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Mechanisms of Glucose Absorption in the Small Intestine in Health and Metabolic Diseases and Their Role in Appetite Regulation.
Gromova, LV, Fetissov, SO, Gruzdkov, AA
Nutrients. 2021;(7)
Abstract
The worldwide prevalence of metabolic diseases such as obesity, metabolic syndrome and type 2 diabetes shows an upward trend in recent decades. A characteristic feature of these diseases is hyperglycemia which can be associated with hyperphagia. Absorption of glucose in the small intestine physiologically contributes to the regulation of blood glucose levels, and hence, appears as a putative target for treatment of hyperglycemia. In fact, recent progress in understanding the molecular and cellular mechanisms of glucose absorption in the gut and its reabsorption in the kidney helped to develop a new strategy of diabetes treatment. Changes in blood glucose levels are also involved in regulation of appetite, suggesting that glucose absorption may be relevant to hyperphagia in metabolic diseases. In this review we discuss the mechanisms of glucose absorption in the small intestine in physiological conditions and their alterations in metabolic diseases as well as their relevance to the regulation of appetite. The key role of SGLT1 transporter in intestinal glucose absorption in both physiological conditions and in diabetes was clearly established. We conclude that although inhibition of small intestinal glucose absorption represents a valuable target for the treatment of hyperglycemia, it is not always suitable for the treatment of hyperphagia. In fact, independent regulation of glucose absorption and appetite requires a more complex approach for the treatment of metabolic diseases.
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Intestinal permeation enhancers: Lessons learned from studies using an organ culture model.
Danielsen, EM
Biochimica et biophysica acta. Biomembranes. 2021;(1):183474
Abstract
Permeation enhancers (PEs) are compounds aimed to increase intestinal uptake of oral drugs with poor bioavailability. This mini-review focuses on results recently obtained with PEs using an intestinal organ culture model. The model predicts which paracellular/transcellular pathways across the epithelium are susceptible to different classes of PEs (mainly surfactants and cell penetrating peptides). PEs: 1) generate a transmembrane transcellular pathway, 2) block apical endocytosis (first step in apical-to-basolateral transcytosis), and 3) perturb normal cell membrane integrity. The results argue that surfactants and cell penetrating peptides are not suitable for use in formulations aimed to exploit transcytosis in oral drug delivery.
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Transport, metabolism and remedial potential of functional food extracts (FFEs) in Caco-2 cells monolayer: A review.
Iftikhar, M, Iftikhar, A, Zhang, H, Gong, L, Wang, J
Food research international (Ottawa, Ont.). 2020;:109240
Abstract
Caco-2, a human intestinal carcinoma cell line, has been used to test the absorption and transport mechanism of functional foods and drugs across the intestinal epithelium in order to study their antioxidant, anticancer and anti-inflammatory activities. Caco-2 cells represent the morphological and functional characteristics of small intestinal cells and capable of expressing brush borders, tight junctions, intestinal efflux and uptake transporters which regulate permeation of drugs and functional food extracts from intestinal lumen to systemic circulation. The integrity of the Caco-2 monolayer is controlled by establishing the TEER between 200 and 1000 O per cm2. FFEs affect intestinal permeability by adjusting the tight junction proteins between the cells in order to maintain the epithelial barrier function. Because of the side effects of medicines, there is an increased interest in functional food extracts (FFEs) as drug substitutes. Functional foods undergo intricate transport processes and biotransformation after oral administration. Metabolism and transport studies of FFEs in Caco-2 cells are very important for determining their bioavailability. Functional foods and their constituents produce anti-proliferative and anti-cancer effects through apoptosis, cell cycle arrest and inhibition of various signal transduction pathways across Caco-2 cell lines. The current review has summarized the anti-inflammation, anticancer, antioxidant and cholesterol lowering potential of FFEs using Caco-2 cells through reducing local inflammatory signals, production of ROS and lipid accumulation. The transport, bioavailability, metabolism, mechanisms of actions, cellular pathways adopted by FFEs across Caco-2 cell lines are predominantly affected by their molecular weight, structures and physicochemical properties. These studies are beneficial for investigating the different mechanisms of action of FFEs in the human body.
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A Guide to Human Zinc Absorption: General Overview and Recent Advances of In Vitro Intestinal Models.
