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Recently, the bioactive potential of several functional ingredients and biomolecules has been evaluated regarding human and animal nutrition. The digestive process from food intake to absorption and metabolism are important events that induce changes in ingredients, which affect their bioactivity. Consequently, there is a need to assess the bioavailability and bioaccessibility of these compounds. The methodology for the simulation of the human gastrointestinal tract has been standardized (INFOGEST protocol), while a gastrointestinal protocol for other animals (e.g., ruminants or broilers) has yet to be established. However, INFOGEST allows us only to predict bioaccessibility, leaving a gap regarding a methodology able to assess bioavailability by mimicking intestinal permeability and absorption. Several approaches—including in vitro, ex vivo, in situ and in vivo methods—can be found in the literature, aiming to tackle transepithelial routes, but leading to different results concerning the bioefficiency of the compounds studied. Therefore, this review aims to assess the current state-of-the-art regarding monogastric intestinal dynamics, absorption, and permeability events. Moreover, it compiled methodologies for simulating intestinal absorption in several biological systems, while reasoning their advantages, disadvantages, applications in ingredient development and the existing gaps.

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]

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]

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]

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]

Vitamin D is precursor of the steroid hormone calcitriol and has important functions throughout the body, including increasing intestinal absorption of calcium, magnesium and phosphate. Vitamin D deficiency has been linked with a range of disorders, including several bone diseases. However, large trials of vitamin D supplementation have produced mixed results. Here, experts from around the world discuss several key questions in the vitamin D research and clinical fields. [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]

BACKGROUND: Citrus pulp (CP) is rich in pectin, and studies have shown that pectin possesses antioxidant, anti-inflammatory, and gut microbiota-regulating properties. However, the application of CP in aquafeed is limited. In this study, the effect of dietary inclusion of CP on the intestinal health of largemouth bass (Micropterus salmoides) was investigated. Juveniles of similar size (6.95 ± 0.07 g) were fed isonitrogenous and isoenergetic diets containing different levels of CP (0%, 3%, 6%, 9%, 12%, or 15%) for 58 days. RESULTS: As the level of CP in the feed for largemouth bass increased, the fish's growth performance and intestinal health initially improved and then declined. Adding low doses of CP (≤9%) to the feed had no significant impact on the growth performance of large-mouth black bass, whereas high doses of CP (>9%) significantly reduced their growth performance. Adding 6%, 9%, or 12% of CP to that feed enhanced the expression of genes related to tight junctions, anti-inflammatory activity, anti-apoptotic activity, and antioxidant activity in the intestines of largemouth bass. It reduced intestinal inflammation and improved intestinal nutrient absorption, intestinal mucosal barrier function, and intestinal antioxidant capacity. Moreover, it improved the α-diversity, structure, and function of the intestinal flora. The addition of 6% CP had the most beneficial effect on the intestinal health of largemouth bass. On the other hand, the addition of 15% CP had adverse effects on the intestinal antioxidant capacity and intestinal mucosal barrier function of largemouth bass. CONCLUSION: Adding 6-9% CP to the feed for largemouth bass can improve their intestinal health without having a significant impact on their growth performance. CP could serve as a novel prebiotic and immunostimulant ingredient in aquafeed. [ABSTRACT FROM AUTHOR]

In clinics, hepcidin levels are elevated in various anemia‐related conditions, particularly in iron‐refractory anemia and in high inflammatory states that suppress iron absorption, which remains an urgent unmet medical need. To identify effective treatment options for various types of iron‐refractory anemia, the potential effect of hypoxia and pharmacologically‐mimetic drug FG‐4592 (Roxadustat) are evaluated, a hypoxia‐inducible factor (HIF)‐prolyl hydroxylase (PHD) inhibitor, on mouse models of iron‐refractory iron‐deficiency anemia (IRIDA), anemia of inflammation and 5‐fluorouracil‐induced chemotherapy‐related anemia. The potent protective effects of both hypoxia and FG‐4592 on IRIDA as well as other 2 tested mouse cohorts are found. Mechanistically, it is demonstrated that hypoxia or FG‐4592 could stabilize duodenal Hif2α, leading to the activation of Fpn transcription regardless of hepcidin levels, which in turn results in increased intestinal iron absorption and the amelioration of hepcidin‐activated anemias. Moreover, duodenal Hif2α overexpression fully rescues phenotypes of Tmprss6 knockout mice, and Hif2α knockout in the gut significantly delays the recovery from 5‐fluorouracil‐induced anemia, which can not be rescued by FG‐4592 treatment. Taken together, the findings of this study provide compelling evidence that targeting intestinal hypoxia‐related pathways can serve as a potential therapeutic strategy for treating a broad spectrum of anemia, especially iron refractory anemia. [ABSTRACT FROM AUTHOR]

Dietary lipids are key ingredients during cooking, processing, and seasoning of carotenoid-rich fruits and vegetables, playing vitals in affecting the absorption and utilization of carotenoids for achieving their health benefits. Besides, dietary lipids have also been extensively studied to construct various delivery systems for carotenoids, such as micro/nanoparticles, micro/nanoemulsions, and liposomes. Currently, the efficacies of these techniques on improving carotenoid bioavailability are often evaluated using the micellization rate or "bioaccessibility" based on in vitro models. However, recent studies have found that dietary lipids may also affect the carotenoid uptake via intestinal epithelial cells and the efflux of intracellular chyle particles via lipid transporters. An increasing number of studies reveal the varied impact of different dietary lipids on the absorption of different carotenoids and some lipids may even have an inhibitory effect. Consequently, it is necessary to clarify the relationship between the addition of dietary lipids and the intestinal absorption of carotenoid to fully understand the role of lipids during this process. This paper first introduces the intestinal absorption mechanism of carotenoids, including the effect of bile salts and lipases on mixed micelles, the types and regulation of lipid transporters, intracellular metabolizing enzymes, and the efflux process of chyle particles. Then, the regulatory mechanism of dietary lipids during intestinal carotenoid absorption is further discussed. Finally, the importance of selecting the dietary lipids for the absorption and utilization of different carotenoids and the design of an efficient delivery carrier are emphasized. This review provides suggestions for precise dietary carotenoid supplementation and offere an important reference for constructing efficient transport carriers for liposoluble nutrients. [ABSTRACT FROM AUTHOR]

