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Calcium, iron, and zinc are essential minerals crucial for human health, yet their deficiencies can lead to debilitating conditions like osteoporosis, anemia, and chronic diseases. While calcium is known to interfere with iron and zinc absorption, the reverse is also true – iron and zinc, as micronutrients, can modulate calcium bioavailability. Unraveling the intricate interplay of these minerals’ absorption mechanisms in the intestine is paramount for developing effective strategies to combat nutritional deficiencies. This review delves into the current understanding of calcium, iron, and zinc absorption dynamics in the gut, exploring the effects of iron or zinc intake on calcium solubility and absorption processes. Furthermore, it elucidates the underlying molecular mechanisms governing these interactions, summarized through inductive methods. By shedding light on iron and zinc’s regulatory mechanisms on calcium bioavailability during intestinal absorption, this comprehensive analysis provides valuable insights for formulating efficient strategies to optimize mineral intake and absorption. Ultimately, this knowledge paves the way for preventing nutritional deficiencies that pose significant public health challenges. [ABSTRACT FROM AUTHOR]

BACKGROUND: Dietary kelp possesses a variety of useful biological qualities but does not have a toxic effect on the host. In this study, we examine how kelp dietary supplementation enhances the serum biochemistry, intestinal immunity, and metabolism of hybrid snakehead. A total of 810 juvenile hybrid snakeheads (Channa maculata ♀ × Channa argus ♂), with an initial average weight of 11.4 ± 0.15 g, were allocated randomly to three treatment groups (three replicates per group). The fish were fed for 60 days with isonitrogenous and isolipidic diets. The groups were the control group (C) (20% high‐gluten flour), the medium replacement group (MR) (10% high‐gluten flour and 10% kelp meal), and the full replacement group (FR) (0% high‐gluten flour and 15% kelp meal). RESULTS: The results showed that dietary kelp increased the activity of serum antioxidant enzymes significantly and decreased the content of serum malondialdehyde (MDA) in hybrid snakeheads, with significant changes in the FR group (P < 0.05). The intestinal morphology results showed that dietary kelp helped to increase the specific surface area of intestinal villi, which was beneficial for intestinal digestion and absorption. According to transcriptome and quantitative real‐time polymerase chain reaction (qRT‐PCR) analysis, dietary kelp can improve the expression of intestinal immunity and metabolism‐related pathways. Among them, immune‐related genes MHC1 and HSPA1 were significantly up‐regulated, and IGH, MHC2, and IL‐8 were significantly down‐regulated (P < 0.05). Lipid metabolism‐related genes DGAT2, FABP2, RXRα, and PLPP1 were all significantly up‐regulated (P < 0.05). CONCLUSION: Dietary kelp can effectively improve the antioxidant function of hybrid snakeheads, improve intestinal morphology, reduce intestinal inflammation, and promote intestinal lipid synthesis and transportation, thereby improving intestinal immunity and metabolic functions. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

X-linked hypophosphataemia is a genetic disease caused by defects in the phosphate regulating endopeptidase homolog X-linked (PHEX) gene and is characterised by X-linked dominant inheritance. The main consequence of PHEX deficiency is increased production of the phosphaturic hormone fibroblast growth factor 23 (FGF23) in osteoblasts and osteocytes. Chronic exposure to circulating FGF23 is responsible for renal phosphate wasting and decreased synthesis of calcitriol, which decreases intestinal phosphate absorption. These mechanisms result in lifelong hypophosphataemia, impaired growth plate and bone matrix mineralisation, and diverse manifestations in affected children and adults, including some debilitating morbidities and possibly increased mortality. Important progress has been made in disease knowledge and management over the past decade; in particular, targeting FGF23 is a therapeutic approach that has substantially improved outcomes. However, patients affected by this complex disease need lifelong care and innovative treatment strategies, such as gene repair of PHEX , are necessary to further limit the disease burden. [ABSTRACT FROM AUTHOR]

Bioactive compounds (BACs) have attracted much attention due to their potential health benefits. However, such substances have problems such as difficulty dissolving in water, poor stability, and low intestinal absorption, leading to serious limitations in practical applications. Nowadays, food colloidal delivery carriers have become a highly promising solution due to their safety, controllability, and efficiency. The use of natural macromolecules to construct delivery carriers can not only regulate the solubility, stability, and intestinal absorption of BACs but also effectively enhance the nutritional added value of functional foods, improve sensory properties, and extend shelf life. Moreover, smart-responsive colloidal delivery carriers can control the release characteristics of BACs, thus improving their absorption rate in the human body. This review describes the characteristics of several typical food colloid delivery carriers, focuses on their physical properties from static structure to dynamic release, summarizes their applications in delivery systems, and provides an outlook on the future development of food colloid delivery carriers. The different compositions and structures of food colloids tend to affect their stability and release behaviors, and the different surface properties and rheological characteristics of the carriers predestine their different application scenarios. The control of in vivo release properties and the effect on food media should be emphasized in the future exploration of safer and more controllable carrier systems. [ABSTRACT FROM AUTHOR]

Introduction: Dietary fatty acids play a pivotal role in energy metabolism and various physical functions. However, the molecular mechanisms underlying the absorption of long-chain fatty acids (LCFA) in ruminant animals remain poorly understood. To address this gap, we investigated the occurrence and distribution of genes and proteins previously characterized in nonruminant models within the gastrointestinal tract of cattle. Methods: Tissue samples from the rumen, descending duodenum, proximal jejunum, medial jejunum, distal jejunum, and distal ileum were collected at slaughter from eight Holstein steers. RT--PCR and capillary electrophoretic-based chemiluminescence were used to determine the mRNA and protein levels of genes and proteins involved in the uptake, activation, intracellular trafficking, re-esterification, and lipoprotein assembly of LCFA. Results and discussion: Measurable mRNA levels were found for 38 genes involved in the intestinal absorption of LCFA in all examined sections of the bovine gastrointestinal tract. The mRNA abundances of all genes were greater in the intestinal sections than in the rumen sections (p < 0.05). At the protein level, the expression of nine key transporters and enzymes, namely, CD36, SLC27A4, ACSL1, FABP1, FABP2, DGAT1, MTP, Apo-AI, and ACAT2, was detected in most of the intestinal sections. The distribution profile of these proteins in the small intestine suggested a prominent role for protein-mediated absorption of LCFA in the proximal and distal intestine in cattle. The low expression levels of most proteins in the rumen suggest little absorption of LCFA at this location in cattle. Overall, the findings from this study support the presence, in cattle, of genes and proteins involved in the intestinal absorption of LCFA described in models of nonruminants. Identifying the proteins involved in the absorption of LCFA in the small intestine is the first step in understanding how the expression of these proteins influences the capacity of the small intestine to absorb fatty acids in cattle. [ABSTRACT FROM AUTHOR]

Antibiotics in poultry feed to boost growth performance are becoming increasingly contentious due to concerns over antimicrobial resistance development. Essential oils (EOs), as natural, plant-derived compounds, have demonstrated antimicrobial and antioxidant properties. EOs may potentially improve poultry health and growth performance when included in poultry feed. Nevertheless, the incorporation of EOs as nutritional additives is hindered by their high volatility, low water solubility, poor intestinal absorption, and sensitivity to environmental conditions. Recently, nanoencapsulation strategies using nanoformulations have emerged as a potential solution to these challenges, improving the stability and bioavailability of EOs, and enabling targeted delivery in poultry feed. This review provides an overview of the antioxidant and antibacterial properties of EOs, the current limitations of their applications in poultry feed, and the recent advancements in nano-engineering to overcome these limitations. Furthermore, we outline the potential future research direction on EO nanoformulations, emphasizing their promising role in advancing sustainable poultry nutrition. Highlights • Essential oils (EOs) are known as powerful antioxidants and antibacterial agents. • EOs have a high potential to replace antibiotics as feed additives. • Nanoformulations of EOs have shown improved bioactivity and storage stability of EOs. • Nanoformulation promotes the bioavailability and gut adsorption of EOs as feed additives. [ABSTRACT FROM AUTHOR]

Background: In the realm of swine production, optimizing body composition and reducing excessive fat accumulation is critical for enhancing both economic efficiency and meat quality. Despite the acknowledged impact of dietary calcium (Ca) and phosphorus (P) on lipid metabolism, the precise mechanisms behind their synergistic effects on fat metabolism remain elusive. Results: Research observations have shown a decreasing trend in the percentage of crude fat in carcasses with increased calcium and phosphorus content in feed. Concurrently, serum glucose concentrations significantly decreased, though differences in other lipid metabolism-related indicators were not significant across groups. Under conditions of low calcium and phosphorus, there is a significant suppression in the expression of FABPs, CD36 and PPARγ in the jejunum and ileum, leading to inhibited intestinal lipid absorption. Concurrently, this results in a marked increase in lipid accumulation in the liver. Conversely, higher levels of dietary calcium and phosphorus promoted intestinal lipid absorption and reduced liver lipid accumulation, with these changes being facilitated through the activation of the CAMKK2/AMPK signaling pathway by high-calcium-phosphorus diets. Additionally, the levels of calcium and phosphorus in the diet significantly altered the composition of liver lipids and the gut microbiota, increasing α-diversity and affecting the abundance of specific bacterial families related to lipid metabolism. Conclusion: The evidence we provide indicates that the levels of calcium and phosphorus in the diet alter body fat content and lipid metabolism by modulating the response of the gut-liver axis to lipids. These effects are closely associated with the activation of the CAMKK2/AMPK signaling pathway. [ABSTRACT FROM AUTHOR]

