Search Results (367)

The enteroendocrine system of the gastrointestinal (GI) tract is the largest endocrine organ in the human body, playing a central role in the regulation of hunger, satiety, digestion, and energy homeostasis. Numerous factors—including dietary components, physical activity, and the gut microbiota—affect the secretion of GI hormones. This study aims to analyze how these factors modulate enteroendocrine function and influence systemic metabolic regulation. This review synthesizes the current scientific literature on the physiology and distribution of enteroendocrine cells and mechanisms of hormone secretion in response to macronutrients, physical activity, and microbial metabolites. Special attention is given to the interactions between gut-derived signals and central nervous system pathways involved in appetite control. Different GI hormones are secreted in specific regions of the digestive tract in response to meal composition and timing. Macronutrients, particularly during absorption, stimulate hormone release, while physical activity influences hormone concentrations, decreasing ghrelin and increasing GLP-1, PYY, and leptin levels. The gut microbiota, through fermentation and metabolite production (e.g., SCFAs and bile acids), modulates enteroendocrine activity. Species such as Akkermansia muciniphila are associated with improved gut barrier integrity and enhanced GLP-1 secretion. These combined effects contribute to appetite regulation and energy balance. Diet composition, physical activity, and gut microbiota are key modulators of gastrointestinal hormone secretion. Their interplay significantly affects appetite regulation and metabolic health. A better understanding of these relationships may support the development of personalized strategies for managing obesity and related disorders. Full article

Sensorimotor integration along the gastrointestinal (GI) tract is crucial for normal gut function yet remains poorly understood in the context of neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD). The genetic tractability of zebrafish allows investigators to generate molecularly defined models that provide a means of studying the functional circuits of digestion in vivo. Optical transparency during development allows for the use of optogenetics and calcium imaging to elucidate the mechanisms underlying GI-related symptoms associated with ASD. The array of commonly reported symptoms implicates altered sensorimotor integration at various points along the GI tract, from the pharynx to the anus. We will examine the reflex arcs that facilitate swallowing, nutrient-sensing, absorption, peristalsis, and evacuation. The high level of conservation of these processes across vertebrates also enables us to explore potential therapeutic avenues to mitigate GI distress in ASD and other NDDs. Full article

Dietary fiber (DF) is one type of carbohydrate that cannot be digested by the gastrointestinal tract. It is widely recognized as an essential ingredient for health due to its remarkable prebiotic properties. Studies have shown that DF is important in the management of metabolic diseases, such as obesity and diabetes, by regulating the balance of gut microbiota and slowing down the absorption of glucose. It is worth noting that patients with metabolic diseases might suffer from intestinal dysfunction (such as constipation), which is triggered by factors such as the disease itself or medication. This increases the complexity of chronic disease treatment. Although medications are the most common treatment for chronic disease, long-term use might increase the financial and psychological burden. DF as a prebiotic has received significant attention not only in the therapy for constipation but also as an adjunctive treatment in metabolic disease. This review focuses on the application of DF in modulating metabolic diseases with special attention on the effect of DF on intestinal dysfunction. Furthermore, the molecular mechanisms through which DF alleviates intestinal disorders are discussed, including modulating the secretion of gastrointestinal neurotransmitters and hormones, the expression of aquaporins, and the production of short-chain fatty acids. Full article

The gastrointestinal tract mediates the absorption of nutrients from the diet, which is increasingly contaminated with toxic metal(loid) species (TMs) and thus threatens food safety. Evidence in support of the influx of TMs into the bloodstream of the general and vulnerable populations (babies, children, pregnant women, and industrial workers) has been obtained by accurately quantifying their blood concentrations. The interpretation of these TM blood concentrations, however, is problematic, as we cannot distinguish between those that are tolerable from those that may cause the onset of environmental diseases. Since TMs that have invaded the bloodstream may perturb biochemical processes therein that will eventually cause organ damage it is crucial to better understand their bioinorganic chemistry as these processes collectively determine their organ availability. Thus, bioinorganic processes of TMs in the bloodstream represent selectivity filters which protect organs from their influx and ultimately determine the corresponding exposure-response relationships. The need to better understand selectivity filters prompted us to mechanistically disentangle them into the major bioinorganic chemistry processes. It is argued that the detoxification of TMs in the bloodstream and the biomolecular mechanisms, which mediate their uptake into target organs, represent critical knowledge gaps to revise regulatory frameworks to reduce the disease burden. Full article