There is control over steroids use and marketing, but also new compounds that mimic their effects, steroid derivatives, are being synthesized. They are frequently produced as dietary supplements intended to improve physical activity, and usually no information is provided regarding their composition, dosages, and efficacy or safety. In this study, a computational approach was used to evaluate the absorption, distribution, metabolism, excretion and toxicity (ADMET) profiles of several steroid derivatives: methasterone, methyl-1-testosterone, 4-hydroxytestosterone, methyldienolone, methyltrienolone and 19-nor-5-androstenedione. The following computational prediction tools were applied: admetSAR2.0, ADMETLab2.0, Endocrine Disruptome, PredSkin3.0. All investigated compounds showed good human intestinal absorption, are not able to penetrate the blood-brain barrier and inhibit cytochrome P450 enzymes involved in the metabolism of xenobiotics. These compounds have potential for skin sensitisation, induce reproductive toxicity and endocrine disruption, and have a low potential for hepatotoxicity and respiratory toxicity. It is important that the results of the study are known by those exposed at workplaces where these compounds are produced and packed as well as by consumers. These predictions can also guide the experimental evaluation of the possible toxicity of the investigated compounds, the results of which can be further used for purposes of regulating the use of these steroid derivatives. [ABSTRACT FROM AUTHOR]

Chitosan nanoparticles have received a lot of attention in recent years due to their beneficial properties as healthy supplement to supply bioactive substances in the food industry and nutrition. The purpose of this study was to investigate the influence of chitosan nanoparticles (CsNPs) as nutritional stimulus at the early feeding for the Nile tilapia (Oreochromis niloticus) fry on the growth performance, feed efficiency, and histomorphological health of the liver and intestine. Graded levels of CsNPs (0.05, 0.1, 0.2, 0.4, 0.8, and 1.6g kg-1 diet) were added to the basal diet, and each experimental diet was fed to three groups of fish with an approximate weight (0.86± 0.04g) for 70 days. The experimental study concluded that CsNPs 0.1 and 0.2g kg-1 diets resulted in significantly higher final weight (FW), weight gain (WG), specific growth rate (SGR), energy efficiency ratio (EER), and survival (S%) compared to the control group (P <0.05). However, the protein efficiency ratio (PER) increased but did not differ substantially (P> 0.05) between the control and other treatments. The intestine of the Nile tilapia fry showed that the villi height increased in the diet-fed groups of 0.1, 0.2, and 0.4g CsNPs kg-1 diet, while the highest villi length was recorded in the group of 0.2g CsNPs kg-1 diet. The group fed on 0.2g CsNPs kg-1 diet demonstrated normal healthy intestinal walls and branched villi with intact enterocytes comprising the intestinal villi. Histopathological structure of the Nile tilapia liver in fry fed with CsNPs revealed that the control group had congested blood sinusoids and fatty vacuolization of hepatocytes, whereas the 0.2g CsNPs kg-1 diet group displayed normal hepatocytes with slight lymphocyte infiltration. Findings of the current study illustrated the positive effect of dietary supplementation of 0.2g kg-1 of chitosan nanoparticles which is considered as a promising compound in improving the growth performance, feed efficiencies, and an increase in villi length to facilitate the absorption process in the intestinal Nile tilapia (Oreochromis niloticus) fry. [ABSTRACT FROM AUTHOR]

Leishmaniasis, a neglected tropical disease, poses a significant global health challenge, necessitating the urgent development of innovative therapies. In this study, we aimed to identify compounds from the COVID Box with potential efficacy against two Leishmania species, laying the foundation for future chemical development. Four promising molecules were discovered, demonstrating notable inhibitory effects against L. amazonensis and L. donovani. Our study revealed that bortezomib, almitrine, and terconazole induced a significant decrease in mitochondrial membrane potential, while the above compounds and ABT239 induced plasma permeability alterations, chromatin condensation, and reactive oxygen species accumulation, indicating early apoptosis in Leishmania amazonensis promastigotes, preventing inflammatory responses and tissue damage, thereby improving patient outcomes. Furthermore, ADME predictions revealed favorable pharmacokinetic profiles for all compounds, with bortezomib and ABT239 standing out as potential candidates. These compounds exhibited intestinal absorption, blood–brain barrier penetration (excluding bortezomib), and good drug-likeness for bortezomib and ABT239. Toxicity predictions for CYP-inhibition enzymes favored bortezomib as the safest candidate. In conclusion, our study identifies bortezomib as a promising aspirant for leishmaniasis treatment, demonstrating potent antiparasitic activity, favorable pharmacokinetics, and low toxicity. These findings emphasize the potential repurposing of existing drugs for neglected diseases and highlight the importance of the COVID Box in drug discovery against tropical diseases. [ABSTRACT FROM AUTHOR]

Food-derived oligopeptides (FOPs) exhibit various bioactivities. However, little was known about their sequence changes in the gastrointestinal tract and the effect of changes on bioactivities. FOPs' sequence features, changes and effects on bioactivities have been summarised. The sequence length of FOPs decreases with increased exposure of hydrophobic and basic amino acids at the terminal during simulated gastrointestinal digestion. A decrease in bioactivities after simulated intestinal absorption has correlated with a decrease of Leu, Ile, Arg, Tyr, Gln and Pro. The sequence of FOPs that pass readily through the intestinal epithelium corresponds to transport modes, and FOPs whose sequences remain unchanged after transport are the most bioactive. These include mainly dipeptides to tetrapeptides, consisting of numerous hydrophobic and basic amino acids, found mostly at the end of the peptide chain, especially at the C-terminal. This review aims to provide a foundation for applications of FOPs in nutritional supplements and functional foods. [ABSTRACT FROM AUTHOR]

Bioactive peptides are currently emerging as nonpharmacological alternatives for treating noncommunicable diseases, including hypertension. Pharmacological treatments for hypertension typically involve angiotensin I converting enzyme inhibitors such as Captopril and enalapril. This study aimed to evaluate the activity of bioactive peptides derived from food sources against this enzyme and show its possible mechanism of inhibitory action. A comprehensive search was conducted in peptide databases to identify peptides with antihypertensive properties. Subsequently, docking studies, simulations, and predictive tests assessing ADME parameters, intestinal stability, and allergenicity were performed using bioinformatics tools. The docking and simulation results demonstrated that PEP2 exhibited superior ACE1 inhibitory potential compared to other peptides, even though it had lower human intestinal absorption. In conclusion, this study suggests that these peptides hold promising potential as nutraceuticals for hypertension treatment. [ABSTRACT FROM AUTHOR]

The solubility and permeability of the Biopharmaceutics Classification System (BCS) class IV drugs, such as furosemide (FUR), are low. Thus, the oral bioavailability of these drugs needs to be augmented. Here, we aimed to design orally disintegrating tablets containing FUR nanoparticles to improve bioavailability after oral administration. The FUR nanoparticles were generated by bead-milling in water containing 0.5% methylcellulose and 0.5% 2-hydroxypropyl-β-cyclodextrin (w/w%). Particle size was approximately 47–350 nm (mean particle size, 188 nm). An orally disintegrating tablet (FUR-NP tablet) comprising FUR nanoparticles (1%) was successfully produced by employing suspensions outlined above that incorporated additives (4% D-mannitol, 0.4% polyvinylpyrrolidone, and 16% gum Arabic, w/w%), followed by freeze-drying. The FUR-NP tablet disaggregated after only 5 s in water, liberating nano-sized FUR particles (172 nm). Experiments using rats showed the absorption of the FUR-NP tablet was significantly improved by comparison with a FUR tablet containing microparticles. In summary, the orally disintegrating tablet containing FUR nanoparticles markedly enhanced the bioavailability of FUR. We anticipate this formulation will also improve the bioavailability of other BCS class IV drugs. [ABSTRACT FROM AUTHOR]