The present study was aimed at preparing stable dry adsorbed nanoparticles (DANs) of olanzapine (OLZ) loaded solid lipid nanoparticles (SLNs) for sustained release. OLZ SLNs were prepared by hot melt emulsification and ultrasonication using Precirol ATO 5 (PRE) as a solid lipid, combination of Kolliphor ELP (KELP) and Tween 80 (T80) as surfactants, after optimising formulation and process variables. The SLN system was subjected to evaluation of particle size, zeta potential, entrapment efficiency (EE), in-vitro drug release and ex-vivo intestinal permeability studies using the chicken intestinal segments (jejunum). Further, these SLNs were converted into stable DANs by adsorbing onto a Neusilin US2 (NUS2) and Avicel CL 611 (ACL) carriers using the granulation-evaporative drying method. The DANs were characterised for redispersion properties, in-vitro drug release, thermal behaviour, crystallinity, and morphology. The SLN and DAN had a particle size of 238.0 nm [0.274 polydispersity index (PdI)] and 302.4 [0.494 PdI] respectively. The zeta potentials of SLN and DAN were found to be −29.3 mV and −26.3 mV, respectively. The SLN had 67% EE, and showed a sustained drug release in various media. The highest permeability of SLNs was observed in ex-vivo permeation model compared to the OLZ suspension, indicating that SLNs have the potential to bypass hepatic metabolism. The adsorption of SLNs onto carriers was confirmed by surface morphology. The DAN had good flow properties and sustained drug release similar to that of SLNs. The X-ray diffraction (XRD) patterns and endothermic peaks confirmed the complete encapsulation of actives in lipid matrices. The encapsulating of OLZ in SLNs and converting it into DAN showed a sustained release and adsorption technique that can be used for improving the stability of NLC dispersion. The DANs can be offered in dosage forms such as filling into sachets, capsules and compressed into tablets. [ABSTRACT FROM AUTHOR]

Endogenous hydrogen sulfide (H 2 S) plays an important role in bone metabolism. However, the exact role of H 2 S in intestinal calcium and phosphorus absorption and its potential in preventing and treating primary osteoporosis remains unknown. Therefore, this study aimed to investigate the potential of H 2 S in promoting intestinal calcium and phosphorus absorption and alleviating primary osteoporosis. We measured the apparent absorptivity of calcium, femoral bone density, expression and sulfhydration of the duodenal endoplasmic reticulum protein of 57 kDa (ERp57), duodenal cystathionine γ-lyase (CSE) expression, and serum H 2 S content in adult and old CSE-knockout and wild-type mice. We also assessed intracellular reactive oxygen species (ROS) and Ca2+ content in CSE-overexpressing or knockout intestinal epithelial cell (IEC)-6 cells. In senile mice, CSE knockout decreased endogenous H 2 S, ERp57 sulfhydration, and intestinal calcium absorption and worsened osteoporosis, which were partially reversed by GYY4137, an H 2 S donor. CSE overexpression in IEC-6 cells increased ERp57 sulfhydration, protein kinase A and C activity, and intracellular Ca2+, whereas CSE knockout exerted the opposite effects. Furthermore, hydrogen peroxide (H 2 O 2) stimulation had similar effects as in CSE knockout, which were reversed by pretreatment with sodium hydrosulfide before H 2 O 2 stimulation and restored by DL-dithiothreitol. These findings suggest that H 2 S attenuates primary osteoporosis by preventing ROS-induced ERp57 damage in intestinal epithelial cells by enhancing ERp57 activity and promoting intestinal calcium absorption, thereby aiding in developing therapeutic interventions to prevent osteoporosis. • H 2 S attenuates primary osteoporosis by promoting intestinal calcium absorption. • H 2 S enhances ERp57 activity by sulfhydration in intestinal epithelial cells. • Sulfhydration prevents ROS-induced ERp57 damage. [ABSTRACT FROM AUTHOR]

The therapeutic response to lithium in patients with bipolar disorder is highly variable and has a polygenic basis. Genome-wide association studies investigating lithium response have identified several relevant loci, though the precise mechanisms driving these associations are poorly understood. We aimed to prioritise the most likely effector gene and determine the mechanisms underlying an intergenic lithium response locus on chromosome 21 identified by the International Consortium on Lithium Genetics (ConLi+Gen). We conducted in-silico functional analyses by integrating and synthesising information from several publicly available functional genetic datasets and databases including the Genotype-Tissue Expression (GTEx) project and HaploReg. The findings from this study highlighted TMPRSS15 as the most likely effector gene at the ConLi+Gen lithium response locus. TMPRSS15 encodes enterokinase, a gastrointestinal enzyme responsible for converting trypsinogen into trypsin and thus aiding digestion. Convergent findings from gene-based lookups in human and mouse databases as well as co-expression network analyses of small intestinal RNA-seq data (GTEx) implicated TMPRSS15 in the regulation of intestinal nutrient absorption, including ions like sodium and potassium, which may extend to lithium. Although the findings from this study indicated that TMPRSS15 was the most likely effector gene at the ConLi+Gen lithium response locus, the evidence was circumstantial. Thus, the conclusions from this study need to be validated in appropriately designed wet-lab studies. The findings from this study are consistent with a model whereby TMPRSS15 impacts the efficacy of lithium treatment in patients with bipolar disorder by modulating intestinal lithium absorption. • TMPRSS15 is a novel regulator of lithium response in patients with bipolar disorder. • It is the most likely effector gene at a known lithium response locus. • The gene encodes enterokinase (ENTK), a key modulator of intestinal absorption. • ENTK likely impacts lithium response through the modulation of lithium absorption. [ABSTRACT FROM AUTHOR]

A sensitive UPLC-HRMS method was developed and validated for simultaneous quantification of four active flavonoids from Chimonanthus nitens Leaf Granules (CNLG) in biological matrix. The method was utilized in pharmacokinetic study of the four flavonoids in rats as well as other evaluation assays in vitro. It was revealed that rutin, nicotiflorin, and astragalin had poor oral bioavailability in rats possibly due to low intestinal permeability and metabolism in intestinal flora. Kaempferol underwent rapid glucuronidation and sulphation in rat plasma with medium permeability coefficient. The results provided valuable data for future research and development of CNLG flavonoids. [ABSTRACT FROM AUTHOR]

Obesity is primarily caused by excessive intake as well as absorption of sugar and lipid. Postprandial surge in distention pressure and intestinal motility accelerates the absorption of nutrients. The response of intestinal epithelial cells to mechanical stimulation is not fully understood. Piezo1, a mechanosensitive ion channel, is widely expressed throughout the digestive tract. However, its function in intestinal nutrient absorption is not yet clear. In our study, excessive lipid deposition was observed in the duodenum of obese patients, while duodenal Piezo1–CaMKK2–AMPK α was decreased when compared to normal-weight individuals. Under high-fat diet condition, the Piezo1 iKO mice exhibited abnormally elevated sugar and lipid absorption as well as severe lipid deposition in the duodenum and liver. These phenotypes were mainly caused by the inhibition of duodenal CaMKK2–AMPK α and the upregulation of SGLT1 and DGAT2. In contrast, Yoda1, a Piezo1 agonist, was found to reduce intestinal lipid absorption in diet induced obese mice. Overexpression of Piezo1, stretch and Yoda1 inhibited lipid accumulation and the expression of DGAT2 and SGLT1, whereas knockdown of Piezo1 stimulated lipid accumulation and DGAT2 in Caco-2 cells. Our study reveals a previously unexplored mechanical regulation of nutrient absorption in intestinal epithelial cells, which may shed new light on the therapy of obesity. This study verified the role of Piezo1 in enterocytes inhibits intestinal sugar and lipid absorption, and revealed a previously unexplored mechano-regulation of nutrient absorption in intestinal epithelial cells, which may shed new light on the therapy of obesity and diabetes. [Display omitted] [ABSTRACT FROM AUTHOR]

