , Citocinas/biossíntese , Mediadores da Inflamação/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Acetato de Tetradecanoilforbol/farmacologia , Animais , Antioxidantes/farmacologia , Linhagem Celular , Orelha , Humanos , Ativação de Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Células RAW 264.7 , Pele/efeitos dos fármacos , Pele/metabolismo
7.
J Dairy Sci ; 102(10): 8874-8882, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31351719

RESUMO

The objectives of this study were to determine the effects of the weaning transition and supplemental rumen-protected butyrate on subacute ruminal acidosis, feed intake, and growth parameters. Holstein bull calves (n = 36; age = 10.7 ± 4.1 d; ± standard deviation) were assigned to 1 of 4 treatment groups: 2 preweaning groups, animals fed milk replacer only (PRE-M) and those fed milk replacer, calf starter, and hay (PRE-S); and 2 postweaning groups, animals fed milk replacer, calf starter, and hay without supplemental rumen-protected butyrate (POST-S) or with supplemental rumen-protected butyrate at a rate of 1% wt/wt during the 2-wk weaning transition (POST-B). Milk replacer was provided at 1,200 g/d; starter, water, and hay were provided ad libitum. Weaning took place over 14 d by reducing milk replacer provision to 900 g/d in wk 7, 600 g/d in wk 8, and 0 g/d in wk 9. Rumen pH was measured continuously for 7 d during wk 6 for PRE-S and PRE-M and during wk 9 for POST-S and POST-B. After rumen pH was measured for 7 d, calves were euthanized, and rumen fluid was sampled and analyzed for volatile fatty acid (VFA) profile. Individual feed intake was recorded daily, whereas, weekly, body weights were recorded, and blood samples were collected. Compared with PRE-M, PRE-S calves tended to have a greater total VFA concentration (35.60 ± 11.4 vs. 11.90 ± 11.8 mM) but mean rumen pH was unaffected (6.25 ± 0.22 vs. 6.17 ± 0.21, respectively). Between PRE-S (wk 6) and POST-S (wk 9), calf starter intake increased (250 ± 219 vs. 2,239 ± 219 g/d), total VFA concentrations increased (35.6 ± 11.4 vs. 154.4 ± 11.8 mM), but mean rumen pH was unaffected (6.25 ± 0.22 vs. 6.40 ± 0.22, respectively). Compared with POST-S, POST-B calves had greater starter intake in wk 7, 8, and 9, but POST-B tended to have lower total VFA concentration (131.0 ± 11.8 vs. 154.4 ± 11.8 mM) and lower mean ruminal pH (5.83 ± 0.21 vs. 6.40 ± 0.22). In conclusion, the weaning transition does not appear to affect rumen pH and VFA profile, but supplementing rumen-protected butyrate during the weaning transition increased starter intake and average daily gain. Further, these data suggest that the ability of the rumen to manage rumen pH changes fundamentally postweaning. Why weaned calves with lower rumen pH can achieve higher calf starter intakes is unclear; these data suggest the effect of rumen pH on feed intake differs between calves and cows.


Assuntos
Ração Animal , Butiratos/farmacologia , Dieta/veterinária , Rúmen/efeitos dos fármacos , Desmame , Ração Animal/análise , Animais , Peso Corporal , Bovinos , Ácidos Graxos Voláteis/metabolismo , Fermentação , Masculino , Leite , Rúmen/metabolismo
8.
Int J Mol Sci ; 20(12)2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31197106

RESUMO

Vascular remodeling is a characteristic feature of cardiovascular diseases. Altered cellular processes of vascular smooth muscle cells (VSMCs) is a crucial component in vascular remodeling. Histone deacetylase inhibitor (HDACI), butyrate, arrests VSMC proliferation and promotes cell growth. The objective of the study is to determine the mechanism of butyrate-induced VSMC growth. Using proliferating VSMCs exposed to 5 mM butyrate, immunoblotting studies are performed to determine whether PI3K/Akt pathway that regulates different cellular effects is a target of butyrate-induced VSMC growth. Butyrate inhibits phosphorylation-dependent activation of PI3K, PDK1, and Akt, eliciting differential effects on downstream targets of Akt. Along with previously reported Ser9 phosphorylation-mediated GSK3 inactivation leading to stability, increased expression and accumulation of cyclin D1, and epigenetic histone modifications, inactivation of Akt by butyrate results in: transcriptional activation of FOXO1 and FOXO3 promoting G1 arrest through p21Cip1/Waf1 and p15INK4B upregulation; inactivation of mTOR inhibiting activation of its targets p70S6K and 4E-BP1 impeding protein synthesis; inhibition of caspase 3 cleavage and downregulation of PARP preventing apoptosis. Our findings imply butyrate abrogates Akt activation, causing differential effects on Akt targets promoting convergence of cross-talk between their complimentary actions leading to VSMC growth by arresting proliferation and inhibiting apoptosis through its effect on dual targets, HDAC activity and PI3K/Akt pathway network.