Pseudo-cereals are an excellent source of nutrients, rich in carbohydrates, dietary fiber, protein, lipids, phytochemicals, and minerals such as magnesium, zinc, copper, sodium, potassium, and calcium. The positive effects of gluten-free pseudo-cereals on the digestive system are an alternative to natural cereals. Pseudo-cereals have prebiotic properties and strengthen digestion by positively affecting the development of probiotic bacteria, especially Lactobacillus. Therefore, the effect of amaranth, a pseudo-cereal, on the activity of L. acidophilus probiotic bacteria, which helps digestion, was determined. First, solvent, acidic, and basic hydrolysis extractions of amaranth in eight different solvent media were performed, and total phenolic content and antioxidant activity values were determined. The total phenolic content values in the gastrointestinal digestion process were investigated by applying three different consumption methods, milling, boiling, and drying, to amaranth grains. L. acidophilus probiotic bacteria were activated with milled, dried, and boiled amaranth, and the increase in viability was examined. While the viability of L. acidophilus activated with milled and dried amaranth increased by 9.47% and 7.46%, respectively, the viability of bacteria activated with boiled amaranth almost did not increase (0.60%). [ABSTRACT FROM AUTHOR]

Digestion and absorption describe the breakdown of food into small particles and their movement from the gastrointestinal (GI) lumen into the body. The main groups of nutrients absorbed from food are carbohydrates, proteins, and lipids. Water, minerals, and vitamins are also absorbed by the GI tract along with orally administered drugs. Carbohydrates are enzymatically broken down into monosaccharides, which are absorbed across the small intestinal epithelium by passive (fructose) and active (glucose and galactose) mechanisms. Similarly, proteins are broken down from polypeptide chains into individual amino acids or dipeptides and tripeptides. Their absorption depends on their chemical properties and occurs via passive and active processes that utilize a variety of membrane transporters. Lipids and lipid-soluble vitamins require bile salts for emulsification to aid absorption. Water follows osmotic gradients generated by the absorption of nutrients. Since the processes of digestion and absorption require mechanical and chemical processes that can damage the mucosa, the GI tract has evolved several defence mechanisms, including a mucous barrier and regular renewal of the epithelial lining. [ABSTRACT FROM AUTHOR]

Background: Ivacaftor is a modern drug used in the treatment of cystic fibrosis. It is highly lipophilic and exhibits a strong positive food effect. These characteristics can be potentially connected to a pronounced lymphatic transport after oral administration. Methods: A series of studies was conducted to describe the basic pharmacokinetic parameters of ivacaftor in jugular vein cannulated rats when dosed in two distinct formulations: an aqueous suspension and an oil solution. Additionally, an anesthetized mesenteric lymph duct cannulated rat model was studied to precisely assess the extent of lymphatic transport. Results: Mean ± SD ivacaftor oral bioavailability was 18.4 ± 3.2% and 16.2 ± 7.8%, respectively, when administered as an aqueous suspension and an oil solution. The relative contribution of the lymphatic transport to the overall bioavailability was 5.91 ± 1.61% and 4.35 ± 1.84%, respectively. Conclusion: Lymphatic transport plays only a minor role in the process of ivacaftor intestinal absorption, and other factors are, therefore, responsible for its pronounced positive food effect. [ABSTRACT FROM AUTHOR]

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Recently, the bioactive potential of several functional ingredients and biomolecules has been evaluated regarding human and animal nutrition. The digestive process from food intake to absorption and metabolism are important events that induce changes in ingredients, which affect their bioactivity. Consequently, there is a need to assess the bioavailability and bioaccessibility of these compounds. The methodology for the simulation of the human gastrointestinal tract has been standardized (INFOGEST protocol), while a gastrointestinal protocol for other animals (e.g., ruminants or broilers) has yet to be established. However, INFOGEST allows us only to predict bioaccessibility, leaving a gap regarding a methodology able to assess bioavailability by mimicking intestinal permeability and absorption. Several approaches—including in vitro, ex vivo, in situ and in vivo methods—can be found in the literature, aiming to tackle transepithelial routes, but leading to different results concerning the bioefficiency of the compounds studied. Therefore, this review aims to assess the current state-of-the-art regarding monogastric intestinal dynamics, absorption, and permeability events. Moreover, it compiled methodologies for simulating intestinal absorption in several biological systems, while reasoning their advantages, disadvantages, applications in ingredient development and the existing gaps. [ABSTRACT FROM AUTHOR]

Proanthocyanidins are important compounds known for their antioxidant and radical scavenging properties, but they are highly sensitive to light, heat, oxygen, and pH. In our study, proanthocyanidin was encapsulated using sodium alginate and carboxymethyl cellulose to enhance controlled release, pH stability, metal ion tolerance, temperature resistance, time release, the microencapsulation of food additives stability, antioxidant capacity analysis, and the storage period tolerance of proanthocyanidin. Fourier transforms infrared (FTIR) analysis and full-wavelength UV scanning indicated the successful immobilization of proanthocyanidins into the polymeric microcapsules. The flowability and mechanical properties of the microcapsules were enhanced. Moreover, proanthocyanidin microcapsules exhibited higher thermal, pH, metal ion, time, and microencapsulation food additive stability. In addition, due to their high antioxidant properties, the proanthocyanidin microcapsules retained a greater amount of proanthocyanidin content during the gastric phase, and the proanthocyanidin was subsequently released in the intestinal phase for absorption. Thus, the study provided a systematic understanding of the antioxidant capabilities and stability of proanthocyanidin microcapsules, which is beneficial for developing preservation methods for food additives. [ABSTRACT FROM AUTHOR]

This study investigated the absorption characteristics of

The modern history of cholesterol-lowering drugs started in 1972 when Dr. Akira Endo identified an active compound (compactin) that inhibited cholesterol biosynthesis from the culture broth of blue–green mold (Penicillium citrinum Pen-51). Since 1987, statins have represented the milestone for the treatment of atherosclerotic cardiovascular disease. A new therapy for the treatment of hypercholesterolemia since the discovery of statins is ezetimibe, the first and only agent inhibiting intestinal cholesterol absorption. Ezetimibe was approved by the FDA in October 2002. A year later, the association between gain-of-function PCSK9 genetic mutations and hypercholesterolemia was reported, and this discovery opened a new era in lipid-lowering therapies. Monoclonal antibodies and small-interfering RNA approaches to reduce PCSK9 were developed and approved for clinical use in 2015 and 2022, respectively. Finally, the newly approved bempedoic acid, an oral adenosine triphosphate citrate lyase inhibitor that lowers LDL-C, is able to reduce major adverse cardiovascular events in both primary and secondary prevention. In the present narrative review, we summarize the pharmacological properties and the clinical efficacy of all these agents currently used for a tailored therapy of hypercholesterolemia in patients with atherosclerotic cardiovascular disease. [ABSTRACT FROM AUTHOR]