Walnuts (Juglans regia L.) are an important source of ellagitannins. They have been linked to positive effects on many pathologies, including cardiovascular disorders, neurodegenerative syndromes, and cancer. The limited bioavailability of ellagitannins prevents them from reaching significant circulatory levels, despite their antioxidant, anti-inflammatory, and chemopreventive properties. Urolithins are ellagitannin gut microbiota-derived metabolites. They have better intestinal absorption and may be responsible for the biological activities of ellagitannins. Recent evidence showed that walnut ellagitannins and their metabolites, urolithins, could have positive outcomes for human health. This study aims to synthesize the current literature on the antioxidant activity and mechanistic pathways involved in the therapeutic potential of walnut ellagitannins and their metabolites. In the eligible selected studies (n = 31), glansreginin A, pedunculagin, and casuarictin were the most prevalent ellagitannins in walnuts. A total of 15 urolithins, their glucuronides, and sulfate metabolites have been identified in urine, blood, feces, breast milk, and prostate tissue in analyzed samples. Urolithins A and B were associated with antioxidant, anti-inflammatory, cardioprotective, neuroprotective, anticarcinogenic, and anti-aging activities, both in preclinical and clinical studies. Despite the promising results, further well-designed studies are necessary to fully elucidate the mechanisms and confirm the therapeutic potential of these compounds in human health. [ABSTRACT FROM AUTHOR]

Crocetin as one of the main components of saffron possesses a lot of pharmacological effects, especially the beneficial effects in the treatment of hyperlipidemia. However, the pharmacokinetics of crocetin in the pathological state of hyperlipidemia has not been reported. In present study, the pharmacokinetics of crocetin in hyperlipidemia rats after oral administration of crocetin was investigated and the possible mechanisms for the pharmacokinetics were explored. High-fat diet was used to induce hyperlipidemia in rats. The pharmacokinetics of crocetin was investigated in hyperlipidemia and normal rats after oral and intravenous administration of crocetin, and the possible mechanisms of the pharmacokinetic changes were investigated in terms of metabolism and absorption using in vitro incubation with liver microsomes and the everted gut sac method, respectively. Results indicated that the AUCs of crocetin in hyperlipidemia rats after oral administration of crocetin were remarkably decreased when compared with those in normal rats. Moreover, crocetin was also metabolized more rapidly in the liver microsomes of hyperlipidemia rats and intestinal absorption of crocetin was significantly reduced in hyperlipidemia rats. It suggested that the remarkably decreased AUCs of crocetin in hyperlipidemia rats might partly result from the result of faster metabolic elimination and reduced absorption of crocetin in the hyperlipidemia pathological state. And the present investigations conducted on rats demonstrate that further investigations into the kinetics of crocetin in humans with hyperlipidemia are necessary in order to ensure an adequate dosage in this indication. [ABSTRACT FROM AUTHOR]

Some glycoside drugs can be transported through intestinal glucose transporters (IGTs). The surfactants used in oral drug preparations can affect the function of transporter proteins. This study aimed to investigate the effect of commonly used surfactants, Poloxamer 188 and Tween 80, on the drug transport capacity of IGTs. Previous studies have shown that gastrodin is the optimal drug substrate for IGTs. Gastrodin was used as a probe drug to evaluate the effect of these two surfactants on intestinal absorption in SD rats through pharmacokinetic and in situ single-pass intestinal perfusion. Then, the effects of the two surfactants on the expression of glucose transporters and tight-junction proteins were examined using RT-PCR and western blotting. Additionally, the effect of surfactants on intestinal permeability was evaluated through hematoxylin-eosin staining. The results found that all experimental for Poloxamer 188 (0.5%, 2.0% and 8.0%) and Tween 80 (0.1% and 2.0%) were not significantly different from those of the blank group. However, the AUC(0-∞) of gastrodin increased by approximately 32% when 0.5% Tween 80 was used. The changes in IGT expression correlated with the intestinal absorption of gastrodin. A significant increase in the expression of IGTs was observed at 0.5% Tween 80. In conclusion, Poloxamer 188 had minimal effect on the drug transport capacity of IGTs within the recommended limits of use. However, the expression of IGTs increased in response to 0.5% Tween 80, which significantly enhanced the drug transport capacity of IGTs. However, 0.1% and 2.0% Tween 80 had no significant effect. [ABSTRACT FROM AUTHOR]

The Caco-2 cell culture model was envisioned by Dr. Ronald T. Borchardt and established by the brilliant work of Dr. Ismael Hidalgo. As a practitioner of the Caco-2 cell culture model, I witnessed its initial explosive adoption by big pharma and academic research institutions, followed by regulatory agencies, and is now a well-established model. Through the tremendous efforts of many researchers in both industrial and academic organizations, fully characterized and developed Caco-2 cell culture model is now used in absorption screening, phase I and phase II metabolism, efflux transporter study, etc. Major challenges associated with the Caco-2 model include lack of mucous membranes, insufficient cytochrome P450 expression, inadequate expression of many nutrient transporters under standard culture conditions, etc. Despite this significant insufficiency, it is still much better characterized than any other cell culture models of the intestine and will remain an excellent tool for pharmaceutical sciences in decades to come. [ABSTRACT FROM AUTHOR]

AbstractDietary flavonoids exhibit a variety of physiological functions in regulating glucose and lipid metabolism, improving cardiovascular function, and enhancing stress resistance. However, poor intestinal absorption limits their health benefits. Previous studies on improving the absorption efficiency of flavonoids have focused on targeted release, enhanced gastrointestinal stability and prolonged retention time in digestive tract. But less attention has been paid to promoting the uptake and transport of flavonoids by intestinal epithelial cells through modulation of transporter protein-mediated pathways. Interestingly, some dietary nutrients have been found to modulate the expression or function of transporter proteins, thereby synergistically or antagonistically affecting flavonoid absorption. Therefore, this paper proposed an innovative regulatory strategy known as the "intestinal transport protein-mediated pathway" to promote intestinal absorption of dietary flavonoids. The flavonoid absorption mechanism in the intestinal epithelium, mediated by intestinal transport proteins, was summarized. The functional differences between the uptake transporter and efflux transporters during flavonoid trans-intestinal cellular transport were discussed. Finally, from the perspective of nutritional synergy promotion of absorption, the feasibility of promoting flavonoid intestinal absorption by regulating the expression/function of transport proteins through dietary nutrients was emphasized. This review provides a new perspective and developing precise dietary nutrient combinations for efficient dietary flavonoid absorption. [ABSTRACT FROM AUTHOR]

The incidence of perturbed gastrointestinal integrity, as well as resulting systemic immune responses and gastrointestinal symptoms, otherwise known as exercised-induced gastrointestinal syndrome (EIGS), is common among individuals who partake in prolonged exercise. EIGS may cause the translocation of pathogenic material, including whole bacteria and bacterial endotoxins, from the lumen into circulation, which may progress into clinical consequences such as sepsis, and potentially subsequent fatality. However, further investigation is warranted to assess the possibility of food allergen and/or digestive enzyme luminal to circulatory translocation in response to exercise, and the clinical consequences. Findings from this narrative literature review demonstrate evidence that whole bacteria and bacterial endotoxins translocation from the gastrointestinal lumen to systemic circulation occurs in response to exercise stress, with a greater propensity of translocation occurring with accompanying heat exposure. It has also been demonstrated that food allergens can translocate from the lumen to systemic circulation in response to exercise stress and initiate anaphylaxis. To date, no research investigating the effect of exercise on the translocation of digestive enzymes from the lumen into systemic circulation exists. It is evident that EIGS and consequential pathogenic translocation presents life-threatening clinical implications, warranting the development and implementation of effective management strategies in at-risk populations. [ABSTRACT FROM AUTHOR]

The life-long adherence to a dietary pattern able to provide a high amount of polyphenols demonstrating beneficial cardiometabolic effects is demanding for the general population. In this study, red grape pomace (GP) was used as an ingredient to increase the daily polyphenols' intake. The incorporation of crude crushed GP at 20 and 30% (w/w) in a control (CTR) biscuit formula improved the nutritional profile by increasing the fiber and reducing lipid and energy content while providing up to 540 mgGAE of polyphenols per 100 g. Besides anthocyanins, GP contains flavonoids and grape-seed procyanidins, contributing to the remarkable antioxidant capacity of 20- and 30-GP biscuits. Upon in vitro gastro-duodenal enzymatic digestion, the concentration of reducing sugars for 20-GP and 30-GP compared to the CTR biscuits dropped significantly, meaning that the combined action of GP fibers and polyphenols could delay the intestinal absorption of glucose. Overall, 60 volatiles were detected in biscuits. All in all, the content of Maillard reaction products was lower in GP than in CTR biscuits, possibly due to the free radical scavenging ability of polyphenols. Despite the high rates of GP utilized, the sensorial attributes and the overall liking of the GP biscuits—especially the 20-GP ones—were not substantially affected. These findings will support nutritional studies to assess the potential role as functional foods of GP biscuits, and, afterwards, the large-scale production of a food mainly based on a waste ingredient turned into a resource. [ABSTRACT FROM AUTHOR]

