Exploring the Hypocholesterolemic Potential of a Fucus vesiculosus Extract: Omic Insights into Molecular Mechanisms at the Intestinal Level.

High blood cholesterol levels are a major risk factor for cardiovascular diseases. A purified aqueous extract of Fucus vesiculosus, rich in phlorotannins and peptides, has been described for its potential to inhibit cholesterol biosynthesis and intestinal absorption. In this work, the effect of this extract on intestinal cells' metabolites and proteins was analysed to gain a deeper understanding of its mode of action on lipids' metabolism, particularly concerning the absorption and transport of exogenous cholesterol. Caco-2 cells, differentiated into enterocytes, were exposed to the extract, and analysed by untargeted metabolomics and proteomics. The results of the metabolomic analysis showed statistically significant differences in glutathione content of cells exposed to the extract compared to control cells, along with an increased expression of fatty acid amides in exposed cells. A proteomic analysis showed an increased expression in cells exposed to the extract compared to control cells of FAB1 and NPC1, proteins known to be involved in lipid metabolism and transport. To the extent of our knowledge, this study is the first use of untargeted metabolomics and a proteomic analysis to investigate the effects of F. vesiculosus on differentiated Caco-2 cells, offering insights into the molecular mechanism of the extract's compounds on intestinal cells.

Increased Intestinal Permeability and Decreased Resiliency of the Intestinal Barrier in Alcoholic Liver Disease.

INTRODUCTION: Only 20%-30% of individuals with alcohol use disorder (AUD) develop alcoholic liver disease (ALD). While the development of gut-derived endotoxemia is understood to be a required cofactor, increased intestinal permeability in ALD is not completely understood. METHODS: We recruited 178 subjects-58 healthy controls (HCs), 32 with ALD, 53 with AUD but no liver disease (ALC), and 35 with metabolic dysfunction-associated steatotic liver disease (MASLD). Intestinal permeability was assessed by a sugar cocktail as a percentage of oral dose. The permeability test was repeated after an aspirin challenge in a subset. RESULTS: Five-hour urinary lactulose/mannitol ratio (primarily representing small intestinal permeability) was not statistically different in HC, ALC, ALD, and MASLD groups ( P = 0.40). Twenty-four-hour urinary sucralose (representing whole gut permeability) was increased in ALD ( F = 5.3, P < 0.01) and distinguished ALD from ALC; 24-hour sucralose/lactulose ratio (primarily representing colon permeability) separated the ALD group ( F = 10.2, P < 0.01) from the MASLD group. After aspirin challenge, intestinal permeability increased in all groups and ALD had the largest increase. DISCUSSION: In a group of patients, we confirmed that (i) the ALD group has increased intestinal permeability compared with the HC, ALC, or MASLD group. In addition, because small bowel permeability (lactulose/mannitol ratio) is normal, the disruption of intestinal barrier seems to be primarily in the large intestine; (ii) decreased resiliency of intestinal barrier to injurious agents (such as NSAID) might be the mechanism for gut leak in subset of AUD who develop ALD.

Physiological functions of poorly absorbed polyphenols via the glucagon-like peptide-1.

Polyphenols are compounds of plant origin with several documented bioactivities related to health promotion. Some polyphenols are hard to be absorbed into the body due to their structural characteristics. This review focuses on the health beneficial effects of polyphenols mediated by intestinal hormones, particularly related to the systemic functions through the secretion of glucagon-like peptide-1 (GLP-1), an enteric hormone that stimulates postprandial insulin secretion. GLP-1 is secreted from L cells in the distal small intestine. Therefore, some poorly absorbed polyphenols are known to have the ability to act on the intestines and promote GLP-1 secretion. It has been reported that it not only reduces hyperglycemia but also prevents obesity by reduction of overeating and improves blood vessel function. This review discusses examples of health effects of polyphenols mediated by GLP-1 secretion.

Aster-dependent nonvesicular transport facilitates dietary cholesterol uptake.