Assuntos
Butiratos/farmacologia , Histona Desacetilases/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais , Animais , Apoptose , Proliferação de Células , Células Cultivadas , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos
9.
Curr Obes Rep ; 8(3): 317-332, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31175629

RESUMO

PURPOSE: In this review, we summarize current evidence on the gut microbiome and microbial metabolites in relation to obesity and obesity-associated metabolic disorders. Special emphasis is given on mechanisms interconnecting gut microbiome and microbial metabolites with metabolic disorders as well as on potential preventive and therapeutic perspectives with a "bench to bedside" approach. RECENT FINDINGS: Recent data have highlighted the role of gut dysbiosis in the etiology and pathogenesis of metabolic disorders, including obesity, metabolic syndrome, type 2 diabetes mellitus, and non-alcoholic fatty liver disease. Overall, most studies have demonstrated a reduction in gut microbiome diversity and richness in obese subjects, but there is still much debate on the exact microbial signature of a healthy or an obese gut microbiome. Despite the controversial role of an altered gut microbiome as a cause or consequence of obesity in human studies, numerous animal studies and certain human studies suggest beneficial metabolic effects of certain microbial intestinal metabolites, such as butyrate, that could be used in the prevention and treatment of obesity and its comorbidities. More randomized controlled trials and larger prospective studies including well-defined cohorts as well as a multi-omics approach are warranted to better identify the associations between the gut microbiome, microbial metabolites, and obesity and its metabolic complications.


Assuntos
Microbioma Gastrointestinal/fisiologia , Doenças Metabólicas/complicações , Metaboloma/fisiologia , Obesidade/complicações , Animais , Butiratos/metabolismo , Butiratos/farmacologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/prevenção & controle , Disbiose/complicações , Humanos , Intestinos/microbiologia , Doenças Metabólicas/metabolismo , Doenças Metabólicas/prevenção & controle , Doenças Metabólicas/terapia , Síndrome Metabólica/complicações , Hepatopatia Gordurosa não Alcoólica/complicações , Obesidade/metabolismo , Obesidade/prevenção & controle , Obesidade/terapia , Polissacarídeos/metabolismo , Prebióticos , Simbióticos
10.
Neurobiol Dis ; 127: 362-373, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30928643

RESUMO

The late-infantile Batten disease or late-infantile neuronal ceroid lipofuscinosis (LINCL) is an autosomal recessive lysosomal storage disorder caused by mutations in the Cln2 gene leading to deficiency of lysosomal enzyme tripeptidyl peptidase 1 (TPP1). At present, available options for this fatal disorder are enzyme replacement therapy and gene therapy, which are extensively invasive and expensive. Our study demonstrates that 3-hydroxy-(2,2)-dimethyl butyrate (HDMB), a brain endogenous molecule, is capable of stimulating TPP1 expression and activity in mouse primary astrocytes and a neuronal cell line. HDMB activated peroxisome proliferator-activated receptor-α (PPARα), which, by forming heterodimer with Retinoid X receptor-α (RXRα), transcriptionally upregulated the Cln2 gene. Moreover, by using primary astrocytes from wild type, PPARα-/- and PPARß-/- mice, we demonstrated that HDMB specifically required PPARα for inducing TPP1 expression. Finally, oral administration of HDMB to Cln2 heterozygous (Cln2+/-) mice led to a marked upregulation of TPP1 expression in the motor cortex and striatum in a PPARα-dependent fashion. Our study suggests that HDMB, a brain endogenous ligand of PPARα, might have therapeutic importance for LINCL treatment.


