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1.
Toxicon ; 187: 57-64, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32882257

RESUMO

There is a lack of information available on the anorexic action of fusarenon-x (FX), which is a sesquiterpenoid mycotoxin. In this study, we investigated the changes in the hypothalamus and small intestine related to appetite after oral FX exposure. The time-course change of food intake after oral FX exposure (0.5, 1.0, and 2.5 mg/kg bw) in B6C3F1 mice showed that 2.5 mg/kg bw of FX significantly suppressed food intake during 3-6 h compared to the control. Furthermore, the total food intake for 24 h was lower in the group exposed to FX than in the control. The FX exposure (2.5 mg/kg bw for 3 h) significantly increased mRNA levels of anorexic hormones (pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcription (CART)) without changing the mRNA levels of orexigenic hormones. In addition, FX exposure indicated significantly higher mRNA levels of possible downstream targets of anorexic POMC neurons, such as the melanocortin 4 receptor (MC4R), brain-derived neurotrophic factor (BDNF) and tyrosine kinase receptor B (TrkB), in the hypothalamus compared to the control. FX exposure also significantly increased the mRNA level of inflammatory cytokines (tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß)) and activated nuclear factor-kappa B (NF-κB), which is a regulatory factor for POMC in the hypothalamus. In the intestine, FX exposure did not affect the mRNA level of anorexic peptide YY but significantly elevated that of anorexic cholecystokinin (CCK) and regulatory factors for CCK (calcium-sensing receptor (CaSR), the transient receptor potential ankyrin-1 channel (TRPA1), and transient receptor potential cation channel subfamily M member 5 (TRPM5)). These results suggest that FX sequentially induces inflammatory cytokine expression, NF-κB activation, and POMC expression in the hypothalamus. FX also induces CCK expression in the intestine possibly via induction of CaSR, TRPM5, and TRPA1 expression. These changes will eventually lead to the anorexic action of FX.


Assuntos
Hipotálamo/efeitos dos fármacos , Intestinos/efeitos dos fármacos , Tricotecenos/toxicidade , Animais , Anorexia , Masculino , Camundongos , NF-kappa B/metabolismo , Pró-Opiomelanocortina , Receptor Tipo 4 de Melanocortina
2.
Life Sci ; 261: 118463, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32950576

RESUMO

AIMS: Ionizing radiation (IR) induces injuries to the hematopoietic and intestinal systems, which are the leading cause of death. Baicalein, a plant-derived flavonoid, shows anti-oxidative stress, anti-apoptosis, anti-inflammation effects in many diseases. In this study, we evaluated the effects and mechanism of baicalein on IR induced intestinal and hematopoietic injuries. MAIN METHODS: Mice were divided into three groups: Control, IR and IR + Baicalein. All of mice were intraperitoneally administered with 100 mg/kg baicalein or normal saline for 1 h before IR, and then a day post-IR. The changes in intestinal structure, function and molecular expression were observed by pathological experiments and western blot. 16S rRNA gene sequencing was performed to analyze gut microbiota and further predicted metabolic pathways through Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Hematopoietic function was evaluated by peripheral blood cells count and by flow cytometry analysis of hematopoietic cells composition. KEY FINDINGS: Baicalein improved intestinal structure and the ability of proliferation and regeneration after mice exposed to IR, in which the rebalance of gut microbial composition played an important role. KEGG results showed that p53-related apoptotic pathways played important roles in the composition changes of gut microbiota. Then we observed that baicalein inhibited the activation of p53 and p53 mediated mitochondrial apoptosis and death receptor apoptosis in the intestine. In addition, IR induced injuries to hematopoietic system also could be ameliorated by baicalein. SIGNIFICANCE: These results provide new insights into the mechanism of baicalein and support the potential of baicalein as a radioprotective medicine.


Assuntos
Flavanonas/uso terapêutico , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos da radiação , Lesões Experimentais por Radiação/tratamento farmacológico , Protetores contra Radiação/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Intestinos/efeitos dos fármacos , Intestinos/patologia , Intestinos/efeitos da radiação , Masculino , Camundongos Endogâmicos C57BL , Lesões Experimentais por Radiação/microbiologia , Lesões Experimentais por Radiação/patologia , Radiação Ionizante
3.
Ecotoxicol Environ Saf ; 205: 111376, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32961488

RESUMO

Deoxynivalenol (DON) is extensively detected in many kinds of foods and feeds to harm human and animal health. This research aims to investigate the effect of chlorogenic acid (CGA) on alleviating inflammation and apoptosis of swine jejunal epithelial cells (IPEC-J2) triggered by DON. The results demonstrated that cell viability was decreased when DON concentrations increased or incubation time expanded. The pretreatment with CGA (40 µg/mL) for 1 h increased cell viability, decreased lactate dehydrogenase (LDH) release and apoptosis in cells triggered by DON at 0.5 µg/mL for 6 h, compared with the DON alone-treated cells. Moreover, the mRNA abundances of IL-8, IL-6, TNF-α, COX-2, caspase-3, Bax and ASCT2 genes, and protein expressions of COX-2, Bax and ASCT2 were significantly down-regulated; while the mRNA abundances of ZO-1, claudin-1, occludin, PePT1 and GLUT2 genes, and protein expressions of ZO-1, claudin-1 and PePT1 were significantly up-regulated in the CGA + DON group, compared with the DON alone group. This study indicated that CGA pretreatment alleviated cytotoxicity, inflammation and apoptosis in DON-triggered IPEC-J2 cells, and protected intestinal cell integrity from DON damages.


