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Background: Iron overload is a principal reason for morbidity and death in transfusion-dependent beta-thalassemia cases. Erythroferrone hormone (ERFE), a member of tumor necrosis family-alpha (TNF-α) superfamily produced by erythroblasts and stimulated by endogenous or exogenous erythropoietin (EPO), Under these conditions, ERFE inhibits the formation of hepcidin, restoring the functionality of ferro-portin, that is accountable for enhancing intestinal iron absorption and mobilizing iron reserves. Objective: The aim of the currents study is to analyze the role of ERFE in children suffering from beta thalassemia major. Patients and methods: A prospective case-control study was conducted at Tanta University Hospital during the period from March 2021 to November 2021. The study included 40 children previously diagnosed with beta thalassemia major, and 40 healthy children matched in sex and age as a control group. Serum ERFE was calculated utilizing enzyme linked immunosorbent assay (ELISA) technique. Results: Serum ERFE level was significant increase in the beta thalassemia patients' group than control group. In the patients group, serum ERFE was higher in non spleenectomized patients, and in patients receiving blood transfusion more than once/month, also, ERFE was higher in those with serum ferritin >1000 ng/ml. There is significant positive correlation between ERFE level and serum levels of ferritin and transferrin saturation (T.SAT %). Receiver Operating Characteristic (ROC) curve analysis demonstrated that ERFE level above 1.6 ng/ml is the cutoff value indicating iron overload with high diagnostic efficacy. Conclusion: ERFE is a possible diagnostic tool in predicting iron overload with sensitivity 95%, specificity 62 %, and accuracy 78%. [ABSTRACT FROM AUTHOR]

The bioavailability of peptides co-delivered with permeation enhancers following oral administration remains low and highly variable. Two factors that may contribute to this are the dilution of the permeation enhancer in the intestinal fluid, as well as spreading of the released permeation enhancer and peptide in the lumen by intestinal motility. In this work we evaluated an Intestinal Administration Device (IAD) designed to reduce the luminal dilution of drug and permeation enhancer, and to minimize movement of the dosage form in the intestinal lumen. To achieve this, the IAD utilizes an expanding design that holds immediate release mini tablets and places these in contact with the intestinal epithelium, where unidirectional drug release can occur. The expanding conformation limits movement of the IAD in the intestinal tract, thereby enabling drug release at a single focal point in the intestine. A pig model was selected to study the ability of the IAD to promote intestinal absorption of the peptide MEDI7219 formulated together with the permeation enhancer sodium caprate. We compared the IAD to intestinally administered enteric coated capsules and an intestinally administered solution. The IAD restricted movement of the immediate release tablets in the small intestine and histological evaluation of the mucosa indicated that high concentrations of sodium caprate were achieved. Despite significant effect of the permeation enhancer on the integrity of the intestinal epithelium, the bioavailability of MEDI7219 was of the same order of magnitude as that achieved with the solution and enteric coated capsule formulations (2.5–3.8%). The variability in plasma concentrations of MEDI7219 were however lower when delivered using the IAD as compared to the solution and enteric coated capsule formulations. This suggests that dosage forms that can limit intestinal dilution and control the position of drug release can be a way to reduce the absorptive variability of peptides delivered with permeation enhancers but do not offer significant benefits in terms of increasing bioavailability. [Display omitted] [ABSTRACT FROM AUTHOR]

Compared to subcutaneous injections, oral administration of insulin would be a preferred route of drug administration for diabetic patients. For oral delivery, both liposomes and alginate hydrogels face many challenges, including early burst release of the encapsulated drug and poor intestinal drug absorption. Also, adhesion to the intestinal mucosa remains weak, which all result in a low bioavailability of the payload. This study reports on an alginate hydrogel loaded with liposomes for oral insulin administration. Liposomes (Lip) loaded with arginine-insulin complexes (AINS) were incorporated into a hydrogel prepared from cysteine modified alginate (Cys-Alg) to form liposome-in-alginate hydrogels (AINS-Lip-Gel). An ex vivo study proves that intestinal permeation of AINS and AINS-Lip is approximately 2.0 and 6.0-fold, respectively, higher than that of free insulin. The hydrogel retarded early release of insulin (∼30%) from the liposomes and enhanced the intestinal mucosal retention. In vivo experiments revealed that the AINS-Lip-Gel released insulin in a controlled manner and possessed strong hypoglycemic effects. We conclude that liposome-in-alginate hydrogels loaded with AINS represent an attractive strategy for the oral delivery of insulin. [Display omitted] • A novel liposome-in-hydrogel complex system was developed for oral delivery of insulin. • The modification of cysteine promotes mucosal retention of alginate. • Complex system only releases ∼10% insulin at pH 1.2. • Arginine modification and liposome encapsulation promotes intestinal absorption of insulin. [ABSTRACT FROM AUTHOR]

Hyperuricemia and gout are metabolic diseases characterized with high serum urate and impact human health significantly. Although some drugs have been developed to treat gout, hyperuricemia represents a substantial health problem. Reducing purine absorption through intestinal microbiota, which can be managed through intake of probiotics, emerges as a promising way to reverse elevated serum urate. Probiotics have shown several benefits such as immune modulation and improvement of intestinal functions. Therefore, this review briefly summarizes purine metabolism and molecular mechanisms for hyperuricemia and gout with the focus on recent development on the use of probiotics to alleviate hyperuricemia and gout. [ABSTRACT FROM AUTHOR]

Background: The increasing morbidity and mortality of cardiovascular disease have become a major factor in human death. Serum cholesterol is considered to be an important risk factor for inducing coronary heart disease, atherosclerosis and other cardiovascular diseases. To screen intestinal absorbable functional small peptides with cholesterol-lowering activity by enzymatic hydrolysis of whey protein and develop cholesterol- based functional food that may become a substitute for chemically synthesized drugs, providing new ideas for diseases caused by high cholesterol. Objective: This study aimed to evaluate the cholesterol-lowering activity of intestinal absorbable whey protein- derived peptides hydrolyzed by alkaline protease, trypsin and chymotrypsin, respectively. Method: The whey protein hydrolysates acquired by enzymatic hydrolysis under optimal conditions were puri- fied by a hollow fiber ultrafiltration membrane with a molecular weight cutoff of 10 kDa. The fractions obtained by Sephadex G-10 gel filtration chromatography were transported through a Caco-2 cell monolayer. The transported peptides were detected in the basolateral aspect of Caco-2 cell monolayers using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS). Results: His-Thr-Ser-Gly-Tyr (HTSGY), Ala-Val-Phe-Lys (AVFK) and Ala-Leu-Pro-Met (ALPM) were unreported peptides with cholesterol-lowering activity. The cholesterol-lowering activities of the three peptides did not change significantly during simulated gastrointestinal digestion. Conclusion: This study not only provides theoretical support for the development of bioactive peptides that can be directly absorbed by the human body, but also provides new treatment ideas for hypercholesterolemia. [ABSTRACT FROM AUTHOR]

Understanding the intestinal transport of particles is critical in several fields ranging from optimizing drug delivery systems to capturing health risks from the increased presence of nano‐ and micro‐sized particles in human environment. While Caco‐2 cell monolayers grown on permeable supports are the traditional in vitro model used to probe intestinal absorption of dissolved molecules, they fail to recapitulate the transcytotic activity of polarized enterocytes. Here, an intestine‐on‐chip model is combined with in silico modeling to demonstrate that the rate of particle transcytosis is ≈350× higher across Caco‐2 cell monolayers exposed to fluid shear stress compared to Caco‐2 cells in standard "static" configuration. This relates to profound phenotypical alterations and highly polarized state of cells grown under mechanical stimulation and it is shown that transcytosis in the microphysiological model is energy‐dependent and involves both clathrin and macropinocytosis mediated endocytic pathways. Finally, it is demonstrated that the increased rate of transcytosis through cells exposed to flow is explained by a higher rate of internal particle transport (i.e., vesicular cellular trafficking and basolateral exocytosis), rather than a change in apical uptake (i.e., binding and endocytosis). Taken together, the findings have important implications for addressing research questions concerning intestinal transport of engineered and environmental particles. [ABSTRACT FROM AUTHOR]

Synthetic antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and tert-butylhydroquinone (TBHQ), have been widely used for many years to stabilise lipids in foods. Nonetheless, their effect on the bioavailability and metabolism of lipids stabilised with them still remains unknown. To investigate this issue, in vitro digestion of a model high-fat product (20 g fat/100 g) without antioxidants and supplemented with BHT, BHA and TBHQ (100 mg/kg) was conducted, followed by studies using the Caco-2 and Hep G2 cell lines. BHT, BHA and TBHQ increased intestinal absorption of triacylglycerols and modified the structure of chylomicrons (CM). The addition of BHT and TBHQ inhibited apolipoprotein-IV (apoA-IV) synthesis. At the same time, smaller chylomicrons were secreted, but their amount was greater than in the model product without antioxidants. In contrast, BHA activated apoA-IV synthesis, resulting in the formation of fewer but very large CMs. Of concern was the significant decrease in apoA-IV in cells upon the use of BHT and TBHQ, which can lead to obesity due to the lack of the sensation of feeling full after eating high-fat foods stabilised with these antioxidants. Furthermore, the efficiency of CM remnant (CMR) uptake by hepatocytes was inversely correlated with their size. The large CMRs generated for samples with BHA were not absorbed by hepatocytes, which can lead to atherosclerosis. The results of our in vitro study shed new light on the role of synthetic phenolic antioxidants used in food technology as potential obesity and atherosclerosis triggers and suggested the need for further research that will clearly separate antioxidants that promote the development of these diseases from those, which do not do that. [ABSTRACT FROM AUTHOR]

