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1.
AAPS PharmSciTech ; 22(3): 114, 2021 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-33763759

RESUMO

Lisofylline (LSF) is an anti-inflammatory molecule with high aqueous solubility and rapid metabolic interconversion to its parent drug, pentoxifylline (PTX) resulting in very poor pharmacokinetic (PK) parameters, necessitating high dose and dosing frequency. In the present study, we resolved the physicochemical and pharmacokinetic limitations associated with LSF and designed its oral dosage form as a tablet for effective treatment in type 1 diabetes (T1D). Self-assembling polymeric micelles of LSF (lisofylline-linoleic acid polymeric micelles (LSF-LA PLM)) were optimized for scale-up (6 g batch size) and lyophilized followed by compression into tablets. Powder blend and tablets were evaluated as per USP. LSF-LA PLM tablet so formed was evaluated for in vitro release in simulated biological fluids (with enzymes) and for cell viability in MIN-6 cells. LSF-LA PLM in tablet formulation was further evaluated for intestinal permeability (in situ) along with LSF and LSF-LA self-assembled micelles (SM) as controls in a rat model using single-pass intestinal perfusion (SPIP) study. SPIP studies revealed 1.8-fold higher oral absorption of LSF-LA from LSF-LA PLM as compared to LSF-LA SM and ~5.9-fold higher than LSF (alone) solution. Pharmacokinetic studies of LSF-LA PLM tablet showed greater Cmax than LSF, LSF-LA, and LSF-LA PLM. Designed facile LSF-LA PLM tablet dosage form has potential for an immediate decrease in the postprandial glucose levels in patients of T1D.


Assuntos
Diabetes Mellitus Tipo 1/metabolismo , Jejuno/metabolismo , Ácido Linoleico/farmacocinética , Nanopartículas/metabolismo , Pentoxifilina/análogos & derivados , Perfusão/métodos , Administração Oral , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Formas de Dosagem , Jejuno/efeitos dos fármacos , Ácido Linoleico/administração & dosagem , Ácido Linoleico/síntese química , Masculino , Camundongos , Nanopartículas/administração & dosagem , Nanopartículas/química , Pentoxifilina/administração & dosagem , Pentoxifilina/síntese química , Pentoxifilina/farmacocinética , Ratos , Ratos Wistar , Comprimidos
2.
Eur J Pharmacol ; 900: 174065, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-33775646

RESUMO

Akt (protein kinase B) signaling is frequently activated in diverse cancers. Akt inhibitors such as perifosine and MK-2206 have been evaluated as potential cancer chemotherapeutics. Although both drugs are generally well tolerated, among their most common side-effects vomiting is a major concern. Here we investigated whether these Akt inhibitors evoke emesis in the least shrew model of vomiting. Indeed, both perifosine and MK-2206 induced vomiting with maximal efficacies of 90% at 50 mg/kg (i.p.) and 100% at 10 mg/kg (i.p.), respectively. MK-2206 (10 mg/kg, i.p.) increased c-Fos immunoreactivity both centrally in the shrew brainstem dorsal vagal complex (DVC) emetic nuclei, and peripherally in the jejunum. MK-2206 also evoked phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in both the DVC emetic nuclei and the enteric nervous system in the jejunum. The ERK1/2 inhibitor U0126 suppressed MK-2206-induced emesis dose-dependently. We then evaluated the suppressive efficacy of diverse antiemetics against MK-2206-evoked vomiting including antagonists/inhibitors of the: L-type Ca2+ channel (nifedipine at 2.5 mg/kg, subcutaneously (s.c.)); glycogen synthase kinase 3 (GSK-3) (AR-A014418 at 10 mg/kg and SB216763 at 0.25 mg/kg, i.p.); 5-hydroxytryptamine 5-HT3 receptor (palonosetron at 0.5 mg/kg, s.c.); substance P neurokinin NK1 receptor (netupitant at 10 mg/kg, i.p.) and dopamine D2/3 receptor (sulpride at 8 mg/kg, s.c.). All tested antagonists/blockers attenuated emetic parameters to varying degrees. In sum, this is the first study to demonstrate how pharmacological inhibition of Akt evokes vomiting via both central and peripheral mechanisms, a process which involves multiple emetic receptors.


Assuntos
Antieméticos/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis , Proteína Oncogênica v-akt/antagonistas & inibidores , Sistema Nervoso Periférico/efeitos dos fármacos , Musaranhos/fisiologia , Vômito/induzido quimicamente , Vômito/fisiopatologia , Animais , Antieméticos/uso terapêutico , Tronco Encefálico/efeitos dos fármacos , Relação Dose-Resposta a Droga , Eméticos/farmacologia , Sistema Nervoso Entérico/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/antagonistas & inibidores , Jejuno/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fosforilação , Proteínas Proto-Oncogênicas c-fos/metabolismo , Vômito/tratamento farmacológico
3.
Life Sci ; 275: 119350, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33737081