Assuntos
Ácido Clorogênico/farmacologia , Substâncias Protetoras/farmacologia , Tricotecenos/toxicidade , Animais , Apoptose/efeitos dos fármacos , Caspase 3 , Contagem de Células , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ácido Clorogênico/metabolismo , Células Epiteliais/efeitos dos fármacos , Inflamação/metabolismo , Intestinos/efeitos dos fármacos , Ocludina/genética , Suínos
4.
PLoS One ; 15(8): e0237505, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32790727

RESUMO

Increased intestinal permeability (IP) and inflammation are both linked with functionality of the intestinal barrier and in particular enterocytes. Currently, almost all assessment methods of the intestinal barrier function are invasive. The present study aimed to quantify selected proteins as novel biomarkers in excreta of broiler chickens to facilitate non-invasive assessment of gut barrier function using enzyme-linked immunosorbent assays (ELISA). It was further hypothesised that probiotics as feed additives may counteract gut barrier dysfunction. A 3 × 2 factorial arrangement of treatments was used with the main factors being gut barrier dysfunction models (control, rye-based diet, and dexamethasone-DEX) with and without probiotic supplementation (a three-strain Bacillus) using 72 male Ross 308 day-old chickens. Each of the 6 experimental treatments was replicated 12 times. On d 21 of age, fluorescein isothiocyanate dextran (FITC-d) uptake into serum was examined to test IP. Fresh excreta samples were collected on d 20. The biomarkers included alpha-1 antitrypsin (A1AT), intestinal fatty acid binding protein (I-FABP), lipocalin-2 (LCN2), fibronectin (FN), intestinal alkaline phosphatase (IAP), ovotransferrin (OVT) and superoxide dismutase [Cu-Zn] (SOD1). Only DEX increased (P<0.001) FITC-d passage to the blood on d 21 of age, indicating a greater IP. The excreta concentrations of A1AT, I-FABP and SOD1 were unaltered by the experimental treatments. DEX increased (P<0.05) FN concentration in excreta compared with control birds. Conversely, inclusion of rye in the diet reduced (P<0.05) FN but increased (P<0.001) OVT in excreta. Independently, DEX decreased IAP (P<0.05) in excreta compared with control and rye-fed birds. The excreta concentration of LCN2 tended (P = 0.086) to increase in birds injected by DEX. There was no demonstrable effect of probiotic addition on any of the studied parameters. Among the tested biomarkers, FN, IAP, and LCN2 revealed promise as biomarkers of intestinal barrier function quantified by ELISA kits.


Assuntos
Ração Animal/análise , Biomarcadores/análise , Dieta/veterinária , Fezes/química , Microbioma Gastrointestinal/efeitos dos fármacos , Intestinos/patologia , Probióticos/farmacologia , Animais , Permeabilidade da Membrana Celular , Galinhas , Suplementos Nutricionais , Intestinos/efeitos dos fármacos , Masculino
5.
Ecotoxicol Environ Saf ; 204: 111124, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32805504

RESUMO

Dechlorane Plus (DP) is a typical polychlorinated flame retardant that has been emerged in chemical products. Due to its accumulation and amplification effect, the toxicity of DP has become a widespread environmental safety issue. However, whether DP can affect the intestinal tract of teleost fish remains largely unclear. To understand its effects on the intestinal barrier, morphological characteristics and intestinal microbiome of common carp, different concentrations (30, 60 and 120 µg/L) of DP were exposed to common carps for 4 weeks. The results indicated that DP evidently shortened the intestinal folds and damaged the intestinal epithelium layer. In addition, the mRNA expression levels of occludin, claudin-2 and zonula occludens-1 (ZO-1) were significantly decreased with increasing DP concentrations. Furthermore, the relative abundance of some microbiota species were also changed significantly. Our study first demonstrated that DP could cause damage to the intestinal epithelium and destroy the intestinal barrier and increase the relative abundance of pathogenic bacteria, thereby increasing the probability of contact between intestinal epithelium and pathogenic bacteria, which in turn lead to an increased susceptibility to various diseases and poor health. In summary, our findings reveal that chronic DP exposure can have a harmful effect on the intestinal flora balance and is potentially linked to human disease.


Assuntos
Carpas/microbiologia , Retardadores de Chama/toxicidade , Microbioma Gastrointestinal/efeitos dos fármacos , Hidrocarbonetos Clorados/toxicidade , Compostos Policíclicos/toxicidade , Animais , Bactérias/efeitos dos fármacos , Mucosa Intestinal , Intestinos/efeitos dos fármacos , Microbiota
6.
PLoS One ; 15(8): e0237357, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32780763

