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1.
Food Chem ; 334: 127586, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32707364

RESUMO

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


Assuntos
Antocianinas/análise , Antocianinas/farmacocinética , Imagem Molecular/métodos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Acilação , Administração Oral , Animais , Antocianinas/administração & dosagem , Cor , Daucus carota/química , Absorção Intestinal/efeitos dos fármacos , Jejuno/efeitos dos fármacos , Jejuno/metabolismo , Masculino , Transportadores de Ânions Orgânicos/metabolismo , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacocinética , Ratos Sprague-Dawley
2.
Int J Nanomedicine ; 15: 9587-9610, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33293809

RESUMO

Bacterial infections are the main infectious diseases and cause of death worldwide. Antibiotics are used to treat various infections ranging from minor to life-threatening ones. The dominant route to administer antibiotics is through oral delivery and subsequent gastrointestinal tract (GIT) absorption. However, the delivery efficiency is limited by many factors such as low drug solubility and/or permeability, gastrointestinal instability, and low antibacterial activity. Nanotechnology has emerged as a novel and efficient tool for targeting drug delivery, and a number of promising nanotherapeutic strategies have been widely explored to overcome these obstacles. In this review, we explore published studies to provide a comprehensive understanding of the recent progress in the area of orally deliverable nano-antibiotic formulations. The first part of this article discusses the functions and underlying mechanisms by which nanomedicines increase the oral absorption of antibiotics. The second part focuses on the classification of oral nano-antibiotics and summarizes the advantages, disadvantages and applications of nanoformulations including lipid, polymer, nanosuspension, carbon nanotubes and mesoporous silica nanoparticles in oral delivery of antibiotics. Lastly, the challenges and future perspective of oral nano-antibiotics for infection disease therapy are discussed. Overall, nanomedicines designed for oral drug delivery system have demonstrated the potential for the improvement and optimization of currently available antibiotic therapies.


Assuntos
Antibacterianos/administração & dosagem , Infecções Bacterianas/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/administração & dosagem , Nanopartículas/química , Administração Oral , Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Humanos , Absorção Intestinal/efeitos dos fármacos , Lipídeos/química , Nanotubos de Carbono/química , Polímeros/química , Dióxido de Silício/química , Solubilidade
3.
PLoS One ; 15(11): e0242820, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33237949

RESUMO

The aim of the study was to determine whether the level and form of Cr in the diet of chickens influences its accumulation in tissues as well as intestinal absorption of P and its deposition in tissues. The experiment was carried out on 405 one-day-old male Ross 308 chickens that were randomly divided into five treatment groups. Control group was fed the diet without supplemental chromium; experimental groups were fed the diet with 3 or 6 mg/kg chromium picolinate (Cr-Pic) and with 3 or 6 mg/kg chromium nanoparticles (Cr-NP). Chromium was found to accumulate in the tissues of the ileum, liver, breast muscle, bones skin and in feathers of chickens. Chromium deposited in the ileum of chickens does not affect the ex vivo estimated intestinal absorption of P. The use of Cr in the diet of chickens carries the risk of lowering P levels in femur.


Assuntos
Osso e Ossos/efeitos dos fármacos , Absorção Intestinal/efeitos dos fármacos , Fósforo/farmacologia , Ácidos Picolínicos/farmacologia , Animais , Glicemia/efeitos dos fármacos , Galinhas , Plumas/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fósforo/química , Distribuição Tecidual/efeitos dos fármacos
4.
Int J Nanomedicine ; 15: 7719-7743, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33116497

RESUMO

Objective: The anticancer efficacy of orally administered chemotherapeutics is often constrained by low intestinal membrane permeability and oral bioavailability. In this context, we designed a solid oral formulation of oxaliplatin (OP), a third-generation cisplatin analog, to improve oral bioavailability and investigate its application in metronomic chemotherapy. Methods: An ion-pairing complex of OP with a permeation enhancer, N α-deoxycholyl-l-lysyl-methylester (DLM), was successfully prepared and then mixed with dispersing agents (including poloxamer 188 and Labrasol) to form the solid, amorphous oral formulation OP/DLM (OP/DLM-SF; hereafter, ODSF). Results: The optimized powder formulation was sized in the nanoscale range (133±1.47 nm). The effective permeability of OP increased by 12.4-fold after ionic complex formation with DLM and was further increased by 24.0-fold after incorporation into ODSF. ODSF exhibited respective increases of 128% and 1010% in apparent permeability across a Caco-2 monolayer, compared to OP/DLM and OP. Furthermore, inhibition of bile acid transporters by actinomycin D and caveola-mediated uptake by brefeldin in Caco-2 cell monolayers reduced the apparent permeability values of ODSF by 58.4% and 51.1%, respectively, suggesting predominant roles for bile acid transporters and caveola-mediated transport in intestinal absorption of ODSF. In addition, macropinocytosis and paracellular and transcellular passive transport significantly influenced the intestinal permeation of ODSF. The oral bioavailabilities of ODSF in rats and monkeys were 68.2% and 277% higher, respectively, than the oral bioavailability of free OP. In vivo analyses of anticancer efficacy in CT26 and HCT116 cell-bearing mice treated with ODSF demonstrated significant suppression of tumor growth, with respective maximal tumor volume reductions of 7.77-fold and 4.07-fold, compared to controls. Conclusion: ODSF exhibits therapeutic potential, constituting an effective delivery system that increases oral bioavailability, with applications to metronomic chemotherapy.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias do Colo/tratamento farmacológico , Portadores de Fármacos/administração & dosagem , Oxaliplatina/administração & dosagem , Oxaliplatina/farmacocinética , Administração Metronômica , Administração Oral , Animais , Antineoplásicos/farmacocinética , Disponibilidade Biológica , Células CACO-2 , Permeabilidade da Membrana Celular/efeitos dos fármacos , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/química , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Feminino , Glicerídeos/química , Humanos , Absorção Intestinal/efeitos dos fármacos , Lisina/análogos & derivados , Lisina/química , Macaca fascicularis , Masculino , Camundongos Endogâmicos BALB C , Poloxâmero/química , Ratos Sprague-Dawley
5.
Am J Physiol Heart Circ Physiol ; 319(6): H1227-H1233, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32986965