Intestinal absorption is an important contributor to systemic cholesterol homeostasis. Niemann-Pick C1 Like 1 (NPC1L1) assists in the initial step of dietary cholesterol uptake, but how cholesterol moves downstream of NPC1L1 is unknown. We show that Aster-B and Aster-C are critical for nonvesicular cholesterol movement in enterocytes. Loss of NPC1L1 diminishes accessible plasma membrane (PM) cholesterol and abolishes Aster recruitment to the intestinal brush border. Enterocytes lacking Asters accumulate PM cholesterol and show endoplasmic reticulum cholesterol depletion. Aster-deficient mice have impaired cholesterol absorption and are protected against diet-induced hypercholesterolemia. Finally, the Aster pathway can be targeted with a small-molecule inhibitor to manipulate cholesterol uptake. These findings identify the Aster pathway as a physiologically important and pharmacologically tractable node in dietary lipid absorption.

The strawberry-derived permeation enhancer pelargonidin enables oral protein delivery.

Although patients generally prefer oral drug delivery to injections, low permeability of the gastrointestinal tract makes this method impossible for most biomacromolecules. One potential solution is codelivery of macromolecules, including therapeutic proteins or nucleic acids, with intestinal permeation enhancers; however, enhancer use has been limited clinically by modest efficacy and toxicity concerns surrounding long-term administration. Here, we hypothesized that plant-based foods, which are well tolerated by the gastrointestinal tract, may contain compounds that enable oral macromolecular absorption without causing adverse effects. Upon testing more than 100 fruits, vegetables, and herbs, we identified strawberry and its red pigment, pelargonidin, as potent, well-tolerated enhancers of intestinal permeability. In mice, an oral capsule formulation comprising pelargonidin and a 1 U/kg dose of insulin reduced blood glucose levels for over 4 h, with bioactivity exceeding 100% relative to subcutaneous injection. Effects were reversible within 2 h and associated with actin and tight junction rearrangement. Furthermore, daily dosing of mice with pelargonidin for 1 mo resulted in no detectable side effects, including weight loss, tissue damage, or inflammatory responses. These data suggest that pelargonidin is an exceptionally effective enhancer of oral protein uptake that may be safe for routine pharmaceutical use.

Sex-specific and concentration-dependent influence of Cremophor RH 40 on ampicillin absorption via its effect on intestinal membrane transporters in rats.

Pharmaceutical excipients are the basic materials and important components of pharmaceutical preparations, and play an important role in improving the efficacy of drugs and reducing adverse reactions. Therefore, selecting suitable excipients for dosage form is an important step in formulation development. An increasing number of studies have revealed that the traditionally regarded "inert" excipients can, however, influence the bioavailability of drugs. Moreover, these effects on the bioavailability of drugs caused by pharmaceutical excipients may differ in between males and females. In this study, the in situ effect of the widely-used pharmaceutical excipient Cremophor RH 40 spanning from 0.001% to 0.1% on the intestinal absorption of ampicillin in male and female rats using closed-loop models was investigated. Cremophor RH 40 ranging from 0.03% to 0.07% increased the absorption of ampicillin in females, however, was decreased in male rats. The mechanism of such an effect on drug absorption is suggested to be due to the interaction between Cremophor RH 40 and two main membrane transporters P-gp and PepT1. Cremophor RH 40 altered the PepT1 protein content in a sex-dependent manner, showing an increase in female rats but a decrease in males. No modification on the PepT1 mRNA abundance was found with Cremophor RH 40, indicating that the excipient may regulate the protein recruitment of the plasma membrane from the preformed cytoplasm pool to alter the PepT1 function. This influence, however, may differ between males and females. As such, the study herein shows that supposedly inert excipient Cremophor RH 40 can influence membrane fluidity, uptake and efflux transporters in a sex- and concentration-dependent manner. These findings, therefore, highlight the need for sex-specific studies in the application of solubilizing excipients in drug formulation development.

Discovery of Gut-Restricted Small-Molecule Inhibitors of Intestinal Sodium-Dependent Phosphate Transport Protein 2b (NaPi2b) for the Treatment of Hyperphosphatemia.