RESUMO

Fermented feeds contain abundant organic acids, amino acids, and small peptides, which improve the nutritional status as well as the morphology and microbiota composition of the intestine. Ginseng polysaccharides exhibit several biological activities and contribute to improving intestinal development. Here, Xuefeng black-bone chickens were fed a basal diet fermented by Bacillus subtilis, Saccharomyces cerevisiae, Lactobacillus plantarum, and Enterococcus faecium, with or without ginseng polysaccharides. The 100% microbially fermented feed (Fe) and 100% microbially fermented feed and ginseng polysaccharide (FP) groups showed significantly increased villus height and villus height to crypt depth ratio, and decreased crypt depth in the jejunum. In the 100% complete feed and ginseng polysaccharide (Po) group, the villus height to crypt depth ratio was significantly increased, crypt depth was reduced, and villus height remained unaffected. Next, we studied the intestinal microbial composition of 32 Xuefeng black-bone chickens. A total of 10 phyla and 442 genera were identified, among which Firmicutes, Proteobacteria, and Bacteroidetes were the most dominant phyla. At the genus level, Sutterella and Asteroleplasma abundance increased and decreased, respectively, in the FP and Po groups. Sutterella abundance was positively correlated to villus height and villus height to crypt depth ratio, and negatively correlated to crypt depth, and Asteroleplasma abundance was positively correlated to crypt depth and negatively correlated to villus height to crypt depth ratio. At the species level, the FP group showed significantly increased Bacteroides_vulgatus and Eubacterium_tortuosum and decreased Mycoplasma_gallinarum and Asteroleplasma_anaerobium abundance, and the Po group showed significantly increased Mycoplasma_gallinarum and Asteroleplasma_anaerobium abundance. Moreover, bacterial abundance was closely related to the jejunum histomorphology. Asteroleplasma_anaerobium abundance was positively correlated with crypt depth and negatively correlated with villus height to crypt depth ratio. Mycoplasma_gallinarum abundance was positively correlated to villus height, and Bacteroides_vulgatus and Eubacterium_tortuosum abundance was positively correlated with villus height to crypt depth ratio and negatively correlated with crypt depth. Therefore, fermented feeds with ginseng polysaccharides may be used as effective alternatives to antibiotics for improving intestinal morphology and microbial composition.


Assuntos
Ração Animal , Galinhas , Fermentação , Intestinos/efeitos dos fármacos , Microbiota/efeitos dos fármacos , Panax/química , Polissacarídeos/farmacologia , Animais , Biodiversidade , Intestinos/citologia , Intestinos/microbiologia
7.
Arterioscler Thromb Vasc Biol ; 40(9): 2084-2094, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32673528

RESUMO

OBJECTIVE: Increased postprandial lipemia (PPL) is an independent risk factor for atherosclerotic cardiovascular diseases. PCSK9 (Proprotein convertase subtilisin kexin type 9) is an endogenous inhibitor of the LDLR (low-density lipoprotein receptor) pathway. We previously showed that PCSK9 inhibition in mice reduces PPL. However, the relative contribution of intracellular intestinal PCSK9 or liver-derived circulating PCSK9 to this effect is still unclear. Approach and Results: To address this issue, we generated the first intestine-specific Pcsk9-deficient (i-Pcsk9-/-) mouse model. PPL was measured in i-Pcsk9-/- as well as in wild-type and streptozotocin-induced diabetic mice following treatment with a PCSK9 monoclonal antibody (alirocumab). Blocking the circulating form of PCSK9 with alirocumab significantly reduced PPL, while overexpressing human PCSK9 in the liver of full Pcsk9-/- mice had the opposite effect. Alirocumab regulated PPL in a LDLR-dependent manner as this effect was abolished in Ldlr-/- mice. In contrast, i-Pcsk9-/- mice did not exhibit alterations in plasma lipid parameters nor in PPL. Finally, PPL was highly exacerbated by streptozotocin-induced diabetes mellitus in Pcsk9+/+ but not in Pcsk9-/- mice, an effect that was mimicked by the use of alirocumab in streptozotocin-treated Pcsk9+/+ mice. CONCLUSIONS: Taken together, our data demonstrate that PPL is significantly altered by full but not intestinal PCSK9 deficiency. Treatment with a PCSK9 monoclonal antibody mimics the effect of PCSK9 deficiency on PPL suggesting that circulating PCSK9 rather than intestinal PCSK9 is a critical regulator of PPL. These data validate the clinical relevance of PCSK9 inhibitors to reduce PPL, especially in patients with type 2 diabetes mellitus.


Assuntos
Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Tipo 2/sangue , Hiperlipidemias/sangue , Intestinos/enzimologia , Lipídeos/sangue , Pró-Proteína Convertase 9/sangue , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/enzimologia , Hiperlipidemias/enzimologia , Hiperlipidemias/genética , Hiperlipidemias/prevenção & controle , Hipolipemiantes/farmacologia , Intestinos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Período Pós-Prandial , Pró-Proteína Convertase 9/antagonistas & inibidores , Pró-Proteína Convertase 9/deficiência , Pró-Proteína Convertase 9/genética , Receptores de LDL/genética , Receptores de LDL/metabolismo
8.
Am J Physiol Cell Physiol ; 319(2): C321-C330, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32551856

RESUMO

Acetylcholine induces robust electrogenic anion secretion in mammalian intestine and it has long been hypothesized that it mediates the epithelial response through the M3 and, to a lesser extent, the M1 muscarinic receptors in the mouse. However, nicotinic receptors have recently been identified in intestinal enterocytes by quantitative real-time (qRT)-PCR/RNAseq, although any direct influence on intestinal transport has not been identified. We tested the hypothesis that cholinergic-induced anion secretion in the intestine is a result of both muscarinic and nicotinic pathways that are intrinsic to the intestinal epithelia. We developed a method to generate mouse jejunal enteroid monolayers which were used to measure active electrogenic anion secretion by the Ussing chamber/voltage-clamp technique. Here, we show that the cholinergic agonist carbachol (CCh) and the muscarinic agonist bethanechol (BCh) stimulate short-lived, concentration-dependent anion secretion in the epithelial cell-only enteroid monolayers. The muscarinic antagonist atropine completely inhibited CCh- and BCh-induced secretion, while the nicotinic antagonist hexamethonium reduced the CCh response by ~45%. While nicotine alone did not alter anion secretion, it increased the BCh-induced increase in short-circuit current in a concentration-dependent manner; this synergy was prevented by pretreatment with hexamethonium. In addition to being sensitive to hexamethonium, monolayers express both classes of cholinergic receptor by qRT-PCR, including 13 of 16 nicotinic receptor subunits. Our findings indicate that an interaction between muscarinic and nicotinic agonists synergistically stimulates anion secretion in mouse jejunal epithelial cells and identify a role for epithelial nicotinic receptors in anion secretion.