RESUMO

AIM: Exposure to pesticides and consumption of high-fat diets are widespread in society. Reports have shown that exposure to glyphosate and a high-fat diet can cause gastrointestinal disorders and increase susceptibility to obesity. Thus, this study evaluated the impacts of perinatal exposure to glyphosate followed by consumption of a high-fat diet in adulthood on the histology and morphometry of jejunums and enteric nervous system of C57BL/6 mice. MATERIAL AND METHODS: After mating, 20 C57BL/6 female mice were separated into a control group (CG) and a glyphosate group (GLY) that received water with 0.5% glyphosate. After the lactation period, some male offspring were randomly separated into CG-SD and GLY-SD (standard diet) groups or CG-HD and GLY-HD (high-fat diet) groups. After 12 weeks, jejunum samples were collected and submitted to histological analysis. KEY FINDINGS: Indirect exposure to glyphosate changed the morphometry of the intestinal wall, increased the proportion of intraepithelial lymphocytes (IELs) and goblet cells, and altered the area occupied by collagen fibers. The hyperlipidemic diet hypertrophied the jejunal total wall, total muscular and submucosal layers, decreased IELs, and increased the proportion of goblet cells. GLY-HD mice had shallower crypts, shorter villi, and less goblet cells and IELs than mice from GLY-SD group. GLY-HD also showed an increased number of neurons in myenteric and submucosal plexuses. Groups exposed to glyphosate and/or fed a high-fat diet had atrophied submucosal neurons. SIGNIFICANCE: This study suggests that perinatal glyphosate exposure combined with a high-fat diet in adulthood increases the risk of jejunum inflammation and dysfunction.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Glicina/análogos & derivados , Herbicidas/efeitos adversos , Jejuno/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Animais , Feminino , Glicina/efeitos adversos , Células Caliciformes/efeitos dos fármacos , Células Caliciformes/patologia , Jejuno/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez
4.
Poult Sci ; 100(3): 100807, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33518310

RESUMO

With global warming and ban on antibiotics, it occurs occasionally that deoxynivalenol (DON) together with Clostridium perfringens impairs the gut health of broiler chickens. However, the interactive effect of DON and C. perfringens on intestinal health is still unknown. A total of 120 one-day-old Arbor Acres broilers were randomly distributed to 4 groups. Birds were gavaged with C. perfringens (8 × 108 CFU/d per bird) or sterile medium and fed a DON diet (0 or 5 mg of DON per kg diet) to investigate the interactive effects. The main effect analysis showed that DON diet significantly downregulated (P < 0.05) the mRNA expression of mucin-2, B-cell lymphoma-2-associated X, and cysteinyl aspartate-specific proteinase-3 of jejunal mucosa; decreased (P < 0.05) the indexes of ACE, Chao1, Shannon, and Simpson; and also decreased the relative abundance of the phylum Bacteroidete and the genera Lactococcus in jejunal contents of broilers chickens. Meanwhile, C. perfringens significantly increased (P < 0.05) crypt depth; decreased (P < 0.05) the ratio of villi height to crypt depth, the activity of jejunal diamine oxidase, and the relative abundance of Lactococcus; and upregulated (P < 0.05) the relative expression of B-cell lymphoma-2 and cysteinyl aspartate-specific proteinase-8. Furthermore, the interactions between DON and C. perfringens were most significant (P < 0.05) in the mRNA expression of lipopolysaccharide-induced TNF factor (LITAF) and TLR-4, the abundance of the genera Lactococcus in jejunal contents, and butyric acid concentrations in cecal contents of birds. Finally, Spearman correlation analysis suggested that the most negative correlations (P < 0.05) with the abundance of the genera except Lactobacillus were observed within the mRNA expression of LITAF. The abundance of Lactococcus had a positive correlation (P < 0.05) with the expression of Caspase-3. Most genera except Lactobacillus negatively correlated (P < 0.05) with acetic acid, butyric acid, and total short-chain fatty acids. In conclusion, dietary deoxynivalenol and C. perfringens challenge had a harmful effect on the jejunal health and should be carefully monitored in broiler production.


Assuntos
Galinhas , Infecções por Clostridium , Suplementos Nutricionais , Jejuno , Doenças das Aves Domésticas , Tricotecenos , Animais , Infecções por Clostridium/tratamento farmacológico , Infecções por Clostridium/fisiopatologia , Infecções por Clostridium/veterinária , Clostridium perfringens , Dieta/veterinária , Regulação da Expressão Gênica/efeitos dos fármacos , Jejuno/efeitos dos fármacos , Jejuno/microbiologia , Doenças das Aves Domésticas/tratamento farmacológico , Doenças das Aves Domésticas/microbiologia , Distribuição Aleatória , Tricotecenos/farmacologia , Tricotecenos/uso terapêutico
5.
Ecotoxicol Environ Saf ; 210: 111870, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33440271

RESUMO

Ammonia is the main harmful gas in livestock houses. However, the toxic mechanism of ammonia is still unclear. Therefore, we examined the effects of ammonia exposure on different tissues of fattening pigs by histological analysis and transcriptome techniques in this study. The results showed that there were varying degrees of pathological changes in liver, kidney, hypothalamus, jejunum, lungs, spleen, heart and trachea of fattening pigs under ammonia exposure. Notably, the extent of damage in liver, kidney, jejunum, lungs, hypothalamus and trachea was more severe than that in heart and spleen. Transcriptome results showed that ammonia exposure caused changes in 349, 335, 340, 229, 120, 578, 407 and 115 differentially expressed genes in liver, kidney, spleen, lung, trachea, hypothalamus, jejunum and heart, respectively. Interestingly, the changes in solute vector (SLC) family genes were found in all 8 tissues, and the verified gene results (SLC11A1, SLC17A7, SLC17A6, SLC6A4, SLC22A7, SLC25A3, SLC28A3, SLC7A2, SLC6A6, SLC38A5, SLC22A12, SLC34A1, SLC26A1, SLC26A6, SLC27A5, SLC22A8 and SLC44A4) were consistent with qRT-PCR results. In conclusion, ammonia exposure can cause pathological changes in many tissues and organs of fattening pigs and changes in the SCL family gene network. Importantly, the SCL family is involved in the toxic mechanism of ammonia. Our findings will provide a new insight for better assessing the mechanism of ammonia toxicity.


