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1.
Nutrients ; 13(7)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34371946

RESUMO

Nutrient sensing plays important roles in promoting satiety and maintaining good homeostatic control. Taste receptors (TAS) are located through the gastrointestinal tract, and recent studies have shown they have a relationship with metabolic disorders. The aim of this study was to analyze the jejunal expression of TAS1R2, TAS1R3, TAS2R14 and TAS2R38 in women with morbid obesity, first classified according to metabolic syndrome presence (MetS; n = 24) or absence (non-MetS; n = 45) and then classified according to hepatic histology as normal liver (n = 28) or nonalcoholic fatty liver disease (n = 41). Regarding MetS, we found decreased expression of TAS2R14 in MetS patients. However, when we subclassified patients according to liver histology, we did not find differences between groups. We found negative correlations between glucose levels, triglycerides and MetS with TAS1R3 expression. Moreover, TAS2R14 jejunal expression correlated negatively with the presence of MetS and ghrelin levels and positively with the jejunal Toll-like receptor (TLR)4, peroxisome proliferator-activated receptor (PPAR)-γ, and interleukin (IL)-10 levels. Furthermore, TAS2R38 expression correlated negatively with TLR9 jejunal expression and IL-6 levels and positively with TLR4 levels. Our findings suggest that metabolic dysfunctions such as MetS trigger downregulation of the intestinal TASs. Therefore, taste receptors modulation could be a possible therapeutic target for metabolic disorders.


Assuntos
Jejuno/metabolismo , Obesidade Mórbida/genética , Receptores Acoplados a Proteínas G/genética , Paladar , Regulação para Baixo , Feminino , Expressão Gênica , Humanos , Metabolismo dos Lipídeos/genética , Fígado/patologia , Síndrome Metabólica/complicações , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade Mórbida/complicações , Obesidade Mórbida/metabolismo , Obesidade Mórbida/patologia , Receptores Acoplados a Proteínas G/metabolismo
2.
Nutrients ; 13(8)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34444916

RESUMO

The study was conducted to explore actions of decanoic acid on regulating intestinal barrier and antioxidant functions in intestinal epithelium cells isolated from porcine jejunum (IPEC-J2) and C57/BL6 mice models. In vitro and vivo assays, mice and IPEC-J2 cells treated by H2O2 were disposed of sodium decanoate and sodium butyrate to determine intestinal barrier and antioxidant functions of the host. Results showed that sodium decanoate upregulated expression of tight junction proteins and improved antioxidant capacity in both IPEC-J2 cells treated by H2O2 and mice models (p < 0.05). Sodium decanoate increased weight gain and ileal villus height of mice compared with control and sodium butyrate treatments (p < 0.05). Sodium decanoate increased α-diversity of ileal microbiota, volatile fatty acids concentration, and G protein-coupled receptor-43 (GPR-43) expression in the ileum and colon of mice (p < 0.05). In conclusion, sodium decanoate improved antioxidant capacity, intestinal morphology, and gut physical barrier of intestinal epithelial cells, resulting in an increase growth performance of mice, which is mediated through activating GPR-43 signaling.


Assuntos
Antioxidantes/metabolismo , Ácidos Decanoicos/metabolismo , Mucosa Intestinal/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animais , Ácido Butírico/metabolismo , Colo/metabolismo , Células Epiteliais/metabolismo , Microbioma Gastrointestinal , Íleo/metabolismo , Jejuno/metabolismo , Camundongos , Modelos Animais , Transdução de Sinais , Suínos , Junções Íntimas/metabolismo , Regulação para Cima
3.
Life Sci ; 283: 119872, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34352261

RESUMO

The interaction of Toxoplasma gondii with the gastrointestinal tract of its host is highly regulated. Once ingested, the parasite crosses the epithelium without altering the permeability of the intestinal barrier. Nevertheless, many studies report alterations ranging from structural to functional damage in cells and tissues that make up the wall of the small and large intestine. Although the immune response to the parasite has been extensively studied, the role of serotonin (5-HT) in toxoplasmosis is poorly understood. Here we investigate the distribution of cells expressing 5-HT and its effects on cells and tissues of the jejunal wall of rats after 2, 3, or 7 days of T. gondii infection. KEY RESULTS: Our results show that transposition of the jejunal epithelium by T. gondii leads to ruptures in the basement membrane and activation of the immune system, as confirmed by the decrease in laminin immunostaining and the increase in the number of mast cells, respectively. CONCLUSIONS AND INFERENCES: We showed an increase in the number of enterochromaffin cells and mast cells expressing 5-HT in the jejunal wall. We also observed that the percentage of serotonergic mast cells increased in the total population. Thus, we can suggest that oral infection by T. gondii oocysts preferentially activates non-neuronal cells expressing 5-HT. Together, these results may explain both the changes in the extracellular matrix and the morphology of the enteric ganglia.