Irritable Bowel Syndrome (IBS) is a common disease characterized by alternate symptoms (diarrhea and constipation) and intestinal gas overproduction. A new medical device (Fibergone®), containing Partially Hydrolyzed Guar Gum (PHGG) and Simethicone (SM) has been proposed for managing patients with bowel disorders. PHGG acts also as a prebiotic so increasing the Short-Chain Fatty Acid (SCFA) production, useful for intestinal physiology. This in vitro study investigated the effects exerted by PHGG+SM on SCFA production and their intestinal absorption following in vitro digestive process and fermentation model. An in vitro model evaluated the digestive process and fermentation using simulated digestive fluids and a human intestinal epithelium in vitro model derived from based on intestinal adenocarcinoma Caco-2 cells (ATCC, HTB-37TM) and organized as a functional monolayer on Transwell® inserts. PHGG+SM was added in experiments and compared with a control (non-treated). SCFA production and absorption were assessed. Viability and barrier integrity of the intestinal epithelium model were also evaluated. PHGG+SM significantly (p<0.05) increased SCFAs content after fermentation, indicating that this medical device is effectively fermented at the large intestine level. However, in relation to SCFAs bioavailability, their absorption did not increase compared to the non-treated condition in the light of the physiological contribution of SCFAs resulting from the microflora. PHGG+SM did not affect intestinal epithelium apparent permeability (Papp) and viability. This in vitro study documented that partially hydrolyzed guar gum combined with simethicone significantly affects short-chain fatty acids production and consequently could be fruitfully employed in managing patients with intestinal disorders. [ABSTRACT FROM AUTHOR]

• Marine algae are prolific source of bioactive secondary metabolites and are found to be active against therapeutic agents. • In vitro and insilico antioxidant and anticancer was evaluated by DPPH, TPC and TFC assay, ADMET and Molecular docking. • Excellent antioxidant and anticancer displayed by majority of the extracts. • Enzyme and antioxidant were impressively inhibited by the Chaetomorpha linum ethanol extract Molecular modeling indicated the interaction of chemical constituents with studied enzymes. Seaweeds are rich in bioactive metabolites that could be used to develop new natural compounds in the pharmaceutical and cosmetic industries. The secondary metabolites, antioxidants, ADMET, Molecular docking and anticancer agents are investigated in the present study. The current research shows that seaweed, Chaetomorpha linum is vital source of natural antioxidants, which confirmed by free radical scavenging activity, DPPH, total phenolic and flavonoid content. The enzyme maximum inhibition of Glutathione respectively. It is noteworthy that glucoside action is dominant over the amylase enzyme. The anti-cancer activity of ethanol extracts showed the IC 50 values 72.8 μg/mL−1 for MCF-7, respectively. The identified phytocompound absorption, distribution, metabolism and excretion assessed by SWISS ADME/T, it provides information about Human intestinal absorption and blood–brain barrier permeability. In addition, phytocompounds interaction with protein was confirmed by molecular docking. The protein 3ERT interaction of compounds 3 (-7.97 kcal/mol), compound 4 (-8.36 kcal/mol) and compound 2 (2,4-Di-tert-butylphenol -6.96 kcal/mol) provides high binding energy in comparison to other proteins. Hence, the present studies indicate that antioxidant, anti- diabetic and anticancer activity of ethanol extract as an alternative to the existing therapeutic approach to diabetic and cancer through a systematic in vitro and in silico approaches supplementing the findings. [ABSTRACT FROM AUTHOR]

Purpose Direct-acting antivirals (DAAs) allow for successful transplantation of livers from hepatitis C nucleic acid test (NAT)–positive donors to negative recipients. However, limited data exist to support crushing DAAs in patients with multiple absorption concerns or significant drug interactions. Summary Crushed sofosbuvir/velpatasvir has been successfully used in nontransplant patients with dysphagia, but data in transplant patients with absorption concerns are limited. A 31-year-old hepatitis C–negative female underwent liver transplantation from a hepatitis C NAT–positive donor. Her postoperative course was complicated by a mucormycosis infection, gastrointestinal bleed, and necrotizing pancreatitis requiring treatment with liposomal amphotericin B and pantoprazole 80 mg twice daily. Surgical interventions included an above-the-knee amputation and ileostomy. Hepatitis C treatment was initially delayed because of concern for reduced absorption with crushed DAA administration through the nasogastric (NG) tube, high ileostomy output, gastrointestinal bleed, pancreatitis, and a known drug interaction with pantoprazole. One month after transplantation, the patient's bilirubin level remained elevated and hepatitis C treatment was initiated with sofosbuvir/velpatasvir. Crushed sofosbuvir/velpatasvir was mixed with 30 mL of water and administered through the NG tube daily. Hepatitis C viral loads were obtained weekly during treatment to monitor efficacy. Although the patient died before evaluation of sustained virological response at 12 weeks, hepatitis C viral clearance was observed within 4 weeks of initiating treatment. Conclusion A liver transplant patient exhibited viral clearance of hepatitis C following administration of crushed sofosbuvir/velpatasvir in the setting of multiple absorption concerns. [ABSTRACT FROM AUTHOR]

The specific activities of gastric and pancreatic lipases were measured using triacylglycerols (TAG) from rapeseed oil, purified 1,3-sn-DAG and 1,2(2,3)-sn-DAG produced from this oil, as well as a rapeseed oil enriched with 40% w/w DAG (DAGOIL). Gastric lipase was more active on 1,3- sn -DAG than on 1,2(2,3)- sn -DAG and TAG, whereas pancreatic lipase displayed a reverse selectivity with a higher activity on TAG than on DAG taken as initial substrates. However, in both cases, the highest activities were displayed on DAGOIL. These findings show that DAG mixed with TAG, such as in the course of digestion, is a better substrate for lipases than TAG. The same rapeseed oil acylglycerols were used to investigate intestinal fat absorption in rats with mesenteric lymph duct cannulation. The levels of TAG synthesized in the intestine and total fatty acid concentration in lymph were not different when the rats were fed identical amounts of rapeseed oil TAG, 1,2(2,3)- sn -DAG, 1,3- sn -DAG or DAGOIL. Since the lipolysis of 1,3- sn -DAG by digestive lipases leads to glycerol and not 2-sn-monoacylglycerol (2- sn -MAG) like TAG lipolysis, these results suggest that the re-synthesis of TAG in the enterocytes can entirely occur through the "glycerol-3-phosphate (G3P)" pathway, with the same efficiency as the 2- sn -MAG pathway predominantly involved in the intestinal fat absorption. These findings shed new light on the role played by DAG as intermediate lipolysis products. Depending on their structure, 1,2(2,3)- sn -DAG versus 1,3- sn -DAG, DAG may control the pathway (2- sn -MAG or G3P) by which TAG are re-synthesized in the enterocytes. [Display omitted] • Gastric lipase shows a higher activity on 1,3-sn-DAG than on 1,2(2,3)-sn-DAG and TAG. • Lipolysis of 1,3-sn-DAG leads to glycerol and not 2-sn-MAG. • Feeding rats with identical amounts of TAG, 1,2(2,3)-sn-DAG or 1,3-sn-DAG does not change intestinal absorption. • TAG synthesis in enterocytes can occur entirely through the glycerol-3-phosphate pathway. • This pathway can be as efficient as the 2-sn-MAG pathway. [ABSTRACT FROM AUTHOR]

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

Diabetes mellitus (DM) characterized by high blood sugar concentration is a major global public health problem and untreated DM results in blindness, kidney failure, heart attack, stroke, and lower extremity amputation. In this structure-based drug design (SBDD) study, the potential inhibitory effects of twelve anthocyanidins (aglycon unit of anthocyanins) components on human pancreatic α-amylase and intestinal α-glucosidase enzymes were investigated using the molecular docking method and a novel approach developed by our research group was used to rank the global binding potentials of ligands to a series of different enzymes simultaneously. In addition, drug-likeness, absorption-distribution-metabolism-excretion-toxicity (ADMET) predictions, and intracellular target-component interaction network analyses of twelve anthocyanidin components were performed using the search tool for interactions of chemicals (STITCH). Petunidin, peonidin, and aurantinidin were determined as 'hit' phytochemicals according to the docking binding energy and relative binding capacity index (RBCI) analyses, whereas, based on the RBCI index, petunidin was found to be the most effective ligand in terms of binding capacity to both enzymes that play an important role in DM. The more accessible and large-volume active site of α-amylase compared to α-glucosidase caused petunidin to bind with higher affinity against α-amylase. Promisingly, petunidin did not violate any of the criteria for drug-likeness consisting of a combination of the Lipinski's rule of 5, Ghose and Veber filters, showed no cytochrome (CYP) P450 or hERG I-II inhibitory activity in the ADMET analysis, however, it was found to have a low gastrointestinal absorption profile. In intracellular target-component network analysis using the STITCH online platform, it was determined that petunidin did not show negative functional interactions with any enzyme in the human protein network. Considering these results, it is recommended that petunidin be advanced to further in vitro and in vivo assays as a potential α-amylase and α-glucosidase inhibitory agent in the treatment of DM. However, the intestinal absorption profile of petunidin must be enhanced by molecular optimization without compromising its pharmacological activity. [ABSTRACT FROM AUTHOR]