RESUMO

The gut microbiome and intestinal dysfunction have emerged as potential contributors to the development of cardiovascular disease (CVD). Alterations in gut microbiome are well documented in hypertension, atherosclerosis, and heart failure and have been investigated as a therapeutic target. However, a perhaps underappreciated but related role for intestinal barrier function has become evident. Increased intestinal permeability is observed in patients and mouse models of CVD. This increased intestinal permeability can enhance systemic inflammation, alter gut immune function, and has been demonstrated as predictive of adverse cardiovascular outcomes. The goal of this review is to examine the evidence supporting a role for intestinal barrier function in cardiovascular disease and its prospect as a novel therapeutic target. We outline key studies that have investigated intestinal permeability in hypertension, coronary artery disease, atherosclerosis, heart failure, and myocardial infarction. We highlight the central mechanisms involved in the breakdown of barrier function and look at emerging evidence for restored barrier function as a contributor to promising treatment strategies such as short chain fatty acid, probiotic, and renin angiotensin system-targeted therapeutics. Recent studies of more selective targeting of the intestinal barrier to improve disease outcomes are also examined. We suggest that although current data supporting a contribution of intestinal permeability to CVD pathogenesis are largely associative, it appears to be a promising avenue for further investigation. Additional studies of the mechanisms of barrier restoration in CVD and testing of intestinal barrier-targeted compounds will be required to confirm their potential as a new class of CVD therapeutic.


Assuntos
Fármacos Cardiovasculares/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Sistema Cardiovascular/efeitos dos fármacos , Fármacos Gastrointestinais/uso terapêutico , Microbioma Gastrointestinal/efeitos dos fármacos , Absorção Intestinal/efeitos dos fármacos , Intestinos/efeitos dos fármacos , Animais , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/microbiologia , Doenças Cardiovasculares/fisiopatologia , Sistema Cardiovascular/fisiopatologia , Humanos , Intestinos/microbiologia , Intestinos/fisiopatologia , Permeabilidade
6.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1865(12): 158808, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32860884

RESUMO

Ezetimibe inhibits Niemann-Pick C1-like 1 (NPC1L1) protein, which mediates intracellular cholesterol trafficking from the brush border membrane to the endoplasmic reticulum, where chylomicron assembly takes place in enterocytes or in the intestinal absorptive epithelial cells. Cholesterol is a minor lipid constituent of chylomicrons; however, whether or not a shortage of cholesterol attenuates chylomicron assembly is unknown. The aim of this study was to examine the effect of ezetimibe, a potent NPC1L1 inhibitor, on trans-epithelial lipid transport, and chylomicron assembly and secretion in enterocytes. Caco-2 cells, an absorptive epithelial model, grown onto culture inserts were given lipid micelles from the apical side, and chylomicron-like triacylglycerol-rich lipoprotein secreted basolaterally were analyzed after a 24-h incubation period in the presence of ezetimibe up to 50 µM. The secretion of lipoprotein and apolipoprotein B48 were reduced by adding ezetimibe (30% and 34%, respectively). Although ezetimibe allowed the cells to take up cholesterol normally, the esterification was abolished. Meanwhile, oleic acid esterification was unaffected. Moreover, ezetimibe activated sterol regulatory element-binding protein 2 by approximately 1.5-fold. These results suggest that ezetimibe limited cellular cholesterol mobilization required for lipoprotein assembly. In such conditions, large lipid droplet formation in Caco-2 cells and the enterocytes of mice were induced, implying that unprocessed triacylglycerol was sheltered in these compartments. Although ezetimibe did not reduce the post-prandial lipid surge appreciably in triolein-infused mice, the results of the present study indicated that pharmacological actions of ezetimibe may participate in a novel regulatory mechanism for the efficient chylomicron assembly and secretion.