This research paper presents an advanced exploration into the utilization of ultrasound-assisted extraction (UAE) combined with natural deep eutectic solvents (NADESs) to achieve higher concentrations of polyphenols from Graševina grape pomace. Focusing on optimizing extraction parameters to maximize the yield of polyphenols, this study evaluates their potential industrial applications, particularly within the food and cosmetics sectors. The effectiveness of betaine/glucose (BGlc) NADESs in producing stable, ready-to-use extracts with enhanced bioavailability and eco-friendly attributes is underscored. The integration of UAE with BGlc NADESs has shown significant scalability and applicability for industrial use, as evidenced by the extracts' collagenase-inhibitory effects, determined using a ninhydrin-based colorimetric assay showing the significant inhibition of gelatine degradation and scratch tests on cultured skin cells, demonstrating enhanced cell migration and wound healing, indicating their potential in anti-aging cosmetic products. Additionally, the results from PAMPA tests demonstrated that NADES extraction significantly enhances the intestinal absorption of polyphenols from grape pomace extracts compared to conventional solvents, highlighting the potential of NADESs to improve the bioavailability of these compounds and offering promising implications for their application in the food industry. Furthermore, the research highlights the practicality of directly incorporating these extracts into products, such as anti-aging creams and functional foods, supporting sustainability initiatives within the cosmetic and food industries. This work aims to provide a comprehensive guide to green extraction techniques on a preparative scale, showcasing the versatility and innovative applications of NADES-extracted compounds across various industries, thereby paving the way for the development of eco-conscious and effective products. [ABSTRACT FROM AUTHOR]

The nutritional quality of plant-based meat analogues compared to traditional meat products has been questioned in recent commentary, particularly in relation to protein quality and micronutrient bioavailability. However, the attributes of specific products within this category are unclear. We therefore undertook a comprehensive assessment of the compositional and functional attributes of v2food® (Sydney, Australia) plant-based mince, including an assessment of the effects of reformulation, including the addition of amino acids, ascorbic acid, and different forms of elemental iron. The protein digestibility and protein quality of v2food® plant-based mince were comparable to beef mince in the standardized INFOGEST system, and favourable effects on microbiota composition and short-chain fatty acid (SCFA) production were demonstrated in an in vitro digestion system. The use of ferrous sulphate as an iron source improved in vitro intestinal iron absorption by ~50% in comparison to other forms of iron (p < 0.05), although levels were ~3-fold lower than beef mince, even in the presence of ascorbic acid. In conclusion, the current study identified some favourable nutritional attributes of plant-based v2food® mince, specifically microbiota and SCFA changes, as well as other areas where further reformulation could be considered to further enhance the bioavailability of key nutrients. Further studies to assess the effect of plant-based meat analogues on health measures in vivo will be important to improve knowledge in this area. [ABSTRACT FROM AUTHOR]

Intestinal absorption of compounds is significant in drug research and development. To evaluate this efficiently, a method combining mathematical modeling and molecular simulation was proposed, from the perspective of molecular structure. Based on the quantitative structure–property relationship study, the model between molecular structure and their apparent permeability coefficients was successfully constructed and verified, predicting intestinal absorption of drugs and interpreting decisive structural factors, such as AlogP98, Hydrogen bond donor and Ellipsoidal volume. The molecules with strong lipophilicity, less hydrogen bond donors and receptors, and small molecular volume are more easily absorbed. Then, the molecular dynamics simulation and molecular docking were utilized to study the mechanism of differences in intestinal absorption of drugs and investigate the role of molecular structure. Results indicated that molecules with strong lipophilicity and small volume interacted with the membrane at a lower energy and were easier to penetrate the membrane. Likewise, they had weaker interaction with P‐glycoprotein and were easier to escape from it and harder to export from the body. More in, less out, is the main reason these molecules absorb well. [ABSTRACT FROM AUTHOR]

To address the prevalent genistein (GST) metabolism and inadequate intestinal absorption, an oral long-acting and gastric in-situ gelling gel was designed to encapsulate and localize the intestinal release of the loaded genistein-ginseng (GST-GNS) solid dispersion. Because of the high breast perfusion of GST upon oral absorption, the GST-GNS solid dispersion was developed to enhance GST's dissolution and penetration while offering a synergistic impact against breast cancer (BC). Physiochemical analysis of the GST-GNS solid dispersion, release analysis, gel characterizations, storage stability, penetration, and in vitro cytotoxicity studies were carried out. GST-GNS solid dispersion showed improved dissolution and penetration as compared to raw GST. GST-GNS solid dispersion homogenous shape particles and hydrophilic contacts were revealed by scanning electron microscopy and Fourier Transform-Infrared analysis, respectively. GST-GNS solid dispersion's diffractogram shows the amorphous character. A second modification involved creating a gastric in-situ gelling system loaded with GST-GNS solid dispersion. This system demonstrated improved GST penetration employing the solid dispersion, as well as the localizing of the GST release at the intestinal media and antitumor synergism against BC. For a better therapeutic approach for BC, the innovative oral GST long-acting gel encasing the GST-GNS solid dispersion would be recommended. [ABSTRACT FROM AUTHOR]

Silymarin, derived from Silybum marianum , has recently demonstrated its potential to improve health in conditions such as obesity and metabolic disturbances. Understanding the impact of nutraceuticals on intestinal morphology is crucial for developing supplements that promote a higher quality of life. Therefore, this study aimed to investigate the effects of nutraceutical supplementation with silymarin on the morphology of the small intestine. Sixty-day-old adult male C57BL/6 mice were divided into two groups: one receiving a standard chow (control) and the other receiving a novel silymarin supplement (experimental). Following the experimental period, the animals were euthanized, and fragments of the small intestine were collected for histochemical analysis using Masson's trichrome and periodic acid-Schiff with Alcian blue staining techniques. Our results revealed an increase in the number of villi per analyzed field in the experimental group, accompanied by a decrease in basic mucin, crypt depth, mucosal thickness, and villus spacing. In conclusion, this novel nutraceutical supplementation may play a crucial role in modulating small intestine morphology and enhancing absorption capacity. [ABSTRACT FROM AUTHOR]

Antimicrobial resistance poses a global health threat, with Staphylococcus aureus emerging as a notorious pathogen capable of forming stubborn biofilms and regulating virulence through quorum sensing (QS). In the quest for novel therapeutic strategies, this groundbreaking study unveils the therapeutic potential of Paederia foetida Linn., an Asian medicinal plant containing various bioactive compounds, contributing to its antimicrobial activities, in the battle against S. aureus. Through a comprehensive approach, we investigated the effect of ethanolic P. foetida leaf extract on S. aureus biofilms, QS, and antimicrobial activity. The extract exhibited promising inhibitory effects against S. aureus including the biofilm-forming strain and MRSA. Real-time PCR analysis revealed significant downregulation of key virulence and biofilm genes, suggesting interference with QS. Biofilm assays quantified the extract's ability to disrupt and prevent biofilm formation. LC-MS/MS analysis identified quercetin and kaempferol glycosides as potential bioactive constituents, while molecular docking studies explored their binding to the QS transcriptional regulator SarA. Computational ADMET predictions highlighted favorable intestinal absorption but potential P-glycoprotein interactions limiting oral bioavailability. While promising anti-virulence effects were demonstrated, the high molecular weights and excessive hydrogen bond donors/acceptors of the flavonoid glycosides raise concerns regarding drug-likeness and permeability. This integrated study offers valuable insights for developing novel anti-virulence strategies to combat antimicrobial resistance. [ABSTRACT FROM AUTHOR]

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.

BACKGROUND & AIMS: Acute diarrheal diseases are the second most common cause of infant mortality in developing countries. This is contributed to by lack of effective drug therapy that shortens the duration or lessens the volume of diarrhea. The epithelial brush border sodium (Na+)/hydrogen (H+) exchanger 3 (NHE3) accounts for a major component of intestinal Na+ absorption and is inhibited in most diarrheas. Because increased intestinal Na+ absorption can rehydrate patients with diarrhea, NHE3 has been suggested as a potential druggable target for drug therapy for diarrhea. METHODS: A peptide (sodium-hydrogen exchanger 3 stimulatory peptide [N3SP]) was synthesized to mimic the part of the NHE3 C-terminus that forms a multiprotein complex that inhibits NHE3 activity. The effect of N3SP on NHE3 activity was evaluated in NHE3-transfected fibroblasts null for other plasma membrane NHEs, a human colon cancer cell line that models intestinal absorptive enterocytes (Caco-2/BBe), human enteroids, and mouse intestine in vitro and in vivo. N3SP was delivered into cells via a hydrophobic fluorescent maleimide or nanoparticles. RESULTS: N3SP uptake stimulated NHE3 activity at nmol/L concentrations under basal conditions and partially reversed the reduced NHE3 activity caused by elevated adenosine 3,5-cyclic monophosphate, guanosine 3,5-cyclic monophosphate, and Ca2+ in cell lines and in in vitro mouse intestine. N3SP also stimulated intestinal fluid absorption in the mouse small intestine in vivo and prevented cholera toxin-, Escherichia coli heat-stable enterotoxin-, and cluster of differentiation 3 inflammation-induced fluid secretion in a live mouse intestinal loop model. CONCLUSIONS: These findings suggest pharmacologic stimulation of NHE3 activity as an efficacious approach for the treatment of moderate/severe diarrheal diseases.

