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1.
Proc Natl Acad Sci U S A ; 117(28): 16292-16301, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32601208

RESUMO

Notch pathway signaling is implicated in several human cancers. Aberrant activation and mutations of Notch signaling components are linked to tumor initiation, maintenance, and resistance to cancer therapy. Several strategies, such as monoclonal antibodies against Notch ligands and receptors, as well as small-molecule γ-secretase inhibitors (GSIs), have been developed to interfere with Notch receptor activation at proximal points in the pathway. However, the use of drug-like small molecules to target the downstream mediators of Notch signaling, the Notch transcription activation complex, remains largely unexplored. Here, we report the discovery of an orally active small-molecule inhibitor (termed CB-103) of the Notch transcription activation complex. We show that CB-103 inhibits Notch signaling in primary human T cell acute lymphoblastic leukemia and other Notch-dependent human tumor cell lines, and concomitantly induces cell cycle arrest and apoptosis, thereby impairing proliferation, including in GSI-resistant human tumor cell lines with chromosomal translocations and rearrangements in Notch genes. CB-103 produces Notch loss-of-function phenotypes in flies and mice and inhibits the growth of human breast cancer and leukemia xenografts, notably without causing the dose-limiting intestinal toxicity associated with other Notch inhibitors. Thus, we describe a pharmacological strategy that interferes with Notch signaling by disrupting the Notch transcription complex and shows therapeutic potential for treating Notch-driven cancers.


Assuntos
Receptores Notch/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Ativação Transcricional/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Sítios de Ligação , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Drosophila , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células HeLa , Humanos , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/química , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/genética , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/metabolismo , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Camundongos , Mutação , Fenótipo , Multimerização Proteica , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/uso terapêutico
2.
Int J Clin Oncol ; 25(8): 1441-1449, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32448950

RESUMO

BACKGROUND: There is no standard chemotherapy available for unresectable or metastatic small bowel adenocarcinoma (SBA) because of its rarity. This systematic review aims to assess the efficacy and safety of chemotherapy for patients with unresectable or metastatic SBA. METHODS: In accordance with the PRISMA statements, literature search was conducted using PubMed, Scopus, and the Cochrane Central Register of Controlled Trials. The included studies were prospective randomized, nonrandomized, or observational studies. Risk of bias was assessed the ROBINS-I tool. RESULTS: Seven prospective single-arm Phase II studies were included in this review. Six of them were assessed as having a moderate risk of bias and one as having a serious risk of bias. A meta-analysis was not performed, because the studies were single-arm. Systemic chemotherapy based on fluoropyrimidine regimens achieved favorable outcomes with acceptable adverse effects as a first therapy; however, the regimens differed in each study. The object response rate was 18-50%, and the disease control rate was 29-87%. With 5-fluorouracil, adriamycin, and mitomycin-C regimen, one treatment-related death occurred. A second line of therapy including chemotherapy with nab-paclitaxel also showed favorable efficacy. The object response rate was 20%, and the disease control rate was 50%. CONCLUSIONS: Systemic chemotherapy based on fluoropyrimidine regimens was mainly used for unresectable or metastatic SBA. While it may achieve favorable outcomes with acceptable adverse effects, further evidence is needed.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Intestinais/tratamento farmacológico , Intestino Delgado/patologia , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Albuminas/administração & dosagem , Doxorrubicina/administração & dosagem , Fluoruracila/administração & dosagem , Humanos , Neoplasias Intestinais/patologia , Neoplasias Intestinais/cirurgia , Intestino Delgado/efeitos dos fármacos , Paclitaxel/administração & dosagem , Estudos Prospectivos , Resultado do Tratamento
3.
Am J Physiol Gastrointest Liver Physiol ; 318(6): G1070-G1087, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32390462