Assuntos
Aminopeptidases/metabolismo , Astrócitos/efeitos dos fármacos , Butiratos/farmacologia , Dipeptidil Peptidases e Tripeptidil Peptidases/metabolismo , Neurônios/efeitos dos fármacos , PPAR alfa/metabolismo , Serina Proteases/metabolismo , Aminopeptidases/genética , Animais , Astrócitos/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Butiratos/uso terapêutico , Linhagem Celular , Dipeptidil Peptidases e Tripeptidil Peptidases/genética , Modelos Animais de Doenças , Camundongos , Camundongos Knockout , Lipofuscinoses Ceroides Neuronais/tratamento farmacológico , Lipofuscinoses Ceroides Neuronais/genética , Lipofuscinoses Ceroides Neuronais/metabolismo , Neurônios/metabolismo , Serina Proteases/genética , Regulação para Cima
11.
Biomed Res Int ; 2019: 7084734, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30941370

RESUMO

Butyrate produced by the intestinal microbiota is essential for proper functioning of the intestinal immune system. Total dependence on parenteral nutrition (PN) is associated with numerous adverse effects, including severe microbial dysbiosis and loss of important butyrate producers. We hypothesised that a lack of butyrate produced by the gut microbiota may be compensated by its supplementation in PN mixtures. We tested whether i.v. butyrate administration would (a) positively modulate intestinal defence mechanisms and (b) counteract PN-induced dysbiosis. Male Wistar rats were randomised to chow, PN, and PN supplemented with 9 mM butyrate (PN+But) for 12 days. Antimicrobial peptides, mucins, tight junction proteins, and cytokine expression were assessed by RT-qPCR. T-cell subpopulations in mesenteric lymph nodes (MLN) were analysed by flow cytometry. Microbiota composition was assessed in caecum content. Butyrate supplementation resulted in increased expression of tight junction proteins (ZO-1, claudin-7, E-cadherin), antimicrobial peptides (Defa 8, Rd5, RegIIIγ), and lysozyme in the ileal mucosa. Butyrate partially alleviated PN-induced intestinal barrier impairment and normalised IL-4, IL-10, and IgA mRNA expression. PN administration was associated with an increase in Tregs in MLN, which was normalised by butyrate. Butyrate increased the total number of CD4+ and decreased a relative amount of CD8+ memory T cells in MLN. Lack of enteral nutrition and PN administration led to a shift in caecal microbiota composition. Butyrate did not reverse the altered expression of most taxa but did influence the abundance of some potentially beneficial/pathogenic genera, which might contribute to its overall beneficial effect.


Assuntos
Butiratos/farmacologia , Suplementos Nutricionais , Microbioma Gastrointestinal , Intestinos/patologia , Nutrição Parenteral , Animais , Biodiversidade , Colo/efeitos dos fármacos , Colo/patologia , Microbioma Gastrointestinal/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Íleo/efeitos dos fármacos , Íleo/patologia , Intestino Delgado/efeitos dos fármacos , Linfonodos/efeitos dos fármacos , Linfonodos/metabolismo , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Masculino , Modelos Animais , Mucinas/biossíntese , Celulas de Paneth/efeitos dos fármacos , Celulas de Paneth/metabolismo , Peptídeos/genética , Peptídeos/metabolismo , Permeabilidade , Fenótipo , Filogenia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Wistar , Proteínas de Junções Íntimas/metabolismo
12.
Drug Metab Dispos ; 47(6): 556-566, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30923035

RESUMO

Generally, diabetes remarkably alters the expression and function of intestinal drug transporters. Nateglinide and bumetanide are substrates of monocarboxylate transporter 6 (MCT6). We investigated whether diabetes down-regulated the function and expression of intestinal MCT6 and the possible mechanism in diabetic rats induced by a combination of high-fat diet and low-dose streptozocin. Our results indicated that diabetes significantly decreased the oral plasma exposure of nateglinide. The plasma peak concentration and area under curve in diabetic rats were 16.9% and 28.2% of control rats, respectively. Diabetes significantly decreased the protein and mRNA expressions of intestinal MCT6 and oligopeptide transporter 1 (PEPT1) but up-regulated peroxisome proliferator-activated receptor γ (PPARγ) protein level. Single-pass intestinal perfusion demonstrated that diabetes prominently decreased the absorption of nateglinide and bumetanide. The MCT6 inhibitor bumetanide, but not PEPT1 inhibitor glycylsarcosine, significantly inhibited intestinal absorption of nateglinide in rats. Coadministration with bumetanide remarkably decreased the oral plasma exposure of nateglinide in rats. High concentrations of butyrate were detected in the intestine of diabetic rats. In Caco-2 cells (a human colorectal adenocarcinoma cell line), bumetanide and MCT6 knockdown remarkably inhibited the uptake of nateglinide. Butyrate down-regulated the function and expression of MCT6 in a concentration-dependent manner but increased PPARγ expression. The decreased expressions of MCT6 by PPARγ agonist troglitazone or butyrate were reversed by both PPARγ knockdown and PPARγ antagonist 2-chloro-5-nitro-N-phenylbenzamide (GW9662). Four weeks of butyrate treatment significantly decreased the oral plasma concentrations of nateglinide in rats, accompanied by significantly higher intestinal PPARγ and lower MCT6 protein levels. In conclusion, diabetes impaired the expression and function of intestinal MCT6 partly via butyrate-mediated PPARγ activation, decreasing the oral plasma exposure of nateglinide.