Assuntos
Agonistas Muscarínicos/farmacologia , Sistema Colinérgico não Neuronal/genética , Receptores Muscarínicos/genética , Receptores Nicotínicos/genética , Acetilcolina/farmacologia , Animais , Ânions/metabolismo , Atropina/farmacologia , Agonistas Colinérgicos/farmacologia , Enterócitos/efeitos dos fármacos , Enterócitos/metabolismo , Hexametônio/farmacologia , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Camundongos , Sistema Colinérgico não Neuronal/efeitos dos fármacos , Receptores Muscarínicos/metabolismo , Receptores Nicotínicos/metabolismo
9.
Am J Physiol Gastrointest Liver Physiol ; 319(1): G63-G73, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32538139

RESUMO

Hyaluronic acid (HA), a glycosaminoglycan in the extracellular matrix, binds to CD44 and Toll-like receptor 4 (TLR4). We previously demonstrated that both CD44 and TLR4, but predominately TLR4, mediated HA stimulation of Lgr5+ stem cell proliferation, crypt fission, and intestinal growth in postnatal mice. Here we address the questions of which cell type expresses the relevant TLR4 in driving intestinal growth and what are the downstream events from TLR4 activation. Studies were done in 14-day-old mice: wild type (WT), mice deficient in cyclooxygenase 2 (COX2), mice deficient in myeloid cell TLR4, and mice deficient in epithelial cell epidermal growth factor receptor (EGFR). Biological end points included crypt fission and Lgr5 cell proliferation. In WT mice, treatment with NS-398 (a COX2 inhibitor), clodronate (a macrophage-depleting agent), or tyrphostin (an EGFR inhibitor) resulted in 30% reductions in crypt fission and Lgr5+ stem cell proliferation compared with control mice. Mice deficient in COX2 or myeloid TLR4 or epithelial cell EGFR all had 30% reductions in crypt fission and Lgr5+ stem cell proliferation compared with WT mice. Administration of dimethyl PGE2, a stable PGE2 analog, increased crypt fission and Lgr5+ stem cell proliferation. Administration of dimethyl PGE2 reversed the effects of NS-398, clodronate, COX2 deficiency, and myeloid TLR4 deficiency but had no effect on mice treated with tyrphostin or mice deficient in epithelial cell EGFR. We conclude that, in postnatal mice, ~30% of intestinal growth as manifested by crypt fission and Lgr5+ stem cell proliferation is driven by a novel pathway: Extracellular HA binds TLR4 on pericryptal macrophages, inducing the production of PGE2 through COX2. PGE2 transactivates EGFR in Lgr5+ epithelial stem cells, resulting in Lgr5+ stem cell proliferation and crypt fission.NEW & NOTEWORTHY This study, in newborn mice, describes a novel molecular pathway regulating Lgr5+ epithelial stem cell proliferation and normal intestinal elongation, as assessed by crypt fission. In this pathway, endogenous extracellular hyaluronic acid binds to Toll-like receptor 4 on pericryptal macrophages releasing PGE2 which binds to epidermal growth factor receptor on Lgr5+ stem cells resulting in proliferation. Lgr5+ stem cell proliferation leads to crypt fission and intestinal elongation. The demonstration that normal growth requires microbial-independent Toll-like receptor activation is novel.


Assuntos
Dinoprostona/metabolismo , Receptores ErbB/efeitos dos fármacos , Ácido Hialurônico/farmacologia , Receptor 4 Toll-Like/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Receptores ErbB/metabolismo , Ácido Hialurônico/antagonistas & inibidores , Intestinos/efeitos dos fármacos , Camundongos Knockout , Receptor 4 Toll-Like/metabolismo , Ativação Transcricional/efeitos dos fármacos
10.
Ecotoxicol Environ Saf ; 201: 110857, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32534332

RESUMO

Caenorhabditis elegans is sensitive to toxicity of environmental pollutants. The alteration in expression of mir-794, a microRNA (miRNA) molecule, mediated a protective response to nanopolystyene (100 nm) at predicted environmental concentration (1 µg/L) in nematodes. However, the underlying molecular basis for mir-794 function in regulating the response to nanopolystyrene remains largely unclear. In this study, we found that intestinal overexpression of mir-794 caused the susceptibility to nanopolystyrene toxicity, suggesting that mir-794 acted in the intestine to regulate the response to nanopolystyrene. Intestinal overexpression of mir-794 further decreased the expressions of daf-16 encoding a FOXO transcriptional factor in insulin signaling pathway, skn-1 encoding a Nrf transcriptional factor in p38 MAPK signaling pathway, and mdt-15 encoding a lipid metabolic sensor acting downstream of SKN-1 in nanopolystyrene exposed nematodes. Meanwhile, intestinal overexpression of mir-794 could suppress the resistance of nematodes overexpressing intestinal daf-16, skn-1, or mdt-15 containing the corresponding 3' untranslated region (3' UTR) to nanopolystyrene toxicity. Therefore, DAF-16, SKN-1, and MDT-15 acted as the downstream targets of intestinal mir-794 to regulate the response to nanopolystyrene. In the intestine, DAF-16 functioned synergistically with SKN-1 or MDT-15 to regulate the response to nanopolystyrene. Our results suggested that the intestinal mir-794 provided an important epigenetic regulation mechanism to control the response to nanopolystyrene by linking insulin and p38 MAPK signaling pathways in nematodes.