Lina Shibib,1 Mo Al-Qaisi,1 Nicola Guess,2 Alexander D Miras,3 Steve E Greenwald,4 Marc Pelling,1 Ahmed Ahmed1 1Department of Surgery and Cancer, Imperial College London, London, UK; 2Nuffield Department of Primary Care Health Sciences, Oxford University, Oxford, UK; 3School of Medicine, Ulster University, Coleraine, UK; 4Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UKCorrespondence: Mo Al-Qaisi, Email mrcgp74@yahoo.co.ukAbstract: This review paper explores post-prandial glycemia in type 2 diabetes. Post-prandial glycemia is defined as the period of blood glucose excursion from immediately after the ingestion of food or drink to 4 to 6 hours after the end of the meal. Post-prandial hyperglycemia is an independent risk factor for cardiovascular disease with glucose “excursions” being more strongly associated with markers of oxidative stress than the fasting or pre-prandial glucose level. High blood glucose is a major promoter of enhanced free radical production and is associated with the onset and progression of type 2 diabetes. Oxidative stress impairs insulin action creating a vicious cycle where repeated post-prandial glucose spikes are key drivers in the pathogenesis of the vascular complications of type 2 diabetes, both microvascular and macrovascular. Some authors suggest post-prandial hyperglycemia is the major cause of death in type 2 diabetes. Proper management of post-prandial hyperglycemia could yield up to a 35% cut in overall cardiovascular events, and a 64% cut in myocardial infarction. The benefits of managing post-prandial hyperglycemia are similar in magnitude to those seen in type 2 diabetes patients receiving secondary prevention with statins – prevention which today is regarded as fundamental by all practitioners. Given all the evidence surrounding the impact of post-prandial glycemia on overall outcome, it is imperative that any considered strategy for the management of type 2 diabetes should include optimum dietary, pharma, and lifestyle interventions that address glucose excursion. Achieving a low post-prandial glucose response is key to prevention and progression of type 2 diabetes and cardiometabolic diseases. Further, such therapeutic interventions should be sustainable and must benefit patients in the short and long term with the minimum of intrusion and side effects. This paper reviews the current literature around dietary manipulation of post-prandial hyperglycemia, including novel approaches. A great deal of further work is required to optimize and standardize the dietary management of post-prandial glycemia in type 2 diabetes, including consideration of novel approaches that show great promise.Keywords: glycemic response, post-prandial, hyperglycemia, diabetes, acarbose, GLP-1, metformin, plant fibre, whey protein, gastric emptying, intestinal absorption, glycemic index, glucose excursion

Intestinal absorption of phosphate is bimodal, consisting of a transcellular pathway and a poorly characterized paracellular mode, even though the latter one contributes to the bulk of absorption under normal dietary conditions. Claudin-3 (Cldn3), a tight junction protein present along the whole intestine in mice, has been proposed to tighten the paracellular pathway for phosphate. The aim of this work was to characterize the phosphate-related phenotype of Cldn3-deficient mice. Cldn3-deficient mice and wildtype littermates were fed standard diet or challenged for 3 days with high dietary phosphate. Feces, urine, blood, intestinal segments and kidneys were collected. Measurements included fecal, urinary, and plasma concentrations of phosphate and calcium, plasma levels of phosphate-regulating hormones, evaluation of trans- and paracellular phosphate transport across jejunum and ileum, and analysis of intestinal phosphate and calcium permeabilities. Fecal and urinary excretion of phosphate as well as its plasma concentration was similar in both genotypes, under standard and high-phosphate diet. However, Cldn3-deficient mice challenged with high dietary phosphate had a reduced urinary calcium excretion and increased plasma levels of calcitriol. Intact FGF23 concentration was also similar in both groups, regardless of the dietary conditions. We found no differences either in intestinal phosphate transport (trans- or paracellular) and phosphate and calcium permeabilities between genotypes. The intestinal expression of claudin-7 remained unaltered in Cldn3-deficient mice. Our data do not provide evidence for a decisive role of Cldn3 for intestinal phosphate absorption and phosphate homeostasis. In addition, our data suggest a novel role of Cldn3 in regulating calcitriol levels. [ABSTRACT FROM AUTHOR]

Background Environmental enteropathy (EE) is a highly prevalent subclinical inflammatory intestinal disorder associated with growth failure, impaired neurocognitive development, poor response to oral vaccines, and micronutrient deficiencies. However, EE research and clinical trials are hampered by the lack of non-invasive tools for measuring intestinal function in detail. This study aims to develop new tools for the measurement of multiple domains of gut functional capacity. Methods The GI TOOLS project is a cross-sectional study that will recruit adults aged 18-65 years with EE in Lusaka, Zambia. Each participant will undergo assessment of gut functional capacity using novel near-point-of-care tools and provide multiple samples for detailed laboratory analyses. Participants will also undergo endoscopy for collection of duodenal biopsies. Novel techniques include stable isotopes approaches to measuring digestion, absorption, and bidirectional transmucosal amino acid flux, a non-invasive fluorescence tool for real-time evaluation of gut permeability, and assessment of reverse permeation of intravenous antibiotics to be carried out separately in Zimbabwe. Stool and duodenal microbiome sequencing using MinION sequencing, metabolome analysis applied to plasma and intestinal fluids, blood immune cell phenotyping, in vitro epithelial barrier models, and duodenal immunohistochemistry will also be used to explore EE in depth. These will all be integrated with gold standard histology and mucosal morphometry, alongside lactulose permeation data, and stool and plasma biomarker analysis. The protocol has been approved by ethics committees and regulators in Zambia, Zimbabwe, and the UK. Participants will give informed consent before they can participate Anticipated outcomes Based on this extensive phenotyping, tests will be developed which can be simplified and refined for use in adults and children with EE, and for clinical trials. Findings from this project will be disseminated through in-person meetings with caregivers and regulatory bodies, presentations at conferences and in peer-reviewed journals.

A high prevalence of iron deficiency exists in athlete populations. Various mechanisms, including increased losses through sweat, haemolysis, haematuria, and gastrointestinal micro-ischemia; inadequate dietary intake; and transient exercise-induced increases in the regulatory hormone, hepcidin, contribute to the increased prevalence in athletes. Indeed, hepcidin has been shown to peak around 3–6 hours post-exercise, limiting iron absorption from the gut. As the practitioner's ability to control losses is limited, the key to treatment of iron deficiency in athletes is optimal timing of dietary and oral iron supplementation around these periods of reduced gut absorption. While timing and dosing schedule strategies might be sufficient to treat iron deficiency non-anaemia, the significant lag to impact iron status is relatively long. Therefore, in iron deficiency anaemia, the use of parenteral iron has the benefit of rapid repletion of iron stores and normalisation of haemoglobin status, while bypassing the action of hepcidin at the gut. Furthermore, newer intravenous formulations can be administered as a single total dose over 15–60 min and have a similar safety profile to oral treatment. This review discusses the existing evidence for parenteral iron use in athletes and the unique context for consideration when choosing the parenteral route in this population. [ABSTRACT FROM AUTHOR]

Background: Peru is one of the most biodiverse countries in the world, which is reflected in its wealth of knowledge about medicinal plants. However, there is a lack of information regarding intestinal absorption and the permeability of natural products. The human colon adenocarcinoma cell line (Caco-2) is an in vitro assay used to measure apparent permeability. This study aims to develop a quantitative structure–property relationship (QSPR) model using machine learning algorithms to predict the apparent permeability of the Caco-2 cell in natural products from Peru. Methods: A dataset of 1817 compounds, including experimental log Papp values and molecular descriptors, was utilized. Six QSPR models were constructed: a multiple linear regression (MLR) model, a partial least squares regression (PLS) model, a support vector machine regression (SVM) model, a random forest (RF) model, a gradient boosting machine (GBM) model, and an SVM–RF–GBM model. Results: An evaluation of the testing set revealed that the MLR and PLS models exhibited an RMSE = 0.47 and R2 = 0.63. In contrast, the SVM, RF, and GBM models showcased an RMSE = 0.39–0.40 and R2 = 0.73–0.74. Notably, the SVM–RF–GBM model demonstrated superior performance, with an RMSE = 0.38 and R2 = 0.76. The model predicted log Papp values for 502 natural products falling within the applicability domain, with 68.9% (n = 346) showing high permeability, suggesting the potential for intestinal absorption. Additionally, we categorized the natural products into six metabolic pathways and assessed their drug-likeness. Conclusions: Our results provide insights into the potential intestinal absorption of natural products in Peru, thus facilitating drug development and pharmaceutical discovery efforts. [ABSTRACT FROM AUTHOR]