Assuntos
Anticolesterolemiantes/farmacologia , Células Epiteliais/efeitos dos fármacos , Ezetimiba/farmacologia , Gotículas Lipídicas/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Animais , Transporte Biológico/efeitos dos fármacos , Células CACO-2 , Células Epiteliais/metabolismo , Humanos , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Gotículas Lipídicas/metabolismo , Camundongos Endogâmicos C57BL
7.
Chem Biol Interact ; 330: 109228, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32827518

RESUMO

This study aimed at exploring the potential mechanism of decreased in vivo exposure of the antiplatelet agent, ticagrelor and its active metabolite, AR-C124910XX, mediated by tea polyphenols, which was first revealed by our previous study, as well as predicting the in vivo drug-drug interaction (DDI) potential utilizing an in vitro to in vivo extrapolation (IVIVE) approach. The bidirectional transport and uptake kinetics of ticagrelor were determined using Caco-2 cells. Inhibition potency of major components of tea polyphenols, epigallocatechin gallate (EGCG) and epigallocatechin (EGC) were obtained from Caco-2 cells, human intestinal and hepatic microsomes (HIMs and HLMs) in vitro. A mean efflux ratio of 2.28 ± 0.38 and active uptake behavior of ticagrelor were observed in Caco-2 cell studies. Further investigation showed that the IC50 values of EGCG and EGC on the uptake of ticagrelor were 42.0 ± 5.1 µM (95% CI 31.9-54.8 µM) and 161 ± 13 µM (95% CI 136-191 µM), respectively. EGCG and EGC also displayed moderate to weak reversible inhibition on the formation of AR-C124910XX and the inactive metabolite, AR-C133913XX in HIMs and HLMs, while no clinically significant time-dependent inhibition was observed for either compound. IVIVE indicated a significant inhibition effect of EGCG on the uptake process of ticagrelor, while no potential DDI risk was found based on microsomal data. A 45% decrease in ticagrelor in vivo exposure was mechanistically predicted by incorporating intestinal and hepatic metabolism as well as intestinal absorption. This dual inhibition of tea polyphenols on ticagrelor revealed the underlying potential of transporter-enzyme interplay, in which the altered uptake process was more critical.


Assuntos
Modelos Teóricos , Polifenóis/farmacologia , Chá/química , Ticagrelor/antagonistas & inibidores , Adenosina/análogos & derivados , Adenosina/metabolismo , Transporte Biológico/efeitos dos fármacos , Células CACO-2 , Catequina/análogos & derivados , Catequina/farmacologia , Linhagem Celular Tumoral , Interações Medicamentosas , Humanos , Absorção Intestinal/efeitos dos fármacos , Cinética , Microssomos Hepáticos/metabolismo , Inibidores da Agregação de Plaquetas/farmacocinética , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Ticagrelor/metabolismo , Ticagrelor/farmacocinética
8.
AAPS PharmSciTech ; 21(7): 245, 2020 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-32856178

RESUMO

The purpose of this study was to investigate the impacts of the formulation parameters on the pharmacokinetics and bioequivalence of risperidone orodispersible film (ODF) using physiologically based pharmacokinetic model. The pharmacokinetic profiles of two risperidone ODFs, which exhibit different in vitro dissolution, were examined in Beagle dogs after supralingual administration. Subsequently, a physiologically based pharmacokinetic (PBPK) model was constructed to evaluate the in vivo performance of risperidone ODF. The parameter sensitivity analysis (PSA) was used to access the impacts of formulation parameters on the pharmacokinetics of risperidone. Moreover, the validated PBPK model was applied to predict human pharmacokinetic profiles and examine the bioequivalence of these two ODFs. These two ODFs displayed similar risperidone pharmacokinetic profiles in dogs. The parameter sensitivity analysis indicated that the changes in the solubility, particle size, particle density, and diffusion coefficient did not have obvious influence on the in vivo properties of risperidone ODF. Alternation of the in vitro complete dissolution time in water from 15 to 30 min led to a 30% decrease in Cmax and 20% of increase in Tmax. AUC0-∞ would be decreased if risperidone was not fully released within 1 h. As both ODFs completely released risperidone within 15 min, the difference in the extent of in vivo absorption, intestinal regional absorption location, and plasma concentration-time curves between these two ODFs was almost negligible. Consequently, a bioequivalence was foreseen in humans. The in vitro cumulative dissolution percentage in water at 15 min was found to be the major determinant on the in vivo properties of risperidone ODF. PBPK modeling appears to be an innovative strategy to guide the development of risperidone ODF.