Assuntos
Caenorhabditis elegans/efeitos dos fármacos , Insulina/metabolismo , Intestinos/efeitos dos fármacos , MicroRNAs/metabolismo , Nanopartículas/toxicidade , Poliestirenos/toxicidade , Poluentes do Solo/toxicidade , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Epigênese Genética , Regulação da Expressão Gênica , Lipídeos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , MicroRNAs/genética , Fatores de Transcrição/genética
11.
J Nutr ; 150(8): 2070-2076, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32470983

RESUMO

BACKGROUND: Dietary supplemental nicotinamide is used to treat hyperphosphatemia in humans. However, the mechanisms of its impact on body phosphorus homeostasis remain unclear. OBJECTIVE: This study was to determine effects and molecular mechanisms of 3 dietary nicotinamide concentrations on body phosphorus homeostasis in laying hens. METHODS: Hy-Line Brown layers (total = 21; 40 wk old; body weight: 1,876 ± 24 g) were individually housed (n = 7) and fed a corn-soybean meal-based diet supplemented with nicotinamide at 20 (N20), 140 (N140), and 1000 (N1000) mg/kg for 21 d. Serum phosphorus and fibroblast growth factor 23 (FGF23) concentrations, phosphorus and calcium excretion, and mRNA and/or protein of type II sodium-phosphate co-transporters (NPt2a, NPt2ab) and FGF23 and FGF23 receptors were measured in the intestines, calvaria, kidney, and liver. RESULTS: Hens in the N1000 group had a 16% lower serum phosphorus concentration and 22% greater phosphorus excretion than those in the N20 or N140 group (P ≤ 0.05). Compared with hens in the N20 group, hens in the N140 and N1000 groups, which did not differ, had 15-21% lower serum FGF23 concentrations, 19-22% greater calcium excretion, 43-56% lower ileum NPT2b protein production, and 1.5- to 1.6-fold greater kidney NPT2a protein production, respectively (all differences at P ≤ 0.05). CONCLUSIONS: Supplementing high concentrations of nicotinamide in diets for laying hens led to accelerated phosphorus and calcium excretions and decreased serum phosphorus and FGF23 concentrations, which were associated with downregulated intestinal NPt2b protein production. Our findings exclude kidney NPt2a protein production as a primary mechanism for the nicotinamide-induced body phosphorus loss.


Assuntos
Galinhas , Regulação da Expressão Gênica/efeitos dos fármacos , Niacinamida/farmacologia , Fósforo/metabolismo , Proteínas Cotransportadoras de Sódio-Fosfato Tipo II/metabolismo , Ração Animal/análise , Fenômenos Fisiológicos da Nutrição Animal , Animais , Dieta/veterinária , Suplementos Nutricionais , Relação Dose-Resposta a Droga , Feminino , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Glucuronidase/genética , Glucuronidase/metabolismo , Intestinos/efeitos dos fármacos , Intestinos/fisiologia , Rim/efeitos dos fármacos , Rim/metabolismo , Niacinamida/administração & dosagem , Oviposição , Receptores de Fatores de Crescimento de Fibroblastos/genética , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Proteínas Cotransportadoras de Sódio-Fosfato Tipo II/genética
12.
Ecotoxicol Environ Saf ; 200: 110742, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32470681

RESUMO

The accumulation of arsenic in rice has become a worldwide concern. In this study, dose-dependency in tissues (intestine, liver and kidney) and blood distribution of inorganic arsenicals and their methylated metabolites were investigated in male C57BL/6 mice exposed to four arsenic species (arsenite [iAs]III, arsenate [iAs]V, monomethylarsonate [MMA]V, and dimethylarsinate [DMA]V) at four doses (control [C]: 0 µg/g, simulation [S]: 0.91 µg/g, medium [M]: 9.1 µg/g and high [H]: 30 µg/g) according to the arsenical composition in rice for 8 and 16 weeks. No adverse effects were observed, while body weight gain decreased in group H. Increases in total arsenic concentrations (CtAs) and histopathological changes in the tissues occurred in all of the test groups. CtAs presented a tendency of kidney > intestine > liver > blood and were time-/dose-dependent in the liver and kidney in groups M and H. In the intestine and blood, abundant iAs (23%-28% in blood and 36%-49% in intestine) was detected in groups M and H, and CtAs decreased in group H from the 8th week to the 16th week. PMI decreased in the liver and SMI decreased in the kidney. These results indicate that the three tissues are injured through food arsenic. The intestine can also accumulate food arsenic, and the high arsenic dose will cause a deficiency in the absorbing function of the intestine. Thus, long-term exposure to arsenic-contaminated rice should be taken seriously attention.


Assuntos
Intoxicação por Arsênico , Arsenicais/farmacocinética , Animais , Arseniatos/farmacocinética , Arseniatos/toxicidade , Intoxicação por Arsênico/metabolismo , Intoxicação por Arsênico/patologia , Arsenitos/farmacocinética , Arsenitos/toxicidade , Ácido Cacodílico/farmacocinética , Ácido Cacodílico/toxicidade , Exposição Dietética , Intestinos/efeitos dos fármacos , Intestinos/patologia , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oryza/metabolismo
13.
PLoS Negl Trop Dis ; 14(5): e0007942, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32453724