Assuntos
Amônia/toxicidade , Proteínas de Membrana Transportadoras/genética , Animais , Feminino , Redes Reguladoras de Genes/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Hipotálamo/patologia , Jejuno/efeitos dos fármacos , Jejuno/metabolismo , Jejuno/patologia , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Miocárdio/patologia , Baço/efeitos dos fármacos , Baço/metabolismo , Baço/patologia , Suínos , Traqueia/efeitos dos fármacos , Traqueia/metabolismo , Traqueia/patologia , Transcriptoma/efeitos dos fármacos
6.
Mar Drugs ; 19(2)2021 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-33503912

RESUMO

The aim of this study was to evaluate the effects of the dietary supplementation of chitosan oligosaccharides (COS) on intestinal integrity, oxidative status, and the inflammation response with hydrogen peroxide (H2O2) challenge. In total, 30 rats were randomly assigned to three groups with 10 replications: CON group, basal diet; AS group, basal diet + 0.1% H2O2 in drinking water; ASC group, basal diet + 200 mg/kg COS + 0.1% H2O2 in drinking water. The results indicated that COS upregulated (p < 0.05) villus height (VH) of the small intestine, duodenum, and ileum; mucosal glutathione peroxidase activity; jejunum and ileum mucosal total antioxidant capacity; duodenum and ileum mucosal interleukin (IL)-6 level; jejunum mucosal tumor necrosis factor (TNF)-α level; duodenum and ileum mucosal IL-10 level; the mRNA expression level of zonula occludens (ZO)-1 in the jejunum and ileum, claudin in the duodenum, nuclear factor-erythroid 2-like 2 in the jejunum, and heme oxygenase-1 in the duodenum and ileum; and the protein expression of ZO-1 and claudin in jejunum; however, it downregulated (p < 0.05) serum diamine oxidase activity and D-lactate level; small intestine mucosal malondialdehyde content; duodenum and ileum mucosal IL-6 level; jejunum mucosal TNF-α level; and the mRNA expression of IL-6 in the duodenum and jejunum, and TNF-α in the jejunum and ileum. These results suggested COS could maintain intestinal integrity under oxidative stress by modulating the intestinal oxidative status and release of inflammatory cytokines.


Assuntos
Quitosana/farmacologia , Mediadores da Inflamação/antagonistas & inibidores , Mucosa Intestinal/efeitos dos fármacos , Oligossacarídeos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Jejuno/efeitos dos fármacos , Jejuno/metabolismo , Jejuno/patologia , Masculino , Estresse Oxidativo/fisiologia , Substâncias Protetoras/farmacologia , Ratos , Ratos Sprague-Dawley
7.
Food Chem ; 334: 127586, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32707364

RESUMO

It is unknown whether intestinal absorption of acylated anthocyanins occurs in their intact or metabolized form. In this study, with the aid of matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) imaging, intestinal absorption of acylated anthocyanins was visually investigated. Anthocyanin extracts from purple carrots were orally administered to Sprague-Dawley rats. Acylated cyanidins were absorbed into portal and circulating blood systems in their intact form, and aglycon; cyanidin 3-O-(6-O-feruloyl-ß-d-glucopyranosyl)-(1 â†’ 6)-[ß-d-xylopyranosyl-(1 â†’ 2)]-ß-d-galactopyranoside (Cy3XFGG), and showed a high absorption of 39.3 ± 0.1 pmol/mL-plasma at 60 min after administration. MALDI-MS imaging analysis of the rat jejunum membranes showed that an organic anion transporting polypeptide (OATP) transporter was involved in Cy3XFGG transport, while deacylated anthocyanins were incorporated through both the glucose transporter 2 and OATP routes. In conclusion, acylated anthocyanin, Cy3XFGG, can be absorbed in its intact form through intestinal OATP.


Assuntos
Antocianinas/análise , Antocianinas/farmacocinética , Imagem Molecular/métodos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Acilação , Administração Oral , Animais , Antocianinas/administração & dosagem , Cor , Daucus carota/química , Absorção Intestinal/efeitos dos fármacos , Jejuno/efeitos dos fármacos , Jejuno/metabolismo , Masculino , Transportadores de Ânions Orgânicos/metabolismo , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacocinética , Ratos Sprague-Dawley
8.
Medicine (Baltimore) ; 99(46): e23249, 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33181715

RESUMO

Levodopa-carbidopa intestinal gel (LCIG) is a method of continuous administration of levodopa - the standard treatment in Parkinson disease (PD, a neurodegenerative disorder characterized by resting tremor, rigidity, gait impairment, and bradykinesia), thought to reduce the short-life and pulsatile problems of oral administration. We aimed to study the effects of Levodopa-Carbidopa therapy in 2 separate groups: one with intrajejunal administration of Levodopa-Carbidopa gel and the second with oral therapy.We performed an observational retrospective Romanian cohort study on 61 patients diagnosed with PD patients, with Hoehn and Jahr 3 and 4 stages, recruited from a single regional tertiary center in Cluj-Napoca, Romania, between 2009 and 2019.The mean adjusted UPDRS III (and similarly for UPDRS II) improved in the LCIG compared to the oral therapy group with 15.6 (95% CI 12.0-19.2, P < .001), and with 18.4 (95% CI 13.8-22.9, P < .001), stratified for the Hoehn and Jahr stages 3 and 4. There was a 41.7% (10) reduction in dyskinesia, and 29.2% reduction in wearing off/on-off at 1 year in the LCIG group compared to 0% (0) dyskinesia reduction, and 2.7% reduction in wearing off/on-off in the oral therapy group.Continuous intrajejunal infusion of LCIG ensures a significant and clinical reduction in motor fluctuations compared to oral therapy in advanced PD, even after adjustment for important confounders.