Maares, M, Haase, H
Nutrients. 2020;(3)
Abstract
Zinc absorption in the small intestine is one of the main mechanisms regulating the systemic homeostasis of this essential trace element. This review summarizes the key aspects of human zinc homeostasis and distribution. In particular, current knowledge on human intestinal zinc absorption and the influence of diet-derived factors on bioaccessibility and bioavailability as well as intrinsic luminal and basolateral factors with an impact on zinc uptake are discussed. Their investigation is increasingly performed using in vitro cellular intestinal models, which are continually being refined and keep gaining importance for studying zinc uptake and transport via the human intestinal epithelium. The vast majority of these models is based on the human intestinal cell line Caco-2 in combination with other relevant components of the intestinal epithelium, such as mucin-secreting goblet cells and in vitro digestion models, and applying improved compositions of apical and basolateral media to mimic the in vivo situation as closely as possible. Particular emphasis is placed on summarizing previous applications as well as key results of these models, comparing their results to data obtained in humans, and discussing their advantages and limitations.
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Absorption and Metabolism of γ-Oryzanol, a Characteristic Functional Ingredient in Rice Bran.
Sawada, K, Rahmania, H, Matsuki, M, Hashimoto, H, Ito, J, Miyazawa, T, Nakagawa, K
Journal of nutritional science and vitaminology. 2019;(Supplement):S180-S184
Abstract
γ-Oryzanol (OZ), a functional substance found in rice bran, consists of multiple molecular species. In both in vitro and in vivo studies, the researches exploring the various function of rice bran OZ have been conducted for a long time, and it has become clear that OZ has a lot of pharmaceutical activities. It is assumed that each type of OZ molecular species may have different effects. In contrast, the profile behaviour of OZ inside the body has not been fully understood. This article reviews the previous studies about the digestion, absorption, metabolism, and effects of rice bran OZ and also introduces the new method to evaluate the OZ metabolic fate by using high-performance liquid chromatography (HPLC) combined with tandem mass-spectrometry (MS/MS) which has higher selectivity and sensitivity.
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Low colonic absorption drugs: risks and opportunities in the development of oral extended release products.
Xu, J, Lin, Y, Boulas, P, Peterson, ML
Expert opinion on drug delivery. 2018;(2):197-211
Abstract
INTRODUCTION Currently numerous drugs have been observed with lower colonic absorption than small intestine absorption, which can significantly impact in vivo performance of their oral extended release (ER) products. AREAS COVERED We reviewed over 300 publications, patents, book chapters, and commercial reports of drug products from regulatory agencies for low colonic absorption (LCA) drugs and critical findings are discussed. The focuses of this article are (1) current findings on the causes of low colonic absorption to support early assessment of LCA candidates, and (2) current knowledge on successful ER strategies and technical platforms used for LCA drugs in commercial drug products to facilitate oral ER product development. EXPERT OPINION Colonic drug absorption is one of the critical considerations in successful development of oral ER products. The root causes of low colonic absorption in many LCA drugs are still unclear. It is recommended to evaluate colonic drug absorption of drug candidate at early stage of oral ER product development. After evaluation, the selection of a formulation platform to develop an oral ER product needs to be carefully considered for LCA drugs. Based on the current commercial oral ER formulation platforms for LCA drugs, compounds are first divided into five types (I-V) and different ER formulation approaches with higher success rate are recommended for each type.
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The role of mucoprotectants in the management of gastrointestinal disorders.
Eutamene, H, Beaufrand, C, Harkat, C, Theodorou, V
Expert review of gastroenterology & hepatology. 2018;(1):83-90
Abstract
The intestinal barrier controls the absorption of nutrients and water whilst helping to prevent the entry of toxins and pathogenic micro-organisms from the lumen into the tissues. Deficiencies in the barrier are associated with various gastrointestinal and extra digestive disorders. Areas covered: This review provides an overview of the relationship between increased intestinal permeability and disease, and considers the role of mucosal protectants (mucoprotectants) in restoring normal intestinal barrier function, with a particular focus on diarrheal disorders. Expert commentary: Impairment of the intestinal barrier characterizes a variety of diseases, and there is ongoing interest in the development of pharmacological approaches targeting the reduction of intestinal permeability. These include corticosteroids, aminosalicylates and anti-tumor necrosis factor-α (TNF-α), which act by reducing inflammation; probiotics, which modulate the production of mucin and epithelial tight junction proteins; and mucoprotectants, which form a protective film over the epithelium. Recently, preclinical and clinical data highlight, the ability of new mucoprotectants, such as gelatin tannate and xyloglucan, to protect the intestinal mucosa and to exert anti-diarrheal effects. In the future the ability of these substances to enhance the intestinal barrier may extend their use in the management of a variety of gastro-intestinal diseases associated with 'leaky gut'.
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8.
Genetic factors involved in the bioavailability of tomato carotenoids.