Background: Peripheral neuropathy is caused by a malfunction in the axons and myelin sheaths of peripheral nerves and motor and sensory neurons. In this context, nonpharmacological treatments with antioxidant potential have attracted much attention due to the issues that some conventional pharmaceutical therapy can generate. Most of these treatments contain lipoic acid, but issues have emerged regarding its use. Considering this, the present study evaluated the beneficial effects of nutraceuticals based on Gastrodiae elata dry extract 10:1 or lipoic acid in combination with other substances (such as citicholine, B vitamins, and acetyl L-carnitine). Method: To assess the combination's absorption and biodistribution and exclude cytotoxicity, its bioavailability was first examined in a 3D intestinal barrier model that replicated oral ingestion. Subsequently, a 3D model of nerve tissue was constructed to investigate the impacts of the new combination on the significant pathways dysregulated in peripheral neuropathy. Results: Our findings show that the novel combination outperformed in initial pain relief response and in recovering the mechanism of nerve healing following Schwann cell injury by successfully crossing the gut barrier and reaching the target site. Conclusion: This article describes a potential alternative nutraceutical approach supporting the effectiveness of combinations with Gastrodiae elata extract in decreasing neuropathy and regulating pain pathways. [ABSTRACT FROM AUTHOR]

Purpose Short bowel syndrome is a malabsorptive condition that occurs due to surgical removal or a congenital absence of a significant portion of the small intestine. Patients with short bowel syndrome often rely on parenteral support for extended periods or even their entire lives. Teduglutide, a glucagon-like peptide-2 analog, has shown promising results in reducing dependency on parenteral support in these patients by promoting intestinal adaptation and enhancing nutrient absorption. However, the long-term safety of teduglutide remains a concern, particularly with respect to its potential for the development of hyperamylasemia and hyperlipasemia. Methods This study involved patients who received teduglutide from December 2012 to December 2022 at Boston Medical Center. We evaluated outcomes and adverse events, focusing on hyperamylasemia and hyperlipasemia, through chart review. Results Thirteen eligible patients were identified who had used teduglutide. Of these, the majority (84.6%) experienced a reduction in parenteral support. A high incidence (72.7%) of nonpathological pancreatic enzyme elevation was observed in patients treated with teduglutide. These elevations were often dose dependent and were not associated with any clinical signs of acute pancreatitis or abnormal imaging findings. Conclusion This study highlights the need for further investigations into the long-term safety of teduglutide and the importance of closely monitoring amylase and lipase levels in patients undergoing treatment with teduglutide. [ABSTRACT FROM AUTHOR]

Edible flowers are regaining interest among both the scientific community and the general population, not only for their appealing sensorial characteristics but also from the growing evidence about their health benefits. Among edible flowers, those that contain anthocyanins are among the most consumed worldwide. However, little is known regarding the bioaccessibility and absorption of their bioactive compounds upon ingestion. The aim of this work was to explore, for the first time, the behavior of anthocyanin-rich extracts from selected edible flowers under different food processing conditions and after ingestion using simulated digestions, as well as their absorption at the intestinal level. Overall, the results showed that the monoglucoside and rutinoside anthocyanin extracts were less stable under different pH, temperature, and time conditions as well as different digestive processes in the gastrointestinal tract. There was a prominent decrease in the free anthocyanin content after the intestinal phase, which was more pronounced for the rutinoside anthocyanin extract (78.41% decrease from the oral phase). In contrast, diglucoside and rutinoside anthocyanin extracts showed the highest absorption efficiencies at the intestinal level, of approximately 5% after 4 h of experiment. Altogether, the current results emphasize the influence of anthocyanins' structural arrangement on both their chemical stability as well as their intestinal absorption. These results bring the first insights about the bioaccessibility and absorption of anthocyanins from wild pansy, cosmos, and cornflower and the potential outcomes of such alternative food sources. [ABSTRACT FROM AUTHOR]

The aim of this study was firstly to investigate the effect of membrane permeability on the intestinal availability (Fg) of 10 cytochrome P450 3A4 substrates with differing permeability (Papp) and metabolic activity (CLint) using Madin‐Darby canine kidney II (MDCKII) cells expressing human CYP3A4 (MDCKII/CYP3A4 cells), and secondly to confirm the essential factors by simulations. A membrane permeation assay using MDCKII/CYP3A4 cells showed a significant correlation between human intestinal extraction ratio (ER) (Eg (=1 − Fg)) and in vitro cellular ER (r = 0.834). This relationship afforded better predictability of Eg values than the relationship between Eg and CLint,HIM values obtained from human intestinal microsomes (r = 0.598). An even stronger correlation was observed between 1 − Fa·Fg and ER (r = 0.874). Simulation with a cellular kinetic model indicated that ER is sensitive to changes of PSpassive and CLint values, but not to the intracellular unbound fraction (fu,cell) or P‐gp‐mediated efflux (PSP − gp). It may be concluded that, based on the concentration–time profile of drugs in epithelial cells, transmembrane permeability influences Fg (or ER) and drug exposure time to metabolizing enzymes for P450 substrate. [ABSTRACT FROM AUTHOR]

ctive: In light of their diverse molecular features and wide range of biological activities, compounds with coumarin-based chemical structures have drawn significant scientific interest. On the other hand, despite the massive development of anti-aerobic bacterial agents, those that fight anaerobic bacteria are less advanced. Methods: In this work, 3-halomequinol derivatives were condensed via a Pechmann coupling reaction with 3-oxopentanedioic acid, affording precursors named 7-halo-6-methoxycoumarin-4-acetic acids and coded (P1–P4). These were esterified with metronidazole by thionyl chloride to give the four new coumarin-metronidazole composites coded (COU–MTZ1–COU–MTZ4). The structural conformation of these composites and their corresponding precursors was determined by analyzing the spectra acquired from FT-IR, 1H NMR, and 13C NMR spectrophotometers. The anti-anaerobic bacterial activity was assessed by determining the composites' inhibitory impact against four strains of pathogenic bacteria using broth dilution as a methodology. The biocompatibility profiles of the synthesized composites were spotlighted by in vitro inspection as well as by following their effects on the cellular growth of two normal-type bacterial strains and three healthy-type cell lines. Finally, the possibility of the composites being drug candidates was checked in silico by calculating their pharmacokinetic and drug-like attributes. Results: The results indicated that the new composites are biocompatible and demonstrated improved activity relative to the reference, with a golden effect attributed to the flouro-based composite. Discussion: This work reports the success in the synthesis and characterization of four (COU–MTZ) composites and their precursors. The synthetic composites showed more promising anti-anaerobic bacterial activity than the parent drug, with better theoretical aqueous solubility, intestinal absorption, and association with plasma proteins. Concerning the biocompatibility study, the synthetic composites did not demonstrate any obvious negative impact on the cellular growth of two normal-type bacterial strains and three healthy-type cell lines. Conclusions: It is concluded that the conjugation of metronidazole with the synthesized coumarins can improve its lipophilicity and consequently the candidate's penetration into the test anaerobic pathogens, affording a promising synthon template for advanced research. [ABSTRACT FROM AUTHOR]