Assuntos
Transporte Biológico/efeitos dos fármacos , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Dieta Hiperlipídica/efeitos adversos , Transportadores de Ácidos Monocarboxílicos/metabolismo , PPAR gama/metabolismo , Estreptozocina/administração & dosagem , Animais , Butiratos/farmacologia , Células CACO-2 , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Humanos , Absorção Intestinal/efeitos dos fármacos , Masculino , Nateglinida/farmacologia , Transportador 1 de Peptídeos/metabolismo , Ratos , Ratos Sprague-Dawley
13.
Dis Model Mech ; 12(4)2019 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-30890583

RESUMO

Acute kidney injury (AKI) is a serious disorder for which there are limited treatment options. Following injury, native nephrons display limited regenerative capabilities, relying on the dedifferentiation and proliferation of renal tubular epithelial cells (RTECs) that survive the insult. Previously, we identified 4-(phenylthio)butanoic acid (PTBA), a histone deacetylase inhibitor (HDI), as an enhancer of renal recovery, and showed that PTBA treatment increased RTEC proliferation and reduced renal fibrosis. Here, we investigated the regenerative mechanisms of PTBA in zebrafish models of larval renal injury and adult cardiac injury. With respect to renal injury, we showed that delivery of PTBA using an esterified prodrug (UPHD25) increases the reactivation of the renal progenitor gene Pax2a, enhances dedifferentiation of RTECs, reduces Kidney injury molecule-1 (Kim-1) expression, and lowers the number of infiltrating macrophages. Further, we found that the effects of PTBA on RTEC proliferation depend upon retinoic acid signaling and demonstrate that the therapeutic properties of PTBA are not restricted to the kidney but also increase cardiomyocyte proliferation and decrease fibrosis following cardiac injury in adult zebrafish. These studies provide key mechanistic insights into how PTBA enhances tissue repair in models of acute injury and lay the groundwork for translating this novel HDI into the clinic.This article has an associated First Person interview with the joint first authors of the paper.


Assuntos
Lesão Renal Aguda/patologia , Lesão Renal Aguda/fisiopatologia , Butiratos/farmacologia , Desdiferenciação Celular , Regeneração , Sulfetos/farmacologia , Peixe-Zebra/fisiologia , Animais , Animais Geneticamente Modificados , Desdiferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Sistema Imunitário/efeitos dos fármacos , Sistema Imunitário/metabolismo , Túbulos Renais/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Fator de Transcrição PAX2/metabolismo , Pró-Fármacos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Tretinoína/farmacologia , Peixe-Zebra/imunologia , Proteínas de Peixe-Zebra/metabolismo
14.
Am J Physiol Cell Physiol ; 316(6): C805-C814, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30892938