Lisinopril is an antihypertensive drug with poor intestinal permeability. Enhancement of intestinal absorption depends on a clear understanding of the permeation pathways and absorption mechanisms. Unfortunately, these are not fully elucidated for lisinopril. Accordingly, the aim was to determine lisinopril permeation pathways and obstacles limiting membrane transport with subsequent nomination of appropriate permeation enhancers. This employed an in situ rabbit intestinal perfusion technique, which revealed site‐dependent absorptive clearance (PeA/L) from a lisinopril simple solution (5 μg/ml), with paracellular absorption playing a role. Regional drug permeability ranked as colon> duodenum> jejunum> ileum opposing intestinal expression rank of P‐glycoprotein (P‐gp) efflux transporters. Duodenal and jejunal perfusion of a higher lisinopril concentration (50 μg/ml) reflected saturable absorption, suggesting carrier‐mediated transport. The effect of piperine and verapamil as P‐gp inhibitors on intestinal absorption of lisinopril was investigated. Coperfusion with either piperine or verapamil significantly enhanced lisinopril absorption, with enhancement being dominant in the ileum segment. This supported the contribution of P‐gp transporters to poor lisinopril permeability. On the other hand, coperfusion of lisinopril with zinc acetate dihydrate significantly multiplied lisinopril PeA/L by 2.3‐ and 6.6‐fold in duodenum and ileum segments, respectively, through magnifying intestinal water flux. The study explored the barriers limiting lisinopril intestinal absorption. Moreover, the study exposed clinically relevant lisinopril interactions with common coadministered cargos that should be considered for an appropriate lisinopril regimen. However, this requires further in vivo verification. [ABSTRACT FROM AUTHOR]

Pumpkin is considered a functional food with beneficial effects on human health due to the presence of interesting bioactives. In this research, the impact of unconventional ultrasound-assisted extraction (UAE) and microwave-assisted extraction techniques on the recovery of total non-polar carotenoids from Cucurbita moschata pulp was investigated. A binary (hexane:isopropanol, 60:40 v/v) and a ternary (hexane:acetone:ethanol, 50:25:25 v/v/v) mixture were tested. The extracts were characterized for their antioxidant properties by in vitro assays, while the carotenoid profiling was determined by high-performance liquid chromatography coupled with a diode array detector. UAE with the binary mixture (30 min, 45 °C) was the most successful extracting technique, taking into consideration all analytical data and their correlations. In parallel, solid lipid nanoparticles (SLN) were optimized for the encapsulation of the extract, using β-carotene as a reference compound. SLN, loaded with up to 1% β-carotene, had dimensions (~350 nm) compatible with increased intestinal absorption. Additionally, the ABTS ((2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) assay showed that the technological process did not change the antioxidant capacity of β-carotene. These SLN will be used to load an even higher percentage of the extract without affecting their dimensions due to its liquid nature and higher miscibility with the lipid with respect to the solid β-carotene. [ABSTRACT FROM AUTHOR]

Cancer is one of the death causes in the world. Many plants act as anticancer, one of them is Curcuma longa. The purpose of this study was to analyze the molecular mechanism of compounds in Curcuma longa as an anticancer using in silico. These research methods included exploration of the active compounds of Curcuma longa plants, prediction of their activity, human intestinal absorption test, test of Lipinski's rule of five, molecular docking, and interactions of receptor with compounds as well as signaling pathways. The results showed that Curcuma longa had 20 compounds that have the potential as an anticancer. As many as 5 of the 20 active compounds, namely α-curcumene, curcumenol, curcumin, curcumin II, and curcumin III had a value of Pa > 0.3 and HIA above 80%. The results of molecular docking of α-curcumene, curcumenol, curcumin, curcumin II, and curcumin III compounds with protein receptors of VEGFR-2, EGFR, and FGFR-1 showed ΔGbind values of -5.0 to -7.5 kcal/mol. The compound in Curcuma longa that had the most effective activity as an anticancer was curcumin with a ΔGbind value of -7.5 kcal/mol at the FGFR-1 receptor. Curcumin molecular mechanism as antiproliferative was revealed computationally through inhibition of the PI3K/AKT/mTOR pathway. [ABSTRACT FROM AUTHOR]

In this current study, the antidiabetic effectiveness of Hibiscus sabdariffa and its protective function against Fe2+‐induced oxidative hepatic injury were elucidated using in vitro, in silico, and ex vivo studies. The oxidative damage was induced in hepatic tissue by incubation with 0.1 mMolar ferrous sulfate (FeSO4) and then treated with different concentrations of crude extracts (ethyl acetate, ethanol, and aqueous) of H. sabdariffa flowers for 30 min at 37°C. When compared to ethyl acetate and aqueous extracts, the ethanolic extract displayed the most potent scavenging activity in ferric‐reducing antioxidant power (FRAP), 1,1‐diphenyl‐2‐picrylhydrazyl (DPPH), and nitric oxide (NO) assays, with IC50 values of 2.8 μl/ml, 3.3 μl/ml, and 9.2 μl/ml, respectively. The extracts significantly suppressed α‐glucosidase and α‐amylase activities (p <.05), with the ethanolic extract demonstrating the highest activity. H. sabdariffa significantly (p <.05) raised reduced glutathione (GSH) levels while simultaneously decreasing malondihaldehyde (MDA) and NO levels and increasing superoxide dismutase (SOD) and catalase activity in Fe2+ induced oxidative hepatic injury. The extract of the plant inhibited intestinal glucose absorption and increased muscular glucose uptake. The extract revealed the presence of several phenolic compounds when submitted to gas chromatography–mass Spectroscopy (GC–MS) screening, which was docked with α‐glucosidase and α‐ amylase. The molecular docking displayed the compound 4‐(3,5‐Di‐tert‐butyl‐4‐hydroxyphenyl)butyl acrylate strongly interacted with α‐glucosidase and α‐amylase and had the lowest free binding energy compared to other compounds and acarbose. These results suggest that H. sabdariffa has promising antioxidant and antidiabetic activity. Practical applications: In recent years, there has been increased concern about the side effects of synthetic anti‐diabetic drugs, as well as their expensive cost, especially in impoverished nations. This has instigated a radical shift towards the use of traditional plants, which are rich in phytochemicals many years ago. Among these plants, H. sabdariffa has been used to treat diabetes in traditional medicine. In this present study, H. sabdariffa extracts demonstrated the ability to inhibit carbohydrate digesting enzymes, facilitate muscle glucose uptake and attenuate oxidative stress in oxidative hepatic injury. Hence, demonstrating H. sabdariffa's potential to protect against oxidative damage and the complications associated with diabetes. Consumption of Hibiscus tea or juice may be a potential source for developing an anti‐diabetic drug. [ABSTRACT FROM AUTHOR]

Isoliquiritigenin (ILQ) is a natural flavonoid with various pharmacological activities. In this study, we optimized the preparation method of self-nano-emulsion-loaded ILQ to further improve its bioavailability based on our previous study. In addition, its effect on the treatment of eosinophilic esophagitis was also evaluated. Combined surfactants and co-surfactants were screened, and the optimal formulation of ILQ-SNEDDS was determined according to droplet size, droplet dispersity index (DDI), and drug loading. The formulation was composed of ethyl oleate (oil phase), Tween 80 & Cremophor EL (surfactant, 7:3), and PEG 400 & 1,2-propylene glycol (cosurfactant, 1:1), with a mass ratio of 3:6:1. Its physicochemical properties, including drug loading, droplets' size, Zeta potential, appearance, and Fourier transform infrared (FTIR) spectroscopy, were characterized. In vitro release profile, in situ intestinal absorption, and in vivo pharmacokinetics were applied to confirm the improvement of oral ILQ bioavailability by NEDDS. Finally, the efficacy of ILQ-SNEDDS in the treatment of food allergy-induced eosinophilic esophagitis (EOE) was further evaluated. When the ILQ drug loading was 77.9 mg/g, ILQ-SNEDDS could self-assemble into sub-spherical uniform droplets with an average size of about 33.4 ± 2.46 nm (PDI about 0.10 ± 0.05) and a Zeta potential of approximately −10.05 ± 3.23 mV. In situ intestinal absorption showed that optimized SNEDDS significantly increased the apparent permeability coefficient of ILQ by 1.69 times, and the pharmacokinetic parameters also confirmed that SNEDDS sharply increased the max plasma concentration and bioavailability of ILQ by 3.47 and 2.02 times, respectively. ILQ-SNEDDS also significantly improved the apparent signs, allergic index, hypothermia and body weight of EoE model mice. ILQ-SNEDDS treatment significantly reduced the levels of inflammatory cytokines, such as TNF-α, IL-4, and IL-5, and the level of PPE-s-IgE in serum, and significantly inhibited the expression of TGF-β1 in esophageal tissue. SNEDDS significantly improved the solubility and bioavailability of ILQ. Additionally, ILQ-SNEDDS treatment attenuated symptomatology of EoE model mice, which was associated with inhibiting the production of TH2 inflammatory cytokines and PPE-s-IgE and the expression of TGF-β1. The above results shows that ILQ-SNEDDS has great potential as a good candidate for the treatment of eosinophilic esophagitis. [ABSTRACT FROM AUTHOR]