NaPi2b is primarily expressed in the small intestine, lungs, and testes and plays an important role in phosphate homeostasis. The inhibition of NaPi2b, responsible for intestinal phosphate absorption, is considered to reduce serum phosphate levels, making it a promising therapeutic approach for hyperphosphatemia. Using a novel phosphate uptake inhibitor 3 (IC50 = 87 nM), identified from an in-house compound collection in human NaPi2b-transfected cells as a prototype compound, we conducted its derivatization based on a Ro5-deviated strategy to develop orally administrable small-molecule NaPi2b inhibitors with nonsystemic exposure. Consequently, compound 15, a zwitterionic compound with a potent in vitro phosphate uptake inhibitory activity (IC50 = 64 nM) and a low membrane permeability (Pe < 0.025 × 10-6 cm/s), was developed. Compound 15 showed a low bioavailability (F = 0.1%) in rats and a reduction in phosphate absorption in the rat intestinal loop assay comparable to sevelamer hydrochloride, a clinically effective phosphate binder for treating hyperphosphatemia.

Tenapanor: A new treatment option for hyperphosphatemia in end stage kidney disease.

PURPOSE: This narrative review explores the currently published studies that have evaluated tenapanor for the treatment of hyperphosphatemia in end-stage kidney disease (ESKD) patients on hemodialysis. This medication's new phosphate lowering mechanism of action reduces intestinal phosphate absorption predominantly through reduction of passive paracellular phosphate flux by inhibition of the sodium/hydrogen exporter isoform 3 (NHE3). Tenapanor additionally prevents active transcellular phosphate absorption compensation by decreasing the expression of sodium phosphorus 2b transport protein (NaPi2b). METHODS: A comprehensive search of the literature was conducted using PubMed and ClinicalTrials.gov search engines. The search term "tenapanor hyperphosphatemia" was used for study retrieval. Results were limited to studies published in the English language and excluded review articles. Human, animal, and in vitro studies were included. No date range was specified. RESULTS: A total of 11 primary studies were identified and included in this review, the largest human study of which enrolled 236 patients. Each study is presented in table format along with measured end points. CONCLUSIONS: Tenapanor is the first drug in its class that lowers hyperphosphatemia in ESKD patients through a novel mechanism of action involving paracellular inactive transport. Although more studies are needed, early results indicate that tenapanor may have a place in managing hyperphosphatemia in ESKD patients both as monotherapy and as an adjunct to existing phosphate binder therapy.

Orally administered intelligent self-ablating nanoparticles: a new approach to improve drug cellular uptake and intestinal absorption.

Oral drug delivery to treat diabetes is being increasingly researched. The mucus and the epithelial cell layers hinder drug delivery. We designed a self-ablating nanoparticle to achieve smart oral delivery to overcome the gastrointestinal barrier. We used the zwitterionic dilauroyl phosphatidylcholine, which exhibits a high affinity toward Oligopeptide transporter 1, to modify poly(lactic-co-glycolic acid) nanoparticles and load hemagglutinin-2 peptide to facilitate its escape from lysosomes. Nanoparticles exhibit a core-shell structure, the lipid layer is degraded by the lysosomes when the nanoparticles are captured by lysosomes, then the inner core of the nanoparticles gets exposed. The results revealed that the self-ablating nanoparticles exhibited higher encapsulation ability than the self-assembled nanoparticles (77% vs 64%) and with better stability. Quantitative cellular uptake, cellular uptake mechanisms, and trans-monolayer cellular were studied, and the results revealed that the cellular uptake achieved using the self-ablating nanoparticles was higher than self-assembling nanoparticles, and the number of uptake pathways via which the self-ablating nanoparticles functioned were higher than the self-assembling nanoparticles. Intestinal mucus permeation, in vivo intestinal circulation, was studied, and the results revealed that the small self-assembling nanoparticles exhibit a good extent of intestinal uptake in the presence of mucus. In vitro flip-flop, intestinal circulation revealed that the uptake of the self-ablating nanoparticles was 1.20 times higher than the self-assembled nanoparticles. Pharmacokinetic study and the pharmacodynamic study showed that the bioavailability and hypoglycemic effect of self-ablating nanoparticles were better than self-assembled nanoparticles.