Assuntos
Absorção Intestinal/efeitos dos fármacos , Absorção Intestinal/fisiologia , Modelos Biológicos , Risperidona/administração & dosagem , Risperidona/farmacocinética , Administração Oral , Animais , Cães , Feminino , Humanos , Masculino , Tamanho da Partícula , Risperidona/química , Antagonistas da Serotonina/administração & dosagem , Antagonistas da Serotonina/química , Antagonistas da Serotonina/farmacocinética , Solubilidade , Equivalência Terapêutica
9.
Int J Nanomedicine ; 15: 4877-4898, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32753869

RESUMO

Background: Although dynamics and uses of modified nanoparticles (NPs) as orally administered macromolecular drugs have been researched for many years, measures of molecule stability and aspects related to important transport-related mechanisms which have been assessed in vivo remain as relatively under characterized. Thus, our aim was to develop a novel type of oral-based delivery system for insulin and to overcome barriers to studying the stability, transport mechanisms, and efficacy in vivo of the delivery system. Methods: NPs we developed and tested were composed of insulin (INS), dicyandiamide-modified chitosan (DCDA-CS), cell-penetrating octaarginine (r8), and hydrophilic hyaluronic acid (HA) and were physically constructed by electrostatic self-assembly techniques. Results: Compared to free-insulin, levels of HA-DCDA-CS-r8-INS NPs were retained at more desirable measures of biological activity in our study. Further, our assessments of the mechanisms for NPs suggested that there were high measures of cellular uptake that mainly achieved through active transport via lipid rafts and the macropinocytosis pathway. Furthermore, investigations of NPs indicated their involvement in caveolae-mediated transport and in the DCDA-CS-mediated paracellular pathway, which contributed to increasing the efficiency of sequential transportation from the apical to basolateral areas. Accordingly, high efficiency of absorption of NPs in situ for intestinal loop models was realized. Consequently, there was a strong induction of a hypoglycemic effect in diabetic rats of NPs via orally based administrations when compared with measures related to free insulin. Conclusion: Overall, the dynamics underlying and influenced by HA-DCDA-CS-r8-INS may hold great promise for stability of insulin and could help overcome interference by the epithelial barrier, and thus showing a great potential to improve the efficacy of orally related treatments.


Assuntos
Quitosana/química , Ácido Hialurônico/química , Insulina/administração & dosagem , Nanopartículas Multifuncionais/química , Nanopartículas/química , Administração Oral , Animais , Transporte Biológico/efeitos dos fármacos , Células CACO-2 , Morte Celular/efeitos dos fármacos , Quitosana/síntese química , Diabetes Mellitus Experimental/tratamento farmacológico , Impedância Elétrica , Endocitose/efeitos dos fármacos , Guanidinas/síntese química , Guanidinas/química , Humanos , Ácido Hialurônico/síntese química , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacologia , Insulina/uso terapêutico , Absorção Intestinal/efeitos dos fármacos , Masculino , Muco/metabolismo , Nanopartículas/ultraestrutura , Ratos , Solubilidade , Suínos
10.
PLoS One ; 15(8): e0237086, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764782

RESUMO

Paramylon is a novel ß-glucan that is stored by Euglena gracilis Z, which is a unicellular photosynthesizing green alga with characteristics of both animals and plants. Recent studies have indicated that paramylon functions as an immunomodulator or a dietary fiber. Currently, chronic kidney disease (CKD) is a global health problem, and there is no effective preventive treatment for CKD progression. However, paramylon may suppress the progression of CKD via the elimination of uremic toxins or modulation of gut microbiota, leading to the alleviation of inflammation. The aim of this study was to evaluate the effect of paramylon in CKD rat model. Eight-week-old male Wistar rats with a 5/6 nephrectomy were given either a normal diet or a diet containing 5% paramylon for 8 weeks. Proteinuria was measured intermittently. Serum and kidney tissues were harvested after sacrifice. We performed a renal molecular and histopathological investigation, serum metabolome analysis, and gut microbiome analysis. The results showed that paramylon attenuated renal function, glomerulosclerosis, tubulointerstitial injury, and podocyte injury in the CKD rat model. Renal fibrosis, tubulointerstitial inflammatory cell infiltration, and proinflammatory cytokine gene expression levels tended to be suppressed with paramylon treatment. Further, paramylon inhibited the accumulation of uremic toxins, including tricarboxylic acid (TCA) cycle-related metabolites and modulated a part of CKD-related gut microbiota in the CKD rat model. In conclusion, we suggest that paramylon mainly inhibited the absorption of non-microbiota-derived uremic solutes, leading to protect renal injury via anti-inflammatory and anti-fibrotic effects. Paramylon may be a novel compound that can act against CKD progression.