Desmarchelier, C, Landrier, JF, Borel, P
Current opinion in clinical nutrition and metabolic care. 2018;(6):489-497
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Abstract
PURPOSE OF REVIEW To provide an update on the genetic factors recently associated with the interindividual variability of tomato carotenoid bioavailability. RECENT FINDINGS Several clinical studies have demonstrated that the main carotenoids found in tomatoes (lycopene, phytoene, phytofluene, β-carotene, lutein) all display relatively large interindividual variabilities of their bioavailability, with coefficients of variations more than 70%. The bioavailability of the parent molecules, and the blood/tissue appearance of their metabolites, is modulated by numerous proteins, involved in intestinal absorption and metabolism, blood lipoprotein transport or tissue uptake. Several single nucleotide polymorphisms (SNPs) have been associated with the interindividual variability of lycopene, lutein and β-carotene bioavailability, with six genes consistently shared between the three carotenoids, and in particular one SNP in ELOVL fatty acid elongase 2. The effects of the genetic variants taken separately are relatively low, that is each variant is usually associated with only a few percentage of the variability but multivariate analyses suggest that the additive effect of several genetic variants can explain a significant fraction of tomato carotenoid bioavailability. SUMMARY Additional studies are needed to improve our knowledge of the genetic determinants of tomato carotenoid bioavailability but progress in this field could one day allow nutritionists to provide more personalized dietary recommendations.
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Glutathione depleting drugs, antioxidants and intestinal calcium absorption.
Moine, L, Rivoira, M, Díaz de Barboza, G, Pérez, A, Tolosa de Talamoni, N
World journal of gastroenterology. 2018;(44):4979-4988
Abstract
Glutathione (GSH) is a tripeptide that constitutes one of the main intracellular reducing compounds. The normal content of GSH in the intestine is essential to optimize the intestinal Ca2+ absorption. The use of GSH depleting drugs such as DL-buthionine-S,R-sulfoximine, menadione or vitamin K3, sodium deoxycholate or diets enriched in fructose, which induce several features of the metabolic syndrome, produce inhibition of the intestinal Ca2+ absorption. The GSH depleting drugs switch the redox state towards an oxidant condition provoking oxidative/nitrosative stress and inflammation, which lead to apoptosis and/or autophagy of the enterocytes. Either the transcellular Ca2+ transport or the paracellular Ca2+ route are altered by GSH depleting drugs. The gene and/or protein expression of transporters involved in the transcellular Ca2+ pathway are decreased. The flavonoids quercetin and naringin highly abrogate the inhibition of intestinal Ca2+ absorption, not only by restoration of the GSH levels in the intestine but also by their anti-apoptotic properties. Ursodeoxycholic acid, melatonin and glutamine also block the inhibition of Ca2+ transport caused by GSH depleting drugs. The use of any of these antioxidants to ameliorate the intestinal Ca2+ absorption under oxidant conditions associated with different pathologies in humans requires more investigation with regards to the safety, pharmacokinetics and pharmacodynamics of them.
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Association Between Exercise-Induced Hyperthermia and Intestinal Permeability: A Systematic Review.
Pires, W, Veneroso, CE, Wanner, SP, Pacheco, DAS, Vaz, GC, Amorim, FT, Tonoli, C, Soares, DD, Coimbra, CC
Sports medicine (Auckland, N.Z.). 2017;(7):1389-1403
Abstract
BACKGROUND Prolonged and strenuous physical exercise increases intestinal permeability, allowing luminal endotoxins to translocate through the intestinal barrier and reach the bloodstream. When recognized by the immune system, these endotoxins trigger a systemic inflammatory response that may affect physical performance and, in severe cases, induce heat stroke. However, it remains to be elucidated whether there is a relationship between the magnitude of exercise-induced hyperthermia and changes in intestinal permeability. OBJECTIVE In this systematic review, we evaluated whether an exercise-induced increase in core body temperature (T Core) is associated with an exercise-induced increase in intestinal permeability. METHODS The present systematic review screened the MEDLINE/PubMed and Web of Science databases in September 2016, without any date restrictions. Sixteen studies that were performed in healthy participants, presented original data, and measured both the exercise-induced changes in T Core and intestinal permeability were selected. These studies assessed intestinal permeability through the measurement of sugar levels in the urine and measurement of intestinal fatty acid binding protein or lipopolysaccharide levels in the blood. RESULTS Exercise increased both T Core and intestinal permeability in most of the 16 studies. In addition, a positive and strong correlation was observed between the two parameters (r = 0.793; p < 0.001), and a T Core exceeding 39 °C was always associated with augmented permeability. CONCLUSION The magnitude of exercise-induced hyperthermia is directly associated with the increase in intestinal permeability.