RESUMO

Efforts to identify new drugs for therapeutic and preventive treatments against parasitic nematodes have gained increasing interest with expanding pathogen omics databases and drug databases from which new anthelmintic compounds might be identified. Here, a novel approach focused on integrating a pan-Nematoda multi-omics data targeted to a specific nematode organ system (the intestinal tract) with evidence-based filtering and chemogenomic screening was undertaken. Based on de novo computational target prioritization of the 3,564 conserved intestine genes in A. suum, exocytosis was identified as a high priority pathway, and predicted inhibitors of exocytosis were tested using the large roundworm (Ascaris suum larval stages), a filarial worm (Brugia pahangi adult and L3), a whipworm (Trichuris muris adult), and the non-parasitic nematode Caenorhabditis elegans. 10 of 13 inhibitors were found to cause rapid immotility in A. suum L3 larvae, and five inhibitors were effective against the three phylogenetically diverse parasitic nematode species, indicating potential for a broad spectrum anthelmintics. Several distinct pathologic phenotypes were resolved related to molting, motility, or intestinal cell and tissue damage using conventional and novel histologic methods. Pathologic profiles characteristic for each inhibitor will guide future research to uncover mechanisms of the anthelmintic effects and improve on drug designs. This progress firmly validates the focus on intestinal cell biology as a useful resource to develop novel anthelmintic strategies.


Assuntos
Anti-Helmínticos/farmacologia , Nematoides/efeitos dos fármacos , Animais , Células Cultivadas , Sistemas de Liberação de Medicamentos , Descoberta de Drogas , Intestinos/citologia , Intestinos/efeitos dos fármacos , Larva/efeitos dos fármacos
14.
Toxicol Appl Pharmacol ; 398: 115032, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32387182

RESUMO

BACKGROUND AND PURPOSE: Irinotecan-induced diarrhea (IID) results from intestinal damages by its active metabolite SN-38. Alleviation of these damages has focused on lowering luminal SN-38 concentrations. However, it is unclear if the enteric bioavailability of SN-38 is mostly dependent on luminal SN-38 concentrations. EXPERIMENTAL APPROACH: Irinotecan (50 mg/kg, i.p. once daily for 6 days) was administered to female wildtype FVB, Mdr1a (-/-), Mrp2 (-/-) and Bcrp1 (-/-) mice for pharmacokinetic (PK), toxicokinetic (TK) and biodistribution studies. Plasma PK/TK profiles and tissues drug distribution were determined after first or sixth daily doses, along with activities of blood and gut esterases and intestinal Ugts. Caco-2 cells and bile-cannulate mice were used to further investigate intestinal and biliary disposition of irinotecan and its metabolites. KEY RESULTS: Significant differences in IID severity were observed with the susceptible rank of Bcrp1(-/-) > wildtype FVB > Mdr1a(-/-) > Mrp2(-/-). This rank order did not correlate with biliary excretion rates of SN-38/SN-38G. Rather, the severity was best correlated (R = 0.805) with the intestinal ratio of Css SN-38/SN-38G, a measure of gut Ugt activity. On the contrary, IID was poorly correlated with plasma AUC ratio of SN-38/SN-38G (R = 0.227). Increased intestinal esterase activities due to repeated dosing and gut efflux transporter functionality are the other key factors that determine SN-38 enteric exposures. CONCLUSION AND IMPLICATIONS: Intestinal SN-38 exposure is mainly affected by intestinal Ugt activities and blood esterase activities, and strongly correlated with severity of IID. Modulating intestinal SN-38 concentration and gut Ugt expression should be the focus of future studies to alleviate IID.


Assuntos
Diarreia/induzido quimicamente , Glucuronosiltransferase/metabolismo , Intestinos/efeitos dos fármacos , Irinotecano/farmacologia , Animais , Antineoplásicos Fitogênicos , Área Sob a Curva , Bile/metabolismo , Sistema Biliar/efeitos dos fármacos , Sistema Biliar/metabolismo , Células CACO-2 , Linhagem Celular Tumoral , Diarreia/metabolismo , Esterases/metabolismo , Feminino , Humanos , Camundongos , Distribuição Tecidual/efeitos dos fármacos
15.
Toxicol Lett ; 331: 130-142, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32417428

RESUMO

Increasing production of corannulene (COR), a non-planar polycyclic aromatic hydrocarbon (PAH) with promising applications in many fields, has raised a concern about its potential toxic effects. However, no study has been undertaken to evaluate its metabolism and toxicity in mammals. In this study, the acute toxicities of COR in mice were compared with benzo[apyrene (BaP), a typical planar PAH with almost the same molecular weight. After 3-day exposures, the concentrations of COR in both plasma and tissues of mice were higher than that of BaP. However, blood chemistry and tissue weight monitoring showed no observable toxicities in COR-exposed mice. Compared to BaP, exposure to COR resulted in less activation of the aryl hydrocarbon receptor (AhR) and thus less induction of hepatic cytochrome P450 1A(CYP1A) enzymes, which play a critical role in metabolism of both COR and BaP. Additionally, COR also elicited less oxidative stress and microbiota alteration in the intestine than did BaP. RNA-seq analysis revealed that liver transcriptomes are responsive to COR and BaP, with less alterations observed in COR-exposed mice. Unlike BaP, exposure to COR had no effects on hepatic lipid and xenobiotic metabolism pathways. Nonetheless, COR appeared to alter the mRNA expressions of genes involved in carcinogenicity, oxidative stress, and immune-suppression. To conclude, this study for the first time unveils a comparative understanding of the acute toxic effects of COR to BaP in mice, and provides crucial insights into the future safety assessment of COR.