Epidermal growth factor (EGF) plays an important role in nutrients transport. The present study was to investigate the effects of EGF on glucose absorption in a cellular injury model (IPEC-J2 cells, in vitro study) and animal injury model (weaned piglets, in vivo study) established by lipopolysaccharide (LPS). In vitro study: porcine intestinal epithelial cells (IPEC-J2) were divided into four treatments: control group (Control); 100 ng/mL EGF treatment group (EGF); 1 μg/mL LPS treatment group (LPS) and 100 ng/mL EGF plus 1 μg/mL LPS treatment group (EGF + LPS). The results showed that EGF significantly increased the alkaline phosphatase (AKP) and sodium/potassium-transporting adenosine triphosphatase (Na+/K+-ATPase) activity, and significantly improved the mRNA and protein expression of SGLT1, GLUT2, EGF receptor (EGFR) and AMP-activated protein kinase α1 (AMPK-α1) in LPS-induced injured cells. In vivo experiment: twenty-four piglets weaned at 21 days were randomly assigned into: (1) control group (basal diets); (2) EGF group (basal diet +2 mg/kg EGF); (3) LPS group (basal diet + injection with 100 μg/kg BW LPS) and (4) EGF + LPS group (basal diet + 2 mg/kg EGF + injection with 100 μg/kg BW LPS). Our results showed that EGF significantly increased the AKP and Na+/K+-ATPase activity, and significantly improved the mRNA expression of SGLT1, GLUT2, EGFR and AMPK-α1 in jejunum mucosa of piglets challenged with LPS. In conclusion, EGF can activate EGFR/AMPK signalling to up-regulate the expression of SGLT1 and GLUT2 as well as improve the AKP and Na+/K+-ATPase activity, thereby promoting intestinal glucose absorption in IPEC-J2 cells and piglets challenged by LPS. EGF promotes SGLT1 and GLUT2 expression and AKP and Na+/K+-ATPase activity in LPS-induced injured porcine intestinal epithelial cells. EGF promotes SGLT1 and GLUT2 expression and AKP and Na+/K+-ATPase activity in jejunum mucosa of piglets challenged by LPS. Dietary supplementation with EGF activates EGFR/AMPK signalling to up-regulate the expression of SGLT1 and GLUT2 as well as improve the AKP and Na+/K+-ATPase activity to promote intestinal glucose absorption in lipopolysaccharide challenged piglets. [ABSTRACT FROM AUTHOR]

Purpose: In order to clarify the effect of rifampicin on the bioavailability of the P-glycoprotein substrate talinolol, its absorption kinetics was modeled after multiple-dose oral administration of talinolol in healthy subjects. Methods: A sum of two inverse Gaussian functions was used to calculate the time course of the input rate into the systemic circulation. Results: The estimated rate of drug entry into the systemic circulation revealed two distinct peaks at 1 and 3.5 h after administration. Rifampicin did not affect bioavailability of talinolol, but did shift the second peak of the input function by 1.3 h to later times. Elimination clearance and one of the intercompartmental distribution clearances increased significantly under rifampicin treatment. Conclusions: Rifampicin changes the time course of absorption rate but not the fraction absorbed of talinolol. The model suggests the existence of two intestinal absorption windows for talinolol. [ABSTRACT FROM AUTHOR]

Transmissible gastroenteritis virus (TGEV) is member of the family Coronaviridae and mainly causes acute diarrhea. TGEV infection is characterized by vomiting, watery diarrhea, and severe dehydration, resulting in high mortality rates in neonatal piglets. TGEV infection symptoms are related to an imbalance of sodium absorption in small intestinal epithelial cells; however, the etiology of sodium imbalance diarrhea caused by TGEV remains unclear. In this study, we performed transcriptomic analysis of intestinal tissues from infected and healthy piglets and observed that the expression of NHE3, encoding Na+/H+ exchanger 3 (NHE3), the main exchanger of electroneutral sodium in intestinal epithelial cells, was significantly reduced upon TGEV infection. We also showed that specific inhibition of intestinal NHE3 activity could lead to the development of diarrhea in piglets. Furthermore, we revealed an interaction between TGEV N protein and NHE3 near the nucleus. The binding of TGEV N to NHE3 directly affected the expression and activity of NHE3 on the cell surface and affected cellular electrolyte absorption, leading to diarrhea. Molecular docking and computer-aided screening techniques were used to screen for the blocker of the interaction between TGEV N and NHE3, which identified irinotecan. We then demonstrated that irinotecan was effective in relieving TGEV-induced diarrhea in piglets. These findings provide new insights into the mechanism of TGEV-induced sodium imbalance diarrhea and could lead to the design of novel antiviral strategies against TGEV. [ABSTRACT FROM AUTHOR]

Pentacyclic triterpenes, including betulin, are widespread natural products with various pharmacological effects. These compounds are the starting material for the synthesis of substances with promising anticancer activity. The chemical modification of the betulin scaffold that was carried out as part of the research consisted of introducing the indole moiety at the C-28 position. The synthesized new 28-indole-betulin derivatives were evaluated for anticancer activity against seven human cancer lines (A549, MDA-MB-231, MCF-7, DLD-1, HT-29, A375, and C32). It was observed that MCF-7 breast cancer cells were most sensitive to the action of the 28-indole-betulin derivatives. The study shows that the lup-20(29)-ene-3-ol-28-yl 2-(1H-indol-3-yl)acetate caused the MCF-7 cells to arrest in the G1 phase, preventing the cells from entering the S phase. The performed cytometric analysis of DNA fragmentation indicates that the mechanism of EB355A action on the MCF-7 cell line is related to the induction of apoptosis. An in silico ADMET profile analysis of EB355A and EB365 showed that both compounds are bioactive molecules characterized by good intestinal absorption. In addition, the in silico studies indicate that the 28-indole-betulin derivatives are substances of relatively low toxicity. [ABSTRACT FROM AUTHOR]

As a functional probiotic, Bacillus subtilis (B. subtilis) can survive and colonize in large quantities under the special environmental conditions of the intestinal tract. The bacteria itself can also secrete nutritional factors, promote the digestion and absorption of intestinal nutrients, improve the production performance of the body, and play an important role in intestinal health. The paper mainly summarizes the research progress of B. subtilis in regulating the intestinal health of broilers in recent years, discusses the biological characteristics and physiological functions of B. subtilis, analyzes its existing problems and future development directions, in order to provide reference for the prevention and control of broiler intestinal health. [ABSTRACT FROM AUTHOR]

Increasing interest is being addressed to the development of a reliable, reproducible and relevant in vitro model of intestinal barrier, mainly for engineered nanomaterials hazard and risk assessment, in order to meet regulatory and scientific demands. Starting from the consolidated Caco-2 cell model, widely used for determining translocation of drugs and chemicals, the establishment of an advanced intestinal barrier model with different level of complexity is important for overcoming Caco-2 monoculture limitations. For this purpose, a tri-culture model, consisting of two human intestinal epithelial cells (Caco-2 and HT29-MTX) and a human lymphocyte B cell (Raji B), was developed by several research groups to mimic the in vivo intestinal epithelium, furnishing appropriate tools for nanotoxicological studies. However, tri-culture model shows high levels of variability in ENM uptake/translocation studies. With the aim of implementing the standardization and optimization of this tri-culture for ENM translocation studies, the present paper intends to identify and discuss such relevant parameters involved in model establishment as: tri-culture condition set-up, barrier integrity evaluation, mucus characterization, M-cell induction. SiO2 fluorescent nanoparticles were used to compare the different models. Although a low level of SiO2 translocation is reported for all the different culture conditions. a relevant role of mucus and M-cells in NPs uptake/translocation has been highlighted. [ABSTRACT FROM AUTHOR]