Cadmium (Cd) is an environmental toxicant of worldwide public health significance. Diet is the main non-workplace Cd exposure source other than passive and active smoking. The intestinal absorption of Cd involves transporters for essential metals, notably iron and zinc. These transporters determine the Cd body burden because only a minuscule amount of Cd can be excreted each day. The International Agency for Research on Cancer listed Cd as a human lung carcinogen, but the current evidence suggests that the effects of Cd on cancer risk extend beyond the lung. A two-year bioassay demonstrated that Cd caused neoplasms in multiple tissues of mice. Also, several non-tumorigenic human cells transformed to malignant cells when they were exposed to a sublethal dose of Cd for a prolonged time. Cd does not directly damage DNA, but it influences gene expression through interactions with essential metals and various proteins. The present review highlights the epidemiological studies that connect an enhanced risk of various neoplastic diseases to chronic exposure to environmental Cd. Special emphasis is given to the impact of body iron stores on the absorption of Cd, and its implications for breast cancer prevention in highly susceptible groups of women. Resistance to cell death and other cancer phenotypes acquired during Cd-induced cancer cell transformation, under in vitro conditions, are briefly discussed. The potential role for the ZnT1 efflux transporter in the cellular acquisition of tolerance to Cd cytotoxicity is highlighted. [ABSTRACT FROM AUTHOR]

Phosphorus is an essential mineral that is, in the form of inorganic phosphate (Pi), required for building cell membranes, DNA and RNA molecules, energy metabolism, signal transduction and pH buffering. In bone, Pi is essential for bone stability in the form of apatite. Intestinal absorption of dietary Pi depends on its bioavailability and has two distinct modes of active transcellular and passive paracellular absorption. Active transport is transporter mediated and partly regulated, while passive absorption depends mostly on bioavailability. Renal excretion controls systemic Pi levels, depends on transporters in the proximal tubule and is highly regulated. Deposition and release of Pi into and from soft tissues and bone has to be tightly controlled. The endocrine network coordinating intestinal absorption, renal excretion and bone turnover integrates dietary intake and metabolic requirements with renal excretion and is critical for bone stability and cardiovascular health during states of hypophosphataemia or hyperphosphataemia as evident from inborn or acquired diseases. This review provides an integrated overview of the biology of phosphate and Pi in mammals. [ABSTRACT FROM AUTHOR]

Background: Thiadiazines are heterocyclic compounds that contain two nitrogen atoms and one sulfur atom in their structure. These synthetic molecules have several relevant pharmacological activities, such as antifungal, antibacterial, and antiparasitic. Objectives: The present study aimed to evaluate the possible in vitro and in silico interactions of compounds derived from thiadiazines. Methods: The compounds were initially synthesized, purified, and confirmed through HPLC methodology. Multi‐drug resistant bacterial strains of Staphylococcus aureus 10 and Pseudomonas aeruginosa 24 were used to evaluate the direct and modifying antibiotic activity of thiadiazine derivatives. ADMET assays (absorption, distribution, metabolism, excretion, and toxicity) were conducted, which evaluated the influence of the compounds against thousands of macromolecules considered as bioactive targets. Results: There were modifications in the chemical synthesis in carbon 4 or 3 in one of the aromatic rings of the structure where different ions were added, ensuring a variability of products. It was possible to observe results that indicate the possibility of these compounds acting through the cyclooxygenase 2 mechanism, which, in addition to being involved in inflammatory responses, also acts by helping sodium reabsorption. The amine group present in thiadiazine analogs confers hydrophilic characteristics to the substances, but this primary characteristic has been altered due to alterations and insertions of other ligands. The characteristics of the analogs generally allow easy intestinal absorption, reduce possible hepatic toxic effects, and enable possible neurological and anti‐inflammatory action. The antibacterial activity tests showed a slight direct action, mainly of the IJ23 analog. Some compounds were able to modify the action of the antibiotics gentamicin and norfloxacin against multi‐drug resistant strains, indicating a possible synergistic action. Conclusions: Among all the results obtained in the study, the relevance of thiadiazine analogs as possible coadjuvant drugs in the antibacterial, anti‐inflammatory, and neurological action with low toxicity is clear. Need for further studies to verify these effects in living organisms is not ruled out. [ABSTRACT FROM AUTHOR]

Many of the pathological consequences of chronic kidney disease can be attributed to an elevation in serum phosphate levels. Current therapies focused on decreasing intestinal phosphate absorption to treat hyperphosphatemia are inadequate. The most effective therapeutic strategy may be to target multiple absorptive pathways. In this study, the ability of a novel inhibitor of the intestinal sodium hydrogen exchanger 3 (NHE3), LY3304000, which inhibits paracellular, diffusional uptake of phosphate, to work in combination with an inhibitor of the active transporter, sodium dependent phosphate cotransporter 2b (NPT2b), LY3358966, was explored. LY3304000 modestly inhibited the acute uptake of phosphate into plasma of rats, while surprisingly, it doubled the rate of phosphate uptake in mice, an animal model dominated by NPT2b mediated acute phosphate uptake. In rats, LY3004000 and LY3358966 work in concert to inhibit acute phosphate uptake. On top of LY3358966, LY3304000 further decreased the acute uptake of phosphate into plasma. Studies measuring the recovery of radiolabeled phosphate in the intestine demonstrated LY3304000 and LY3358966 synergistically inhibited the absorption of phosphate in rats. We hypothesize the synergism is because the NHE3 inhibitor, LY3304000, has two opposing effects on intestinal phosphate absorption in rats, first it decreases diffusion mediated paracellular phosphate absorption, while second, it simultaneously increases phosphate absorption through the NPT2b pathway. NHE3 inhibition decreases proton export from enterocytes and raises the cell surface pH. In vitro, NPT2b mediated phosphate transport is increased at higher pHs. The increased NPT2b mediated transport induced by NHE3 inhibition is masked in rats which have relatively low levels of NPT2b mediated phosphate transport, by the more robust inhibition of diffusion mediated phosphate absorption. Thus, the inhibition of NPT2b mediated phosphate transport in rats in the presence of NHE3 inhibition has an effect that exceeds its effect in the absence of NHE3 inhibition, leading to the observed synergism on phosphate absorption between NPT2b and NHE3 inhibition. [ABSTRACT FROM AUTHOR]