Assuntos
Glucanos/farmacologia , Rim/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Proteinúria/tratamento farmacológico , Insuficiência Renal Crônica/tratamento farmacológico , Administração Oral , Animais , Ciclo do Ácido Cítrico/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Euglena gracilis/química , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/imunologia , Glucanos/isolamento & purificação , Glucanos/uso terapêutico , Humanos , Mediadores da Inflamação/metabolismo , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Rim/imunologia , Rim/patologia , Masculino , Substâncias Protetoras/isolamento & purificação , Substâncias Protetoras/uso terapêutico , Proteinúria/sangue , Proteinúria/patologia , Ratos , Ratos Wistar , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/urina , Toxinas Biológicas/sangue , Toxinas Biológicas/metabolismo
11.
Biochem Pharmacol ; 180: 114142, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32653591

RESUMO

Patients with diabetic mellitus tend to have a poor response to clopidogrel (Clop) due to reduced generation of active metabolite (Clop-AM). However, the underlying mechanism is not elucidated. A type 2 diabetic mellitus (T2DM) rat model was established by combining high-fat diet feeding and low-dose streptozotocin (STZ) injection. The reduced Clop-AM exposure was observed in T2DM rats after oral administration of Clop. However, in vitro liver microsomes incubated with Clop exhibited increased Clop-AM levels in T2DM rats due to a significant decrease in carboxylesterase (CES)1 expression and activity and a significant increase in the expression or activity of CYP1A2 and CYP3A. Interestingly, different from oral administration, the significantly increased Cmax of Clop-AM was observed in T2DM rats after intravenous injection, with no difference in AUC0-t and t1/2 values between the two strains. Meanwhile, in situ single -pass intestinal perfusion study showed lower absorption rate constant (Ka) and effective apparent permeability values (Peff) of Clop in T2DM rats than in control rats. It is explained by the increased expression or function of P-glycoprotein (P-gp) and pregnane X receptor (PXR) in duodenum and jejunum of T2DM rats. Moreover, the decreased Clop-AM level in T2DM rats was eliminated by the pretreatment of cyclosporin A, a P-gp inhibitor. It suggests that intestinal absorption, not hepatic metabolism is responsible for the reduced Clop-AM exposure in T2DM rats. P-gp might be the key factor causing the reduction of Clop absorption, consequently making less Clop available for Clop-AM formation.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/biossíntese , Clopidogrel/administração & dosagem , Clopidogrel/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Tipo 2/sangue , Regulação para Cima/fisiologia , Animais , Diabetes Mellitus Experimental/dietoterapia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dieta Hiperlipídica/efeitos adversos , Absorção Intestinal/efeitos dos fármacos , Absorção Intestinal/fisiologia , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Inibidores da Agregação de Plaquetas/administração & dosagem , Inibidores da Agregação de Plaquetas/metabolismo , Ratos , Ratos Sprague-Dawley , Regulação para Cima/efeitos dos fármacos
12.
PLoS One ; 15(6): e0228758, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32497052

RESUMO

Nutritional Programming (NP) has been studied as a means of mitigating the negative effects of dietary plant protein (PP), but the optimal timing and mechanism behind NP are still unknown. The objectives of this study were: 1) To determine whether zebrafish (Danio rerio) can be programmed to soybean meal (SBM) through early feeding and broodstock exposure to improve SBM utilization; 2) To determine if NP in zebrafish affects expression of genes associated with intestinal nutrient uptake; 3) To determine if early stage NP and/or broodstock affects gene expression associated with intestinal inflammation or any morphological changes in the intestinal tract that might improve dietary SBM utilization. Two broodstocks were used to form the six experimental groups. One broodstock group received fishmeal (FM) diet (FMBS), while the other was fed ("programmed with") SBM diet (PPBS). The first ((+) Control) and the second group ((-) Control) received FM and SBM diet for the entire study, respectively, and were progeny of FMBS. The last four groups consisted of a non-programmed (FMBS-X-PP and PPBS-X-PP) and a programmed group (FMBS-NP-PP and PPBS-NP-PP) from each of the broodstocks. The programming occurred through feeding with SBM diet during 13-23 dph. The non-control groups underwent a PP-Challenge, receiving SBM diet during 36-60 dph. During the PP-Challenge, both PPBS groups experienced significantly lower weight gains than the (+) Control group. NP in early life stages significantly increased the expression of PepT1 in PPBS-NP-PP, compared to PPBS-X-PP. NP also tended to increase the expression of fabp2 in the programmed vs. non-programmed groups of both broodstocks. The highest distal villus length-to-width ratio was observed in the dual-programmed group, suggesting an increase in surface area for nutrient absorption within the intestine. The results of this study suggest that NP during early life stages may increase intestinal absorption of nutrients from PP-based feeds.


Assuntos
Dieta , Proteínas na Dieta/metabolismo , Absorção Intestinal/efeitos dos fármacos , Plantas/química , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Vegetais Comestíveis , Fatores de Tempo , Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimento , Peixe-Zebra/metabolismo
13.
Proc Natl Acad Sci U S A ; 117(27): 16009-16018, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32571913