Assuntos
Células Enterocromafins , Jejuno , Oocistos/metabolismo , Serotonina/biossíntese , Toxoplasma/metabolismo , Toxoplasmose/metabolismo , Doença Aguda , Animais , Células Enterocromafins/metabolismo , Células Enterocromafins/parasitologia , Jejuno/metabolismo , Jejuno/parasitologia , Masculino , Ratos , Ratos Wistar
4.
Int J Mol Sci ; 22(16)2021 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-34445450

RESUMO

Tumor necrosis factor alpha (TNFα) has been shown to impair the intestinal barrier, inducing and maintaining inflammatory states of the intestine. The aim of the current study was to analyze functional, molecular and regulatory effects of TNFα in a newly established non-transformed jejunal enterocyte model, namely IPEC-J2 monolayers. Incubation with 1000 U/mL TNFα induced a marked decrease in transepithelial electrical resistance (TEER), and an increase in permeability for the paracellular flux marker [3H]-D-mannitol compared to controls. Immunoblots revealed a significant decrease in tight junction (TJ) proteins occludin, claudin-1 and claudin-3. Moreover, a dose-dependent increase in the TNF receptor (TNFR)-1 was detected, explaining the exponential nature of pro-inflammatory effects, while TNFR-2 remained unchanged. Recovery experiments revealed reversible effects after the removal of the cytokine, excluding apoptosis as a reason for the observed changes. Furthermore, TNFα signaling could be inhibited by the specific myosin light chain kinase (MLCK) blocker ML-7. Results of confocal laser scanning immunofluorescence microscopy were in accordance with all quantitative changes. This study explains the self-enhancing effects of TNFα mediated by MLCK, leading to a differential regulation of TJ proteins resulting in barrier impairment in the intestinal epithelium.


Assuntos
Mucosa Intestinal/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Proteínas de Junções Íntimas/genética , Junções Íntimas , Fator de Necrose Tumoral alfa/metabolismo , Animais , Linhagem Celular , Claudina-1/genética , Claudina-3/genética , Regulação da Expressão Gênica , Mucosa Intestinal/fisiologia , Jejuno/metabolismo , Jejuno/fisiologia , Manitol/metabolismo , Quinase de Cadeia Leve de Miosina/metabolismo , Ocludina/genética , Permeabilidade , Transdução de Sinais , Sus scrofa/metabolismo , Sus scrofa/fisiologia , Fator de Necrose Tumoral alfa/farmacologia
5.
Biomed Pharmacother ; 138: 111094, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34311521

RESUMO

Currently, several studies propose that the dominant intestinal bacteria are core flora. Besides keeping the homeostasis of the intestinal environment, the intestinal microflora also plays a role in body metabolism, production of some vitamins, and control of barrier function. The study aimed to investigate the jejunum microbiota in diabetic rats as well as it's the relationship with Ceftriaxone sodium-mediated gut dysbiosis, diabetic parameters, and intestinal permeability. Thirty-two Wistar rats (Male) were enrolled and divided into four groups (A, B, C, and D; N = 8). Subsequently, T2DM was induced in C and D groups by HFD/STZ model and then gut dysbiosis in B and D groups via intragastric administration of Ceftriaxone sodium for two weeks. The food-water intake, body weight, fasting blood glucose, plasma insulin, HOMA-IR, intestinal permeability, and jejunum microbiota and it's histology were investigated. In this study, T2DM was associated with a significant decrease in the richness and diversity of jejunum microbiota, elevation in the intestinal permeability, and higher abundance of some opportunistic pathogens. Ceftriaxone sodium-induced gut dysbiosis declined food-water intake, damagedthe villi of jejunum tissue, increased intestinal permeability, and affected the diversity of jejunum microbiota. In diabetic rats, Ceftriaxone sodium-mediated gut dysbiosis also declined the abundance of someSCFAs bacteria and raised the abundant of some opportunistic bacteria such as Staphylococcus_sciuri. Interestingly, we found that several bacteria were negatively correlated with HOMA-IR, fasting blood glucose, body weight, and intestinal permeability. Overall, the study highlighted the jejunum microflora alterations in HFD/STZ diabetic rats and assessed the effect of Ceftriaxone sodium-induced gut dysbiosis on diabetic parameters, jejunum microbiota and histology, and intestinal permeability, which are of potential for further studies.