Background: Some glucoside drugs can be transported via intestinal glucose transporters (IGTs), and the presence of carbohydrate excipients in pharmaceutical formulations may influence the absorption of them. This study, using gastrodin as probe drug, aimed to explore the effects of fructose, lactose, and arabic gum on intestinal drug absorption mediated by the glucose transport pathway. Methods: The influence of fructose, lactose, and arabic gum on gastrodin absorption was assessed via pharmacokinetic experiments and single-pass intestinal perfusion. The expression of sodium-dependent glucose transporter 1 (SGLT1) and sodium-independent glucose transporter 2 (GLUT2) was quantified via RT‒qPCR and western blotting. Alterations in rat intestinal permeability were evaluated through H&E staining, RT‒qPCR, and immunohistochemistry. Results: Fructose reduced the area under the curve (AUC) and peak concentration (Cmax) of gastrodin by 42.7% and 63.71%, respectively (P < 0.05), and decreased the effective permeability coefficient (Peff) in the duodenum and jejunum by 58.1% and 49.2%, respectively (P < 0.05). SGLT1 and GLUT2 expression and intestinal permeability remained unchanged. Lactose enhanced the AUC and Cmax of gastrodin by 31.5% and 65.8%, respectively (P < 0.05), and increased the Peff in the duodenum and jejunum by 33.7% and 26.1%, respectively (P < 0.05). SGLT1 and GLUT2 levels did not significantly differ, intestinal permeability increased. Arabic gum had no notable effect on pharmacokinetic parameters, SGLT1 or GLUT2 expression, or intestinal permeability. Conclusion: Fructose, lactose, and arabic gum differentially affect intestinal drug absorption through the glucose transport pathway. Fructose competitively inhibited drug absorption, while lactose may enhance absorption by increasing intestinal permeability. Arabic gum had no significant influence. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the pharmacokinetic properties and inhibitory binding interaction between naturally occurring phytochemicals and a mutated human estrogen receptor (hERa) using an in silico approach. Methods: Naturally occurring small molecules, viz, myricetin, catechin, pinobanksin, pinocembrin, gelagin and pinostrobin, were investigated for their drug-likeness and pharmacokinetic properties. After that, molecular docking was used to study their binding affinities to Y537S (Tyr537Ser: a mutated estrogen receptor alpha, prominent in metastatic breast cancers). The structure of the ligand-binding domain (LBD) of human estrogen receptor was retrieved from Protein Data Bank while the structures of the studied compounds were collected from PubChem database. Using Schrodinger docking studio, the binding interactions of each phytochemical were investigated with the mutated estrogen receptor. Results: All studied compounds were observed to be drug-like with good physicochemical properties. Myricetin, catechin, pinobanksin, pinocembrin, gelagin and pinostrobin showed good solubilities in human oral absorption and good intestinal permeability, which are the rate-limiting barriers for oral drug absorption. The distribution of the studied ligands and their plasma protein binding parameters were better than those of tamoxifen, which has previously been reported with high potential binding to albumin. None of the studied compounds showed central nervous system toxicity. The binding studies revealed good inhibition of the LBD of Y537S-hERa. This is a targeted approach to selectively inhibit this receptor which has been reported to confer ligand-independent functions to ERa. This inhibition prevents downstream signaling and metastasis, rendering breast cancer cells harboring such mutations susceptible to apoptosis upon treatment with endocrine therapies. Conclusion: The compounds have the potential to mitigate de novo resistance in breast cancer cells harboring mutated estrogen receptors and should be further investigated as they are promising for oral delivery. [ABSTRACT FROM AUTHOR]

The postprandial glucose response is an independent risk factor for type 2 diabetes. Observationally, early glucose response after an oral glucose challenge has been linked to intestinal glucose absorption, largely influenced by the expression of sodium–glucose cotransporter 1 (SGLT1). This study uses Mendelian randomization (MR) to estimate the causal effect of intestinal SGLT1 expression on early glucose response. Involving 1,547 subjects with class II/III obesity from the Atlas Biologique de l'Obésité Sévère cohort, the study uses SGLT1 genotyping, oral glucose tolerance tests, and jejunal biopsies to measure SGLT1 expression. A loss-of-function SGLT1 haplotype serves as the instrumental variable, with intestinal SGLT1 expression as the exposure and the change in 30-min postload glycemia from fasting glycemia (Δ30 glucose) as the outcome. Results show that 12.8% of the 1,342 genotyped patients carried the SGLT1 loss-of-function haplotype, associated with a mean Δ30 glucose reduction of −0.41 mmol/L and a significant decrease in intestinal SGLT1 expression. The observational study links a 1-SD decrease in SGLT1 expression to a Δ30 glucose reduction of −0.097 mmol/L. MR analysis parallels these findings, associating a statistically significant reduction in genetically instrumented intestinal SGLT1 expression with a Δ30 glucose decrease of −0.353. In conclusion, the MR analysis provides genetic evidence that reducing intestinal SGLT1 expression causally lowers early postload glucose response. This finding has a potential translational impact on managing early glucose response to prevent or treat type 2 diabetes Article Highlights: Loss-of-function variant of SGLT1 is associated with reduced intestinal SGLT1 expression and early postload glucose response. Mendelian randomization supports the causal relationship between intestinal glucose absorption and postprandial glucose. Modulating intestinal SGLT1 expression/function is a promising avenue for the prevention and treatment of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Tea is a daily drink for most people, and one of its major ingredients, epigallocatechin-3-gallate (EGCG), has been widely recognized as a potent antioxidant with diverse biological activities. However, its low stability and bioavailability hinder its further clinical applications. In this study, we designed and synthesized a novel EGCG-valine derivative 4 by replacing the gallic acid with a valine moiety in four steps. The structural elucidation of derivative 4 was performed using NMR, IR, mass, and UV spectroscopies. Additionally, the physicochemical properties of 4 were predicted by SwissADME, showing improved drug-like parameters and intestinal absorption compared to the parent compound EGCG. [ABSTRACT FROM AUTHOR]

Fucoxanthin is a special kind of keto-carotenoid found only in algae. The unique structure of fucoxanthin endows it with extraordinary biological activities, which are of great significance to improve food quality and enhance human health. However, due to its highly unsaturated structure, fucoxanthin also suffers from some limitations, such as instability, poor water solubility and low bioavailability. Therefore, although its content is relatively abundant, its applications in the food industry are extremely scarce. In recent years, there have been many reports on the preparation and characterization of delivery systems for fucoxanthin. These well-designed delivery systems can efficaciously alleviate the instability of fucoxanthin under adverse conditions, thereby improving its oral bioavailability. Thus, this review emphatically summarizes the delivery systems that are widely used to encapsulate, protect and release fucoxanthin. Besides, the influence of delivery systems on the absorption of fucoxanthin by intestinal epithelial cells is highlighted. The applications and future development trends of delivery systems for fucoxanthin are also discussed. The extraction of fucoxanthin, development of novel delivery systems, sensory evaluation and toxicity studies, and industrial production may be promising research directions in the future. Overall, this review provides guidance for the development of fucoxanthin-loaded delivery systems. [ABSTRACT FROM AUTHOR]

The presence of mutagenic and carcinogenic N-nitrosamine impurities in medicinal products poses a safety risk. While incorporating antioxidants in formulations is a potential mitigation strategy, concerns arise regarding their interference with drug absorption by inhibiting intestinal drug transporters. Our study screened thirty antioxidants for inhibitory effects on key intestinal transporters—OATP2B1, P-gp, and BCRP in HEK-293 cells (OATP2B1) or membrane vesicles (P-gp, BCRP) using 3H-estrone sulfate, 3H-N-methyl quinidine, and 3H-CCK8 as substrates, respectively. The screen identified that butylated hydroxyanisole (BHA) and carnosic acid inhibited all three transporters (OATP2B1, P-gp, and BCRP), while ascorbyl palmitate (AP) inhibited OATP2B1 by more than 50%. BHA had IC50 values of 71 ± 20 µM, 206 ± 14 µM, and 182 ± 49 µM for OATP2B1, BCRP, and P-gp, respectively. AP exhibited IC50 values of 23 ± 10 µM for OATP2B1. The potency of AP and BHA was tested with valsartan, an OATP2B1 substrate, and revealed IC50 values of 26 ± 17 µM and 19 ± 11 µM, respectively, in HEK-293-OATP2B1 cells. Comparing IC50 values of AP and BHA with estimated intestinal concentrations suggests an unlikely inhibition of intestinal transporters at clinical concentrations of drugs formulated with antioxidants. [ABSTRACT FROM AUTHOR]