Assuntos
Carbidopa/administração & dosagem , Jejuno/efeitos dos fármacos , Levodopa/administração & dosagem , Doença de Parkinson/tratamento farmacológico , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Carbidopa/uso terapêutico , Estudos de Coortes , Combinação de Medicamentos , Feminino , Humanos , Injeções/métodos , Injeções/normas , Levodopa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Romênia
9.
Toxicol Lett ; 333: 159-169, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32783910

RESUMO

The intestinal epithelium is the first barrier against food contaminants and is highly sensitive to Fusarium toxins, especially deoxynivalenol (DON) and zearalenone (ZEA). Here, we explored the effects of low doses of DON and/or ZEA in naturally moldy diets on intestinal functions in piglets, including inflammatory responses, epithelial barrier, and microbial composition. Piglets were treated with a control diet (CON), DON diet (1000.6 µg/kg), ZEA diet (269.1 µg/kg), and DON + ZEA diet (1007.5 + 265.4 µg/kg), respectively, for 3 weeks and then switched to the same CON diet for another 2 weeks. In the first period, even the selected low doses of DON or ZEA in the diet resulted in intestinal inflammation, diminish protein expression (claudin-4) and altered gut microbiota populations. Whereas upon switching to the CON diet for another 2 weeks, the deleterious effect of ZEA and DON on IL-1ß and Bifidobacterium population could not be recovered. Additionally, combined DON and ZEA negatively affected body weight gain and feed consumption of piglets, as well as shown synergistic effects on evoking pro-inflammatory cytokines contents (TNF-α, IL-1ß, and IL-6) and perturbing the cecum microbiota profile (E. coli, Lactobacillus, and Bifidobacterium). Collectively, chronic consumption of DON and ZEA contaminated feed or food, even at low doses, can induce intestinal damage and may have consequences for animal and human health.


Assuntos
Ração Animal/microbiologia , Imunidade nas Mucosas/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Suínos , Tricotecenos/toxicidade , Zearalenona/toxicidade , Animais , Peso Corporal/efeitos dos fármacos , Ceco/efeitos dos fármacos , Ceco/imunologia , Ceco/metabolismo , Citocinas/sangue , Citocinas/genética , Citocinas/metabolismo , Dieta , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Feminino , Contaminação de Alimentos/análise , Fusarium/crescimento & desenvolvimento , Fusarium/isolamento & purificação , Expressão Gênica/efeitos dos fármacos , Hordeum/microbiologia , Inflamação , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Jejuno/efeitos dos fármacos , Jejuno/imunologia , Jejuno/metabolismo , Proteínas de Junções Íntimas/genética , Proteínas de Junções Íntimas/metabolismo , Zea mays/microbiologia
10.
J Anim Sci ; 98(9)2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32780110

RESUMO

The objective was to study the effects of microencapsulated organic acids (OA) and essential oils (EO) on growth performance, immune system, gut barrier function, nutrient digestion and absorption, and abundance of enterotoxigenic Escherichia coli F4 (ETEC F4) in the weaned piglets challenged with ETEC F4. Twenty-four ETEC F4 susceptible weaned piglets were randomly distributed to 4 treatments including (1) sham-challenged control (SSC; piglets fed a control diet and challenged with phosphate-buffered saline (PBS)); (2) challenged control (CC; piglets fed a control diet and challenged with ETEC F4); (3) antibiotic growth promoters (AGP; CC + 55 mg·kg-1 of Aureomycin); and (4) microencapsulated OA and EO [P(OA+EO); (CC + 2 g·kg-1 of microencapsulated OA and EO]. The ETEC F4 infection significantly induced diarrhea at 8, 28, 34, and 40 hr postinoculation (hpi) (P < 0.05) in the CC piglets. At 28 d postinoculation (dpi), piglets fed P(OA+EO) had a lower (P < 0.05) diarrhea score compared with those fed CC, but the P(OA+EO) piglets had a lower (P < 0.05) diarrhea score compared with those fed the AGP diets at 40 dpi. The ETEC F4 infection tended to increase in vivo gut permeability measured by the oral gavaging fluorescein isothiocyanate-dextran 70 kDa (FITC-D70) assay in the CC piglets compared with the SCC piglets (P = 0.09). The AGP piglets had higher FITC-D70 flux than P(OA+EO) piglets (P < 0.05). The ETEC F4 infection decreased mid-jejunal VH in the CC piglets compared with the SCC piglets (P < 0.05). The P(OA+EO) piglets had higher (P < 0.05) VH in the mid-jejunum than the CC piglets. The relative mRNA abundance of Na+-glucose cotransporter and B0AT1 was reduced (P < 0.05) by ETEC F4 inoculation when compared with the SCC piglets. The AGP piglets had a greater relative mRNA abundance of B0AT1 than the CC piglets (P < 0.05). The ETEC F4 inoculation increased the protein abundance of OCLN (P < 0.05), and the AGP piglets had the lowest relative protein abundance of OCLN among the challenged groups (P < 0.05). The supplementation of microencapsulated OA and EO enhanced intestinal morphology and showed anti-diarrhea effects in weaned piglets challenged with ETEC F4. Even if more future studies can be required for further validation, this study brings evidence that microencapsulated OA and EO combination can be useful within the tools to be implemented in strategies for alternatives to antibiotics in swine production.