RESUMO

Food and drug products contain diverse and abundant small-molecule additives (excipients) with unclear impacts on human physiology, drug safety, and response. Here, we evaluate their potential impact on intestinal drug absorption. By screening 136 unique compounds for inhibition of the key intestinal transporter OATP2B1 we identified and validated 24 potent OATP2B1 inhibitors, characterized by higher molecular weight and hydrophobicity compared to poor or noninhibitors. OATP2B1 inhibitors were also enriched for dyes, including 8 azo (R-N=N-R') dyes. Pharmacokinetic studies in mice confirmed that FD&C Red No. 40, a common azo dye excipient and a potent inhibitor of OATP2B1, decreased the plasma level of the OATP2B1 substrate fexofenadine, suggesting that FD&C Red No. 40 has the potential to block drug absorption through OATP2B1 inhibition in vivo. However, the gut microbiomes of multiple unrelated healthy individuals as well as diverse human gut bacterial isolates were capable of inactivating the identified azo dye excipients, producing metabolites that no longer inhibit OATP2B1 transport. These results support a beneficial role for the microbiome in limiting the unintended effects of food and drug additives in the intestine and provide a framework for the data-driven selection of excipients. Furthermore, the ubiquity and genetic diversity of gut bacterial azoreductases coupled to experiments in conventionally raised and gnotobiotic mice suggest that variations in gut microbial community structure may be less important to consider relative to the high concentrations of azo dyes in food products, which have the potential to saturate gut bacterial enzymatic activity.


Assuntos
Bactérias/metabolismo , Excipientes/metabolismo , Aditivos Alimentares/metabolismo , Alimentos , Microbioma Gastrointestinal/fisiologia , Absorção Intestinal/fisiologia , Transportadores de Ânions Orgânicos/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Animais , Antialérgicos/metabolismo , Antialérgicos/farmacocinética , Compostos Azo , Bactérias/isolamento & purificação , Excipientes/farmacocinética , Feminino , Aditivos Alimentares/farmacocinética , Antagonistas dos Receptores Histamínicos H1 não Sedativos/metabolismo , Antagonistas dos Receptores Histamínicos H1 não Sedativos/farmacocinética , Humanos , Absorção Intestinal/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Terfenadina/análogos & derivados
14.
PLoS One ; 15(5): e0227844, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32470043

RESUMO

Morroniside is a biologically active polyphenol found in Cornus officinalis Sieb. et Zucc (CO) that exhibits a broad spectrum of pharmacological activities, such as protecting nerves, and preventing diabetic liver damage and renal damage. However, little data are available regarding the mechanism of its intestinal absorption. Here, an in vitro human intestinal epithelial cell model of cultured Caco-2 cells was applied to study the absorption and transport of morroniside. The effects of donor concentration, pH and inhibitors were investigated. The bidirectional permeability of morroniside from the apical (AP) to the basolateral (BL) side and in the reverse direction was studied. When administered at three tested concentrations (5, 25 and 100 µM), the apparent permeability coefficient (Papp) values in the AP-to-BL direction ranged from 1.59 × 10-6 to 2.66 × 10-6 cm/s. In the reverse direction, BL-to-AP, the value was ranged from 2.67 × 10-6 to 4.10 × 10-6 cm/s. The data indicated that morroniside transport was pH-dependent. The permeability of morroniside was affected by treatment with various inhibitors, such as multidrug resistance protein inhibitors MK571 and indomethacin, as well as the breast cancer resistance protein inhibitor apigenin. The mechanisms of the intestinal absorption of morroniside may involve multiple transport pathways, such as the passive diffusion and efflux protein-mediated active transport especially involving multidrug resistance protein 2 and breast cancer resistance protein. After the addition of CO, the Papp values in the AP-to-BL direction increased significantly, therefore, it can be assumed that some ingredients in the CO promote morroniside absorption in the small intestine.


Assuntos
Cornus/química , Glicosídeos/farmacologia , Absorção Intestinal/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Células CACO-2 , Proliferação de Células/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Indometacina/farmacologia , Absorção Intestinal/genética , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Neoplasias/patologia , Permeabilidade/efeitos dos fármacos , Propionatos/farmacologia , Quinolinas/farmacologia
15.
Sci Rep ; 10(1): 7803, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-32385331

RESUMO

Oral rehydration solutions (ORSs) is the key treatment of acute diarrhea in children, as it restores the electrolyte balance by stimulating the intestinal sodium/glucose transporter SGLT1 to induce fluid absorption. The World Health Organization (WHO) and The European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) proposed ORSs with different chemical compositions. The main agent of childhood acute gastroenteritis is rotavirus (RV). We evaluate the effects of ORS with different concentration of glucose and sodium on RV induced secretion. Ussing chambers technique was used for electophysiology experiments to evaluate ion fluid flux. ESPGHAN ORS (sodium 60 mmol/L and glucose 111 mmol/L) induced a more potent proabsorptive effect in Caco-2 cells than WHO ORS, and this effect depended on the sodium/glucose ratio. Titration experiments showed that RV-induced fluid secretion can be reverted to a proabsorptive direction when sodium and glucose concentration fall in specific ranges, specifically 45-60 mEq/L and 80-110 mM respectively. The results were confirmed by testing commercial ORSs. These findings indicated that ORS proabsorptive potency depends on sodium and glucose concentrations. Optimal ORS composition should be tailored to reduce RV-induced ion secretion by also considering palatability. These in vitro data should be confirmed by clinical trials.