Assuntos
Antibacterianos/farmacologia , Bactérias/crescimento & desenvolvimento , Diabetes Mellitus Experimental/microbiologia , Diabetes Mellitus Tipo 2/microbiologia , Microbioma Gastrointestinal , Jejuno/microbiologia , Animais , Bactérias/efeitos dos fármacos , Bactérias/metabolismo , Ceftriaxona/farmacologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica , Disbiose , Microbioma Gastrointestinal/efeitos dos fármacos , Absorção Intestinal , Jejuno/efeitos dos fármacos , Jejuno/metabolismo , Masculino , Permeabilidade , Ratos Wistar , Estreptozocina
6.
Toxicology ; 460: 152873, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34303734

RESUMO

Oxidative stress (OS) is a key factor in the development of gastrointestinal disorders, in which the intestinal barrier is altered. However, the Multidrug resistance-associated protein 2 (Mrp2) status, an essential component of the intestinal transcellular barrier exhibiting pharmaco-toxicological relevance by limiting the orally ingested toxicants and drugs absorption, has not been investigated. We here evaluated the short-term effect of OS on Mrp2 by treatment of isolated rat intestinal sacs with tert-butyl hydroperoxide (TBH) for 30 min. OS induction by TBH (250 and 500 µM) was confirmed by increased lipid peroxidation end products, decreased reduced glutathione (GSH) content and altered antioxidant enzyme activities. Under this condition, assessment of Mrp2 distribution between brush border (BBM) and intracellular (IM) membrane fractions, showed that Mrp2 protein decreased in BBM and increased in IM, consistent with an internalization process. This was associated with decreased efflux activity and, consequently, impaired barrier function. Subsequent incubation with N-Acetyl-L-Cysteine (NAC, 1 mM) reestablished GSH content and reverted concomitantly the alteration in Mrp2 localization and function induced by TBH. Cotreatment with a specific inhibitor of classic calcium-dependent Protein Kinase C (cPKC) implicated this kinase in TBH-effects. In conclusion, we demonstrated a negative posttranslational regulation of rat intestinal Mrp2 after short-term exposition to OS, a process likely mediated by cPKC and dependent on intracellular GSH content. The concomitant impairment of the Mrp2 barrier function may have implications in xenobiotic absorption and toxicity in a variety of human diseases linked to OS, with notable consequences on the toxicity/safety of therapeutic agents.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Mucosa Intestinal/metabolismo , Jejuno/metabolismo , Microvilosidades/metabolismo , Estresse Oxidativo/fisiologia , Processamento de Proteína Pós-Traducional/fisiologia , Animais , Relação Dose-Resposta a Droga , Mucosa Intestinal/efeitos dos fármacos , Jejuno/efeitos dos fármacos , Masculino , Microvilosidades/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Ratos , Ratos Wistar , terc-Butil Hidroperóxido/toxicidade
7.
DNA Repair (Amst) ; 106: 103178, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34311271

RESUMO

Tumors of Lynch syndrome (LS) patients display high levels of microsatellite instability (MSI), which results from complete loss of DNA mismatch repair (MMR), in line with Knudson's two-hit hypothesis. Why some organs, in particular those of the gastrointestinal (GI) tract, are prone to tumorigenesis in LS remains unknown. We hypothesized that MMR is haploinsufficient in certain tissues, compromising microsatellite stability in a tissue-specific manner before tumorigenesis. Using mouse genetics, we tested how levels of MLH1, a central MMR protein, affect age- and tissue-specific microsatellite stability in vivo and whether elevated MSI is detectable prior to loss of MMR function and to neoplastic growth. To assess putative tissue-specific MMR haploinsufficiency, we determined relevant molecular phenotypes (MSI, Mlh1 promoter methylation status, MLH1 protein and RNA levels) in jejuna of Mlh1+/- mice and compared them to those in spleen, as well as to MMR-proficient and -deficient controls (Mlh1+/+ and Mlh1-/- mice). While spleen MLH1 levels of Mlh1+/- mice were, as expected, approximately 50 % compared to wildtype mice, MLH1 levels in jejunum varied substantially between individual Mlh1+/- mice and moreover, decreased with age. Mlh1+/- mice with soma-wide Mlh1 promoter methylation often displayed severe MLH1 depletion in jejunum. Reduced (but still detectable) MLH1 levels correlated with elevated MSI in Mlh1+/- jejunum. MSI in jejunum increased with age, while in spleens of the same mice, MLH1 levels and microsatellites remained stable. Thus, MLH1 expression levels are particularly labile in intestine of Mlh1+/- mice, giving rise to tissue-specific MSI long before neoplasia. A similar mechanism likely also operates also in the human GI epithelium and could explain the wide range in age-of-onset of LS-associated tumorigenesis.