Doxorubicin is a potent chemotherapy drug, but its oral bioavailability is limited due to its low membrane permeability. Thus, absorption enhancers such as zonula occludens toxin and its six-mer fragment, FCIGRL, have been studied to address this issue. This study aimed to evaluate the effectiveness of four peptides (Pep1, Pep2, Pep3, and Pep4) derived from FCIGRL and investigate the changes in the absorption of doxorubicin, to propose an absorption enhancer for doxorubicin. Pep1 is a modified version of FCIGRL in which the hydroxyl group at the C-terminus is replaced with an amino group. Pep2 is a modified Pep1 in which cysteine is replaced with N3-substituted dipropionic acid. Pep3 and Pep4 are Pep2-modified homodimers. Pharmacokinetic analysis was performed in rats after the intraduodenal administration of doxorubicin solutions containing each FCIGRL-modified peptide and the stabilizer levan or benzalkonium chloride (BC). The results showed that Pep3 and Pep4 administered with levan each significantly increased the intestinal absorption of doxorubicin, as did Pep2 administered with levan/BC. In particular, 10 mg·kg−1 of Pep4 with levan significantly increased the area under the curve (AUC)0–240min of doxorubicin by 2.38-fold (p < 0.01) and the peak concentration (Cmax) by 3.30-fold (p < 0.01) compared to the control solution. The study findings indicate that Pep2, Pep3, and primarily Pep4 are novel absorption enhancers that can open tight junctions for doxorubicin, and the effectiveness of the peptides was directly affected by the presence of levan or levan/BC. [ABSTRACT FROM AUTHOR]

Purpose: Olmesartan medoxomil (olmesartan-MX), an ester-type prodrug of the angiotensin II receptor blocker (ARB) olmesartan, is predominantly anionic at intestinal pH. Human organic anion transporting polypeptide 2B1 (OATP2B1) is expressed in the small intestine and is involved in the absorption of various acidic drugs. This study was designed to test the hypothesis that OATP2B1-mediated uptake contributes to the enhanced intestinal absorption of olmesartan-MX, even though olmesartan itself is not a substrate of OATP2B1. Methods: Tetracycline-inducible human OATP2B1- and rat Oatp2b1-overexpressing HEK 293 cell lines (hOATP2B1/T-REx-293 and rOatp2b1/T-REx-293, respectively) were established to characterize OATP2B1-mediated uptake. Rat jejunal permeability was measured using Ussing chambers. ARBs were quantified by liquid chromatography-tandem mass spectrometry. Results: Significant olmesartan-MX uptake was observed in hOATP2B1/T-REx-293 and rOatp2b1/T-REx-293 cells, whereas olmesartan uptake was undetectable or much lower than olmesartan-MX uptake, respectively. Furthermore, olmesartan-MX exhibited several-fold higher uptake in Caco-2 cells and greater permeability in rat jejunum compared to olmesartan. Olmesartan-MX uptake in hOATP2B1/T-REx-293 cells and in Caco-2 cells was significantly decreased by OATP2B1 substrates/inhibitors such as 1 mM estrone-3-sulfate, 100 µM rifamycin SV, and 100 µM fluvastatin. Rat Oatp2b1-mediated uptake and rat jejunal permeability of olmesartan-MX were significantly decreased by 50 µM naringin, an OATP2B1 inhibitor. Oral administration of olmesartan-MX with 50 µM naringin to rats significantly reduced the area under the plasma concentration–time curve of olmesartan to 76.9%. Conclusion: Olmesartan-MX is a substrate for OATP2B1, and the naringin-sensitive transport system contributes to the improved intestinal absorption of olmesartan-MX compared with its parent drug, olmesartan. [ABSTRACT FROM AUTHOR]

Breakfast cereals play a crucial role in children's diets, providing essential nutrients that are vital for their growth and development. Children are known to be more susceptible than adults to the harmful effects of food contaminants, with mycotoxins being a common concern in cereals. This study specifically investigated aflatoxin B1 (AFB1), enniatin B (ENNB), and sterigmatocystin (STG), three well-characterized mycotoxins found in cereals. The research aimed to address existing knowledge gaps by comprehensively evaluating the bioaccessibility and intestinal absorption of these three mycotoxins, both individually and in combination, when consumed with breakfast cereals and milk. The in vitro gastrointestinal method revealed patterns in the bioaccessibility of AFB1, ENNB, and STG. Overall, bioaccessibility increased as the food progressed from the stomach to the intestinal compartment, with the exception of ENNB, whose behavior differed depending on the type of milk. The ranking of overall bioaccessibility in different matrices was as follows: digested cereal > cereal with semi-skimmed milk > cereal with lactose-free milk > cereal with soy beverage. Bioaccessibility percentages varied considerably, ranging from 3.1% to 86.2% for AFB1, 1.5% to 59.3% for STG, and 0.6% to 98.2% for ENNB. Overall, the inclusion of milk in the ingested mixture had a greater impact on bioaccessibility compared to consuming the mycotoxins as a single compound or in combination. During intestinal transport, ENNB and STG exhibited the highest absorption rates when ingested together. This study highlights the importance of investigating the combined ingestion and transport of these mycotoxins to comprehensively assess their absorption and potential toxicity in humans, considering their frequent co-occurrence and the possibility of simultaneous exposure. [ABSTRACT FROM AUTHOR]

Neuropathy affects 7–10% of the general population and is caused by a lesion or disease of the somatosensory system. The limitations of current therapies highlight the necessity of a new innovative approach to treating neuropathic pain (NP) based on the close correlation between oxidative stress, inflammatory process, and antioxidant action. The advantageous outcomes of a novel combination composed of Hop extract, Propolis, Ginkgo Biloba, Vitamin B, and palmitoylethanolamide (PEA) used as a treatment was evaluated in this study. To assess the absorption and biodistribution of the combination, its bioavailability was first examined in a 3D intestinal barrier model that replicated intestinal absorption. Further, a 3D nerve tissue model was developed to study the biological impacts of the combination during the essential pathways involved in NP. Our findings show that the combination could cross the intestinal barrier and reach the peripheral nervous system, where it modulates the oxidative stress, inflammation levels, and myelination mechanism (increased NRG, MPZ, ERB, and p75 levels) under Schwann cells damaging. This study proves the effectiveness of Ginkgo Biloba, Propolis, Hop extract, Vitamin B, and PEA in avoiding nerve damage and suggests a potential alternative nutraceutical treatment for NP and neuropathies. [ABSTRACT FROM AUTHOR]

The primary goal of this study was to establish an in vitro-in vivo correlation (IVIVC) for tamoxifen (TAM)- loaded polycaprolactone-chitosan nanospheres. The plasma attention of TAM and time records have been used to calculate the pharmacokinetic parameters. Cmax for the nano spheres stayed determined to be 459.20 ng mL-1, compared to 442.20 ng mL-1 for natural TAM. Furthermore, the Wagner-Nelson technique was employed to compare the drug release profile by determining the in vivo fixation time data. In line with this, a level between the intestinal absorption in rats and the dissolution % for nanospheres loaded with TAM was created. Plotting the share absorbed in vivo vs the share launched in vitro simultaneously is the best way to illustrate a relationship. [ABSTRACT FROM AUTHOR]

Grain polyphenols are known to possess several health properties. However, their digestive stability and intestinal absorption have not been fully elucidated. This study investigated the fate of pigmented grain polyphenols in the digestive system. Purple rice, purple barley, purple wheat, and blue wheat extracts were subjected to simulated gastric and intestinal phase digestion, followed by Caco‐2 cellular transport. Phenolic profiling and antioxidant activity were determined using benchtop assays and an ultra‐high‐performance liquid chromatography–2,2′‐azino‐bis(3‐ethylbenzothiazoline‐6‐sulfonic acid free radical) (UHPLC‐ABTS•+) system. The results demonstrated a decrease in the total phenolic content of extracts after digestion, with purple rice extract retaining the highest phenolic content (79%) and ABTS•+antioxidant activity (31%). Antioxidant activity was retained the most during the gastric phase; however, dominant antioxidant compounds were not detected after intestinal digestion. Significant variations in phenolic composition and radical scavenging activity were detected after digestion. Protocatechuic acid, vanillic acid, apigenin, and chrysoeriol were all transported across the intestinal barrier. The findings of this study provide novel insights into the in vitro stability and antioxidant activity of cereal grain polyphenols after simulated digestion. [ABSTRACT FROM AUTHOR]

Hyperphosphataemia represents a significant challenge in the management of chronic kidney disease, exerting a pronounced influence on the pathogenesis of cardiovascular complications and mineral bone disorders. Traditional approaches to address hyperphosphataemia involve implementing dietary phosphate restrictions, administering phosphate binders, and, in cases of end-stage renal disease, resorting to dialysis. Unfortunately, these interventions frequently prove inadequate in maintaining phosphate levels within recommended ranges. Additionally, commonly employed pharmacological agents are not immune to eliciting adverse events, thereby limiting their prescription and therapeutic adherence. There is a growing focus on exploring novel therapeutic strategies in this context. The current discussion centres on tenapanor, a pharmacological agent predominantly acting as a selective inhibitor of sodium/hydrogen exchanger isoform 3 (NHE3). Its mechanism of action involves modulating tight junctions, resulting in reduced sodium absorption and intestinal paracellular permeability to phosphate. Furthermore, tenapanor downregulates sodium-dependent phosphate 2b transport protein (NaPi2b) expression, thereby impeding active transcellular phosphate transport. Clinical trials have elucidated the efficacy and safety profile of tenapanor. This evidence hints at a potential paradigm shift in the management of hyperphosphataemia. However, the burgeoning optimism surrounding tenapanor warrants tempered enthusiasm, as further research remains indispensable. The imperative lies in meticulously delineating its efficacy and safety contours within the crucible of clinical practice. In this review, we synthesize the intricate interplay between hyperphosphataemia and Chronic Kidney Disease-Mineral Bone Disorder, and we discuss the existing pharmacological interventions for hyperphosphataemia and explore emerging treatment paradigms that offer novel perspectives in managing elevated phosphate levels in CKD patients. [ABSTRACT FROM AUTHOR]