RESUMO

The apically localized riboflavin (RF) transporter-3 (RFVT-3) is involved in intestinal absorption of vitamin B2. Previous studies have characterized different physiological/biological aspects of the RFVT-3, but there is a lack of knowledge regarding possible existence of interacting partner(s) and consequence of interaction(s) on its function/cell biology. To address the latter, we performed yeast two-hybrid (Y2H) screening of a human colonic cDNA library and have identified transmembrane protein 237 (TMEM237) as a putative interactor with the human (h)RFVT-3; the interaction was further confirmed via "1-by-1" Y2H assay that involved appropriate positive and negative controls. TMEM237 was found to be highly expressed in human native intestine and in human intestinal epithelial cell lines; further, confocal images showed colocalization of the protein with hRFVT-3. The interaction between TMEM237 with hRFVT-3 in human intestinal epithelial HuTu-80 cells was established by coimmunoprecipitation. Expressing TMEM237 in HuTu-80 cells led to a significant induction in RF uptake, while its knockdown (with the use of gene-specific siRNA) led to a significant reduction in uptake. Transfecting TMEM237 into HuTu-80 cells also led to a marked enhancement in hRFVT-3 protein stability (reflected by an increase in the protein half-life). Interestingly, the level of expression of TMEM237 was found to be markedly reduced following treatment with TNF-α (a proinflammatory cytokine that inhibits intestinal RF uptake), while its expression was significantly upregulated following treatment with butyrate (an inducer of intestinal RF uptake). These findings identify TMEM237 as an interactor with the intestinal hRFVT-3 and show that the interaction has physiological/biological significance.


Assuntos
Mucosa Intestinal/citologia , Mucosa Intestinal/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Butiratos/farmacologia , Células CACO-2 , Humanos , Mucosa Intestinal/efeitos dos fármacos , Proteínas de Membrana/agonistas , Proteínas de Membrana/antagonistas & inibidores , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Fator de Necrose Tumoral alfa/farmacologia
15.
J Pharmacol Sci ; 139(4): 266-274, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30871870

RESUMO

Butyrate is widely accepted as a proliferation inhibitor in colon cancer but less thoroughly characterized in the colonic epithelium of objects with type 2 diabetes mellitus. The present study investigated the regulatory effect of butyrate on proliferation, the related molecule high-mobility group box 1 (HMGB1) and the receptor for advanced glycation end products (RAGE) in the colon of db/db type 2 diabetic model mice and non-cancerous NCM460 colon cells. Proliferation and the expression of HMGB1 and RAGE were increased and could be partially reversed by butyrate treatment in the colon of db/db mice, which were consistent in NCM460 cells under a high glucose state. In NCM460 cells, under the normal glucose state, proliferation increased by overexpression of HMGB1. Under a high glucose state, increased expression of HMGB1 was accompanied with a release from cell nuclei into the cytoplasm and extracellular matrix. Down-regulation of HMGB1 could lower the expression of RAGE and attenuate the abnormally increased proliferation. And overexpression of HMGB1 reversed the suppressing effect of butyrate on abnormally increased proliferation. Conclusively, butyrate suppressed the abnormally increased proliferation in colonic epithelial cells under diabetic state by targeting HMGB1.


Assuntos
Butiratos/farmacologia , Proliferação de Células/efeitos dos fármacos , Colo/citologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Células Epiteliais/fisiologia , Expressão Gênica/efeitos dos fármacos , Proteína HMGB1/metabolismo , Animais , Células Cultivadas , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Proteína HMGB1/genética , Masculino , Camundongos Endogâmicos , Receptor para Produtos Finais de Glicação Avançada/genética , Receptor para Produtos Finais de Glicação Avançada/metabolismo
16.
Mol Med Rep ; 19(5): 3941-3947, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30864709

RESUMO

Butyrate, a histone deacetylase inhibitor, is a typical short chain fatty acid produced by gut microbiota, the dysmetabolism of which has been consistently associated with colorectal diseases. However, its role in tumorigenesis and progression of colorectal cancer cells remains under­investigated. The present study examined the antitumor function of butyrate in the colorectal cancer cell line HCT116 and investigated the underlying molecular mechanism. MTT assay was used to measure cell proliferation and ELISA assay was used to determine cell apoptosis by measuring histone release and caspase­3 activation. The results demonstrated that butyrate treatment significantly inhibited proliferation and induced apoptosis in HCT116 cells with an increased B­cell lymphoma-2 (Bcl­2)­associated X protein/Bcl­2 ratio. Western blotting demonstrated that the phosphorylation of mammalian target of rapamycin (mTOR) at Ser2448, ribosomal protein S6 kinase ß­1 (S6K1) at Thr389, S6 at Ser235/236 and expression of silent mating type information regulation 2 homolog (SIRT)1 were decreased following butyrate treatment, while the acetylation of S6K1 was indicated to be increased. Silencing of SIRT1 by small interfering RNA technology demonstrated a similar inhibition on growth, induction of apoptosis, elevation of S6K1 acetylation and deactivation of mTOR/S6K1 signaling. Butyrate treatment also enhanced the inhibition of SIRT1 silencing on cell proliferation and activity of mTOR/S6K1. The activation of mTOR/S6K1 signaling and upregulation of cell proliferation mediated by overexpression of SIRT1 were blocked by butyrate. These data suggested that butyrate inhibited proliferation and induced apoptosis in HCT116 cells by deactivating mTOR/S6K1 signaling, possibly through its inhibition of SIRT1.