Assuntos
Benzo(a)pireno/toxicidade , Intestinos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Receptores de Hidrocarboneto Arílico/metabolismo , Administração Oral , Animais , Benzo(a)pireno/farmacocinética , Citocromo P-450 CYP1A1/biossíntese , Citocromo P-450 CYP1A2/biossíntese , Injeções Intraperitoneais , Intestinos/patologia , Fígado/metabolismo , Fígado/patologia , Testes de Função Hepática , Masculino , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos , Hidrocarbonetos Policíclicos Aromáticos/sangue , Hidrocarbonetos Policíclicos Aromáticos/farmacocinética , Ratos Sprague-Dawley , Superóxido Dismutase/sangue , Distribuição Tecidual
16.
Arch Anim Nutr ; 74(4): 325-342, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32362138

RESUMO

The objective of this study was to evaluate the effects of in ovo injection with glycerol (GLY) and insulin-like growth factor (IGF-I) on hatchability, biochemical parameters, intestinal morphometry, performance, and carcass characteristics of broiler chickens. A total of 400 fertilised eggs were distributed into five experimental groups. The treatments were arranged as non-injected (control), saline solution injected (0.9% NaCl solution), GLY solution injected (10 nmol/ml), IGF-I solution injected (100 ng/ml), and GLY + IGF-I solution injected. At 17.5 d of incubation, 0.5 ml of each solution was injected into the amniotic fluid of each egg of the injected groups. The injection of different solutions did not influence the hatchability and incubation time of the eggs. Compared to intact eggs, IGF-I and IGF-I+ GLY increased (p < 0.01) the blood IGF-I at hatching. Higher hepatic glycogen was observed (p < 0.05) with GLY or IGF-I. The tested substances decreased (p = 0.02) the fructose 1,6-biphosfate phosphatase activity but did not affect glycaemia. No difference in performance was observed in the first week. Higher feed intake and weight gain with lower feed conversion ratio was obtained ( p  < 0.05) with IGF-I at 14 d. At 21 d, higher weight gain was obtained (p = 0.05) with IGF-I, GLY, IGF-I, and GLY + IGF-I, resulting (p < 0.01) in birds with greater weight gain at 35 and 42 d of age. GLY provided higher villus height in the ileum at hatching and at 7 d of age. The tested solutions increased the relative weight of the liver at hatching. At 42 d of age, no carcass characteristics were influenced. It is concluded that GLY and IGF-I, together or separately, can be used in the in ovo feeding to improve the post-hatch performance of broilers, without affecting hatchability and carcass composition.


Assuntos
Galinhas/fisiologia , Glicerol/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Intestinos/efeitos dos fármacos , Ração Animal/análise , Animais , Peso Corporal/efeitos dos fármacos , Galinhas/anatomia & histologia , Galinhas/crescimento & desenvolvimento , Dieta/veterinária , Glicerol/administração & dosagem , Injeções/veterinária , Fator de Crescimento Insulin-Like I/administração & dosagem , Intestinos/anatomia & histologia , Óvulo/efeitos dos fármacos
17.
Aliment Pharmacol Ther ; 51(12): 1332-1341, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32406112

RESUMO

BACKGROUND: Linaclotide, a guanylate cyclase C agonist relieves irritable bowel syndrome with predominant constipation (IBS-C) symptoms, but how it improves pain in humans is unknown. AIMS: To investigate the effects of linaclotide and placebo on the afferent and efferent gut-brain-gut signalling in IBS-C patients, in a randomised clinical trial. METHODS: Patients with IBS-C (Rome III) and rectal hypersensitivity were randomised (2:1) to receive linaclotide (290 µg) or placebo for 10 weeks and undergo bi-directional gut and brain axis assessment using anorectal electrical stimulations and transcranial/transspinal-anorectal magnetic stimulations. Rectal sensations were examined by balloon distention. Assessments included abdominal pain, bowel symptoms and quality of life (QOL) scores. Primary outcomes were latencies of recto-cortical and cortico-rectal evoked potentials. RESULTS: Thirty-nine patients participated; 26 received linaclotide and 13 received placebo. Rectal cortical evoked potentials latencies (milliseconds) were significantly prolonged with linaclotide compared to baseline (P1:Δ 19 ± 6, P < 0.005; N1:Δ 20 ± 7, P < 0.02) but not with placebo (P1:Δ 3 ± 5; N1:Δ 4.7 ± 5,P = 0.3) or between groups. The efferent cortico-anorectal and spino-anorectal latencies were unchanged. The maximum tolerable rectal volume (cc) increased significantly with linaclotide compared to baseline (P < 0.001) and placebo (Δ 29 ± 10 vs 4 ± 20, (P < 0.03). Abdominal pain decreased (P < 0.001) with linaclotide but not between groups. Complete spontaneous bowel movement frequency increased (P < 0.001), and IBS-QOL scores improved (P = 0.01) with linaclotide compared to baseline and placebo. There was no difference in overall responders between linaclotide and placebo (54% vs 23%, P = 0.13). CONCLUSIONS: Linaclotide prolongs afferent gut-brain signalling from baseline but both afferent and efferent signalling were unaffected compared to placebo. Linaclotide significantly improves rectal hypersensitivity, IBS-C symptoms and QOL compared to placebo. These mechanisms may explain the effects of linaclotide on pain relief in IBS-C patients. ClinicalTrials.Gov: Registered at Clinical trials.gov no NCT02078323.