RESUMO

Lipopolysaccharides (LPS) are potent pro-inflammatory molecules that enter the systemic circulation from the intestinal lumen by uncertain mechanisms. We investigated these mechanisms and the effect of exogenous glucagon-like peptide-2 (GLP-2) on LPS transport in the rodent small intestine. Transmucosal LPS transport was measured in Ussing-chambered rat jejunal mucosa. In anesthetized rats, the appearance of fluorescein isothiocyanate (FITC)-LPS into the portal vein (PV) and the mesenteric lymph was simultaneously monitored after intraduodenal perfusion of FITC-LPS with oleic acid and taurocholate (OA/TCA). In vitro, luminally applied LPS rapidly appeared in the serosal solution only with luminal OA/TCA present, inhibited by the lipid raft inhibitor methyl-ß-cyclodextrin (MßCD) and the CD36 inhibitor sulfosuccinimidyl oleate (SSO), or by serosal GLP-2. In vivo, perfusion of FITC-LPS with OA/TCA rapidly increased FITC-LPS appearance into the PV, followed by a gradual increase of FITC-LPS into the lymph. Rapid PV transport was inhibited by the addition of MßCD or by SSO, whereas transport into the lymph was inhibited by chylomicron synthesis inhibition. Intraveous injection of the stable GLP-2 analog teduglutide acutely inhibited FITC-LPS transport into the PV, yet accelerated FITC-LPS transport into the lymph via Nω-nitro-l-arginine methyl ester (l-NAME)- and PG97-269-sensitive mechanisms. In vivo confocal microscopy in mouse jejunum confirmed intracellular FITC-LPS uptake with no evidence of paracellular localization. This is the first direct demonstration in vivo that luminal LPS may cross the small intestinal barrier physiologically during fat absorption via lipid raft- and CD36-mediated mechanisms, followed by predominant transport into the PV, and that teduglutide inhibits LPS uptake into the PV in vivo.NEW & NOTEWORTHY We report direct in vivo confirmation of transcellular lipopolysaccharides (LPS) uptake from the intestine into the portal vein (PV) involving CD36 and lipid rafts, with minor uptake via the canonical chylomicron pathway. The gut hormone glucagon-like peptide-2 (GLP-2) inhibited uptake into the PV. These data suggest that the bulk of LPS absorption is via the PV to the liver, helping clarify the mechanism of LPS transport into the PV as part of the "gut-liver" axis. These data do not support the paracellular transport of LPS, which has been implicated in the pathogenesis of the "leaky gut" syndrome.


Assuntos
Gorduras/metabolismo , Intestino Delgado/metabolismo , Lipopolissacarídeos/metabolismo , Animais , Transporte Biológico/efeitos dos fármacos , Transporte Biológico/fisiologia , Fármacos Gastrointestinais/farmacologia , Células HEK293 , Humanos , Intestino Delgado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Peptídeos/química , Peptídeos/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
4.
J Nutr ; 150(7): 1722-1730, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32386219

RESUMO

BACKGROUND: High intakes of fructose are associated with metabolic diseases, including hypertriglyceridemia and intestinal tumor growth. Although small intestinal epithelia consist of many different cell types, express lipogenic genes, and convert dietary fructose to fatty acids, there is no information on the identity of the cell type(s) mediating this conversion and on the effects of fructose on lipogenic gene expression. OBJECTIVES: We hypothesized that fructose regulates the intestinal expression of genes involved in lipid and apolipoprotein synthesis, that regulation depends on the fructose transporter solute carrier family 2 member a5 [Slc2a5 (glucose transporter 5)] and on ketohexokinase (Khk), and that regulation occurs only in enterocytes. METHODS: We compared lipogenic gene expression among different organs from wild-type adult male C57BL mice consuming a standard vivarium nonpurified diet. We then gavaged twice daily for 2.5 d fructose or glucose solutions (15%, 0.3 mL per mouse) into wild-type, Slc2a5-knockout (KO), and Khk-KO mice with free access to the nonpurified diet and determined expression of representative lipogenic genes. Finally, from mice fed the nonpurified diet, we made organoids highly enriched in enterocyte, goblet, Paneth, or stem cells and then incubated them overnight in 10 mM fructose or glucose. RESULTS: Most lipogenic genes were significantly expressed in the intestine relative to the kidney, liver, lung, and skeletal muscle. In vivo expression of Srebf1, Acaca, Fasn, Scd1, Dgat1, Gk, Apoa4, and Apob mRNA and of Scd1 protein increased (P < 0.05) by 3- to 20-fold in wild-type, but not in Slc2a5-KO and Khk-KO, mice gavaged with fructose. In vitro, Slc2a5- and Khk-dependent, fructose-induced increases, which ranged from 1.5- to 4-fold (P < 0.05), in mRNA concentrations of all these genes were observed only in organoids enriched in enterocytes. CONCLUSIONS: Fructose specifically stimulates expression of mouse small intestinal genes for lipid and apolipoprotein synthesis. Secretory and stem cells seem incapable of transport- and metabolism-dependent lipogenesis, occurring only in absorptive enterocytes.


Assuntos
Frutoquinases/metabolismo , Frutose/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Intestino Delgado/efeitos dos fármacos , Animais , Frutoquinases/genética , Regulação da Expressão Gênica/fisiologia , Intestino Delgado/enzimologia , Camundongos
5.
Mutat Res ; 850-851: 503136, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32247553