Assuntos
Reparo de Erro de Pareamento de DNA , Regulação da Expressão Gênica , Haploinsuficiência , Mucosa Intestinal/metabolismo , Instabilidade de Microssatélites , Proteína 1 Homóloga a MutL/genética , Animais , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/metabolismo , Modelos Animais de Doenças , Feminino , Jejuno/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Especificidade de Órgãos , Regiões Promotoras Genéticas , Baço/metabolismo
8.
Nutrients ; 13(5)2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-34064724

RESUMO

Macronutrients in the gastrointestinal (GI) lumen are able to activate "intestinal brakes", feedback mechanisms on proximal GI motility and secretion including appetite and energy intake. In this review, we provide a detailed overview of the current evidence with respect to four questions: (1) are regional differences (duodenum, jejunum, ileum) present in the intestinal luminal nutrient modulation of appetite and energy intake? (2) is this "intestinal brake" effect macronutrient specific? (3) is this "intestinal brake" effect maintained during repetitive activation? (4) can the "intestinal brake" effect be activated via non-caloric tastants? Recent evidence indicates that: (1) regional differences exist in the intestinal modulation of appetite and energy intake with a proximal to distal gradient for inhibition of energy intake: ileum and jejunum > duodenum at low but not at high caloric infusion rates. (2) the "intestinal brake" effect on appetite and energy appears not to be macronutrient specific. At equi-caloric amounts, the inhibition on energy intake and appetite is in the same range for fat, protein and carbohydrate. (3) data on repetitive ileal brake activation are scarce because of the need for prolonged intestinal intubation. During repetitive activation of the ileal brake for up to 4 days, no adaptation was observed but overall the inhibitory effect on energy intake was small. (4) the concept of influencing energy intake by intra-intestinal delivery of non-caloric tastants is intriguing. Among tastants, the bitter compounds appear to be more effective in influencing energy intake. Energy intake decreases modestly after post-oral delivery of bitter tastants or a combination of tastants (bitter, sweet and umami). Intestinal brake activation provides an interesting concept for preventive and therapeutic approaches in weight management strategies.


Assuntos
Apetite , Ingestão de Energia/fisiologia , Trato Gastrointestinal/metabolismo , Bases de Dados Factuais , Carboidratos da Dieta , Gorduras na Dieta , Proteínas na Dieta , Duodeno/metabolismo , Motilidade Gastrointestinal , Humanos , Íleo/metabolismo , Jejuno/metabolismo
9.
PLoS One ; 16(4): e0249179, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33844694

RESUMO

There is no FDA approved therapy for the treatment of celiac disease (CeD), aside from avoidance of dietary gluten. Larazotide acetate (LA) is a first in class oral peptide developed as a tight junction regulator, which is a lead candidate for management of CeD. A delayed release formulation was tested in vitro and predicted release in the mid duodenum and jejunum, the target site of CeD. The aim of this study was to follow the concentration versus time profile of orally administered LA in the small intestine using a porcine model. A sensitive liquid chromatography/tandem mass spectrometry method was developed to quantify LA concentrations in porcine intestinal fluid samples. Oral dosing of LA (1 mg total) in overnight fasted pigs resulted in time dependent appearance of LA in the distal duodenum and proximal jejunum. Peak LA concentrations (0.32-1.76 µM) occurred at 1 hour in the duodenum and in proximal jejunum following oral dosing, with the continued presence of LA (0.02-0.47 µM) in the distal duodenum and in proximal jejunum (0.00-0.43 µM) from 2 to 4 hours following oral dosing. The data shows that LA is available in detectable concentrations at the site of CeD.


Assuntos
Doença Celíaca/tratamento farmacológico , Oligopeptídeos/farmacocinética , Administração Oral , Animais , Liberação Controlada de Fármacos , Duodeno/metabolismo , Jejuno/metabolismo , Oligopeptídeos/administração & dosagem , Oligopeptídeos/uso terapêutico , Suínos
10.
Int J Biol Macromol ; 182: 595-611, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33836198

RESUMO

This study investigated the effects of Moringa oleifera polysaccharides (MOP) on the serum indexes, small intestinal morphology, small intestinal metabolic profile, and caecal microbiota of mice. A new type of polysaccharides with 104,031 Da molecular weight and triple helix structure was isolated from M. oleifera leaves for in vivo experiment. Forty male SPF C57BL/6 mice aged 4 weeks were average divided into four groups randomly according to the MOP gavaged daily (0, 20, 40 and 60 mg/kg body weight MOP). After a 7-day preliminary trial period and a 28-day official trial period, the mice were slaughtered. Results showed that MOP reduced glucose, total cholesterol, and malondialdehyde. It also improved superoxide dismutase and catalase in serum (P < 0.05). For small intestinal morphology, MOP improved the villi length and crypt depth in both ileum and jejunum (P < 0.05); the ratio of villi length to crypt depth in jejunum increased (P < 0.05). MOP could cause the increase of beneficial bacteria and the decrease of harmful bacteria in caecum, further affecting the function of microbiota. In addition, MOP regulated 114 metabolites enriched in the pathway related to the synthesis and metabolism of micromolecules. In sum, MOP exerted positive effects on the serum indexes and intestinal health of mice.