Assuntos
Dor Abdominal/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Intestinos/efeitos dos fármacos , Síndrome do Intestino Irritável/tratamento farmacológico , Peptídeos/uso terapêutico , Dor Abdominal/etiologia , Dor Abdominal/microbiologia , Adulto , Encéfalo/fisiologia , Constipação Intestinal/tratamento farmacológico , Constipação Intestinal/etiologia , Constipação Intestinal/microbiologia , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Humanos , Intestinos/fisiologia , Síndrome do Intestino Irritável/complicações , Síndrome do Intestino Irritável/microbiologia , Masculino , Pessoa de Meia-Idade , Placebos , Qualidade de Vida , Reto/efeitos dos fármacos , Reto/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Resultado do Tratamento
18.
Poult Sci ; 99(4): 2026-2032, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32241487

RESUMO

Yeast culture (YC) positively affects the performance of laying hens. The purpose of the present study was to explore the underlying mechanism for the YC-mediated performance improvement. Sixty 67-week-old Hy-Line Brown laying hens were randomly allocated into 2 experimental groups with 5 replicates of 6 birds each. One group was fed a control diet, whereas the other received the control diet supplemented with YC at 3.0 g/kg; treatment lasted for 8 wk. The results showed that dietary YC supplementation increased (P < 0.05) the total egg weight (11.2-13.6%) and egg-laying rate (13.0-13.5%) but decreased (P < 0.05) the feed/egg ratio by 9.3 to 11.0% during weeks 5 to 6 and 7 to 8 compared with the control. However, egg quality, including eggshell strength, eggshell thickness, egg weight, albumen height, egg yolk color, and Haugh unit, was not affected (P > 0.05) by YC supplementation. Furthermore, dietary YC supplementation increased (P < 0.05) chymotrypsin and ɑ-amylase activities by 54.8 to 62.5% in the duodenal chyme and reduced (P < 0.05) plasma endotoxin by 44.1%. YC dietary supplementation also upregulated (P < 0.05) the mRNA levels of intestinal barrier-related genes (occludin and claudin 1) and antimicrobial peptides genes (ß-defensin 1 and 7 and cathelicidin 1 and 3) in the duodenum or jejunum compared with the control. In conclusion, dietary YC supplementation improved the performance of aged laying hens, potentially through the upregulation of intestinal digestive enzyme activities and intestinal health-related gene expression.


Assuntos
Fenômenos Fisiológicos da Nutrição Animal , Galinhas/fisiologia , Digestão , Intestinos/enzimologia , Fermento Seco/metabolismo , Ração Animal/análise , Fenômenos Fisiológicos da Nutrição Animal/efeitos dos fármacos , Animais , Dieta/veterinária , Suplementos Nutricionais/análise , Digestão/efeitos dos fármacos , Feminino , Nível de Saúde , Intestinos/efeitos dos fármacos , Distribuição Aleatória , Fermento Seco/administração & dosagem
19.
Tissue Cell ; 63: 101324, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32223952

RESUMO

Three-dimensional (3D) cell culture is more similar to in vivo studies and suitable for studies of interactions between cells and extracellular matrix. CD44 is a cell surface receptor that can relate with the extracellular matrix molecules. CD44 in gastric cancer (GC) is a metastatic and drug resistance marker. In this study the quantity of CD44+ cells in MKN-45 cell line in response to half maximal inhibitory concentration (IC50) dose of Docetaxel (DOC) was measured in 2D and 3D cultures. MKN-45 cell line was cultured in 2D and 3D environments. For 3D culture, rat gastric tissue was separated and decellularized and MKN-45 cells were injected and cultured in the prepared matrix. The frequency of CD44+ cells in 2D and 3D cultures were analyzed before and after treatment with IC50 of DOC by flow cytometry and immunohistochemistry. Despite different environmental conditions, The frequency of CD44+ cells increased significantly in 2D and 3D environments after treatment with IC50 of DOC (P < 0.05). Given the advantages of 3D, this environment seems more appropriate for study about CD44+ cells and drug resistance in GC.


Assuntos
Técnicas de Cultura de Células , Docetaxel/farmacologia , Receptores de Hialuronatos/genética , Neoplasias Gástricas/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Matriz Extracelular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Intestinos/citologia , Intestinos/efeitos dos fármacos , Ratos , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia
20.
PLoS One ; 15(4): e0230871, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32275718

RESUMO

In general, honey bees (Apis mellifera L.) feed on honey produced from collected nectar. In the absence of nectar, during certain times of the year or in monocultural landscapes, honey bees forage on honeydew. Honeydew is excreted by different herbivores of the order Hemiptera that consume phloem sap of plant species. In comparison to nectar, honeydew is composed of a higher variety of sugars and additional sugars with higher molecular weight, like the trisaccharide melezitose that can be a major constituent of honeydew. However, melezitose-containing honey is known to cause malnutrition in overwintering honey bees. Following the hypothesis that melezitose may be the cause for the so called 'honeydew flow disease', three independent feeding experiments with caged bees were conducted in consecutive years. Bees fed with melezitose showed increased food uptake, higher gut weights and elevated mortality compared to bees fed a control diet. Moreover, severe disease symptoms, such as swollen abdomen, abdomen tipping and impaired movement were observed in melezitose-fed bees. 16S-amplicon sequencing indicated that the melezitose diet changed the species composition of the lactic acid bacteria community within the gut microbiota. Based on these results, we conclude that melezitose cannot be easily digested by the host and may accumulate in the hindgut. Within cages or during winter, when there is no opportunity for excretion, the accumulated melezitose can cause severe intestinal symptoms and death of the bees, probably as result of poor melezitose metabolism capabilities in the intestinal microbiota. These findings confirm the causal relation between the trisaccharide melezitose and the honeydew flow disease and indicate a possible mechanism of pathogenesis.


Assuntos
Abelhas , Microbioma Gastrointestinal/efeitos dos fármacos , Trissacarídeos/farmacologia , Animais , Ingestão de Líquidos/efeitos dos fármacos , Intestinos/anatomia & histologia , Intestinos/efeitos dos fármacos , Tamanho do Órgão/efeitos dos fármacos , Análise de Sobrevida
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