Assuntos
Diarreia/veterinária , Escherichia coli Enterotoxigênica/crescimento & desenvolvimento , Infecções por Escherichia coli/veterinária , Microbioma Gastrointestinal/efeitos dos fármacos , Óleos Voláteis/farmacologia , Doenças dos Suínos/microbiologia , Animais , Antibacterianos/farmacologia , Ácidos Carboxílicos/farmacologia , Clortetraciclina/farmacologia , Diarreia/microbiologia , Dieta/veterinária , Composição de Medicamentos/veterinária , Escherichia coli Enterotoxigênica/efeitos dos fármacos , Infecções por Escherichia coli/microbiologia , Feminino , Imunidade , Jejuno/efeitos dos fármacos , Masculino , Nutrientes/metabolismo , Distribuição Aleatória , Suínos , Desmame
11.
J Anim Sci ; 98(8)2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32756964

RESUMO

The purpose of the present study was to discover the effects of iron on the intestinal development and epithelial maturation of suckling piglets. Twenty-seven newborn male piglets from 9 sows (3 piglets per sow), with similar body weight, were selected. The 3 piglets from the same sow were randomly divided into 1 of the 3 groups. The piglets were orally administrated with 2 mL of normal saline (CON group) or with 25 mg of iron by ferrous sulfate (OAFe group; dissolved in normal saline) on the 2nd, 7th, 12th, and 17th day, respectively, or intramuscularly injected with 100 mg of iron by iron dextran (IMFe group) on the 2nd day. The slaughter was performed on the 21st day and intestinal samples were collected. Compared with the CON group, iron supplementation significantly increased the length (P < 0.001), weight (P < 0.001), relative weight (P < 0.001), and the length:weight ratio (P < 0.001) of the small intestine in both OAFe and IMFe groups. The villus height (P < 0.001), crypt depth (CD) (P < 0.001), villus width (P = 0.002), and surface area (P < 0.001) in the jejunum of IMFe and OAFe piglets were also greater than those in CON piglets. The mRNA expression of trehalase (Treh; P = 0.002) and sucrase isomaltase (Sis; P = 0.043), markers of epithelial maturation, increased in OAFe and IMFe piglets, respectively. Moreover, enterocyte vacuolization, observed in fetal-type enterocyte, was reduced in OAFe and IMFe piglets, compared with CON piglets. However, no significant difference in the expression of the target genes of wnt/ß-catenin signaling pathway was observed. The results indicated that both oral administration and intramuscular injection with iron promoted intestinal development and epithelial maturation in suckling piglets and that the effects of iron may be independent of wnt/ß-catenin signaling.


Assuntos
Suplementos Nutricionais/análise , Ferro/administração & dosagem , Suínos/crescimento & desenvolvimento , Administração Oral , Animais , Epitélio/efeitos dos fármacos , Epitélio/crescimento & desenvolvimento , Feminino , Injeções Intramusculares , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Intestinos/crescimento & desenvolvimento , Ferro/metabolismo , Jejuno/efeitos dos fármacos , Jejuno/crescimento & desenvolvimento , Jejuno/metabolismo , Masculino , Distribuição Aleatória
12.
Ecotoxicol Environ Saf ; 204: 111072, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32758694

RESUMO

Zearalenone (ZEN) is a mycotoxin that causes serious health problems in humans and animals. However, few studies have focused on the destruction of the intestinal barrier caused by ZEN. In this study, rats were exposed to different dosages of ZEN (0, 0.2, 1.0 and 5.0 mg/kg bw) by gavage for 4 weeks. The results showed that 1.0 and 5.0 mg/kg ZEN impaired gut morphology, induced the inflammatory response, reduced mucin expression, increased intestinal permeability, decreased the expression of TJ proteins and activated the RhoA/ROCK pathway. However, 0.2 mg/kg ZEN had no significant effect on intestinal barrier except for reducing the expression of some TJ proteins and mucins. Moreover, exposure to ZEN led to slight imbalance in microbiota. In conclusion, ZEN exposure resulted in intestinal barrier dysfunction by inducing intestinal microbiota dysbiosis, decreasing the expression of TJ proteins, activating the RhoA/ROCK pathway, and inducing the inflammatory response.


Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Jejuno/efeitos dos fármacos , Zearalenona/toxicidade , Animais , Relação Dose-Resposta a Droga , Disbiose/induzido quimicamente , Feminino , Microbioma Gastrointestinal/genética , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Jejuno/microbiologia , Jejuno/patologia , Masculino , Mucinas/metabolismo , Permeabilidade , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo
13.
PLoS One ; 15(7): e0236511, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32722717

RESUMO

The severe side effects of chemosynthetic anti-diarrhea drugs have created an interest in low-toxic alternative plant-derived compounds. FengLiao consists of Polygonum hydropiper Linn. and Daphniphyllum calycinum Bench., and is widely used in China to treat diarrhea due to low levels of toxicity. In this study, the effects of FengLiao were analyzed in a castor oil-induced diarrhea model, using the anti-diarrhea drug, loperamide, as the positive control. The effects were evaluated using stool characteristics and the expression levels of various diarrhea-related factors in the jejunum and liver, as well as changes in the microbiota of the jejunum. The symptoms of diarrhea and stool consistency were improved through FengLiao and loperamide treatment. Furthermore, FengLiao down-regulated alpha 1-acid glycoprotein (AGP) and C-reactive protein (CRP) levels, and up-regulated transferrin (TRF) mRNA levels in the liver, and down-regulated Aquaporin 3 (AQP3) and Na+/H+ exchanger isoform 8 (NHE8) expression in the epithelial cells of the jejunum. It also increased the relative abundance of Bifidobacterium, Aerococcus, Corynebacterium_1 and Pseudomonas, and lowered the Firmicutes/Bacteroidetes (F/B) ratio, which maintained the balance between immunity and intestinal health. Taken together, FengLiao alleviated castor oil-induced diarrhea by altering gut microbiota, and levels of jejunum epithelial transport proteins and acute phase proteins.