Assuntos
Ceco/efeitos dos fármacos , Microbioma Gastrointestinal , Metaboloma , Moringa oleifera/química , Polissacarídeos/farmacologia , Animais , Glicemia/análise , Catalase/sangue , Ceco/metabolismo , Ceco/microbiologia , Colesterol/sangue , Íleo/efeitos dos fármacos , Íleo/metabolismo , Jejuno/efeitos dos fármacos , Jejuno/metabolismo , Masculino , Malondialdeído/sangue , Camundongos , Camundongos Endogâmicos C57BL , Superóxido Dismutase/sangue
11.
PLoS One ; 16(4): e0250165, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33886649

RESUMO

Intestinal ischemia results in mucosal injury, including paracellular barrier loss due to disruption of tight junctions. Larazotide acetate (LA), a small peptide studied in Phase III clinical trials for treatment of celiac disease, regulates tight junctions (TJs). We hypothesized that LA would dose-dependently hasten recovery of intestinal ischemic injury via modulation of TJs. Ischemia-injured tissue from 6-8-week-old pigs was recovered in Ussing chambers for 240-minutes in the presence of LA. LA (1 µM but not 0.1 µM or 10 µM) significantly enhanced transepithelial electrical resistance (TER) above ischemic injured controls and significantly reduced serosal-to-mucosal flux LPS (P<0.05). LA (1 µM) enhanced localization of the sealing tight junction protein claudin-4 in repairing epithelium. To assess for the possibility of fragmentation of LA, an in vitro enzyme degradation assay using the brush border enzyme aminopeptidase M, revealed generation of peptide fragments. Western blot analysis of total protein isolated from uninjured and ischemia-injured porcine intestine showed aminopeptidase M enzyme presence in both tissue types, and mass spectrometry analysis of samples collected during ex vivo analysis confirmed formation of LA fragments. Treatment of tissues with LA fragments had no effect alone, but treatment with a fragment missing both amino-terminus glycines inhibited barrier recovery stimulated by 1 µM LA. To reduce potential LA inhibition by fragments, a D-amino acid analog of larazotide Analog #6, resulted in a significant recovery response at a 10-fold lower dose (0.1 µM) similar in magnitude to that of 1 µM LA. We conclude that LA stimulates repair of ischemic-injured epithelium at the level of the tight junctions, at an optimal dose of 1 µM LA. Higher doses were less effective because of inhibition by LA fragments, which could be subverted by chirally-modifying the molecule, or microdosing LA.


Assuntos
Mucosa Intestinal/efeitos dos fármacos , Isquemia/tratamento farmacológico , Jejuno/irrigação sanguínea , Oligopeptídeos/uso terapêutico , Junções Íntimas/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Feminino , Mucosa Intestinal/metabolismo , Isquemia/metabolismo , Jejuno/efeitos dos fármacos , Jejuno/metabolismo , Masculino , Oligopeptídeos/farmacologia , Permeabilidade/efeitos dos fármacos , Suínos , Junções Íntimas/metabolismo
12.
Food Funct ; 12(8): 3405-3419, 2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33900307

RESUMO

This study aimed to determine the effects of an early-life lactoferrin (LF) intervention on liver metabolism in suckling piglets. Sixty newborn piglets with an average initial body weight (BW) of 1.51 ± 0.05 kg were assigned to a control (CON) group and an LF group. At age 1 to 7 days, the piglets in the LF group were orally administered LF solution (0.5 g per kg BW daily), whereas the piglets in the CON group were orally administered the same dose of physiological saline. Plasma, jejunum and liver samples were collected on days 8 and 21. The LF piglets showed a decreased plasma urea nitrogen level on day 8 and an increased plasma albumin level on day 21. Pathway analysis of the metabolomic profiles showed that the LF treatment affected amino acid metabolism in the liver. In addition, the LF treatment upregulated the gene expression levels of proteolytic enzymes and amino acid transporters (APA, APN, EAAC1, Pept1, CAT1, B0AT1 and ASCT2) in the jejunum, and it enhanced the phosphorylation levels of mTOR and p70S6K in the liver. The LF treatment also upregulated the expression of a ß-oxidation-related gene (CPT1) and affected the tricarboxylic acid cycle in the liver on day 21. Furthermore, the LF piglets showed a decreased level of malondialdehyde and increased levels of GSH, GSH-Px and GCLC in the liver mitochondria. Overall, the early-life LF intervention affected the protein synthesis, energy production and antioxidative capacity in the liver of the neonatal piglets.