Impact of Intestinal Concentration and Colloidal Structure on the Permeation-Enhancing Efficiency of Sodium Caprate in the Rat.

In this work, we set out to better understand how the permeation enhancer sodium caprate (C10) influences the intestinal absorption of macromolecules. FITC-dextran 4000 (FD4) was selected as a model compound and formulated with 50-300 mM C10. Absorption was studied after bolus instillation of liquid formulation to the duodenum of anesthetized rats and intravenously as a reference, whereafter plasma samples were taken and analyzed for FD4 content. It was found that the AUC and Cmax of FD4 increased with increasing C10 concentration. Higher C10 concentrations were associated with an increased and extended absorption but also increased epithelial damage. Depending on the C10 concentration, the intestinal epithelium showed significant recovery already at 60-120 min after administration. At the highest studied C10 concentrations (100 and 300 mM), the absorption of FD4 was not affected by the colloidal structures of C10, with similar absorption obtained when C10 was administered as micelles (pH 8.5) and as vesicles (pH 6.5). In contrast, the FD4 absorption was lower when C10 was administered at 50 mM formulated as micelles as compared to vesicles. Intestinal dilution of C10 and FD4 revealed a trend of decreasing FD4 absorption with increasing intestinal dilution. However, the effect was smaller than that of altering the total administered C10 dose. Absorption was similar when the formulations were prepared in simulated intestinal fluids containing mixed micelles of bile salts and phospholipids and in simple buffer solution. The findings in this study suggest that in order to optimally enhance the absorption of macromolecules, high (≥100 mM) initial intestinal C10 concentrations are likely needed and that both the concentration and total dose of C10 are important parameters.

Intestinal permeation enhancers enable oral delivery of macromolecules up to 70 kDa in size.

The decades-long effort to deliver peptide drugs orally has resulted in several clinically successful formulations. These formulations are enabled by the inclusion of permeation enhancers that facilitate the intestinal absorption of peptides. Thus far, these oral peptide drugs have been limited to peptides less than 5 kDa, and it is unclear whether there is an upper bound of protein size that can be delivered with permeation enhancers. In this work, we examined two permeation enhancers, 1-phenylpiperazine (PPZ) and sodium deoxycholate (SDC), for their ability to increase intestinal transport of a model macromolecule (FITC-Dextran) as a function of its size. Specifically, the permeability of dextrans with molecular weights of 4, 10, 40, and 70 kDa was assessed in an in vitro and in vivo model of the intestine. In Caco-2 monolayers, both PPZ and SDC significantly increased the permeability of only FD4 and FD10. However, in mice, PPZ and SDC behaved differently. While SDC improved the absorption of all tested sizes of dextrans, PPZ was effective only for FD4 and FD10. This work is the first report of PPZ as a permeation enhancer in vivo, and it highlights the ability of permeation enhancers to improve the absorption of macromolecules across a broad range of sizes relevant for protein drugs.

In Silico-Based Experiments on Mechanistic Interactions between Several Intestinal Permeation Enhancers with a Lipid Bilayer Model.

Oral administration of drugs is generally considered convenient and patient-friendly. However, oral administration of biological drugs exhibits low oral bioavailability (BA) due to enzymatic degradation and low intestinal absorption. A possible approach to circumvent the low BA of oral peptide drugs is to coformulate the drugs with permeation enhancers (PEs). PEs have been studied since the 1960s and are molecules that enhance the absorption of hydrophilic molecules with low permeability over the gastrointestinal epithelium. In this study, we investigated the impact of six PEs on the structural properties of a model membrane using molecular dynamics (MD) simulations. The PEs included were the sodium salts of the medium chain fatty acids laurate, caprate, and caprylate and the caprylate derivative SNAC─all with a negative charge─and neutral caprate and neutral sucrose monolaurate. Our results indicated that the PEs, once incorporated into the membrane, could induce membrane leakiness in a concentration-dependent manner. Our simulations suggest that a PE concentration of at least 70-100 mM is needed to strongly affect transcellular permeability. The increased aggregation propensity seen for neutral PEs might provide a molecular-level mechanism for the membrane disruptions seen at higher concentrations in vivo. The ability for neutral PEs to flip-flop across the lipid bilayer is also suggestive of possible intracellular modes of action other than increasing membrane fluidity. Taken together, our results indicate that MD simulations are useful for gaining insights relevant to the design of oral dosage forms based around permeability enhancer molecules.