Assuntos
Diarreia/terapia , Glucose/metabolismo , Soluções para Reidratação/farmacologia , Bicarbonatos/farmacologia , Células CACO-2 , Criança , Diarreia/metabolismo , Diarreia/prevenção & controle , Hidratação/métodos , Glucose/farmacologia , Humanos , Absorção Intestinal/efeitos dos fármacos , Concentração Osmolar , Potássio/metabolismo , Cloreto de Potássio/farmacologia , Solução Salina/farmacologia , Sódio/metabolismo , Cloreto de Sódio/farmacologia , Transportador 1 de Glucose-Sódio/genética , Equilíbrio Hidroeletrolítico/efeitos dos fármacos
16.
Pharm Res ; 37(5): 87, 2020 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-32356106

RESUMO

PURPOSE: Different anesthetic regimens are used during single pass intestinal perfusion (SPIP) experiments for the study of intestinal drug absorption in rats. We examined the ketamine/xylazine anesthetic combination to evaluate its influence on drug absorption compared to older regimens. Additionally, we examined whether supplementary analgesia has any effect on drug absorption and the effect of the different anesthetic regimens on induction time and stress response. METHODS: Rats were anesthetized using four different anesthetic regimens; ketamine/midazolam, pentobarbital, ketamine/xylazine and ketamine/xylazine/butorphanol. Three model drugs were administered to rat intestines and Peff was calculated. Stress response was evaluated by quantifying blood corticosterone levels and induction time was recorded. RESULTS: We found absorption under pentobarbital to be higher or similar to absorption under ketamine/midazolam. These results partly correlate with past literature data. Ketamine/xylazine was found to give similar or higher Peff compared to pentobarbital and ketamine/midazolam. Addition of butorphanol did not affect absorption and reduced induction time and stress. CONCLUSIONS: In studies of intestinal drug absorption, the ketamine/xylazine combination is superior to other anesthetic regimens as it is more convenient and seems to affect absorption to a lesser extent. Addition of butorphanol is highly recommended as it did not affect absorption but led to a more effective and less stress inducing experiment.


Assuntos
Anestésicos/administração & dosagem , Anestésicos/uso terapêutico , Absorção Intestinal/efeitos dos fármacos , Anestesia , Animais , Butorfanol , Corticosterona/sangue , Ketamina , Masculino , Midazolam , Pentobarbital , Ratos , Ratos Sprague-Dawley , Xilazina
17.
Curr Pharm Biotechnol ; 21(15): 1603-1615, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32410561

RESUMO

In recent decades, there has been a very rapid increase in the prevalence of diabetes globally, with serious health and economic implications. Although today there are several therapeutic treatments for this disease, these do not address the causes of the disease and have serious side effects, so it is necessary to seek new treatments to replace or complement the existing ones. Among these complementary treatments, a strong link between the intestinal microbiota and diabetes has been demonstrated, which has focused attention on the use of biotherapy to regulate the function of the intestinal microbiota and, thus, treat diabetes. In this way, the main objective of this work is to provide a review of the latest scientific evidence on diabetes, gathering information about new trends in its management, and especially, the influence of the intestinal microbiota and microbiome on this pathology. It is possible to conclude that the relationship between the intestinal microbiota and diabetes is carried out through alterations in energy metabolism, the immune system, changes in intestinal permeability, and a state of low-intensity systemic inflammation. Although, currently, most of the experimental work, using probiotics for diabetes management, has been done on experimental animals, the results obtained are promising. Thus, the modification of the microbiota through biotherapy has shown to improve the symptoms and severity of diabetes through various mechanisms related to these alterations.


Assuntos
Diabetes Mellitus/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Prebióticos/administração & dosagem , Probióticos/uso terapêutico , Animais , Diabetes Mellitus/imunologia , Diabetes Mellitus/metabolismo , Diabetes Mellitus/microbiologia , Metabolismo Energético/efeitos dos fármacos , Humanos , Inflamação , Absorção Intestinal/efeitos dos fármacos , Absorção Intestinal/imunologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Permeabilidade
18.
J Steroid Biochem Mol Biol ; 200: 105670, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32283207

RESUMO

Intestinal calcium (Ca) absorption depends upon vitamin D signaling through the vitamin D receptor (VDR) in the proximal and distal intestine while lower VDR content causes intestinal resistance to 1,25 dihydroxyvitamin D (1,25(OH)2 D) action. We tested whether intestinal responsiveness to 1,25(OH)2 D is increased in mice with higher than normal VDR levels resulting from transgenic VDR expression in the whole intestine (villin promoter-human VDR transgene, HV2). Wild type (WT) and HV2 mice were treated with 0, 0.15, or 0.3 ng 1,25(OH)2 D/g body weight (BW) (n = 6/dose) for 6 h. 1,25(OH)2 D significantly induced Cyp24a1, Trpv6, and S100 g mRNA in duodenum (Dd) of WT mice but induction was not higher in HV2 mice. We next tested whether higher intestinal VDR could protect mice from the consequences of low dietary Ca intake. WT and HV2 mice were fed diets with 0.125, 0.25, 0.5 (reference), or 1% Ca from weaning to 3 months of age (n = 9/diet/genotype). Dietary Ca restriction caused a dose dependent increase in serum 1,25(OH)2 D, Dd TRPV6, and Dd S100 g mRNA in WT mice and the effect was greater in HV2 mice. While Ca absorption was increased by low Ca intake, there was no difference in Ca absorption between HV2 and WT mice. Similarly, while bone density and microstructure were reduced by low Ca intake in WT mice, high intestinal VDR in HV2 mice did not protect bone in mice fed low Ca diets. Thus, while intestinal VDR and vitamin D signaling are essential for normal Ca metabolism during growth, our data demonstrate that higher than normal intestinal VDR levels do not improve the intestinal response to either 1,25(OH)2 D injection or to elevated 1,25(OH)2 D levels resulting from the physiologic adaptation to low Ca diets.