Assuntos
Antioxidantes/farmacologia , Jejuno/metabolismo , Lactoferrina/farmacologia , Fígado/metabolismo , Biossíntese de Proteínas/efeitos dos fármacos , Administração Oral , Animais , Animais Recém-Nascidos , Antioxidantes/administração & dosagem , Lactoferrina/administração & dosagem , Suínos
13.
Int J Mol Sci ; 22(8)2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33919829

RESUMO

The HIF prolyl 4-hydroxylases (HIF-P4H) control hypoxia-inducible factor (HIF), a powerful mechanism regulating cellular adaptation to decreased oxygenation. The gastrointestinal epithelium subsists in "physiological hypoxia" and should therefore have an especially well-designed control over this adaptation. Thus, we assessed the absolute mRNA expression levels of the HIF pathway components, Hif1a, HIF2a, Hif-p4h-1, 2 and 3 and factor inhibiting HIF (Fih1) in murine jejunum, caecum and colon epithelium using droplet digital PCR. We found a higher expression of all these genes towards the distal end of the gastrointestinal tract. We detected mRNA for Hif-p4h-1, 2 and 3 in all parts of the gastrointestinal tract. Hif-p4h-2 had significantly higher expression levels compared to Hif-p4h-1 and 3 in colon and caecum epithelium. To test the roles each HIF-P4H isoform plays in the gut epithelium, we measured the gene expression of classical HIF target genes in Hif-p4h-1-/-, Hif-p4h-2 hypomorph and Hif-p4h-3-/- mice. Only Hif-p4h-2 hypomorphism led to an upregulation of HIF target genes, confirming a predominant role of HIF-P4H-2. However, the abundance of Hif-p4h-1 and 3 expression in the gastrointestinal epithelium implies that these isoforms may have specific functions as well. Thus, the development of selective inhibitors might be useful for diverging therapeutic needs.


Assuntos
Regulação Enzimológica da Expressão Gênica , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Hipóxia/enzimologia , Hipóxia/genética , Mucosa Intestinal/enzimologia , Envelhecimento/metabolismo , Animais , Ceco/metabolismo , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Isoenzimas/metabolismo , Jejuno/metabolismo , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais
14.
Sci Rep ; 11(1): 6113, 2021 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-33731752

RESUMO

The aim of this study was to determine the possible impact of early socialization and an enriched neonatal environment to improve adaptation of piglets to weaning. We hypothesized that changes in the microbiota colonization process and in their metabolic response and intestinal functionality could help the animals face weaning stress. A total of 48 sows and their litters were allotted into a control (CTR) or an enriched treatment (ENR), in which piglets from two adjacent pens were combined and enriched with toys. The pattern of caecal microbial colonization, the jejunal gene expression, the serum metabolome and the intestinal physiology of the piglets were assessed before (-2 d) and after weaning (+ 3d). A differential ordination of caecal microbiota was observed after weaning. Serum metabolome suggested a reduced energetic metabolism in ENR animals, as evidenced by shifts in triglycerides and fatty acids, VLDL/LDL and creatine regions. The TLR2 gene showed to be downregulated in the jejunum of ENR pigs after weaning. The integration of gene expression, metabolome and microbiota datasets confirmed that differences between barren and enriched neonatal environments were evident only after weaning. Our results suggest that improvements in adaptation to weaning could be mediated by a better response to the post-weaning stress.


Assuntos
Ceco/microbiologia , Microbioma Gastrointestinal , Jejuno , Lactação , Animais , Feminino , Jejuno/metabolismo , Jejuno/microbiologia , Suínos , Desmame
15.
Nutrients ; 13(2)2021 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-33672967

RESUMO

The process of obtaining ascorbic acid (AA) via intestinal absorption and blood circulation is carrier-mediated utilizing the AA transporters SVCT1 and SVCT2, which are expressed in the intestine and brain (SVCT2 in abundance). AA concentration is decreased in Alzheimer's disease (AD), but information regarding the status of intestinal AA uptake in the AD is still lacking. We aimed here to understand how AA homeostasis is modulated in a transgenic mouse model (5xFAD) of AD. AA levels in serum from 5xFAD mice were markedly lower than controls. Expression of oxidative stress response genes (glutathione peroxidase 1 (GPX1) and superoxide dismutase 1 (SOD1)) were significantly increased in AD mice jejunum, and this increase was mitigated by AA supplementation. Uptake of AA in the jejunum was upregulated. This increased AA transport was caused by a marked increase in SVCT1 and SVCT2 protein, mRNA, and heterogeneous nuclear RNA (hnRNA) expression. A significant increase in the expression of HNF1α and specific protein 1 (Sp1), which drive SLC23A1 and SLC23A2 promoter activity, respectively, was observed. Expression of hSVCT interacting proteins GRHPR and CLSTN3 were also increased. SVCT2 protein and mRNA expression in the hippocampus of 5xFAD mice was not altered. Together, these investigations reveal adaptive up-regulation of intestinal AA uptake in the 5xFAD mouse model.