Assuntos
Apoptose/efeitos dos fármacos , Butiratos/farmacologia , Proliferação de Células/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismo , Regulação para Baixo/efeitos dos fármacos , Células HCT116 , Humanos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/genética , Serina-Treonina Quinases TOR/metabolismo , Proteína X Associada a bcl-2/metabolismo
17.
Life Sci Alliance ; 2(2)2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30894406

RESUMO

Mechanisms driving cognitive improvements following nuclear receptor activation are poorly understood. The peroxisome proliferator-activated nuclear receptor alpha (PPARα) forms heterodimers with the nuclear retinoid X receptor (RXR). We report that PPARα mediates the improvement of hippocampal synaptic plasticity upon RXR activation in a transgenic mouse model with cognitive deficits. This improvement results from an increase in GluA1 subunit expression of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, eliciting an AMPA response at the excitatory synapses. Associated with a two times higher PPARα expression in males than in females, we show that male, but not female, PPARα null mutants display impaired hippocampal long-term potentiation. Moreover, PPARα knockdown in the hippocampus of cognition-impaired mice compromises the beneficial effects of RXR activation on synaptic plasticity only in males. Furthermore, selective PPARα activation with pemafibrate improves synaptic plasticity in male cognition-impaired mice, but not in females. We conclude that striking sex differences in hippocampal synaptic plasticity are observed in mice, related to differences in PPARα expression levels.


Assuntos
Dosagem de Genes/genética , Potenciação de Longa Duração/genética , Plasticidade Neuronal/genética , PPAR alfa/genética , PPAR alfa/metabolismo , Animais , Benzoxazóis/farmacologia , Butiratos/farmacologia , Células Cultivadas , Disfunção Cognitiva/genética , Disfunção Cognitiva/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Camundongos , Camundongos Transgênicos , PPAR alfa/agonistas , Ratos , Ratos Wistar , Receptores de AMPA/metabolismo , Receptores X Retinoide/metabolismo , Fatores Sexuais , Transdução de Sinais/efeitos dos fármacos
18.
J Dairy Sci ; 102(5): 4190-4197, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30879822

RESUMO

The objectives of this study were to determine the effects of supplemental butyrate on (1) Ig production in dams and (2) Ig absorption in their calves. Twenty dry dams fed a close-up total mixed ration were assigned to either a control treatment (CTRL-D) or a butyrate treatment where the close-up total mixed ration was supplemented with butyrate at 1% of dry matter intake (wt/wt; BUT-D). At calving, calves were assigned to 1 of 2 treatments: a control group fed colostrum replacer only (CTRL-C) and a butyrate group fed colostrum replacer with supplemental butyrate at 2.5% (wt/vol; BUT-C). Serum IgG, glucose, and ß-hydroxybutyrate were measured weekly in both dams and calves. Additionally, calves were weighed weekly to determine average daily gain. In dams, serum IgG concentration was not different between CTRL-D and BUT-D (1,785 ± 117 vs. 1,736 ± 137 mg/dL, respectively), nor was there a change in Ig levels in the colostrum between control and butyrate groups. Serum total protein did not differ between CTRL-D and BUT-D dams. Dam dry matter intake did not differ between CTRL-D and BUT-D but did decrease 1 wk before parturition. Compared with CTRL-C calves, BUT-C calves had significantly decreased serum IgG concentration at 24 h (2,110 ± 124 vs. 1,400 ± 115 mg/dL), wk 1 (1,397 ± 121 vs. 866 ± 115 mg/dL), and wk 2 (1,310 ± 121 vs. 797 ± 115 mg/dL). Additionally, apparent efficiency of absorption was lower for the BUT-C group compared with the CTRL-C group (35.3 ± 2.1 vs. 25.9 ± 2.0). Differences in serum Ig concentrations between the CTRL-C and BUT-C groups did not affect average daily gain (0.59 ± 0.05 vs. 0.48 ± 0.05 kg/d, respectively), serum glucose concentrations, or serum ß-hydroxybutyrate concentrations. These data demonstrate that butyrate inclusion in colostrum negatively affects IgG absorption in newborn calves, whereas calf body weight gains were unaffected.