RESUMO

Tumorigenesis induced by oxidative stress is thought to be initiated by mutagenesis, but via an indirect mechanism. The dose-response curves for agents that act by this route usually show a threshold, for unknown reasons. To gain insight into these phenomena, we have analyzed the dose response for mutagenesis induced by the oral administration of potassium bromate, a typical oxidative-stress-generating agent, to gpt delta mice. The agent was given orally for 90 d to either Nrf2+ or Nrf2-knockout (KO) mice and mutants induced in the small intestine were analyzed. In Nrf2+mice, the mutant frequency was significantly greater than in the vehicle controls at a dose of 0.6 g/L but not at 0.2 g/L, indicating that a practical threshold for mutagenesis lies between these doses. At 0.6 g/L, the frequencies of G-to-T transversions (landmark mutations for oxidative stress) and G-to-A transitions were significantly elevated. In Nrf2-KO mice, too, the total mutant frequency was increased only at 0.6 g/L. G-to-T transversions are likely to have driven tumorigenesis in the small intestine. A site-specific G-to-T transversion at guanine (nucleotide 406) in a 5'-TGAA-3' sequence in gpt, and our primer extension reaction showed that formation of the oxidative DNA base modification 8-oxo-deoxyguanosine (8-oxo-dG) at nucleotide 406 was significantly increased at doses of 0.6 and 2 g/L in the gpt delta mice. In the Apc oncogene, guanine residues in the same or similar sequences (TGAA or AGAA) are highly substituted by thymine (G-to-T transversions) in potassium bromate-induced tumors. We propose that formation of 8-oxo-dG in the T(A)GAA sequence is an initiating event in tumor formation in the small intestine in response to oxidative stress.


Assuntos
Bromatos/toxicidade , Mutagênese/genética , Estresse Oxidativo/genética , Pentosiltransferases/genética , 8-Hidroxi-2'-Desoxiguanosina/genética , Administração Oral , Animais , Bromatos/farmacologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , DNA/efeitos dos fármacos , DNA/genética , Relação Dose-Resposta a Droga , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/patologia , Camundongos , Camundongos Knockout , Mutagênese/efeitos dos fármacos , Mutação , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/efeitos dos fármacos
6.
Anticancer Res ; 40(4): 2373-2377, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32234940

RESUMO

BACKGROUND/AIM: The clinical significance of surgery for secondary small intestinal non-Hodgkin's lymphomas (NHL) remains unknown. This study aimed to investigate the efficacy of resection for both primary and secondary small intestinal NHL. PATIENTS AND METHODS: Twenty patients with small intestinal lymphoma who underwent surgical resection at our Institute between 2009 and 2017 were retrospectively evaluated. The clinicopathological and surgery-related factors were reviewed. We also analyzed their surgical outcomes such as postoperative complications, perforation rate, and overall survival (OS). RESULTS: In total, 13 (65%) and 7 (35%) patients had primary and secondary lymphomas, respectively. A total of 70% of patients were diagnosed with aggressive-type lymphomas. A total of 15 (75%) patients had Lugano system stage IV. Only one (5%) patient experienced postoperative grade II deep vein thrombosis and pulmonary embolism. The 3-year OS rate after surgery was 59.6%. CONCLUSION: Surgical resection prior to chemotherapy is a feasible and safe therapeutic strategy for small intestinal NHL.


Assuntos
Intestino Delgado/cirurgia , Linfoma não Hodgkin/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Intervalo Livre de Doença , Feminino , Humanos , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/patologia , Linfoma não Hodgkin/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
7.
Am J Physiol Gastrointest Liver Physiol ; 318(5): G980-G987, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32308039

RESUMO

Glucagon-like peptide (GLP)-1 and -2-secreting L cells have been shown to express the bile acid receptor Takeda G protein-receptor-5 (TGR5) and increase secretion upon receptor activation. Previous studies have explored GLP-1 secretion following acute TGR5 activation, but chronic activation and GLP-2 responses have not been characterized. In this study, we aimed to investigate the consequences of pharmacological TGR5 receptor activation on L cell hormone production in vivo using the specific TGR5 agonist RO5527239 and the GLP-2 receptor knockout mouse. Here, we show that 1) TGR5 receptor activation led to increased GLP-1 and GLP-2 content in the colon, which 2) was associated with an increased small intestinal weight that 3) was GLP-2 dependent. Additionally, we report that TGR5-mediated gallbladder filling occurred independently of GLP-2 signaling. In conclusion, we demonstrate that pharmacological TGR5 receptor activation stimulates L cells, triggering GLP-2-dependent intestinal adaption in mice.NEW & NOTEWORTHY Using the specific Takeda G protein-receptor-5 (TGR5) agonist RO5527239 and GLP-2 receptor knockout mice, we show that activation of TGR5 led to the increase in colonic GLP-1 and GLP-2 concomitant with a GLP-2 dependent growth response in the proximal portion of the small intestine.