To study the effects of nanocrystallisation technology on the intestinal absorption properties and antibacterial activity of florfenicol (FF). The florfenicol nanocrystals (FF-NC) were prepared by wet grinding and spray drying. Additionally, changes in particle size, charge, morphology, and dissolution of FF-NC in the long-term stability were monitored by laser particle sizer, TEM, SEM, paddle method, and the structure of FF-NC powder was characterised by nuclear magnetic resonance (NMR) test. The antibacterial activity, intestinal absorption and intestinal histocompatibility of FF-NC were investigated by the stiletto, mini broth dilution susceptibility test, in situ single-pass intestinal perfusion (SPIP) and haematoxylin–eosin (H–E) staining. After 12 months of storage, the particle size and zeta potential of FF-NC were 280.43 ± 8.21 nm and −19.64 ± 3.45 mV, and the electron microscopy results showed that FF-NC were nearly circular with no adhesion between particles. In addition, the drug loading, encapsulation efficiency, and dissolution of FF-NC did not change significantly during storage. The inhibition zone of FF-NC against Escherichia coli and Staphylococcus aureus was 21.37 ± 1.70 mm and 25.17 ± 2.47 mm, respectively. Compared with the FF, the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of FF-NC are reduced, and the absorption rate constant (Ka) and efficient permeability coefficient (Peff) of FF-NC in the three intestinal segments were increased by 1.28, 0.25, and 9.10 times and 0.59, 0.17, and 6.0 times, respectively. The results of tissue sections showed that FF-NC had little damage to the small intestinal. Nanocrystallisation technology is an effective method to increase the intestinal absorption and antibacterial activity of FF. [ABSTRACT FROM AUTHOR]

Despite its physiological and pathological importance, the mechanical relationship between glucose uptake in the intestine and intestinal flows is unclear. In the intestine of the nematode Caenorhabditis elegans, the defecation motor program (DMP) causes reciprocating intestinal flows. Although the DMP is frequently activated in the intestines, its physiological function is unknown. We evaluated the mechanical signature of enhanced glucose uptake by the DMP in worms. Glucose uptake tended to increase with increasing flow velocity during the DMP because of mechanical mixing and transport. However, the increase in input energy required for the DMP was low compared with the calorie intake. The findings suggest that animals with gastrointestinal motility exploit the reciprocating intestinal flows caused by peristalsis to promote nutrient absorption by intestinal cells. [ABSTRACT FROM AUTHOR]

Zinc stimulates intestinal iron absorption via induction of divalent metal ion transporter (DMT1) and hephaestin (HEPH). While the increase in DMT1 is mediated via a PI3K/IPR2 axis, the mechanisms of Zn-induced HEPH expression downstream of PI3K remain elusive. In the current study we probed the role of Caudal-related homeobox transcription factor-2 (CDX2) on Zn-induced HEPH expression. Zn treatment of Caco-2 cells increased CDX2 phosphorylation and HEPH protein and mRNA expression. siRNA-silencing of CDX2 inhibited Zn-induced HEPH expression. LY294002, an antagonist of PI3K inhibited Zn-induced phosphorylation of CDX2, and downstream HEPH expression. These results suggest that increased expression of HEPH in intestinal cells following Zn treatment is mediated via a PI3K-CDX2 pathway. • Zinc stimulated CDX2 phosphorylation and hephaestin expression in Caco-2 cells. • SiRNA silencing of CDX2 abrogated the zinc induced hephaestin expression. • Antagonist of PI3K abrogated the zinc induced CDX2 phosphorylation as well as hephaestin expression. • Zinc induced hephaestin expression is mediated via a Pi3K -CDX2 dependent mechanism. [ABSTRACT FROM AUTHOR]

Herein, we described the synthesis of some new aromatic amides of 4β‐imidazolopodophyllotoxin (6 a–p) and their anticancer evaluation against four human cancer cell lines like MCF‐7 (breast), A549 (lung), Hela (cervical) and DU‐145 (prostate). Out of all, compounds 6 d, 6 e, 6 g, 6 i, 6 j, 6 l, 6 n and 6 o were found to be active with IC50 values in the range of 0.59‐10 μM. Specifically, compound 6 o showed greater potency against all the cell lines than the standard etoposide. Predominantly, compounds 6 e, 6 j and 6 o observed to be 3 to 4 times more potent against DU‐145 than the standard. The molecular docking studies of three active compounds 6 e, 6 j and 6 o on target protein DNA topoisomerase II were also conducted and found that binding affinity and free energies obtained were in good covenant with the corresponding IC50 values. Finally, the results of in silico ADMET revealed that, compounds 6 e, 6 j and 6 o have shown 100 % intestinal absorption and none of them exhibited AMES and hepato toxicity. [ABSTRACT FROM AUTHOR]

In this study, Syzygium polyanthum was standardized against gallic acid (GA), and a complete pharmacokinetic test was conducted using in vitro and in vivo models against this phytochemical. High-performance liquid chromatography showed that GA is a major phytochemical in aqueous extract of S. polyanthum. It exhibited a low equilibrium solubility and physiochemical stability at pH 2.0 and 7.4, but it deteriorated rapidly at pH 9.2. It showed low permeability toward Caco-2 intestinal absorption with eight times slower absorption in oral than intravenous administration. GA was unstable in mouse, rat, and dog plasma sera with in vitro half-lives (t1/2) of 60, 53, and 56 min, respectively, but was relatively stable in human plasma serum (t1/2 = 185 min). Approximately 5.6% of GA (10 µM) bound to the human plasma proteins. GA was stable in mouse, rat, dog, and human microsomal extracts with in vitro microsomal intrinsic clearance values of 72, 68, 6, and 22 µL/min/mg, respectively. GA selectively inhibited or stimulated the activity of the tested CYP450 enzymes. The in vivo oral bioavailability of GA was 54%, with short elimination half-life and a high volume of distribution. Thus, the mention pharmacokinetic features of GA must be considered during the development of GA-based products to yield the optimum dosage and pharmacological effect. [ABSTRACT FROM AUTHOR]

Background: To combat Iron deficiency anemia, an innovative pilot project, anemia prevention among adolescent girls and lactating mothers through nonpharmacological measures has been started at few places in Gujarat. To evaluate the acceptability of intervention kits provided to the beneficiaries. Material and Methods: A cross-sectional study design where 182 beneficiaries were randomly selected for interview from 12 randomly selected Anganwadi centers of intervention taluka of Junagadh district. Results: Information Education and Communication (IEC) material though available was unread by majority of beneficiaries. Iron utensils were used by 65% of beneficiaries for cooking. Only few beneficiaries (7%) daily use the provided moringa powder. Only half of the beneficiaries (53%) had grown some of the crops from the kitchen garden kit provided and knowledge of beneficiaries regarding iron-rich food was satisfactory in less than one-fifth (19%) of them. Conclusion: Study results concluded that providing nonpharmacological material is of little use until beneficiaries were properly guided and motivated by regular follow-up visits and addressing their problems; otherwise, it just stands as a mere matter of rock only. [ABSTRACT FROM AUTHOR]

Zinc oxide (ZnO) nanoparticles (NPs) are used as a food additive Zn supplement due to the role of Zn in biological functions. They are directly added to complex processed foods or Zn-fortified functional foods. Hence, the interactions between ZnO NPs and nutritional or functional components can occur. In this study, the effects of ZnO NP interactions with two polyphenols (quercetin and rutin) on cytotoxicity, antioxidant activity, ex vivo intestinal absorption, and solubility were evaluated. Moreover, the characterization on the interactions was carried out by analyzing crystallinity, surface chemical bonding, chemical composition, and surface chemistry. The results demonstrate that the interactions caused higher cytotoxicity, ex vivo intestinal transport, and solubility of ZnO NPs than pristine ZnO NPs but did not affect antioxidant activity nor intestinal absorption of the polyphenols. The interaction effects were more evident by ZnO NPs interacted with quercetin than with rutin. The crystallinity of ZnO NPs was not influenced, but the degree of exposure of the chemical bondings, elemental compositions, and chemical group intensities on the surface of ZnO NPs, quercetin, or rutin were quenched or decreased to some extent by the interactions, especially by ZnO NPs interacted with quercetin. It is, therefore, concluded that the interactions affect chemical characteristics and surface chemical sates of ZnO NPs, quercetin, or rutin, which can cause high cytotoxicity, intestinal absorption, and solubility of ZnO NPs. Further study is required to elucidate the mechanism of action of the interactions. [ABSTRACT FROM AUTHOR]

A portion of absorbed dietary triglycerides (TG) is retained in the intestine after the postprandial period, within intracellular and extracellular compartments. This pool of TG can be mobilized in response to several stimuli, including oral glucose. The objective of this study was to determine whether oral glucose must be absorbed and metabolized to mobilize TG in rats and whether high-fat feeding, a model of insulin resistance, alters the lipid mobilization response to glucose. Lymph flow, TG concentration, TG output, and apolipoprotein B48 (apoB48) concentration and output were assessed after an intraduodenal lipid bolus in rats exposed to the following intraduodenal administrations 5 h later: saline (placebo), glucose, 2-deoxyglucose (2-DG, absorbed but not metabolized), or glucose + phlorizin (intestinal glucose absorption inhibitor). Glucose alone, but not 2-DG or glucose þ phlorizin treatments, stimulated lymph flow, TG output, and apoB48 output compared with placebo. The effects of glucose in high-fat-fed rats were similar to those in chow-fed rats. In conclusion, glucose must be both absorbed and metabolized to enhance lymph flow and intestinal lipid mobilization. This effect is qualitatively and quantitatively similar in high-fat- and chowfed rats. The precise signaling mechanism whereby enteral glucose enhances lymph flow and mobilizes enteral lipid remains to be determined. NEW & NOTEWORTHY Glucose potently enhances mesenteric lymph flow in chow- and high-fat-fed rats. The magnitude of glucose effect on lymph flow is no different in chow- and high-fat-fed rats. Glucose must be absorbed and metabolized to enhance lymph flow and mobilize intestinal lipid. [ABSTRACT FROM AUTHOR]