This research aims to identify regional differences in vildagliptin absorption across the intestinal membrane. Furthermore, it was to investigate the effect of verapamil or metformin on vildagliptin absorptive clearance. The study utilized an in situ rabbit intestinal perfusion technique to determine vildagliptin oral absorption from duodenum, jejunum, ileum, and ascending colon. This was conducted both with and without perfusion of metformin or verapamil. The findings revealed that the vildagliptin absorptive clearance per unit length varied by site and was in the order as follows: ileum < jejunum < duodenum < ascending colon, implying that P‐gp is significant in the reduction of vildagliptin absorption. Also, the arrangement cannot reverse intestinal P‐gp, but the observations suggest that P‐gp is significant in reducing vildagliptin absorption. Verapamil co‐perfusion significantly increased the vildagliptin absorptive clearance by 2.4 and 3.2 fold through the jejunum and ileum, respectively. Metformin co‐administration showed a non‐significant decrease in vildagliptin absorptive clearance through all tested segments. Vildagliptin absorption was site‐dependent and may be related to the intestinal P‐glycoprotein content. This may aid in understanding the important elements that influence vildagliptin absorption, besides drug–drug interactions that can occur in type 2 diabetic patients taking vildagliptin in conjunction with other drugs that can modify the P‐glycoprotein level. [ABSTRACT FROM AUTHOR]

The purpose of this experiment was to study the effects of adding Modified Zhizhu Powder to diet on the growth performance, blood routine examination, serum biochemical indexes, and intestinal digestive enzymes of weaned rabbits. Ninety 35-day-old healthy New Zealand white rabbits with similar weight were randomly divided into five groups with six replicates in each group and three rabbits in each replicate. The rabbits in the control group were fed with basal diet, while the experimental group was fed with 2‰ enrofloxacin powder and 1‰, 3‰, and 5‰ Modified Zhizhu Powder, respectively. The pre-test period was seven days, and the formal test period was 14 days. The results showed that compared with the control group, the average daily gain of weaned rabbits in the Modified Zhizhu Powder group increased significantly (P<0.05), the diarrhea rate decreased significantly, and there was no death of rabbits. Compared with the control group, the immune organ index of weaned rabbits in the Modified Zhizhu Powder group increased significantly (P<0.05), and it was dose-dependent. Compared with the control group, the number of white blood cells, lymphocytes, and neutrophils in the Modified Zhizhu Powder group decreased significantly (P<0.05). The content of immunoglobulin in 5‰ Modified Zhizhu Powder group increased significantly (P<0.05). Modified Zhizhu Powder can enhance the secretion of lipase, α-amylase, cellulase, and trypsin in small intestine, and promote the absorption of energy in intestinal tract of young rabbits by up-regulating the gene expression level of glucose transporter in small intestine. The study indicates that the addition of Modified Zhizhu Powder in the diet of weaned rabbits can improve the growth performance, enhance the immune function, reduce the inflammatory level of the body, and improve the digestion and absorption capacity of intestinal tract. The suitable addition level of Modified Zhizhu Powder in diet is 3‰~5‰. [ABSTRACT FROM AUTHOR]

Oral drug absorption involves drug permeation across the apical and basolateral membranes of enterocytes. Although transporters mediating the influx of anionic drugs in the apical membranes have been identified, transporters responsible for efflux in the basolateral membranes remain unclear. Monocarboxylate transporter 6 (MCT6/SLC16A5) has been reported to localize to the apical and basolateral membranes of human enterocytes and to transport organic anions such as bumetanide and nateglinide in the Xenopus oocyte expression system; however, its transport functions have not been elucidated in detail. In this study, we characterized the function of MCT6 expressed in HEK293T cells and explored fluorescent probes to more easily evaluate MCT6 function. The results illustrated that MCT6 interacts with CD147 to localize at the plasma membrane. When the uptake of various fluorescein derivatives was examined in NaCl-free uptake buffer (pH 5.5), the uptake of 5-carboxyfluorescein (5-CF) was significantly greater in MCT6 and CD147-expressing cells. MCT6-mediated 5-CF uptake was saturable with a K m of 1.07 mM and inhibited by several substrates/inhibitors of organic anion transporters and extracellular Cl ion with an IC 50 of 53.7 mM. These results suggest that MCT6 is a chloride-sensitive organic anion transporter that can be characterized using 5-CF as a fluorescent probe. [Display omitted] [ABSTRACT FROM AUTHOR]

Flavonoids exhibit various bioactivities including anti-oxidant, anti-tumor, anti-inflammatory, and anti-viral properties. Methylated flavonoids are particularly significant due to their enhanced oral bioavailability, improved intestinal absorption, and greater stability. The heterologous production of plant flavonoids in bacterial factories involves the need for enough biosynthetic precursors to allow for high production levels. These biosynthetic precursors are malonyl-CoA and l-tyrosine. In this work, to enhance flavonoid biosynthesis in Streptomyces albidoflavus, we conducted a transcriptomics study for the identification of candidate genes involved in l-tyrosine catabolism. The hypothesis was that the bacterial metabolic machinery would detect an excess of this amino acid if supplemented with the conventional culture medium and would activate the genes involved in its catabolism towards energy production. Then, by inactivating those overexpressed genes (under an excess of l-tyrosine), it would be possible to increase the intracellular pools of this precursor amino acid and eventually the final flavonoid titers in this bacterial factory. The RNAseq data analysis in the S. albidoflavus wild-type strain highlighted the hppD gene encoding 4-hydroxyphenylpyruvate dioxygenase as a promising target for knock-out, exhibiting a 23.2-fold change (FC) in expression upon l-tyrosine supplementation in comparison to control cultivation conditions. The subsequent knock-out of the hppD gene in S. albidoflavus resulted in a 1.66-fold increase in the naringenin titer, indicating enhanced flavonoid biosynthesis. Leveraging the improved strain of S. albidoflavus, we successfully synthesized the methylated flavanones hesperetin, homoeriodictyol, and homohesperetin, achieving titers of 2.52 mg/L, 1.34 mg/L, and 0.43 mg/L, respectively. In addition, the dimethoxy flavanone homohesperetin was produced as a byproduct of the endogenous metabolism of S. albidoflavus. To our knowledge, this is the first time that hppD deletion was utilized as a strategy to augment the biosynthesis of flavonoids. Furthermore, this is the first report where hesperetin and homoeriodictyol have been synthesized from l-tyrosine as a precursor. Therefore, transcriptomics is, in this case, a successful approach for the identification of catabolism reactions affecting key precursors during flavonoid biosynthesis, allowing the generation of enhanced production strains. [ABSTRACT FROM AUTHOR]

The present study was based on an exploration of NCI database for searching specific CDK-7 kinase inhibitor by HTVS, SP, XP, molecular docking, molecular dynamic simulation, and ADMET evaluation. The best CDK-7 kinase inhibitors (NCI613391, NCI169676, NCI281246, NCI339580) were identified via NCI database screening. The stability of binding interaction between receptor protein and protein-ligand complex of potent finding compounds (NCI613391) was further confirmed by dynamics simulations and MM--GBSA. The RMSD value of receptor and receptor-ligand complexes was analysed, and it revealed the stability of binding interactions and remained stable throughout the simulation. The RMSF values and gyration radius of the unbound receptor and backbone atoms of the complex were found to be equal, which indicates that the drug molecule inside the CDK7 receptor is also stable. The study of MM-GBSA data also revealed stronger binding interactions of ligands to CDK7 receptors. With the exception of NCI169676, all compounds were shown to be substrates for CYP450 2D6, CYP450 3A4, inhibitors of CYP450 2C9, and non-inhibitors of p-glycoprotein. All compounds were qualified and found suitable to be as drug-likeness according to the Lipinski rule, Ghose filter, MDDR like rule and CMC-like rule. The compound (NCI613391) exhibited human intestinal absorption (76.08%), displayed negative AMES and T.E.S.T (US-EPA) toxicity with OSIRIS property and found to be a promising CDK-7 kinase inhibitor and its efficacy may be further explored in clinical trials. [ABSTRACT FROM AUTHOR]