Assuntos
Proliferação de Células/efeitos dos fármacos , Células Enteroendócrinas/efeitos dos fármacos , Peptídeo 2 Semelhante ao Glucagon/metabolismo , Intestino Delgado/efeitos dos fármacos , Ácidos Isonipecóticos/farmacologia , Oximas/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Animais , Colo/efeitos dos fármacos , Colo/crescimento & desenvolvimento , Colo/metabolismo , Células Enteroendócrinas/metabolismo , Feminino , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 2/genética , Receptor do Peptídeo Semelhante ao Glucagon 2/metabolismo , Intestino Delgado/crescimento & desenvolvimento , Intestino Delgado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Acoplados a Proteínas-G/metabolismo , Transdução de Sinais
8.
Artigo em Chinês | MEDLINE | ID: mdl-32314717

RESUMO

Objective To investigate the effect of hydroxychloroquine (HCQ) on 5-fluorouracil (5-FU)-induced enteritis in mice and its mechanism. Methods Thirty C57B6/J mice were randomly divided into 0-, 1-, 3-, 5- and 7-day groups and sacrificed separately at day 0, 1, 3, 5, and 7 after intraperitoneal administration of 5-FU 200 µL/d (50 mg/kg) at day 1-3. The double-stranded DNA (dsDNA) levels in serum and small intestinal fluid were detected by dsDNA quantification kit. Severity of enteritis was evaluated by diarrhea score. HCT-116 cells were cultured in vitro and treated with 5-FU at different concentrations (0, 0.01, 0.1, 0.5, 1, 10 µmol/L) for 72 hours or 5-FU at 1 µmol/L for different time (24, 48, 72 hours). The dsDNA concentration in the cell culture supernatant of each group was detected by dsDNA quantification kit. Twenty-four C57B6/J mice were randomly divided into 4 groups: control group (intraperitoneal injection and intragastric administration of 200 µL/d saline), model group (intraperitoneal injection of 50 mg/kg 5-FU of 200 µL/d, intragastric administration of saline 200 µL/d), HCQ treatment group (intragastric administration of 60 mg/kg HCQ of 200 µL/d, starting at 1 day before the first intraperitoneal injection of 50 mg/kg 5-FU of 200 µL/d) and HCQ group (intragastric administration of 60 mg/kg HCQ solution of 200 µL/d). And they were sacrificed after 6 days. Small intestine lesions were observed by HE staining. Apoptotic cells in the small intestine were detected by TUNEL staining. The expression levels of CD11c, Toll-like receptor 9 (TLR9) and nuclear factor κB (NF-κB) in the small intestine were assessed by immunofluorescence staining. Interleukin-1ß (IL-1ß) levels in the serum were detected by ELISA. Mouse bone marrow-derived dendritic cells (BMDCs) were cultured in vitro and stimulated by dsDNA using LipofectamineTM 3000. The expression of TLR9 and NF-κB in BMDCs were detected by Western blotting and immunofluorescent staining, respectively. IL-1ß level in the cell supernatant was detected by ELISA. Results Large amounts of apoptotic cells were observed in the small intestine of 5-FU-treated mice and the dynamic changes of dsDNA levels in the serum and small intestinal lavage fluid were consistent with that of diarrhea score. 5-FU triggered dsDNA release from HCT-116 cells in a dose- and time-dependent manner. HCQ alleviated the destruction in small intestinal epithelium and inhibited the expression levels of TLR9, NF-κB and IL-1ß in the serum. The infiltration of a large number of dendritic cells in the small intestine of model mice was observed. After BMDCs were stimulated with dsDNA, the expression of TLR9, NF-κB, and IL-1ß all significantly increased and HCQ significantly decreased. Conclusion HCQ alleviates 5-FU-induced enteritis in mice and inhibit TLR9 and NF-κB-dependent DNA sensing pathways and the secretion of IL-1ß in dendritic cells.


Assuntos
Enterite/tratamento farmacológico , Fluoruracila/efeitos adversos , Hidroxicloroquina/farmacologia , Animais , Linhagem Celular Tumoral , Células Dendríticas/citologia , Enterite/induzido quimicamente , Humanos , Interleucina-1beta/metabolismo , Intestino Delgado/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Distribuição Aleatória , Receptor Toll-Like 9/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
9.
Cancer Chemother Pharmacol ; 85(5): 869-880, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32240335

RESUMO

PURPOSE: Capecitabine is a prodrug of 5-fluorouracil (5-FU) used for the treatment of colorectal cancer, with a two-week course of administration. However, the variance in plasma concentration and metabolic enzyme activities after multiple administration of capecitabine and its metabolites is unknown. The aim of this study was to identify the variance and predict the plasma concentration profile of capecitabine and its metabolites, using metabolic enzyme activities, to develop a more effective and safer medication. METHODS: Rats orally received 180 mg/kg of capecitabine once a day for two weeks. Blood samples were collected nine times, and plasma concentration was measured on day 1, 7, and 14. The liver and small intestine were removed after blood sampling and were used in vitro to evaluate metabolic enzyme activities of carboxylesterase, cytidine deaminase, and thymidine phosphorylase. A physiologically based pharmacokinetic (PBPK) model was developed using in vitro results. RESULTS: Area under the plasma concentration-time curve from 0 h to infinity of 5-FU on day 7 and day 14 was significantly lower than that on day 1. Intrinsic clearance of thymidine phosphorylase in the liver on day 7 and day 14 was 1.4 and 1.3 times lower than that on day 1, respectively. The PBPK model described the observed plasma concentration of capecitabine and its metabolites. CONCLUSION: The decreased plasma concentration of capecitabine was caused by decreased metabolic enzyme activity. Efficacy can be improved by dose adjustment of capecitabine based on metabolic enzyme activities, using the PBPK model.