Assuntos
Doença de Alzheimer/metabolismo , Ácido Ascórbico/metabolismo , Jejuno/metabolismo , Transportadores de Sódio Acoplados à Vitamina C/metabolismo , Regulação para Cima/genética , Oxirredutases do Álcool/metabolismo , Animais , Transporte Biológico/genética , Proteínas de Ligação ao Cálcio/metabolismo , Suplementos Nutricionais , Modelos Animais de Doenças , Glutationa Peroxidase/metabolismo , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Hipocampo/metabolismo , Homeostase/genética , Absorção Intestinal/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Estresse Oxidativo/genética , RNA Mensageiro/metabolismo , Superóxido Dismutase-1/metabolismo
16.
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
17.
Cell Death Dis ; 12(2): 195, 2021 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-33602915

RESUMO

Amifostine has been the only small molecule radio-protector approved by FDA for decades; however, the serious adverse effects limit its clinical use. To address the toxicity issues and maintain the good potency, a series of modified small polycysteine peptides had been prepared. Among them, compound 5 exhibited the highest radio-protective efficacy, the same as amifostine, but much better safety profile. To confirm the correlation between the radiation-protective efficacy and the DNA binding capability, each of the enantiomers of the polycysteine peptides had been prepared. As a result, the L-configuration compounds had obviously higher efficacy than the corresponding D-configuration enantiomers; among them, compound 5 showed the highest DNA binding capability and radiation-protective efficacy. To our knowledge, this is the first study that has proved their correlations using direct comparison. Further exploration of the mechanism revealed that the ionizing radiation (IR) triggered ferroptosis inhibition by compound 5 could be one of the pathways for the protection effect, which was different from amifostine. In summary, the preliminary result showed that compound 5, a polycysteine as a new type of radio-protector, had been developed with good efficacy and safety profile. Further study of the compound for potential use is ongoing.


Assuntos
Ferroptose/efeitos dos fármacos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Jejuno/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Peptídeos/farmacologia , Lesões por Radiação/prevenção & controle , Protetores contra Radiação/farmacologia , Amifostina/farmacologia , Animais , Linhagem Celular , DNA/metabolismo , Modelos Animais de Doenças , Ferroptose/efeitos da radiação , Glutationa/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Células-Tronco Hematopoéticas/efeitos da radiação , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Mucosa Intestinal/efeitos da radiação , Jejuno/metabolismo , Jejuno/patologia , Jejuno/efeitos da radiação , Peroxidação de Lipídeos/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Pulmão/efeitos da radiação , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Estresse Oxidativo/efeitos dos fármacos , Peptídeos/síntese química , Peptídeos/metabolismo , Doses de Radiação , Lesões por Radiação/genética , Lesões por Radiação/metabolismo , Lesões por Radiação/patologia , Protetores contra Radiação/síntese química , Protetores contra Radiação/metabolismo , Ratos , Irradiação Corporal Total
18.
Commun Biol ; 4(1): 173, 2021 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-33564097

RESUMO

Glycoproteins and glycolipids at the plasma membrane contribute to a range of functions from growth factor signaling to cell adhesion and migration. Glycoconjugates undergo endocytic trafficking. According to the glycolipid-lectin (GL-Lect) hypothesis, the construction of tubular endocytic pits is driven in a glycosphingolipid-dependent manner by sugar-binding proteins of the galectin family. Here, we provide evidence for a function of the GL-Lect mechanism in transcytosis across enterocytes in the mouse intestine. We show that galectin-3 (Gal3) and its newly identified binding partner lactotransferrin are transported in a glycosphingolipid-dependent manner from the apical to the basolateral membrane. Transcytosis of lactotransferrin is perturbed in Gal3 knockout mice and can be rescued by exogenous Gal3. Inside enterocytes, Gal3 is localized to hallmark structures of the GL-Lect mechanism, termed clathrin-independent carriers. These data pioneer the existence of GL-Lect endocytosis in vivo and strongly suggest that polarized trafficking across the intestinal barrier relies on this mechanism.