Ceftriaxone causes dysbiosis and changes intestinal structure in adjuvant obesity treatment.

BACKGROUND: Obesity is still a worldwide public health problem, requiring the development of adjuvant therapies to combat it. In this context, modulation of the intestinal microbiota seems prominent, given that the composition of the intestinal microbiota contributes to the outcome of this disease. The aim of this work is to investigate the treatment with an antimicrobial and/or a potential probiotic against overweight. METHODS: Male C57BL/6J mice were subjected to a 12-week overweight induction protocol. After that, 4-week treatment was started, with mice divided into four groups: control, treated with distilled water; potential probiotic, with Lactobacillus gasseri LG-G12; antimicrobial, with ceftriaxone; and antimicrobial + potential probiotic with ceftriaxone in the first 2 weeks and L. gasseri LG-G12 in the subsequent weeks. RESULTS: The treatment with ceftriaxone in isolated form or in combination with the potential probiotic provided a reduction in body fat. However, such effect is supposed to be a consequence of the negative action of ceftriaxone on the intestinal microbiota composition, and this intestinal dysbiosis may have contributed to the destruction of the intestinal villi structure, which led to a reduction in the absorptive surface. Also, the effects of L. gasseri LG-G12 apparently have been masked by the consumption of the high-fat diet. CONCLUSIONS: The results indicate that the use of a ceftriaxone in the adjuvant treatment of overweight is not recommended due to the potential risk of developing inflammatory bowel disease.

Fenretinide inhibits vitamin A formation from ß-carotene and regulates carotenoid levels in mice.

N-[4-hydroxyphenyl]retinamide, commonly known as fenretinide, a synthetic retinoid with pleiotropic benefits for human health, is currently utilized in clinical trials for cancer, cystic fibrosis, and COVID-19. However, fenretinide reduces plasma vitamin A levels by interacting with retinol-binding protein 4 (RBP4), which often results in reversible night blindness in patients. Cell culture and in vitro studies show that fenretinide binds and inhibits the activity of ß-carotene oxygenase 1 (BCO1), the enzyme responsible for endogenous vitamin A formation. Whether fenretinide inhibits vitamin A synthesis in mammals, however, remains unknown. The goal of this study was to determine if the inhibition of BCO1 by fenretinide affects vitamin A formation in mice fed ß-carotene. Our results show that wild-type mice treated with fenretinide for ten days had a reduction in tissue vitamin A stores accompanied by a two-fold increase in ß-carotene in plasma (P < 0.01) and several tissues. These effects persisted in RBP4-deficient mice and were independent of changes in intestinal ß-carotene absorption, suggesting that fenretinide inhibits vitamin A synthesis in mice. Using Bco1-/- and Bco2-/- mice we also show that fenretinide regulates intestinal carotenoid and vitamin E uptake by activating vitamin A signaling during short-term vitamin A deficiency. This study provides a deeper understanding of the impact of fenretinide on vitamin A, carotenoid, and vitamin E homeostasis, which is crucial for the pharmacological utilization of this retinoid.

In vivo antidiabetic activity of nimesulide due to inhibition of amino acid transport.