Assuntos
Capecitabina/farmacocinética , Carboxilesterase/metabolismo , Neoplasias Colorretais , Citidina Desaminase/metabolismo , Fluoruracila/farmacocinética , Timidina Fosforilase/metabolismo , Animais , Antimetabólitos Antineoplásicos/farmacocinética , Biomarcadores Farmacológicos/metabolismo , Neoplasias Colorretais/sangue , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Relação Dose-Resposta a Droga , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Intestino Delgado/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Pró-Fármacos/farmacocinética , Ratos , Distribuição Tecidual
10.
Georgian Med News ; (298): 128-132, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32141865

RESUMO

Experimental modeling of dysbacterioses associated with antibiotics is an urgent issue of morphological studies. The present paper was aimed at the detection and study of the primordial forms of Peyer's patches developed in the small intestine of albino rats after administration of clarithromycin. 30 mature albino male rats weighing 200.0 ± 20.0 g were involved into the experiment. Antibiotic was administered to the rodents as a supplement to food during their two-meals-a-day feeding. Areas of the small intestine with Peyer's patches have been studied. Serial paraffin sections have been analyzed using the "Konus" light microscope. Morphometric characteristics of the tissue structures were obtained using the Sigeta X 1 mm / 100 Div.x0.01mm stage micrometer. Administration of clarithromycin caused a significant increase in the amount of Peyer's patches, the appearance in the mucous membrane of newly formed aggregated lymphoid nodules, being the primordial forms of Peyer's patches, the appearance of which can be explained by only one factor, namely, impaired microbiocenosis in the small intestine under the influence of the broad-spectrum antibacterial drug, clarithromycin, which has immunotropic effect.


Assuntos
Antibacterianos/administração & dosagem , Claritromicina/administração & dosagem , Intestino Delgado/efeitos dos fármacos , Nódulos Linfáticos Agregados , Animais , Antibacterianos/efeitos adversos , Claritromicina/efeitos adversos , Desenvolvimento Embrionário , Intestino Delgado/metabolismo , Masculino , Ratos
11.
PLoS One ; 15(3): e0229463, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32214355

RESUMO

Food and feeds contaminated with mycotoxins have been a threat to the rearing industry by causing some of the most fatal toxic reactions not only in the farm animals but also in humans who consume them. Toxicity to juvenile goats was induced by feed contamination with T-2 toxin (at 10 and 20 ppm dosage; group I and II, respectively). The toxicity impact was assessed on days 15 and 30 post treatment with respect to growth performance, oxidative stress, apoptotic studies and detailed pathomorphology. The study revealed that apart from the obvious clinical toxicosis (weakness, lethargy, and retardation in growth), the toxin fed groups also exhibited significant haematological (reduced hemoglobin, total leukocyte and thrombocyte counts) and biochemical changes (increased levels of oxidative stress markers with concomitant decrease in levels of serum and tissue catalase and superoxide dismutase). The pathomorphological and histological alterations suggested that the liver and intestine were the most affected organs. Ultra-structurally, varying degrees of degeneration, cytoplasmic vacuolations and pleomorphic mitochondria were observed in the hepatocytes and the enterocytes of the intestine. Kidney also revealed extensive degeneration of the cytoplasmic organelles with similar condensation of the heterochromatin whereas the neuronal degeneration was characterized by circular, whirling structures. In addition, the central vein and portal triad of the hepatocytes, cryptic epithelial cells of the intestine, MLNs in the lymphoid follicles, PCT and DCT of the nephronal tissues and the white pulp of the spleen exhibited extensive apoptosis. In this study, it was also observed that the expression of HSPs, pro-apoptotic proteins and pro-inflammatory cytokines were significantly upregulated in response to the toxin treatment. These results suggest that the pathogenesis of T-2 toxicosis in goats employs oxidative, apoptotic and inflammatory mechanisms.