Assuntos
Enterócitos/metabolismo , Galectina 3/metabolismo , Glicoesfingolipídeos/metabolismo , Jejuno/metabolismo , Lactoferrina/metabolismo , Transcitose , Animais , Proteínas Sanguíneas/metabolismo , Enterócitos/ultraestrutura , Galectina 3/deficiência , Galectina 3/genética , Galectinas/metabolismo , Jejuno/ultraestrutura , Camundongos Endogâmicos C57BL , Camundongos Knockout
19.
J Sci Food Agric ; 101(12): 5190-5201, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33608932

RESUMO

BACKGROUND: Dietary supplemental carbohydrases are able to degrade non-starch polysaccharides and generate oligosaccharides in the gastrointestinal tract. This study was conducted to investigate the influence of dietary fiber and protein levels on growth performance, nutrient utilization, digesta oligosaccharides profile and cecal short-chain fatty acid (SCFA) profile in broilers receiving diets supplemented with xylanase or protease individually or in combination. RESULTS: Enzyme supplementation had no effect on growth performance. There was significant (P < 0.05) fiber × protein × xylanase interaction for ileal nitrogen digestibility and significant (P < 0.01) protein × xylanase × protease interaction for nitrogen-corrected apparent metabolizable energy. Birds fed high-fiber diets had higher (P < 0.05) jejunal oligosaccharides and cecal SCFA concentrations. Xylanase and protease combination produced the greatest pentose (Pent) levels in low fiber-adequate protein diets but lowest levels in highfiber-low protein diets. There was significant (P < 0.05) fiber × xylanase × protease interaction explained by the digesta concentrations of (Pent)3 , (Pent)4 and (Pent)5 being greatest (P < 0.5) in protease-only supplemented high-fiber diets but lowest in protease-only supplemented low-fiber diets. CONCLUSION: These results suggest that, of all the factors investigated, dietary fiber level had the greatest effect on modulating digesta concentration of oligosaccharides and cecal SCFA. Evidence points to the fact that there is considerable capacity for generating pentose oligosaccharides in the digestive tract of broilers receiving diets rich in fibrous feedstuffs, and that this may have a beneficial effect on microbial profile in the digestive tract. © 2021 Society of Chemical Industry.


Assuntos
Ração Animal/análise , Ceco/metabolismo , Galinhas/metabolismo , Fibras na Dieta/metabolismo , Ácidos Graxos Voláteis/química , Jejuno/metabolismo , Oligossacarídeos/química , Fenômenos Fisiológicos da Nutrição Animal , Animais , Ceco/química , Galinhas/crescimento & desenvolvimento , Fibras na Dieta/análise , Suplementos Nutricionais/análise , Digestão , Ácidos Graxos Voláteis/metabolismo , Feminino , Jejuno/química , Masculino , Oligossacarídeos/metabolismo
20.
J Nutr Biochem ; 90: 108576, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33388346

RESUMO

This study compared the relative mRNA expression of all mammal zinc (Zn) transporter genes in selected tissues of weaned piglets challenged with short-term subclinical Zn deficiency (SZD). The dietary model involved restrictive feeding (450 g/animal*day-1) of a high-phytate diet (9 g/kg) supplemented with varying amounts of zinc from ZnSO4*7H2O ranging from deficient to sufficient supply levels (total diet Zn: 28.1, 33.6, 38.8, 42.7, 47.5, 58.2, 67.8, 88.0 mg Zn/kg). Total RNA preparations comprised jejunal and colonic mucosa as well as hepatic and nephric tissue. Statistical modelling involved broken-line regression (P≤.05). ZIP10 and ZIP12 mRNAs were not detected in any tissue and ZnT3 mRNA was only identified in the kidney. All other genes were expressed in all tissues but only a few gene expression patterns allowed a significant (P<.0001) fitting of broken-line regression models, indicating homeostatic regulation under the present experimental conditions. Interestingly, these genes could be subcategorized by showing significant turnarounds in their response patterns, either at ~40 or ~60 mg Zn/kg diet (P<.0001). In conclusion, the present study showed clear differences in Zn transporter gene expression in response to SZD compared to the present literature on clinical models. We recognized that certain Zn transporter genes were regulated under the present experimental conditions by two distinct homeostatic networks. For the best of our knowledge, this represents the first comprehensive screening of Zn transporter gene expression in a highly translational model to human physiology.


Assuntos
Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , RNA Mensageiro/metabolismo , Zinco/deficiência , Fenômenos Fisiológicos da Nutrição Animal , Animais , Colo/metabolismo , Dieta , Suplementos Nutricionais , Modelos Animais de Doenças , Feminino , Expressão Gênica , Humanos , Mucosa Intestinal/metabolismo , Jejuno/metabolismo , Fígado/metabolismo , Masculino , Suínos , Desmame , Zinco/metabolismo
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