Vitamin K is a lipophilic vitamin, whose absorption, transportation, and distribution are influenced by lipids. The plasma vitamin K level after supplementation is predominantly a lipid-driven effect and independent of existing vitamin K status. However, previous studies examining the efficacy of vitamin K supplementation often overlooked the influence of lipid levels on vitamin K absorption, resulting in inconsistent outcomes. Recent research discovered that impaired transportation of vitamin K2 within uremic high-density lipoproteins (HDL) in individuals with uremia might elucidate the lack of beneficial effects in preventing calcification observed in multiple trials involving menaquinone-7 (MK-7) supplementation among patients with chronic kidney disease. Clinical findings have shown that drugs used to regulate hyperlipidemia interact with the vitamin K antagonist warfarin, because cholesterol and vitamin K share common transport receptors, such as Niemann-Pick C1-like 1 (NPC1L1) and ATP-binding cassette protein G5/G8 (ABCG5/ABCG8), in enterocytes and hepatocytes. Additionally, cholesterol and vitamin K share a common biosynthetic intermediate called geranylgeranyl pyrophosphate (GGPP). It is important to note that statins, which hinder cholesterol synthesis, can also impede vitamin K conversion, ultimately impacting the functionality of vitamin K-dependent proteins. Furthermore, certain studies have indicated that vitamin K supplementation holds potential in managing hyperlipidemia, potentially opening a novel avenue for controlling hyperlipidemia using dietary vitamin K supplements. Therefore, attaining a more comprehensive understanding of the intricate interplay between vitamin K and lipids will yield valuable insights concerning the utilization of vitamin K and lipid regulation. [ABSTRACT FROM AUTHOR]

Poor aqueous solubility often results in poor dissolution behavior and, consequently, poor bioavailability for those drugs whose intestinal absorption is dissolution rate limited. It is essential for formulation scientists to identify strategies to improve the solubility and dissolution rate of candidate drugs in order to improve their bioavailability. The present study investigated electrospun polymeric nanofibers for efavirenz (an antiretroviral drug), a Class II drug in the Biopharmaceutical Classification System. In order to fabricate nanofibers, hydrophilic spinnable polymer like Soluplus was used. Statistical design of experiments was used to optimize electrospinning parameters. Scanning electron microscopy (SEM) studies confirmed the presence of nanofibrous material in the mat. The x-ray diffraction (XRD) and differential scanning calorimetry (DSC) studies advocated the amorphization of efavirenz in the nanofiber samples. The optimized nanofiber-based platform significantly improved in vitro dissolution of efavirenz (89.0 ± 3.2% in 120 minutes) compared to pure efavirenz crystals (27.3 ± 2.4%). [ABSTRACT FROM AUTHOR]

Biotherapeutics exhibit high efficacy in targeted therapy, but their oral delivery is impeded by the harsh conditions of the gastrointestinal (GI) tract and limited intestinal absorption. This article presents a strategy to overcome the challenges of poor intestinal permeability by using a protein shuttle that specifically binds to an intestinal target, the leptin receptor (LepR), and exploiting its capacity to perform a receptor-mediated transport. Our proof-of-concept study focuses on the characterization and transport of robust affinity proteins, known as Nanofitins, across an ex vivo porcine intestinal model. We describe the potential to deliver biologically active molecules across the mucosa by fusing them with the Nanofitin 1-F08 targeting the LepR. This particular Nanofitin was selected for its absence of competition with leptin, its cross-reactivity with LepR from human, mouse, and pig hosts, and its shuttle capability associated with its ability to induce a receptor-mediated transport. This study paves the way for future in vivo demonstration of a safe and efficient oral-to-systemic delivery of targeted therapies. [ABSTRACT FROM AUTHOR]

Intestinal absorption is a complex process involving the permeability of the epithelial barrier, efflux transporter activity, and intestinal metabolism. Identifying the key factors that govern intestinal absorption for each investigational drug is crucial. To assess and predict intestinal absorption in humans, it is necessary to leverage appropriate in vitro systems. Traditionally, Caco-2 monolayer systems and intestinal Ussing chamber studies have been considered the 'gold standard' for studying intestinal absorption. However, these methods have limitations that hinder their universal use in drug discovery and development. Recently, there has been an increasing number of reports on complex in vitro models (CIVMs) using human intestinal organoids derived from intestinal tissue specimens or iPSC-derived enterocytes plated on 2D or 3D in microphysiological systems. These CIVMs provide a more physiologically relevant representation of key ADME-related proteins compared to conventional in vitro methods. They hold great promise for use in drug discovery and development due to their ability to replicate the expressions and functions of these proteins. This review highlights recent advances in gut CIVMs employing intestinal organoid model systems compared to conventional methods. It is important to note that each CIVM should be tailored to the investigational drug properties and research questions at hand. [ABSTRACT FROM AUTHOR]

Iron deficiency is the most common nutritional deficiency worldwide, with significant adverse health consequences in the presence or absence of anaemia. Total dose intravenous iron replacement is recommended for replacement of iron in patients with severe iron deficiency, especially in the presence of anaemia, intolerance or inefficacy following oral iron, or states of inflammation where upregulation of hepcidin may impair gastrointestinal absorption of iron. Currently, available intravenous iron formulations have been demonstrated to have an excellent overall safety profile, but potential adverse effects, including skin staining, infusion‐related reactions and hypophosphataemia, have been described. Knowledge of differences in administration and safety profiles of currently available iron formulations will allow appropriate prescription, counselling, as well as recognition and management of adverse events in patients requiring intravenous iron. [ABSTRACT FROM AUTHOR]

Oral administration of peptide therapeutics faces challenges because of the distinct environment of the gastrointestinal tract. An oral formulation of semaglutide, a glucagon-like peptide 1 receptor agonist, was approved by the U.S. Food and Drug Administration in 2019 as a peptide therapy for the treatment of type 2 diabetes. Oral semaglutide uses sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC) technology to enhance the absorption of semaglutide in the stomach and protect it from degradation by gastric enzymes. This article presents a summary of studies investigating SNAC technology as an absorption enhancer for a number of molecules and, in particular, explores how SNAC, once coformulated with oral semaglutide, facilitates increased absorption and bioavailability. Practical advice and dispensing information for pharmacists is also provided. [ABSTRACT FROM AUTHOR]

Non‐alcoholic fatty liver disease (NAFLD) is considered as one of the most common diseases of lipid metabolism disorders, which is closely related to bile acids disorders and gut microbiota disorders. Bile acids are synthesized from cholesterol in the liver, and processed by gut microbiota in intestinal tract, and participate in metabolic regulation through the enterohepatic circulation. Bile acids not only promote the consumption and absorption of intestinal fat but also play an important role in biological metabolic signaling network, affecting fat metabolism and glucose metabolism. Studies have demonstrated that exercise plays an important role in regulating the composition and function of bile acid pool in enterohepatic axis, which maintains the homeostasis of the enterohepatic circulation and the health of the host gut microbiota. Exercise has been recommended by several health guidelines as the first‐line intervention for patients with NAFLD. Can exercise alter bile acids through the microbiota in the enterohepatic axis? If so, regulating bile acids through exercise may be a promising treatment strategy for NAFLD. However, the specific mechanisms underlying this potential connection are largely unknown. Therefore, in this review, we tried to review the relationship among NAFLD, physical exercise, bile acids, and gut microbiota through the existing data and literature, highlighting the role of physical exercise in rebalancing bile acid and microbial dysbiosis. [ABSTRACT FROM AUTHOR]