Assuntos
Proteínas de Fase Aguda/genética , Aquaporinas/genética , Diarreia/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Trocadores de Sódio-Hidrogênio/genética , Animais , Óleo de Rícino/toxicidade , Daphniphyllum/química , Diarreia/genética , Diarreia/microbiologia , Medicamentos de Ervas Chinesas/uso terapêutico , Jejuno/efeitos dos fármacos , Jejuno/metabolismo , Jejuno/microbiologia , Camundongos , Polygonum/química
14.
PLoS One ; 15(7): e0236950, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32730335

RESUMO

The use of natural products as feed additives in the poultry industry is increasing; however, most studies focus on performance and growth with little regard for determining mechanism. Our laboratory designed a chicken (Gallus gallus)-specific immunometabolic kinome peptide array. Using this tool to examine the active enzymes responsible for phosphorylation events (kinases) provides important information on host and cellular functions. The objective of this project was to determine if feeding a microencapsulated product comprised of a blend of organic acids and botanicals (AviPlus®P) impacts the intestinal kinome of broiler chickens (Gallus gallus). Day-of-hatch chicks were provided 0 or 500g/MT of the additive and jejunal and ileal segments collected for kinome analysis to determine the mode-of-action of the additive. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was performed by uploading the statistically significant peptides to the Search Tool for the Retrieval of Interacting Genes database. As a whole, GO and KEGG analysis showed similar activities in the ileum and jejunum. However, there were a small number of KEGG pathways that were only activated in either the ileum or jejunum, but not both. Analysis of the adipocytokine and PI3K-AKT signaling pathways showed differences between ileal and jejunal activity that were controlled, in part, by AKT3. Additionally, cytokine/chemokine evaluation showed the ileum had higher IL1ß, IL6, IL10, TNFα, IFNγ, CXCL8, and CCL4 mRNA expression levels (P<0.05). As a whole, the data showed the addition of microencapsulated organic acids and botanicals to a broiler diet activated many of the same signaling pathways in the ileum and jejunum; however, distinctions were observed. Taken together, the findings of this study begin to define the mode-of-action that microencapsulated organic acids and botanicals have on two important intestinal segments responsible for nutrient digestion and absorption in chickens.


Assuntos
Ácidos/farmacologia , Dieta/veterinária , Íleo/metabolismo , Jejuno/metabolismo , Compostos Fitoquímicos/farmacologia , Proteínas Quinases/metabolismo , Ração Animal/análise , Animais , Galinhas , Perfilação da Expressão Gênica , Íleo/efeitos dos fármacos , Jejuno/efeitos dos fármacos , Plantas/química , Análise Serial de Proteínas , Proteínas Quinases/genética
15.
PLoS One ; 15(6): e0234920, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32559224

RESUMO

Sanguinarine is a bioactive compound as a quaternary benzophenanthridine alkaloid from plant of the Macleaya cordata, Papaveraceae family. The present study was conducted to investigate the effects of dietary sanguinarine supplementation on growth performance, serum biochemistry parameters, intestinal mucosal morphology and gut microbiome in yellow feathered broilers. Two hundred and seventy 1-d-old female broilers were randomly assigned to 3 treatments ① Basal diet (NG); ② Basal diet containing bacitracin methylene disalicylate (50mg/Kg diet) (ANT); ③ Basal diet containing sanguinarine (0.7 mg/ kg of feed) (SAG). The statistical results showed that dietary sanguinarine supplementation enhanced growth performance and decreased glucose, uric acid as well as urea nitrogen levels of broilers at 28d of age (P<0.05). The 16S rRNA gene sequence analysis revealed that sanguinarine significantly decreased the species from the phyla Bacteroidetes, and increased the species from phyla Firmicutes. Moreover, dietary sanguinarine supplementation improved mucosal morphology to achieve higher ratio of intestinal villus height to crypt depth (P < 0.05), and decreased the concentrations of TNF-α and IL-4 in jejunum mucosal. This study demonstrated that sanguinarine supplementation in the diet of yellow feathered broilers improved intestinal morphology and microbiota community structure to promote growth performance on 1-28d.