As one of the most important organs in animals, the intestine is responsible for nutrient absorption and acts as a barrier between the body and the environment. Intestinal physiology and function require the participation of energy. 5′‐adenosine monophosphate‐activated protein kinase (AMPK), a classical and highly expressed energy regulator in intestinal cells, regulates the process of nutrient absorption and barrier function and is also involved in the therapy of intestinal diseases. Studies have yielded findings that AMPK regulates the absorption of glucose, amino acids, and fatty acids in the intestine primarily by regulating transportation systems, as we detailed here. Moreover, AMPK is involved in the regulation of the intestinal mechanical barrier and immune barrier through manipulating the expression of tight junctions, antimicrobial peptides, and secretory immunoglobulins. In addition, AMPK also participates in the regulation of intestinal diseases, which indicates that AMPK is a promising therapeutic target for intestinal diseases and cancer. In this review, we summarized the current understanding regarding how AMPK regulates intestinal nutrient absorption, barrier function, and intestinal diseases. [ABSTRACT FROM AUTHOR]

Certain polyphenols exhibit low permeability; precise prediction of their intestinal absorption is important for understanding internal exposure in humans. Intestinal availability, which represents the fraction of administered compounds that reach the portal blood (FaFg), is calculated by dividing bioavailability (F) by hepatic availability (Fh), and F is obtained from pharmacokinetic data from both intravenous (i.v.) and oral (p.o.) administration. However, human FaFg of polyphenols is hardly reported, as human i.v. data are extremely scarce. In this study, we developed an estimation method for FaFg of polyphenols in humans based on the extrapolation of rat clearance using allometric scaling (allometric scaling-based FaFg calculation method, AS- FaFgCM). First, for quercetin, for which human i.v. data have been reported, we compared the FaFg obtained by AS-FaFgCM with the traditional approach using human i.v. and p.o. data. Less than two-fold difference in FaFg values was observed between the two approaches. Next, we obtained FaFg of structurally diverse polyphenols (genistein, baicalein, resveratrol, and epicatechin) using AS-FaFgCM, demonstrating that all of them were poorly absorbable. Furthermore, to utilize the pharmacokinetic data of the total concentration, including aglycones and metabolites, we modified the AS-FaFgCM to focus on their excretion. The FaFg value of naringenin was obtained using modified AS-FaFgCM and was nearly equal to that of baicalein, a structural isomer of naringenin. This study provides quantitative information on the intestinal absorption of polyphenols using comprehensive estimation methods. [ABSTRACT FROM AUTHOR]

Objective: To explore the probable in vitro, in situ and in vivo mechanisms of gallic acid (GA) and p-coumaric acid (PCA) as anti-hyperglycemic agents. Animals and methods: Male albino rats were allocated into four groups, group1 was used as normal control. Group 2 was established as a diabetic control and group3 and 4 were treated with an oral dose of GA and PCA, respectively. Results: GA and PCA revealed a significant decrease in the activity of α-amylase, a noticeable rise in glucose induced-insulin secretion and glucose-uptake in peripheral glucose-uptake in vitro, increase also liver glycogen and serum insulin levels in vivo. Further, GA and PCA exhibited a significant reduction in intestinal glucose absorption in situ compared to blank. Conclusion: The antihyperglycemic activities of GA and PCA can be mediated through delaying intestinal glucose absorption, enhancing β-cell activity and promoting glucose uptake by peripheral tissue via enhancing insulin sensitivity. [ABSTRACT FROM AUTHOR]

Background: Increased cholesterol absorption and reduced synthesis are processes that have been associated with cardiovascular disease risk in a controversial way. However, most of the studies involving markers of cholesterol synthesis and absorption include conditions, such as obesity, diabetes, dyslipidemia, which can be confounding factors. The present study aimed at investigating the relationships of plasma cholesterol synthesis and absorption markers with cardiovascular disease (CVD) risk factors, cIMT (carotid intima-media thickness), and the presence of carotid plaques in asymptomatic subjects. Methods: A cross-sectional study was carried out in 270 asymptomatic individuals and anthropometrical parameters, fasting plasma lipids, glucometabolic profiles, high-sensitivity C-reactive protein (hs-CRP), markers of cholesterol synthesis (desmosterol and lathosterol), absorption (campesterol and sitosterol), cIMT, and the presence of atherosclerotic plaques were analyzed. Results: Among the selected subjects aged between 19 and 75 years, 51% were females. Age, body mass index, systolic and diastolic blood pressure, total cholesterol, non-HDL-C, triglycerides, glucose, and lathosterol/sitosterol ratios correlated positively with cIMT (p ≤ 0.05). Atherosclerotic plaques were present in 19% of the subjects. A direct association of carotid plaques with campesterol, OR = 1.71 (95% CI = 1.04–2.82, p ≤ 0.05) and inverse associations with both ratios lathosterol/campesterol, OR = 0.29 (CI = 0.11–0.80, p ≤ 0.05) and lathosterol/sitosterol, OR = 0.45 (CI = 0.22–0.95, p ≤ 0.05) were observed in univariate logistic regression analysis. Conclusions: The findings suggested that campesterol may be associated with atherosclerotic plaques and the lathosterol/campesterol or sitosterol ratios suggested an inverse association. Furthermore, synthesis and absorption of cholesterol are inverse processes, and the absorption marker, campesterol, may reflect changes in body cholesterol homeostasis with atherogenic potential. [ABSTRACT FROM AUTHOR]

The phenolic drug molecules can be metabolized, among others, by the small intestine's enterocytes. The conjugation reactions (glucuronidation and sulfation) show great importance in these transformations, although the oxidation reactions can be significant. These processes are dependent on the substituents of the phenolic compounds or the reacting functional groups (hydroxyl or carboxyl). Pathologic conditions, e.g., permanent hyperglycemia and diabetes, can alter the activities of the conjugative and possibly the oxidative enzymes, thus forming a change in the metabolic pattern and eventually provoking oxidative stress. A rat intestinal perfusion model was used to investigate the way in which experimental hyperglycemia affects the paracetamol's intestinal elimination and metabolism. Hyperglycemia was induced by the administration of streptozotocin. Two hundred and fifty µM paracetamol was used in the intestinal perfusion solution. For the quantitation of the paracetamol and its major metabolites in the intestinal perfusate, an isocratic high-performance liquid chromatography method with UV-Vis detection was developed. The results revealed that quantities of all of the measured metabolites (glucuronide, sulfate, cysteine, and mercapturic acid conjugates) increased as the effect of the streptozotocin-induced hyperglycemia also did. In the small intestine's homogenate, the glutathione levels showed that there was a decrease in the hyperglycemia levels after the paracetamol administration. In contrast, the tissue levels of the cysteine were lower in the streptozotocin-induced hyperglycemia and increased after the administration of the paracetamol. The changes in the activity of the intestinal CYP 3A4, CYP 2E1, and cyclooxygenase (COX) enzymes were determined in the control and the hyperglycemic cases. Still, there was a significant observable enzyme activity elevation in the intestinal COX enzymes, but there was a decrease in the amount of activity of the intestinal CYP3A4 enzymes, and the CYP2E1 enzyme activity was practically changeless. The results on the cysteine levels in the intestinal homogenate, at least partly, can be explained by the regulation function of the cysteine during the occurrence of oxidative stress. [ABSTRACT FROM AUTHOR]

Pterostilbene (PTS), a compound most abundantly found in blueberries, is a natural analog of resveratrol. Several plant species, such as peanuts and grapes, produce PTS. While resveratrol has been extensively studied for its antioxidant properties, recent evidence also points out the diverse therapeutic potential of PTS. Several studies have identified the robust pharmacodynamic features of PTS, including better intestinal absorption and elevated hepatic stability than resveratrol. Indeed, due to its higher bioavailability paired with reduced toxicity compared to other stilbenes, PTS has become an attractive drug candidate for the treatment of several disease conditions, including diabetes, cancer, cardiovascular disease, neurodegenerative disorders, and aging. This review article provides an extensive summary of the nutraceutical potential of PTS in various disease conditions while discussing the crucial mechanistic pathways implicated. In particular, we share insights from our studies about the Nrf2-mediated effect of PTS in diabetes and associated complications. Moreover, we elucidate the important sources of PTS and discuss in detail its pharmacokinetics and the range of formulations and routes of administration used across experimental studies and human clinical trials. Furthermore, this review also summarizes the strategies successfully used to improve dietary availability and the bio-accessibility of PTS. [ABSTRACT FROM AUTHOR]