Assuntos
Apoptose , Regulação da Expressão Gênica/efeitos dos fármacos , Cabras/fisiologia , Mediadores da Inflamação/metabolismo , Fígado/patologia , Estresse Oxidativo/efeitos dos fármacos , Toxina T-2/toxicidade , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Citocinas/metabolismo , Proteínas de Choque Térmico/metabolismo , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Intestino Delgado/patologia , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Linfonodos/efeitos dos fármacos , Linfonodos/metabolismo , Linfonodos/patologia , Baço/efeitos dos fármacos , Baço/metabolismo , Baço/patologia
12.
Food Chem ; 318: 126463, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32135421

RESUMO

The stability behaviours of whey-protein-stabilised emulsions under gastric conditions and the effects on the lipolysis of the emulsions were investigated using an in vitro dynamic human gastric simulator and a subsequent small intestinal model. Under gastric conditions, heated whey-protein-stabilised emulsions flocculated to a greater extent and with a larger floc size, whereas unheated emulsions were more prone to coalescence. The greater extent of flocculation delayed the delivery of oil droplets to the small intestine, leading to a lower amount of oil in the emptied gastric digesta from the heated emulsion in the early period of digestion. The differences in oil content, droplet size and interfacial composition led to a greater rate and extent of lipolysis in the subsequent intestinal digestion in the heated emulsion than the unheated emulsion. The results suggest that the lipid digestion of whey-protein-stabilised emulsions in the intestinal stage could be manipulated by thermal treatment.


Assuntos
Digestão , Emulsões/química , Emulsões/farmacocinética , Proteínas do Soro do Leite/química , Floculação , Temperatura Alta , Humanos , Concentração de Íons de Hidrogênio , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Lipídeos/farmacocinética , Lipólise , Tamanho da Partícula
13.
Cardiovasc Pathol ; 47: 107193, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32151788

RESUMO

Eosinophilic granulomatosis with polyangiitis (EGPA), formerly called Churg-Strauss syndrome, is an uncommon disease with pathological features consisting of systemic necrotizing vasculitis, eosinophilic infiltration, and granulomatous or nongranulomatous extravascular eosinophilic inflammation. EGPA preferentially affects certain organ systems, including the airways, peripheral nerves, heart, kidney, and gastrointestinal tract. Although gastrointestinal involvement, such as ulcerations, is common in EGPA, gastrointestinal perforation is relatively uncommon and is associated with a poor prognosis. Ulceration, perforation, and stenosis of the gastrointestinal tract are assumed to be the result of ischemia caused by vasculitis. The histological finding in the biopsy specimens of EGPA is generally only eosinophil infiltration, and vasculitis is not often seen. Therefore, in biopsy specimens, it is difficult to distinguish eosinophilic gastroenteritis from the gastrointestinal involvement of EGPA. In addition, in general, steroid therapy is the first-choice treatment for EGPA, but some reports have described the frequent occurrence of acute ulcer or perforation of the gastrointestinal tract in association with steroid treatment. We herein report an EGPA patient who was treated with steroid therapy and subsequently developed perforation of the small intestine.


Assuntos
Síndrome de Churg-Strauss/tratamento farmacológico , Glucocorticoides/efeitos adversos , Perfuração Intestinal/induzido quimicamente , Intestino Delgado/efeitos dos fármacos , Úlcera/induzido quimicamente , Idoso , Síndrome de Churg-Strauss/patologia , Progressão da Doença , Evolução Fatal , Humanos , Perfuração Intestinal/diagnóstico por imagem , Perfuração Intestinal/patologia , Perfuração Intestinal/cirurgia , Intestino Delgado/diagnóstico por imagem , Intestino Delgado/patologia , Intestino Delgado/cirurgia , Masculino , Metilprednisolona , Recidiva , Fatores de Risco , Resultado do Tratamento , Úlcera/diagnóstico por imagem , Úlcera/patologia , Úlcera/cirurgia
14.
Endocrinology ; 161(4)2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32147716

RESUMO

Glucagon-like peptide-2 (GLP-2) is an intestinotrophic hormone that promotes intestinal growth and proliferation through downstream mediators, including epidermal growth factor (EGF) and insulin-like growth factor-1 (IGF-1). EGF synergistically enhances the proliferative actions of IGF-1 in intestinal cell lines, and both of these factors are known to be essential for the trophic effects of GLP-2 in vivo. However, whether EGF and IGF-1 interact to mediate the proliferative actions of GLP-2 in vivo remains unknown. Normal and knockout (KO) mice lacking the intestinal epithelial IGF-1 receptor (IE-IGF-1R) were therefore treated chronically with EGF and/or long-acting human hGly2GLP-2, followed by determination of intestinal growth parameters. Intestines from control and IE-IGF-1R KO mice were also used to generate organoids (which lack the GLP-2 receptor) and were treated with EGF and/or IGF-1. Combination treatment with EGF and hGly2GLP-2 increased small intestinal weight and crypt-villus height in C57Bl/6 mice in an additive manner, whereas only hGly2GLP-2 treatment increased crypt cell proliferation. However, although combination treatment also increased small intestinal weight and crypt-villus height in IE-IGF-1R KO mice, the proliferative responses to hGly2GLP-2 alone or with EGF were diminished in these animals. Finally, IGF-1 treatment of organoids undergoing EGF withdrawal was not additive to the effect of EGF replacement on proliferation, but could restore normal proliferation in the absence of EGF. Together, these findings demonstrate that the intestinal proliferative effects of hGly2GLP-2 are augmented by exogenous EGF in a manner that is partially dependent upon IE-IGF-1R signaling.