Supplementing with edible herbal medicine is an important strategy because of its role in nutrition. Many polyphenols, which are universal components in edible herbal medicines, have low bioavailability. Therefore, gut microbiota is a key determinant of polyphenol bioactivity. Polyphenols can alter the abundance of flora associated with neuroinflammation by reversing intestinal microbiota dysbiosis. Intestinal flora-mediated chemical modification of polyphenols can result in their conversion into active secondary metabolites. The current review summarizes the main edible medicines used in anti-depression and details the interactions between polyphenols and gut microbiota; in addition, it provides insights into the mechanisms underlying the possible suppression of neuroinflammation associated with depression, by polyphenols in edible herbal medicine. A better understanding of polyphenols with bioactivities that are crucial in edible herbal medicine may facilitate their use in the prevention and treatment of neuroinflammation associated with depression. As active components universal exist in edible herbal medicine, many polyphenols rely on intestinal microbes for absorption and metabolism. Interaction with gut microbes emerges as a novel target for suppressing depressive symptoms by herbal medicine. The interaction between polyphenols and intestinal flora is reflected in two aspects: ①Polyphenols can alter the abundance of flora associated with neuroinflammation by reversing intestinal microbiota dysbiosis. ②Through chemical modification mediated by intestinal flora, polyphenols can be converted into secondary metabolites with biological functions of inhibiting neuroinflammation in the CNS. [ABSTRACT FROM AUTHOR]

Gastroenteritis is among the leading causes of mortality globally in infants and young children, with rotavirus (RV) causing ~258 million episodes of diarrhea and ~128,000 deaths annually in infants and children. RV-induced mechanisms that result in diarrhea are not completely understood, but malabsorption is a contributing factor. RV alters cellular lipid metabolism by inducing lipid droplet (LD) formation as a platform for replication factories named viroplasms. A link between LD formation and gastroenteritis has not been identified. We found that diacylglycerol O-acyltransferase 1 (DGAT1), the terminal step in triacylglycerol synthesis required for LD biogenesis, is degraded in RV-infected cells by a proteasome-mediated mechanism. RV-infected DGAT1-silenced cells show earlier and increased numbers of LD-associated viroplasms per cell that translate into a fourfold-to-fivefold increase in viral yield (P < 0.05). Interestingly, DGAT1 deficiency in children is associated with diarrhea due to altered trafficking of key ion transporters to the apical brush border of enterocytes. Confocal microscopy and immunoblot analyses of RV-infected cells and DGAT1−/− human intestinal enteroids (HIEs) show a decrease in expression of nutrient transporters, ion transporters, tight junctional proteins, and cytoskeletal proteins. Increased phospho-eIF2α (eukaryotic initiation factor 2 alpha) in DGAT1−/− HIEs, and RV-infected cells, indicates a mechanism for malabsorptive diarrhea, namely inhibition of translation of cellular proteins critical for nutrient digestion and intestinal absorption. Our study elucidates a pathophysiological mechanism of RV-induced DGAT1 deficiency by protein degradation that mediates malabsorptive diarrhea, as well as a role for lipid metabolism, in the pathogenesis of gastroenteritis. [ABSTRACT FROM AUTHOR]

Background. Irritable bowel syndrome (IBS) is a common chronic gut-brain interaction disorder with limited effective treatment options. Intestinal adsorbents have a high adsorption capacity for gut irritants and may provide nonpharmacological alternatives. Objectives. This post marketing study is aimed at providing up-to-date evidence to support the safety and efficacy in normal use of an established medical device for IBS treatment. Methods. In this open-label, observational study, adults with IBS with predominant diarrhoea (IBS-D) or IBS with mixed bowel habits (IBS-M), according to Rome IV criteria, received 4 weeks of treatment with the enteroadsorbent Silicol®gel, a CE-certified, licenced, medical device containing colloidal silicic acid. Eligible participants were assessed at baseline (visit 1; in-clinic) and after 1 (visit 2; telephone), 2 (visit 3; telephone), and 4 (visit 4; in-clinic) weeks of treatment. The primary endpoint was the proportion of participants with an overall reduction in the IBS severity scoring system IBS SSS > 50 , representing clinically meaningful improvement. Key secondary endpoints were a reduction in common IBS symptoms and improved quality of life (QoL). Results. Among the 67 treated participants (IBS-D: 37; IBS-M: 30), 65 completed the study. At visit 4, 83.6% (56/67) of participants achieved a reduction in IBS SSS > 50. The mean (standard deviation [SD]) IBS SSS was 323.4 (55.7) at visit 1 and 160.3 (90.3) at visit 4 (overall change: -163.1 (101.7); 95% confidence interval [CI] 138.3, 187.9, p < 0.001). Compared with visit 1, significant reductions in the severity of all key IBS symptoms and overall improvement in QoL were observed at visit 4 (p < 0.001), with improvements observed from visits 1 and 2. Conclusions. In this open-label study of participants with IBS-D and IBS-M, Silicol®gel provided clinically significant improvement in IBS symptoms, demonstrating that enteroadsorbents may be clinically beneficial in this population. [ABSTRACT FROM AUTHOR]

The compounds were synthesized by refluxing 6-chlorooxindole with 2,3-dichlorobenzaldehyde and 2,6-dichlorobenzaldehyde in the presence of piperidine as a catalyst and characterized by spectroscopic analysis using 1H NMR, 13C NMR, and mass spectrometry as (E)-3-(2,3-dichlorobenzylidene)-6-chloroindolin-2-one (C-1) and (E)-3-(2,6-dichlorobenzylidene)-6-chloroindolin-2-one (C-2). Additionally, in silico ADME studies indicated that C-1 and C-2 with 1,1 rotatable bonds could have moderate water solubility and therefore could have the potential ability to cross the blood-brain barrier. Both showed high GI absorption, indicating that they are suitable for intestinal absorption while the compounds showed CYP1A2, CYP2C19, and CYP2C9 inhibition. The five drug-likeness criteria, which were Lipinski, Muegge, Ghose, Veber, and Egan, and the principles of drug-likeness are not violated by compounds C-1 and C-2. Also, the DFT computations were performed at the B3LYP level and at 6-311++G ∗ ∗ basis set to evaluate and support the obtained results from the experiment. The FMO results revealed that C-1 could likely prefer the intramolecular interactions rather than the intermolecular interactions, and vice versa for C-2. In addition, the NBO results indicated that the resonance interaction, especially the shift of electron to empty orbitals from lone pair electrons of nitrogen, would contribute to the stabilization of both compounds greatly. In DPPH assay, the compounds showed IC50 values of 37.390 and 34.676 μM, respectively. Similarly, in ABTS assay, the calculated IC50 values for the compounds were 25.381 and 33.706 μM, respectively. In short, these results provided a solid ground for further preclinical studies in quest of new effective therapeutic agents. [ABSTRACT FROM AUTHOR]