Assuntos
Calcitriol/farmacologia , Cálcio/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Receptores de Calcitriol/metabolismo , Vitaminas/farmacologia , Animais , Cálcio/urina , Fêmur/diagnóstico por imagem , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores de Calcitriol/genética
19.
Food Chem ; 324: 126837, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32339791

RESUMO

Evidences have shown that phytosome assemblies are novel drug delivery system. However, studies of phytosomes in food applications are scarce. The characteristics of milk phospholipid assemblies and their functionality in terms of in vitro digestibility and bioavailability of encapsulated nutrients (ascorbic acid and α-tocopherol) were studied. The phytosomes were fabricated using ethanolic evaporation technique. Spectral analysis revealed that polar parts of phospholipids formed hydrogen bonds with ascorbic acid hydroxyl groups, further, incorporating ascorbic acid or α-tocopherol into the phospholipid assembly changed the chemical conformation of the complexes. Phospholipid-ascorbic acid phytosomes yielded an optimal complexing index of 98.52 ± 0.03% at a molar ratio of 1:1. Phytosomes exhibited good biocompatibility on intestinal epithelial cells. The cellular uptake of ascorbic acid was 29.06 ± 1.18% for phytosomes. It was higher than that for liposomes (24.14 ± 0.60%) and for ascorbic acid aqueous solution (1.17 ± 0.70%).


Assuntos
Antioxidantes/química , Ácido Ascórbico/química , Lipossomos/química , Leite/química , Fosfolipídeos/química , alfa-Tocoferol/química , Animais , Ácido Ascórbico/farmacocinética , Varredura Diferencial de Calorimetria , Linhagem Celular , Liberação Controlada de Fármacos , Células Epiteliais/efeitos dos fármacos , Ligação de Hidrogênio , Absorção Intestinal/efeitos dos fármacos , Fosfolipídeos/farmacocinética , Ratos , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier
20.
Nat Med ; 26(4): 589-598, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32235930

RESUMO

Direct evidence in humans for the impact of the microbiome on nutrient absorption is lacking. We conducted an extended inpatient study using two interventions that we hypothesized would alter the gut microbiome and nutrient absorption. In each, stool calorie loss, a direct proxy of nutrient absorption, was measured. The first phase was a randomized cross-over dietary intervention in which all participants underwent in random order 3 d of over- and underfeeding. The second was a randomized, double-blind, placebo-controlled pharmacologic intervention using oral vancomycin or matching placebo (NCT02037295). Twenty-seven volunteers (17 men and 10 women, age 35.1 ± 7.3, BMI 32.3 ± 8.0), who were healthy other than having impaired glucose tolerance and obesity, were enrolled and 25 completed the entire trial. The primary endpoints were the effects of dietary and pharmacological intervention on stool calorie loss. We hypothesized that stool calories expressed as percentage of caloric intake would increase with underfeeding compared with overfeeding and increase during oral vancomycin treatment. Both primary endpoints were met. Greater stool calorie loss was observed during underfeeding relative to overfeeding and during vancomycin treatment compared with placebo. Key secondary endpoints were to evaluate the changes in gut microbial community structure as evidenced by amplicon sequencing and metagenomics. We observed only a modest perturbation of gut microbial community structure with under- versus overfeeding but a more widespread change in community structure with reduced diversity with oral vancomycin. Increase in Akkermansia muciniphila was common to both interventions that resulted in greater stool calorie loss. These results indicate that nutrient absorption is sensitive to environmental perturbations and support the translational relevance of preclinical models demonstrating a possible causal role for the gut microbiome in dietary energy harvest.


Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Absorção Intestinal/efeitos dos fármacos , Desnutrição/metabolismo , Desnutrição/microbiologia , Nutrientes/farmacocinética , Vancomicina/administração & dosagem , Administração Oral , Adolescente , Adulto , Restrição Calórica , Estudos Cross-Over , Dieta , Método Duplo-Cego , Metabolismo Energético/efeitos dos fármacos , Fezes/microbiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Vancomicina/farmacologia , Verrucomicrobia/isolamento & purificação , Adulto Jovem
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