Inhibiting the intestinal and renal neutral amino acid transporter B0AT1 by genetic means has improved insulin sensitivity in mice, but there are no antagonists available for preclinical or clinical use. Since the anti-inflammatory agent nimesulide selectively inhibited B0AT1 in vitro, we hypothesized that nimesulide exhibits in vivo potential to restrict neutral amino acid absorption and, therefore, may improve insulin sensitivity. The dose-related effect of nimesulide (10 to 100 mg/kg, PO) on intestinal absorption of neutral amino acids was estimated in C57 mice. The effect of nimesulide (50 mg/kg, PO) on renal resorption of amino acids was also assessed. The effect of chronic nimesulide (50 mg/kg, PO, BID for 14 days) was assessed in high protein diet-fed C57 mice, diet-induced obese mice and obese and diabetic db/db mice. Acute and chronic nimesulide treatment decreased absorption of neutral amino acids and increased their urinary excretion. Nimesulide treatment improved insulin sensitivity and glycemic control, increased GLP-1, decreased liver lipids and improved FGF-21 in serum. Nimesulide improved insulin sensitivity and glucose tolerance by inhibiting neutral amino acid transport in the intestine and kidneys. Thus, it can serve as a tool compound for in vivo B0AT1 inhibition.

Microcystin-leucine arginine exposure induced intestinal lipid accumulation and MC-LR efflux disorder in Lithobates catesbeianus tadpoles.

Few studies exist on the toxic effects of chronic exposure to microcystins (MCs) on amphibian intestines, and the toxicity mechanisms are unclear. Here, we evaluated the impact of subchronic exposure (30 days) to environmentally realistic microcystin-leucine arginine (MC-LR) concentrations (0 µg/L, 0.5 µg/L and 2 µg/L) on tadpole (Lithobates catesbeianus) intestines by analyzing the histopathological and subcellular microstructural damage, the antioxidative and oxidative enzyme activities, and the transcriptome levels. Histopathological results showed severe damage accompanied by inflammation to the intestinal tissues as the MC-LR exposure concentration increased from 0.5 µg/L to 2 µg/L. RNA-sequencing analysis identified 634 and 1,147 differentially expressed genes (DEGs) after exposure to 0.5 µg/L and 2 µg/L MC-LR, respectively, compared with those of the control group (0 µg/L). Biosynthesis of unsaturated fatty acids and the peroxisome proliferator-activated receptor (PPAR) signaling pathway were upregulated in the intestinal tissues of the exposed groups, with many lipid droplets being observed on transmission electron microscopy, implying that MC-LR may induce lipid accumulation in frog intestines. Moreover, 2 µg/L of MC-LR exposure inhibited the xenobiotic and toxicant biodegradation related to detoxification, implying that the tadpoles' intestinal detoxification ability was weakened after exposure to 2 µg/L MC-LR, which may aggravate intestinal toxicity. Lipid accumulation and toxin efflux disorder may be caused by MC-LR-induced endoplasmic reticular stress. This study presents new evidence that MC-LR harms amphibians by impairing intestinal lipid metabolism and toxin efflux, providing a theoretical basis for evaluating the health risks of MC-LR to amphibians.

Lipoproteins and cancer: The role of HDL-C, LDL-C, and cholesterol-lowering drugs.

Cholesterol is an amphipathic sterol molecule that is vital for maintaining normal physiological homeostasis. It is a relatively complicated molecule with 27 carbons whose synthesis starts with 2-carbon units. This in itself signifies the importance of this molecule. Cholesterol serves as a precursor for vitamin D, bile acids, and hormones, including estrogens, androgens, progestogens, and corticosteroids. Although essential, high cholesterol levels are associated with cardiovascular and kidney diseases and cancer initiation, progression, and metastasis. Although there are some contrary reports, current literature suggests a positive association between serum cholesterol levels and the risk and extent of cancer development. In this review, we first present a brief overview of cholesterol biosynthesis and its transport, then elucidate the role of cholesterol in the progression of some cancers. Suggested mechanisms for cholesterol-mediated cancer progression are plentiful and include the activation of oncogenic signaling pathways and the induction of oxidative stress, among others. The specific roles of the lipoprotein molecules, high-density lipoprotein (HDL) and low-density lipoprotein (LDL), in this pathogenesis, are also reviewed. Finally, we hone on the potential role of some cholesterol-lowering medications in cancer.

Comparative pharmacokinetics, intestinal absorption and urinary excretion of six alkaloids from herb pair Phellodendri Chinensis cortex-Atractylodis Rhizoma.