Simple Summary: Oligopeptide transporter 1 (PepT1) plays a role in the transportation and absorption of oligopeptides, which is an important part of protein nutrition and affects the growth of animals. Tributyrin (TB), the precursor of butyrate, exhibits similar functions to those of the butyrate in intestinal nutrients absorption. The analysis of TB on the growth of grass carp and its regulation pathway on PepT1 may help us to better understand the functions of TB and oligopeptide transportation via PepT1, which can be modulated by diet. In this study, we demonstrated that an appropriate level of tributyrin supplementation in the diet promoted the growth of juvenile grass carp and elevated the expressions of caudal type homeobox 2 (CDX2), specificity protein 1 (SP1), and PepT1 in the grass carp intestine and primary intestine cell. In addition, CDX2 and SP1 regulating the expression of PepT1 was investigated. Finally, CDX2/SP1-mediating tributyrin regulation on PepT1 was elucidated. This study verified the effect of tributyrin on the growth of juvenile grass carp and clarified the tributyrin regulation pathway on CDX2/SP1-PepT1. The nutritional functions of tributyrin (TB) have been extensively studied, but questions remain regarding its influence on the growth of juvenile grass carp (Ctenopharyngodon idellus) and the regulation pathway to PepT1 in the intestine of grass carp. To answer the remaining questions, feeding trials, cell trials, and peritoneal injection trials were conducted in this study. The results showed that an appropriate level of TB (0.5 g/kg and 1.0 g/kg) supplementation in feed significantly promoted the growth performance of juvenile grass carp. The expressions of intestine genes (CDX2, SP1 and PepT1) related to oligopeptide transportation increased in the 0.5 g/kg TB group of feeding trials and both the 5 mM and 10 mM TB groups of the intestine cell trials, respectively. Subsequently, the injection trials of inhibitors CDX2 and SP1 demonstrated that the inhibition of CDX2 or SP1 decreased the mRNA expression of PepT1. Finally, the results of independent or combined treatments of TB and the inhibitors suggested that CDX2/SP1 mediated TB regulation on PepT1. These findings may help us to better understand the functions of TB on growth and PepT1 oligopeptide transportation, which could be modulated by dietary TB through the CDX2/SP1-PepT1 pathway in juvenile grass carp. [ABSTRACT FROM AUTHOR]

Avenanthramides are phenolic compounds unique to oats and may contribute to health‐promoting properties associated with oat consumption. This study used Xenopus laevis oocytes expressing the glucose transporters, glucose transporter 2 (GLUT2) or sodium–glucose transport protein 1 (SGLT1) and human Caco‐2 cells models to investigate the effect of oat avenanthramides on human intestinal glucose transporters. The presence of avenanthramide reduced the glucose uptake in a dose‐dependent manner in Caco‐2 cells. Glucose uptake in oocytes expressing either GLUT2 or SGLT1 was nullified by oat avenanthramide. There was no significant difference between the inhibition potencies of avenanthramides C and B. Thus, our results suggest that avenanthramides may contribute to the antidiabetic properties of oats. Practical applications: The present research focus on the antidiabetic properties of avenanthramides, which are unique phenolic compounds found in oats. Inhibiting the activities of the glucose transport proteins expressed in the small intestine is a known strategy to improve the control of postprandial glucose level. We therefore examined the inhibitory effects of avenanthramides on two glucose transporters, glucose transporter 2 and sodium–glucose transport protein 1, predominantly found in the small intestine using the human small intestinal cell model Caco‐2 cell line and by heterologously expressing these two transporters in the Xenopus laevis oocytes. Based on our results, we have confirmed for the first time that the glucose uptake is indeed inhibited by the presence of avenanthramides, suggesting the possibility of incorporating avenanthramides in foods to enhance postprandial glucose response, and ultimately improve the management of diabetes. Therefore, future research could consider utilizing this evidence in the development of diabetic‐friendly functional foods or nutraceuticals containing avenanthramides. [ABSTRACT FROM AUTHOR]

The current investigation explores the possible mechanism of the microemulsion drug delivery system to improve the oral bioavailability of cinnamaldehyde (CA), an important food spice, from the perspective of the microemulsion–mucus system. The cinnamaldehyde microemulsion (CA‐ME) was prepared by the water titration method combined with the pseudo‐ternary phase diagram. The dynamic analysis was applied to detect the drug release in vitro. An intestinal mucosal injury test was conducted to evaluate the safety of CA‐ME and drug absorption across the intestinal tract of rats was investigated through an Ussing chamber system. The rheology of blank mucus and drug‐loaded mucus was investigated using a rheometer. The bioavailability of CA‐ME in rats was evaluated through pharmacokinetic characteristics. The ratio of optimal prescription was Tween 80: 1,2‐propanediol: vitamin E oil: CA: water = 24.3:4.8:5:7.5:58.4. The droplets were uniform in size and evenly dispersed. Rheological studies showed that the microemulsion–mucus system all exhibit pseudoplastic fluid behavior, and CA‐ME increased the viscosity of the mucus to a certain extent. Compared with CA solution, CA‐ME promoted the absorption of CA in various intestinal segments, especially the ileum. Pharmacokinetic experiments showed that the relative bioavailability of CA‐ME was enhanced 2.5‐fold higher than that of CA solution. ME as a carrier for lipophobic substances, may increase the viscosity of the intestine mucus system to obtain longer residue time and better absorption. Practical applications: In this study, in vitro absorption Ussing model was combined with rheological and pharmacokinetic analysis to systematically analyze the intestinal mucus mechanism of microemulsion to improve the oral bioavailability of cinnamic aldehyde. It laid the foundation for exploring the absorption and transport of drugs in the intestinal mucus barrier. [ABSTRACT FROM AUTHOR]

Simple Summary: Hypertension is the predominant risk factor for cardiovascular disease, which is the leading cause of mortality and morbidity worldwide. The search for natural compounds with antihypertensive properties, such as bioactive peptides from brewing by-products (spent grain and yeast), which are less likely to cause severe side effects compared with anti-hypertensive drugs, is of major importance to reduce cardiovascular events. Since oral intake of these peptides may modify their expected effects, the aim of the present study was to simulate oral administration and evaluate the impact of gastrointestinal digestion, intestinal absorption, and liver metabolism on the effectiveness of those bioactive peptides and determine their potential to be used as supplements or nutraceuticals as well as anti-hypertensive drugs before moving forward to animal studies. Results showed that peptides derived from the brewing industry maintain or present higher antihypertensive activity after simulation of oral administration, validating the usefulness of these peptides to reduce the risk, ameliorate, or treat primary hypertension. In conclusion, this study reinforces, through in vitro studies, the benefits of oral administrated brewing bioactive peptides to directly manage hypertension by lowering blood pressure, thus being promising compounds. The treatment of hypertension is of major importance to reduce the risk of cardiovascular disease, the leading cause of death worldwide. Angiotensin-converting enzyme (ACE) inhibitors are anti-hypertensive drugs associated with several side effects. Natural products, namely bioactive peptides from brewing by-products, brewers' spent grain (BSG), and yeast (BSY), are promising alternatives since they can inhibit ACE in vitro. However, the oral intake of these peptides may modify their expected inhibitory effect owing to possible changes in active peptides' bioavailability, which have not been assessed so far. The goal of this study was to simulate oral administration to evaluate BSG/BSY peptides' effectiveness by submitting protein hydrolysates sequentially to simulated gastrointestinal digestion, intestinal absorption (Caco-2 cells), and liver metabolism (HepG2 cells). MTT assay was used to assess BSG/BSY protein hydrolysates safeness. The ACE-inhibitory potential of initial and final protein hydrolysates (BSY, BSG, and a new product, MIX) were tested using a fluorometric assay and compared with captopril (1 µM, an ACE-inhibitory drug). Simulation of oral administration greatly increased BSY and MIX protein hydrolysates' ACE-inhibitory capacity, though final MIX and BSG revealed greater ACE-inhibitory potential than captopril. Notwithstanding, all final protein hydrolysates presented ACE-inhibitory capacity, thus being promising compounds to manage hypertension. [ABSTRACT FROM AUTHOR]

Purpose : Oral delivery of therapeutic peptides has been challenging due to multiple physiological factors and physicochemical properties of peptides. We report a systematic approach to identify formulation compositions combining a permeation enhancer and a peptidase inhibitor that minimize proteolytic degradation and increase absorption of a peptide across the small intestine. Methods: An acylated glucagon-like peptide-1/glucagon co-agonist peptide (4.5 kDa) was selected as a model peptide. Proteolytic stability of the peptide was investigated in rat and pig SIF. Effective PEs and multiple component formulations were identified in rats. Relative bioavailability of the peptide was determined in minipigs via intraduodenal administration (ID) of enteric capsules. Results: The peptide degraded rapidly in the rat and pig SIF. Citric acid, SBTI, and SBTCI inhibited the enzymatic degradation. The peptide self-associated into trimers in solution, however, addition of PEs monomerized the peptide. C10 was the most effective PE among tested PEs (DPC, LC, rhamnolipid, C12-maltosides, and SNAC) to improve intestinal absorption of the peptide in the rat IJ-closed loop model. A combination of C10 and SBTI or SBTCI increased the peptide exposure 5–tenfold compared to the exposure with the PE alone in the rat IJ-cannulated model, and achieved 1.06 ± 0.76% bioavailability in minipigs relative to subcutaneous via ID administration using enteric capsules. Conclusion: We identified SBTI and C10 as an effective peptidase inhibitor and PE for intestinal absorption of the peptide. The combination of SBTI and C10 addressed the peptide physiochemical properties and provides a formulation strategy to achieve intestinal delivery of this peptide. [ABSTRACT FROM AUTHOR]