AbstractBioengineered strategies enable gut chips to faithfully replicate essential features of intestinal microsystems, encompassing geometric properties, peristalsis, intraluminal fluid flow, oxygen gradients, and the microbiome. This emerging technique serves as a powerful tool for nutrition studies by emulating the absorption and distribution processes in a manner highly relevant to human physiology. It offers unprecedented accessibility for investigating the mechanisms governing nutrition metabolism. While the application of gut-on-chip models in disease modeling and drug screening has been extensively explored, their potential in dietary nutrition research remains relatively unexplored. This comprehensive review provides an overview of the different approaches employed in constructing gut-on-chip platforms using diverse cell sources and niche mimics. Furthermore, it explores the applications and prospects of gut-on-chips in nutrition-related investigations, with a specific focus on carotenoid transport, absorption, and metabolism. Lastly, this review discusses the future development trajectory of this groundbreaking technology paradigm, highlighting its broad applicability in the field of food technology. By harnessing the capabilities of these state-of-the-art techniques within gut chip platforms, researchers can establish a robust scientific foundation for unraveling the intricate mechanisms that govern the behavior and functional properties of carotenoids. [ABSTRACT FROM AUTHOR]

Purpose: Croscarmellose sodium, generally used as a superdisintegrant in pharmaceutical formulations, is hydrolyzed to form the gel structure under basic pH conditions. Utilizing this property of croscarmellose sodium, we developed a novel sustained release (SR) system. Methods: Immediate release (IR) and SR tablets containing croscarmellose sodium, alkaline excipients and/or hydroxypropyl methylcellulose (HPMC) were prepared and examined for wet strength and in vitro drug release behavior. In vivo oral drug absorption was evaluated for IR tablets, HPMC tablets and our novel SR tablets in fasted Beagle dogs. Results: To form the gel structure even under the physiological condition, alkaline excipients were added into the formulation containing croscarmellose sodium. Furthermore, HPMC was used to make the gel structure strong enough against mechanical destructive forces. The novel alkalized croscarmellose sodium-HPMC (ACSH) SR tablet, consisting of croscarmellose sodium, alkaline excipients, and HPMC, successfully sustained the release of acetaminophen, ibuprofen, or nicardipine hydrochloride, compared with the IR tablets. The ACSH SR system provided a better release of acetaminophen than the HPMC tablet without croscarmellose sodium in the release study using a small volume of liquid, suggesting that substantial release and subsequent absorption would be expected in the distal intestinal segments after oral dosing. The in vivo oral absorption study revealed that the ACSH SR system successfully suppressed and prolonged the plasma concentrations of acetaminophen. Conclusion: This novel ACSH SR system prepared with croscarmellose sodium, alkaline excipients, and HPMC, would be a promising SR formulation for enabling substantial drug absorption in the distal intestinal segments. [ABSTRACT FROM AUTHOR]

Many evaluation tools for predicting human absorption are well-known for using cultured cell lines such as Caco-2, MDCK, and so on. Since the combinatorial chemistry and high throughput screening system, pharmacological assay, and pharmaceutical profiling assay are mainstays of drug development, PAMPA has been used to evaluate human drug absorption. In addition, cultured cell lines from iPS cells have been attracting attention because they morphologically resemble human intestinal tissues. In this review, we used human intestinal tissues to estimate human intestinal absorption and metabolism. The Ussing chamber uses human intestinal tissues to directly assay a drug candidate's permeability and determine the electrophysiological parameters such as potential differences (PD), short circuit current (Isc), and resistance (R). Thus, it is an attractive tool for elucidating human intestinal permeability and metabolism. We have presented a novel prediction method for intestinal absorption and metabolism by utilizing a mini-Ussing chamber using human intestinal tissues and animal intestinal tissues, based on the transport index (TI). The TI value was calculated by taking the change in drug concentrations on the apical side due to precipitation and the total amounts accumulated in the tissue (Tcorr) and transported to the basal side (Xcorr). The drug absorbability in rank order, as well as the fraction of dose absorbed (Fa) in humans, was predicted, and the intestinal metabolism of dogs and rats was also predicted, although it was not quantitative. However, the metabolites formation index (MFI) values, which are included in the TI values, can predict the evaluation of intestinal metabolism and absorption by using ketoconazole. Therefore, the mini-Ussing chamber, equipped with human and animal intestinal tissues, would be an ultimate method to predict intestinal absorption and metabolism simultaneously. [ABSTRACT FROM AUTHOR]

Because of the increasing sophistication of formulation technology and the increasing polymerization of compounds directed toward undruggable drug targets, the influence of the mucus layer on gastrointestinal drug absorption has received renewed attention. Therefore, understanding the complex structure of the mucus layer containing highly glycosylated glycoprotein mucins, lipids bound to the mucins, and water held by glycans interacting with each other is critical. Recent advances in cell culture and engineering techniques have led to the development of evaluation systems that closely mimic the ecological environment and have been applied to the evaluation of gastrointestinal drug absorption while considering the mucus layer. This review provides a better understanding of the mucus layer components and the gastrointestinal tract's biological defense barrier, selects an assessment system for drug absorption in the mucus layer based on evaluation objectives, and discusses the overview and features of each assessment system. [ABSTRACT FROM AUTHOR]

Maintaining proper blood flow is critical to promoting good health. Nattokinase is a serine protease from Bacillus subtilis that has significant in vitro thrombolytic activity, but its mechanism as a dietary supplement to prevent thrombosis through intestinal absorption and transport is still unclear. The purpose of this study is to study the transport and internalisation mechanism of NK in the small intestine using animal models and Caco-2 cell monolayer models. This study first evaluated the preventive effect of supplementing low dose (4000 FU (Fibrin Unit)/kg, n = 6), medium dose (8000 FU/kg, n = 6), and high dose (12000 FU/kg, n = 6) of nattokinase on carrageenan induced thrombosis in mice. Subsequently, we used the rat gut sac model, ligated intestinal loop model, and Caco-2 cell uptake model to study the intestinal transport mechanism of NK. Results indicate that NK is a moderately absorbed biomolecule whose transport through enterocytes is energy- and time-dependent. Chlorpromazine, nystatin and EIPA all inhibited the endocytosis of NK to varying degrees, indicating that the endocytosis of NK in Caco-2 cells involves macropinocytosis, clathrin-mediated and caveolae-mediated pathway. These findings offer a theoretical basis for investigating the mechanism of oral NK supplementation in greater depth. [ABSTRACT FROM AUTHOR]