Assuntos
Fator de Crescimento Epidérmico/farmacologia , Peptídeo 2 Semelhante ao Glucagon/metabolismo , Mucosa Intestinal/metabolismo , Intestino Delgado/efeitos dos fármacos , Receptor IGF Tipo 1/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Intestino Delgado/metabolismo , Camundongos , Camundongos Knockout , Receptor IGF Tipo 1/genética , Transdução de Sinais/efeitos dos fármacos
15.
J Pharmacol Exp Ther ; 373(3): 347-352, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32144124

RESUMO

Long-acting glucagon-like peptide-2 receptor (GLP-2R) agonists are well-established to increase intestinal growth in rodents and, most notably, humans with short bowel syndrome. Most of the trophic effects of GLP-2R agonists are reported to be mediated through increased growth of the crypt-villus axis, resulting in enhanced mucosal mass and improved intestinal function. The present study examined the effects of apraglutide, a novel GLP-2R agonist, on the growth of the small intestine and colon after 3, 7, and 10 weeks of treatment in male and female mice. Apraglutide (3 mg/kg; three times per week) significantly increased small intestinal weight (P < 0.001) and length (P < 0.001) after 3 weeks of administration, with a further increase in effectiveness after 10 weeks (P < 0.01). Crypt depth and villus height were both markedly increased after 3 weeks of apraglutide administration (P < 0.001) but did not show any further increase with duration of treatment, whereas crypt number and intestinal circumference were increased after 7 and 10 weeks (P < 0.01) but not after 3 weeks of apraglutide treatment. Both the weight and the length of the colon were also enhanced by apraglutide treatment for 3 weeks (P < 0.001), and these effects were maintained but did not improve further with continued apraglutide administration. The results of this study demonstrate that the novel, long-acting GLP-2R agonist, apraglutide, demonstrates an unexpected marked ability to increase intestinal length as well as exert time- and location-dependent specificity in its intestinotrophic actions. SIGNIFICANCE STATEMENT: The novel long-acting glucagon-like peptide 2 receptor agonist, apraglutide, enhances intestinal weight as well as intestinal length in a time- and site-dependent fashion.


Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 2/agonistas , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Intestino Delgado/efeitos dos fármacos , Animais , Colo/efeitos dos fármacos , Feminino , Masculino , Camundongos
16.
Biochem J ; 477(4): 817-831, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-32016357

RESUMO

Inorganic phosphate (Pi) homeostasis is regulated by intestinal absorption via type II sodium-dependent co-transporter (Npt2b) and by renal reabsorption via Npt2a and Npt2c. Although we previously reported that vitamin A-deficient (VAD) rats had increased urine Pi excretion through the decreased renal expression of Npt2a and Npt2c, the effect of vitamin A on the intestinal Npt2b expression remains unclear. In this study, we investigated the effects of treatment with all-trans retinoic acid (ATRA), a metabolite of vitamin A, on the Pi absorption and the Npt2b expression in the intestine of VAD rats, as well as and the underlying molecular mechanisms. In VAD rats, the intestinal Pi uptake activity and the expression of Npt2b were increased, but were reduced by the administration of ATRA. The transcriptional activity of reporter plasmid containing the promoter region of the rat Npt2b gene was reduced by ATRA in NIH3T3 cells overexpressing retinoic acid receptor (RAR) and retinoid X receptor (RXR). On the other hand, CCAAT/enhancer-binding proteins (C/EBP) induced transcriptional activity of the Npt2b gene. Knockdown of the C/EBP gene and a mutation analysis of the C/EBP responsible element in the Npt2b gene promoter indicated that C/EBP plays a pivotal role in the regulation of Npt2b gene transcriptional activity by ATRA. EMSA revealed that the RAR/RXR complex inhibits binding of C/EBP to Npt2b gene promoter. Together, these results suggest that ATRA may reduce the intestinal Pi uptake by preventing C/EBP activation of the intestinal Npt2b gene.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Intestino Delgado/metabolismo , Rim/metabolismo , Regiões Promotoras Genéticas , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIb/genética , Transcrição Genética/efeitos dos fármacos , Tretinoína/farmacologia , Animais , Antineoplásicos/farmacologia , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Hipofosfatemia Familiar/metabolismo , Hipofosfatemia Familiar/patologia , Hipofosfatemia Familiar/prevenção & controle , Intestino Delgado/efeitos dos fármacos , Rim/efeitos dos fármacos , Masculino , Camundongos , Células NIH 3T3 , Ratos , Ratos Wistar , Receptores do Ácido Retinoico/genética , Receptores do Ácido Retinoico/metabolismo , Receptores X Retinoide/genética , Receptores X Retinoide/metabolismo , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIb/metabolismo
17.
Int J Mol Sci ; 21(3)2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32041147