Phellodendri Chinensis Cortex (PCC) and Atractylodis Rhizoma (AR) are frequently used as herb pair to treat eczema and gout owing to their synergistic effects. Alkaloids are the major ingredients from PCC and the effect of their combination on the in vivo processing of alkaloids remains unclear. In this study, a simple and reliable UPLC-MS/MS method for simultaneous determination of six alkaloids in rat plasma was developed. This method was applied to a comparative pharmacokinetic study between PCC and PCC-AR in rats. Effect of AR on absorption of alkaloids was investigated by a single-pass intestinal perfusion study. The effect of AR on urinary excretion of alkaloids was studied. Pharmacokinetic studies showed that the values of rea under the concentration-time curve of phellodendrine, magnoflorine and palmatine were greater in the PCC-AR group than in the PCC group. The intestinal absorptive parameters absorption rate constant and effective permeability of phellodendrine and jatrorrhizine in PCC-AR groups were higher than those in the PCC group. Urinary excretion studies revealed that the excreted amount of alkaloids in the PCC-AR group was lower than that in the PCC group. The results revealed that the combination of PCC and AR improves intestinal absorption of alkaloids and reduces their urinary excretion, which enhances their systemic exposure. This study may explain the synergetic effects of PCC and AR in clinical applications.

Exposure of Caenorhabditis elegans to Dietary Nε-Carboxymethyllysine Emphasizes Endocytosis as a New Route for Intestinal Absorption of Advanced Glycation End Products.

The impact of dietary advanced glycation end products (dAGEs) on human health has been discussed in many studies but, to date, no consensual pathophysiological process has been demonstrated. The intestinal absorption pathways which have so far been described for dAGEs, the passive diffusion of free AGE adducts and transport of glycated di-tripeptides by the peptide transporter 1 (PEPT-1), are not compatible with certain pathophysiological processes described. To get new insight into the intestinal absorption pathways and the pathophysiological mechanisms of dAGEs, we initiated an in vivo study with a so-called simple animal model with a complete digestive tract, Caenorhabditis elegans. Dietary bacteria were chemically modified with glyoxylic acid to mainly produce Nε-carboxymethyllysine (CML) and used to feed the worms. We performed different immunotechniques using an anti-CML antibody for the relative quantification of ingested CML and localization of this AGE in the worms' intestine. The relative expression of genes encoding different biological processes such as response to stresses and intestinal digestion were determined. The physiological development of the worms was verified. All the results were compared with those obtained with the control bacteria. The results revealed a new route for the intestinal absorption of dietary CML (dCML), endocytosis, which could be mediated by scavenger receptors. The exposure of worms to dCML induced a reproductive defect and a transcriptional response reflecting oxidative, carbonyl and protein folding stresses. These data, in particular the demonstration of endocytosis of dCML by enterocytes, open up new perspectives to better characterize the pathophysiological mechanisms of dAGEs.

Thiolated Chitosan as an Intestinal Absorption Carrier with Hesperidin Encapsulation for Obesity Treatment.

Obesity is characterized as abnormal or excessive fat accumulation harmful to one's health, linked to hormonal imbalances, cardiovascular illness, and coronary artery disease. Since the disease stems mainly from overconsumption, studies have aimed to control intestinal absorption as a route for treatment. In this study, chitosan-thioglycolic acid (CT) was developed as a physical barrier in the gastrointestinal tracts to inhibit nutrient uptake. CT exhibits a superior mucoadhesive property compared to chitosan both in vitro and in vivo for the ability to form disulfide bonds with the intestinal mucosa. For CT as a potential drug delivery platform, hesperidin, a herb for bodyweight control in traditional Chinese medication, is encapsulated in CT and can be released consistently from this absorption barrier. In animal studies, CT encapsulated with hesperidin (CTH) not only results in a weight-controlling effect but limits adipose accumulation by hindering absorption, suggesting a potential role in obesity treatment. Neither CT nor CTH exhibit cytotoxicity or produce adverse immunological reactions in vivo.