Assuntos
Anti-Infecciosos/farmacologia , Benzofenantridinas/farmacologia , Galinhas/microbiologia , Microbioma Gastrointestinal , Isoquinolinas/farmacologia , Jejuno/efeitos dos fármacos , Animais , Anti-Infecciosos/administração & dosagem , Proteínas Aviárias/genética , Proteínas Aviárias/metabolismo , Bacteroidetes/efeitos dos fármacos , Bacteroidetes/patogenicidade , Benzofenantridinas/administração & dosagem , Glicemia/metabolismo , Galinhas/crescimento & desenvolvimento , Suplementos Nutricionais , Feminino , Firmicutes/efeitos dos fármacos , Firmicutes/patogenicidade , Interleucina-4/genética , Interleucina-4/metabolismo , Isoquinolinas/administração & dosagem , Jejuno/crescimento & desenvolvimento , Jejuno/metabolismo , Jejuno/microbiologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Ácido Úrico/sangue
16.
J Nutr ; 150(7): 1782-1789, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32359147

RESUMO

BACKGROUND: Methionine is an essential amino acid (AA) with many fundamental roles. Humans often supplement l-Met, whereas dl-Met and dl-2-hydroxy-4-(methylthio)butanoic acid (dl-HMTBA) are more frequently used to supplement livestock. OBJECTIVES: The study aimed to investigate whether dietary Met source alters the absorptive capacity for Met isomers in the small intestine of piglets. METHODS: A total of 27 male 10-wk-old piglets in 3 feeding groups received a diet supplemented with 0.21% dl-Met, 0.21% l-Met, or 0.31% dl-HMTBA to meet the Met + cystine requirement. After ≥10 d, absorptive fluxes of d-Met or l-Met were measured at a physiological concentration of 50 µM and a high concentration of 5 mM in duodenum, middle jejunum, and ileum ex vivo. Data were compared by 2-factor ANOVA. RESULTS: Across diets, fluxes of both Met isomers at both tested concentrations increased from duodenum to ileum by a factor of ∼2-5.5 (P < 0.05). Pigs supplemented with dl-Met had greater (P < 0.085) absorptive fluxes at 50 µM l-Met (0.50, 2.07, and 3.86 nmol · cm-2 · h-1) and d-Met (0.62, 1.41, and 1.19 nmol · cm-2 · h-1) than did pigs supplemented with dl-HMTBA (l-Met: 0.28, 0.76, and 1.08 nmol · cm-2 · h-1; d-Met: 0.34, 0.58, and 0.64 nmol · cm-2 · h-1) in duodenum, jejunum, and ileum, respectively. Only in jejunum of dl-Met-fed pigs, fluxes at 50 µM l-Met were reduced by the omission of luminal Na+ (from 3.27 to 0.86 nmol · cm-2 · h-1; P < 0.05) and by a cocktail of 22 luminal AAs (to 1.05 nmol · cm-2 · h-1; P < 0.05). CONCLUSIONS: Dietary supplementation of dl-Met increases the efficiency of l-Met and d-Met absorption at physiologically relevant luminal Met concentrations along the small intestine of pigs, including a very prominent induction of an Na+-dependent transport system with preference for l-Met in the mid-jejunum. Dietary supplementation with dl-Met could be a promising tool to improve the absorption of Met and other AAs.


Assuntos
Jejuno/efeitos dos fármacos , Jejuno/fisiologia , Metionina/farmacologia , Sódio/farmacologia , Suínos , Aminoácidos , Ração Animal , Fenômenos Fisiológicos da Nutrição Animal , Animais , Transporte Biológico , Dieta/veterinária , Suplementos Nutricionais , Masculino , Metionina/administração & dosagem , Sódio/administração & dosagem
17.
Arch Anim Nutr ; 74(4): 296-308, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32308036

RESUMO

Grape pomace (GP) is an abundant by-product from wine production and is rich in phenolic compounds, unsaturated fatty acids, dietary fibre and beneficial bacteria. In this study, weaned piglets were fed a basic diet supplemented with 5% GP for 4 weeks. Compared with those in the control (CON) group, it was found that the proportion of Lactobacillus delbrueckii, Olsenella umbonata and Selenomonas bovis in the caecum and the villus height and villus height/crypt depth ratio (VCR) of the jejunum were both significantly increased in the GP group (p < 0.05). Meanwhile, at the mRNA expression level, several proinflammatory cytokines (IL-1ß, IL-8, IL-6 and TNF-α) were significantly downregulated (p < 0.05) in piglet caecal tissue, and the short-chain fatty acid receptors (GPR41 and GPR43) were not significantly upregulated. In contrast, the levels of IgG was significantly increased (p < 0.05) in the sera of weaned piglets in the GP group. However, no difference in growth performance between the two groups of piglets was detected. These results show that GP had no adverse effects on the growth performance of piglets, but GP can promote the content of some beneficial bacteria in the caecum; this effect is conducive to improving the disease resistance potential of piglets.


Assuntos
Bactérias/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Sus scrofa/crescimento & desenvolvimento , Sus scrofa/microbiologia , Vitis/química , Actinobacteria/metabolismo , Ração Animal/análise , Animais , Ceco/efeitos dos fármacos , Ceco/microbiologia , DNA Bacteriano/análise , DNA Ribossômico/análise , Dieta/veterinária , Suplementos Nutricionais/análise , Feminino , Frutas/química , Jejuno/efeitos dos fármacos , Jejuno/fisiologia , Lactobacillus delbrueckii/metabolismo , Masculino , Probióticos , Distribuição Aleatória , Selenomonas/metabolismo
18.
J Med Chem ; 63(8): 4306-4314, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32223141

RESUMO

We report for the first time a novel series of tellurides bearing sulfonamide as selective and potent inhibitors of the ß-class carbonic anhydrase (CA; EC 4.2.1.1) enzyme expressed in Leishmania donovani protozoa. Such derivatives showed high activity against axenic amastigotes, and among them, compound 5g (4-(((3,4,5-trimethoxyphenyl)tellanyl)methyl)benzenesulfonamide) showed an IC50 of 0.02 µM being highly selective for the parasites over THP-1 cells with a selectivity index of 300. The in vitro and in vivo toxicity experiments showed compound 5g to possess a safe profile and thus paving the way for tellurium-containing compounds as novel drug entities.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Leishmania donovani/efeitos dos fármacos , Sulfonamidas/farmacologia , Tripanossomicidas/farmacologia , Animais , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Feminino , Jejuno/efeitos dos fármacos , Jejuno/patologia , Leishmania donovani/fisiologia , Técnicas de Cultura de Órgãos , Ratos , Ratos Wistar , Sulfonamidas/química , Tripanossomicidas/química
19.
PLoS One ; 15(4): e0224720, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32348301