RESUMO

Bisphenol A (BPA) is a substance used in the production of plastics which has a negative impact on many internal organs. Because BPA is normally toxic for the gastrointestinal (GI) tract, the intestine is especially vulnerable to the adverse effects of this substance. The aim of this investigation was to study the influence of two doses of BPA (0.05 mg and 0.5 mg/kg body weight/day) on the number of mucosal cells in the porcine small intestine and containing serotonin (5-hydroxytryptamine, 5-HT). During the experiment, it was demonstrated that both applied BPA doses caused an increase in the number of 5-HT-positive cells located in the mucosal layer of the duodenum, jejunum, and ileum. These changes may be connected with the direct impact of BPA on the intestinal mucosa, the pro-inflammatory and immunomodulatory properties of this substance, and/or the influence of BPA on the neurochemical characterization of nervous structures supplying the intestine.


Assuntos
Compostos Benzidrílicos/toxicidade , Intestino Delgado/citologia , Fenóis/toxicidade , Serotonina/metabolismo , Animais , Feminino , Mucosa Intestinal/citologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Suínos
18.
Nanotoxicology ; 14(3): 388-403, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31958026

RESUMO

Well-absorbed iron-based nanoparticulated materials are a promise for the oral management of iron deficient anemia. In this work, a battery of in vitro and in situ experiments are combined for the evaluation of the uptake, distribution and toxicity of new synthesized ultrasmall (4 nm core) Fe2O3 nanoparticles coated with tartaric/adipic acid with potential to be used as oral Fe supplements. First, the in vitro simulated gastric acid solubility studies by TEM and HPLC-ICP-MS reveal a partial reduction of the core size of about 40% after 90 min at pH 3. Such scenario confirms the arrival of the nanoparticulate material in the small intestine. In the next step, the in vivo absorption through the small intestine by intestinal perfusion experiments is conducted using the sought nanoparticles in Wistar rats. The quantification of Fe in the NPs suspension before and after perfusion shows Fe absorption levels above 79%, never reported for other Fe treatments. Such high absorption levels do not seem to compromise cell viability, evaluated in enterocytes-like models (Caco-2 and HT-29) using cytotoxicity, ROS production, genotoxicity and lipid peroxidation tests. Moreover, regional differences in terms of Fe concentration are obtained among different parts of the small intestine as duodenum > jejunum > ileum. Complementary transmission electron microscopy (TEM) images show the presence of the intact particles around the intestinal microvilli without significant tissue damage. These studies show the high potential of these NP preparations for their use as oral management of anemia.


Assuntos
Compostos Férricos/farmacocinética , Compostos Férricos/toxicidade , Absorção Intestinal/efeitos dos fármacos , Intestino Delgado/metabolismo , Nanopartículas/toxicidade , Administração Oral , Animais , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Compostos Férricos/química , Células HT29 , Humanos , Intestino Delgado/efeitos dos fármacos , Masculino , Microscopia Eletrônica de Transmissão , Nanopartículas/química , Tamanho da Partícula , Ratos , Ratos Wistar , Distribuição Tecidual
20.
Biol Pharm Bull ; 43(1): 116-123, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31902916

RESUMO

We examined CYP induction and recovery at various doses of Coleus forskohlii extract (CFE) to assess potential drug interactions by a mechanism involving intestinal CYP. Mice were administered diets with various doses of CFE up to 0.5% (equivalent to 700-800 mg/kg body weight) for 2 weeks, then CFE was withdrawn for 3 d. Changes in CYP activities and mRNA expression in the small intestine and liver were then evaluated. CFE induced CYP in the small intestine at a higher dose compared to the liver; CYP3A was induced at 0.5% and 0.005% CFE in the small intestine and liver, respectively. There was no sex difference in CFE dose for CYP induction. CYP induction quickly reverted after withdrawal of CFE, especially for CYP3A, in the small intestine; whereas, a gradual recovery was observed in the liver. In conclusion, CFE induced CYP in the small intestine and liver; however, a higher dose of CFE was needed for the small intestine. Moreover, the induction was soon recovered, suggesting actual interactions of CFE with prescription drugs are unlikely to occur through CYP in the small intestine.


Assuntos
Sistema Enzimático do Citocromo P-450/genética , Indução Enzimática/efeitos dos fármacos , Intestino Delgado/efeitos dos fármacos , Fígado/efeitos dos fármacos , Extratos Vegetais/farmacologia , Plectranthus , Animais , Feminino , Intestino Delgado/enzimologia , Fígado/enzimologia , Masculino , Camundongos Endogâmicos ICR , Caracteres Sexuais
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