Assuntos
Butiratos/farmacologia , Bovinos/imunologia , Dieta/veterinária , Imunidade Materno-Adquirida/efeitos dos fármacos , Ácido 3-Hidroxibutírico/sangue , Animais , Animais Recém-Nascidos , Glicemia/análise , Colostro/química , Colostro/imunologia , Suplementos Nutricionais , Feminino , Imunoglobulina G/sangue , Masculino , Gravidez
19.
Pak J Pharm Sci ; 32(1(Supplementary)): 277-283, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30829204

RESUMO

Magnesium (Mg) is an essential biomineral that acts as an intracellular cofactor for more than 300 enzymes. It is an important modulator of the N-methyl-D-aspartate (NMDA) receptor which is involved in memory function and depression. The purpose of this study was to compare the dose dependent effect of oral supplementation of Magnesium chloride (MgCl2), Magnesium sulphate (MgSO4) and Magnesium-L-threonate (MgT) on memory and depression-related behaviors in rats. Rats were orally administered with different doses (50 mg/kg, 100 mg/kg and 150 mg/kg) of each Mg salt. Following 28 days of oral supplementation, animals were subjected to behavioral tests. After completion of behavioral test, rats were decapitated. Brain and plasma samples were used for neurochemical and biochemical analysis. Assessment of behaviors in elevated plus maze (EPM) test and forced swim test (FST) showed that MgT more significantly improved memory of rats and decreased depression-like symptoms in healthy rats as compared to controls. Biochemical analysis indicated significant increase in plasma Mg levels dose dependently following MgT administration. This increase might be related to observe enhanced cholinergic functions and decline in oxidative stress in rats in the present study. This comparative study highlights that MgT (100mg/kg) is the most appropriate Mg salt and dose for oral treatment that strengthens cholinergic system and improves brain related functions through attenuation of oxidative burden in adult healthy rats.


Assuntos
Encéfalo/efeitos dos fármacos , Butiratos/farmacologia , Cloreto de Magnésio/farmacologia , Sulfato de Magnésio/farmacologia , Memória/efeitos dos fármacos , Acetilcolina/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Butiratos/administração & dosagem , Depressão/tratamento farmacológico , Relação Dose-Resposta a Droga , Magnésio/sangue , Cloreto de Magnésio/administração & dosagem , Sulfato de Magnésio/administração & dosagem , Masculino , Ratos Wistar
20.
Urol Int ; 102(3): 348-355, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30844816

RESUMO

BACKGROUND: Renal ischemia-reperfusion injury (IRI) usually causes acute kidney injury. There is an urgent need to develop an effective agent to prevent renal IRI. This study aimed to examine the effect of butyrate on renal IRI in rats. MATERIALS AND METHODS: Rats were randomly assigned into 3 groups (10 rats in each group): the sham group, the IRI group, and the butyrate group. Rats were injected intravenously with 300 mg/kg of sodium butyrate in the butyrate group and with a saline solution in the sham group and IRI group 30 min before renal ischemia. After 24 h of reperfusion, renal function and histologic damage were examined. Myeloperoxidase (MPO) activity assay, in situ apoptosis examination, enzyme-linked immunosorbent assay, immunohistochemical assay, and Western blot were performed as well. RESULTS: Butyrate pretreatment significantly reduced renal dysfunction and histologic damage induced by renal IRI. Butyrate pretreatment caused a significant attenuation of neutrophil infiltration, which was reflected by the reduction of renal MPO activity. Butyrate also reduced apoptotic tubular cell death and improved caspase-3 activation. The expression of TNF-α was decreased following butyrate pretreatment. CONCLUSIONS: Butyrate pretreatment protects rats from renal IRI by inhibiting inflammation and apoptosis. Therefore, butyrate may be a potential therapeutic agent for preventing renal IRI.


Assuntos
Butiratos/farmacologia , Rim/efeitos dos fármacos , Rim/patologia , Traumatismo por Reperfusão/patologia , Lesão Renal Aguda/patologia , Animais , Anti-Inflamatórios/farmacologia , Apoptose , Ensaio de Imunoadsorção Enzimática , Imuno-Histoquímica , Inflamação , Masculino , Neutrófilos/citologia , Peroxidase/metabolismo , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo
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