RESUMO

Small intestinal strangulation associated with ischaemia-reperfusion injury (IRI) is common in horses. In laboratory animals IRI can be ameliorated by ischaemic preconditioning (IPC) and pharmacological preconditioning (PPC) with dexmedetomidine. The aim of this study was to determine the effect of PPC with dexmedetomidine or IPC in an equine model of small intestinal ischaemia-reperfusion (IR). In a randomized controlled experimental trial, 15 horses were assigned to three groups: control (C), IPC, and PPC with dexmedetomidine (DEX). All horses were placed under general anaesthesia and 90% jejunal ischaemia was induced for 90 minutes, followed 30 minutes of reperfusion. In group IPC, three short bouts of ischaemia and reperfusion were implemented, and group DEX received a continuous rate infusion of dexmedetomidine prior to the main ischaemia. Jejunal biopsies were collected before ischaemia (P), and at the end of ischaemia (I) and reperfusion (R). Mucosal injury was assessed by the Chiu-Score, inflammatory cells were stained by cytosolic calprotectin. The degree of apoptosis and cell necrosis was assessed by cleaved-caspase-3 and TUNEL. Parametric data were analyzed by two-way ANOVA for repeated measurements followed by Dunnetts t-test. Non parametric data were compared between groups at the different time points by a Kruskal-Wallis-Test and a Wilcoxon-2-Sample-test. The mucosal injury score increased during I in all groups. After reperfusion, IRI further progressed in group C, but not in IPC and DEX. In all groups the number of cleaved caspase-3 and TUNEL positive cells increased from P to I. The number of TUNEL positive cells were lower in group DEX compared to group C after I and R. Infiltration with calprotectin positive cells was less pronounced in group DEX compared to group C, whereas in group IPC more calprotectin positive cells were seen. In conclusion, IPC and DEX exert protective effects in experimental small intestinal ischaemia in horses.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Dexmedetomidina/uso terapêutico , Isquemia/terapia , Precondicionamento Isquêmico/métodos , Jejuno/irrigação sanguínea , Traumatismo por Reperfusão/terapia , Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Dexmedetomidina/administração & dosagem , Dexmedetomidina/farmacologia , Cavalos , Isquemia/tratamento farmacológico , Jejuno/efeitos dos fármacos , Jejuno/patologia , Distribuição Aleatória , Traumatismo por Reperfusão/tratamento farmacológico
20.
Poult Sci ; 99(4): 2078-2086, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32241493

RESUMO

This study was conducted to evaluate the effects of grape seed extract (GSE) on growth performance, immunity, antioxidant capacity, relative organ weight, jejunum morphology, ileal microflora, and meat quality in Pekin ducks. A total of 1,500 female 1-day-old Pekin ducklings (52.0 ± 0.2 g) were blocked based on body weight (BW) and randomly allocated into 3 treatments with 10 replicates of 50 birds each. The experiment lasted for 6 wk, and dietary treatments included corn-soybean meal-based diet supplemented with 0, 0.01, and 0.02% GSE. The supplementation of GSE increased (P < 0.05) body weight gain (BWG) and final BW linearly but decreased (P < 0.05) feed-to-gain ratio (F/G) linearly during day (D) 22 to 42 and the entire experiment. The inclusion of GSE increased (P < 0.05) serum superoxide dismutase, glutathione peroxidase, total antioxidative capacity, catalase, complement4, immunoglobin G, interleukin-2, and interferon-γ linearly but decreased (P < 0.05) serum malondialdehyde linearly. The relative weight of carcass, breast meat, and spleen in GSE treatments was increased (P < 0.05) linearly, whereas the relative weight of abdominal fat was decreased linearly (P < 0.05). Birds fed GSE1 and GSE2 diets had lower (P < 0.05) cook loss, 2-thiobarbituric acid reactive substances, and drip loss on day 3 and 5 linearly but higher (P < 0.05) pH24h and water-holding capacity. The addition of GSE decreased (P < 0.05) jejunum crypt depth and ileal Escherichia coli counts linearly but increased (P < 0.05) jejunum villus height: crypt depth ratio and ileal Lactobacilli linearly. Taken together, the inclusion of GSE increased final BW and BWG, decreased F/G during day 22 to 42 and day 1 to 42, partially improved antioxidant activities, immunity, meat quality, and gut health in Pekin ducks.


Assuntos
Antioxidantes/metabolismo , Patos/fisiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Extrato de Sementes de Uva/metabolismo , Imunidade/efeitos dos fármacos , Jejuno/efeitos dos fármacos , Carne/análise , Ração Animal/análise , Animais , Dieta/veterinária , Suplementos Nutricionais/análise , Relação Dose-Resposta a Droga , Patos/crescimento & desenvolvimento , Patos/imunologia , Patos/microbiologia , Feminino , Extrato de Sementes de Uva/administração & dosagem , Íleo/microbiologia , Jejuno/anatomia & histologia , Tamanho do Órgão/efeitos dos fármacos , Distribuição Aleatória
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