Little is known about the impact of age on the processes governing human intestinal drug absorption. The Ussing chamber is a system to study drug transport across tissue barriers, but it has not been used to study drug absorption processes in children. This study aimed to explore the feasibility of the Ussing chamber methodology to assess pediatric intestinal drug absorption. Furthermore, differences between intestinal drug transport processes of children and adults were explored as well as the possible impact of age. Fresh terminal ileal leftover tissues from both children and adults were collected during surgery and prepared for Ussing chamber experiments. Paracellular (enalaprilat), transcellular (propranolol), and carrier‐mediated drug transport by MDR1 (talinolol) and BCRP (rosuvastatin) were determined with the Ussing chamber methodology. We calculated apparent permeability coefficients and efflux ratios and explored their relationship with postnatal age. The success rate for the Ussing chamber experiments, as determined by electrophysiological measurements, was similar between children (58%, N = 15, median age: 44 weeks; range 8 weeks to 17 years) and adults (67%, N = 13). Mean serosal to mucosal transport of talinolol by MDR1 and rosuvastatin by BCRP was higher in adult than in pediatric tissues (p = 0.0005 and p = 0.0091). In contrast, within our pediatric cohort, there was no clear correlation for efflux transport across different ages. In conclusion, the Ussing chamber is a suitable model to explore pediatric intestinal drug absorption and can be used to further elucidate ontogeny of individual intestinal pharmacokinetic processes like drug metabolism and transport. [ABSTRACT FROM AUTHOR]

Despite its physiological and pathological importance, the mechanical relationship between glucose uptake in the intestine and intestinal flows is unclear. In the intestine of the nematode Caenorhabditis elegans, the defecation motor program (DMP) causes reciprocating intestinal flows. Although the DMP is frequently activated in the intestines, its physiological function is unknown. We evaluated the mechanical signature of enhanced glucose uptake by the DMP in worms. Glucose uptake tended to increase with increasing flow velocity during the DMP because of mechanical mixing and transport. However, the increase in input energy required for the DMP was low compared with the calorie intake. The findings suggest that animals with gastrointestinal motility exploit the reciprocating intestinal flows caused by peristalsis to promote nutrient absorption by intestinal cells. [ABSTRACT FROM AUTHOR]

The experiment was to explore the feasibility of using the extractive liquid sediment (SXBS) produced in pharmaceutical process of Shengxuebao mixture as a feed additive. The research used UPLC-TOF-MS and other technologies to analyze the small molecule chemical composition and nutritional composition of SXBS, and SXBS was added into diet of New Zealand rabbits for 60 d. The effect of SXBS on growth performance, nutrient apparent digestibility, slaughter performance and intestinal flora of New Zealand rabbits were investigated. The feeding safety of SXBS was reflected by blood routine, blood biochemical analysis and histopathological observation. The results showed that SXBS was rich in nutrients such as carbohydrates, crude fiber, crude protein and crude fat, and contained a lot of active ingredients such as flavonoids, amino acids, terpenes, polyphenols and saponins. SXBS had no effect on growth performance of New Zealand rabbits. SXBS could significantly regulate the bacterial and fungal flora structure of New Zealand rabbits' gut, up-regulate linoleic acid, propionic acid, taurine, galactose and other metabolic functions related to the digestion and absorption of intestinal carbohydrates, and increase the abundance of Zygosaccharomyces ruberii. SXBS had no obvious toxic effect on New Zealand rabbits within 60 d, and the safety was good. The study indicates that SXBS can be used in rabbit breeding as a rabbit feed additive for regulating intestinal microecology. [ABSTRACT FROM AUTHOR]

Cancer remains one of the diseases with the highest worldwide incidence. Several cytotoxic approaches have been used over the years to overcome this public health threat, such as chemotherapy, radiotherapy, and photodynamic therapy (PDT). Cyanine dyes are a class of compounds that have been extensively studied as PDT sensitisers; nevertheless, their antiproliferative potential in the absence of a light source has been scarcely explored. Herein, the synthesis of eighteen symmetric mono-, tri-, and heptamethine cyanine dyes and their evaluation as potential anticancer agents is described. The influences of the heterocyclic nature, counterion, and methine chain length on the antiproliferative effects and selectivities were analysed, and relevant structure–activity relationship data were gathered. The impact of light on the cytotoxic activity of the most promising dye was also assessed and discussed. Most of the monomethine and trimethine cyanine dyes under study demonstrated a high antiproliferative effect on human tumour cell lines of colorectal (Caco-2), breast (MCF-7), and prostate (PC-3) cancer at the initial screening (10 µM). However, concentration–viability curves showed higher potency and selectivity for the Caco-2 cell line. A monomethine cyanine dye derived from benzoxazole was the most promising compound (IC50 for Caco-2 = 0.67 µM and a selectivity index of 20.9 for Caco-2 versus normal human dermal fibroblasts (NHDF)) and led to Caco-2 cell cycle arrest at the G0/G1 phase. Complementary in silico studies predicted good intestinal absorption and oral bioavailability for this cyanine dye. [ABSTRACT FROM AUTHOR]

The pH–induced crystallization of weakly basic drugs in the small intestine limits oral bioavailability. In this study, we investigated the solubilization and inhibitory effects on nintedanib in the presence of enteric polymers (HPMCAS LG, HPMCAS MG, Eudragit L100 55, and Eudragit L100). These polymers provided maintenance of supersaturation by increasing the solubility of nintedanib in PBS 6.8 in a concentration-dependent manner, and the improved ranking was as follows: Eudragit L100 > Eudragit L100 55 > HPMCAS MG > HPMCAS LG. After being formulated into amorphous solid dispersions (ASDs) by a solvent evaporation method, the drug exhibited an amorphous state. The pH shift dissolution results of polymer-ASDs demonstrated that four polymers could effectively maintain the drug supersaturation even at the lowest ratio of nintedanib and polymer (1:1, w/w). Eudragit L100–ASD could provide both acid resistance and the favorable mitigation of crystallization in GIF. In comparison to the coarse drug, the relative bioavailability of Eudragit L100–ASD was 245% after oral administration in rats, and Tmax was markedly delayed from 2.8 ± 0.4 h to 5.3 ± 2.7 h. Our findings indicate that enteric ASDs are an effective strategy to increase the intestinal absorption of nintedanib by improving physiologically generated supersaturation and subsequent crystallization. [ABSTRACT FROM AUTHOR]

Background: Ficus deltoidea (Ficus: Moraceae) has great potential as a functional food. Administration of F. deltoidea has been reported to reduce hyperglycemia, oxidative stress and increase insulin secretion in diabetic rats and humans. However, the poor bioavailability and intestinal absorption of F. deltoidea impede its therapeutic effectiveness at a lower dosage, thus integrating F. deltoidea into brown rice will provide additional advantages. This study aimed to examine the phyto-physicochemical profile, antioxidant properties, consumer acceptance, and safety of beverages formulated from fine powder mixtures of F. deltoidea leaves and brown rice. Methods: The new beverage formulations were prepared by mixing the fine powders of F. deltoidea leaves with brown rice at ratios of 1:6 and 1:13, respectively. Physicochemical, phytochemical, and antioxidant analyses were performed to characterize the prepared beverages. Consumer acceptance was assessed utilising a 9-point hedonic scale and an acute toxicity study was employed to determine the safety of F. deltoidea-added formulations. Results: F. deltoidea decreased the pH and increased the moisture content, ash, and viscosity of a brown rice beverage. The total phenolic, flavonoid, and tannin content as well as antioxidant activities increased significantly in both F. deltoidea-added formulations. The oral LD50 of the F. deltoidea-added formulation was higher than 2000 mg/kg body weight. Conclusions: These results suggest that adding F. deltoidea leaves to brown rice beverages is safe to consume and improves the phyto-physicochemical profile, antioxidant activities, and consumers' acceptance of the formulation. [ABSTRACT FROM AUTHOR]

Weakly basic compounds propose biopharmaceutics risks due to the possibility of precipitation out of solution when passing from the stomach to the intestine. This behavior would limit the available drug for absorption and in turn reduces the plasma exposure at dose escalation scenarios in phase 1 clinical trials. In vitro precipitation studies along with computational models are often used to assess the risks of intestinal precipitation and provide insights about the parameters that should be controlled to minimize the risks of low absorption at high doses. In this work, both parameter sensitivity analysis and pH shift precipitation methods were used to guide the formulation approach and select excipients to reduce the risks associated with intestinal absorption of a weakly basic model compound. The simulations showed that absorption is sensitive to gastric pH and precipitation time which could be manipulated by formulation approaches. Other factors such as particle size and gastric residence time showed no impact. Precipitation studies using pH shift method were used to screen acidic excipients and polymers that will be added in a combination to boost supersaturation and retard precipitation. Hydroxy propyl methyl cellulose acetate succinate (HPMCAS) polymer middle grade was selected along with para-toluene sulfonic acid as the two excipients that would provide the highest supersaturation among the tested excipients. Merging both in vitro testing and computational models showed great merit in reducing time for selecting excipient for enabling formulation by focusing on the most influential formulation parameter for drug absorption. [ABSTRACT FROM AUTHOR]