Familial hypercholesterolemia (FH) is a genetic disorder marked by significantly elevated levels of low-density lipoprotein cholesterol (LDL-C) since childhood, substantially increasing the risk of premature atherosclerosis and cardiovascular disease. While dysfunction of hepatic LDL-C receptors is the main underlying cause, the gastrointestinal tract plays a key role in cholesterol homeostasis and represents an important therapeutic target. Inhibition of intestinal cholesterol absorption has emerged as an effective strategy in the management of pediatric FH, particularly in patients for whom statins may not be the ideal first-line treatment. Ezetimibe, an inhibitor of the Niemann-Pick C1-like 1 (NPC1L1) protein, has been shown to reduce LDL-C levels in children with FH, with a greater efficacy observed when used in combination with statins. Bile acid sequestrants also enhance cholesterol excretion but are often limited by gastrointestinal side effects, while dietary interventions, such as phytosterol supplementation and fiber-enriched diets, provide additional benefits in lowering LDL-C and are generally well tolerated. Emerging therapies, including microbiota-targeted strategies and novel cholesterol absorption inhibitors, show promise for expanding future treatment options. This review explores the mechanisms of intestinal cholesterol absorption and their relevance to pediatric FH. We examine key pathways, including dietary cholesterol uptake through NPC1L1, bile acid reabsorption, and cholesterol efflux mediated by ATP-binding cassette transporters, while also discussing clinical and experimental evidence on pharmacological and dietary interventions that modulate these pathways. A deeper understanding of cholesterol metabolism, the emerging role of the gut microbiota, and innovative therapeutic agents can support the development of more effective and personalized approaches to the treatment of children with FH. Full article

Bariatric surgery involves major changes in the anatomy and physiology of the gastrointestinal tract, which may alter oral drug bioavailability and efficacy. Phosphodiesterase-5 inhibitor (PDE5i) drugs are the first-line treatment of erectile dysfunction, a condition associated with a higher BMI. In this paper, we examine the PDE5i vardenafil for possible post-bariatric changes in solubility/dissolution and absorption. Vardenafil solubility was determined in vitro, as well as ex vivo using aspirated gastric contents from patients prior to vs. following bariatric procedures. Dissolution was tested in vitro under unoperated stomach vs. post-gastric sleeve/bypass conditions. Lastly, the gathered solubility/dissolution data were used to produce an in silico physiologically based pharmacokinetic (PBPK) model (GastroPlus^®), where gastric volume, pH, and transit time, as well as proximal GI bypass (when relevant) were all adjusted for, evaluating vardenafil dissolution, gastrointestinal compartmental absorption, and pharmacokinetics before vs. after different bariatric procedures. pH-dependent solubility was demonstrated for vardenafil with low (pH 7) vs. high solubility (pH 1–5), which was confirmed ex vivo. The impaired dissolution of all vardenafil doses under post-gastric bypass conditions was demonstrated, contrary to complete (100%) dissolution under pre-surgery and post-sleeve gastrectomy conditions. Compared to unoperated individuals, PBPK simulations revealed altered pharmacokinetics post-gastric bypass (but not after sleeve gastrectomy), with 30% lower peak plasma concentration (C_max) and 40% longer time to C_max (T_max). Complete absorption after gastric bypass is predicted for vardenafil, which is attributable to significant absorption from the large intestine. The biopharmaceutics and PBPK analysis indicate that vardenafil may be similarly effective after sleeve gastrectomy as before the procedure. However, results after gastric bypass question the effectiveness of this PDE5i. Specifically, vardenafil’s onset of action might be delayed and unpredictable, negatively affecting the practicality of the intended use. Full article

Chronic alcohol consumption induces oxidative stress not only in the liver but also in the gastrointestinal tract, where prolonged intestinal ethanol absorption plays a pivotal and underrecognized role. This review reframes ethanol pharmacokinetics to emphasize sustained jejunal and ileal uptake, which maintains elevated blood alcohol levels and perpetuates redox imbalance across the gut–liver axis. We integrate recent findings on ethanol-induced barrier dysfunction, CYP2E1-mediated ROS production, microbial dysbiosis, and mitochondrial disruption, proposing that the intestine is an active site of injury and a driver of systemic inflammation. Key mechanistic insights reveal that gut-derived endotoxins, compromised epithelial integrity, and microbiome–mitochondria interactions converge to exacerbate hepatic and extrahepatic damage. We further explore emerging therapeutic strategies—ranging from NAD⁺ repletion and probiotics to fecal microbiota transplantation—that target this upstream pathology. Recognizing prolonged intestinal ethanol absorption as a clinically meaningful phase offers new directions for early intervention and redox-based treatment in alcohol-associated disease. Full article

Recently, there has been a gradual increase in the demand for chicken and eggs. The gut, as the vital place of nutrient digestion and absorption, is highly associated with the development of livestock and poultry and the quality of meat, eggs, and milk. Intestinal stem cells, as an important source of intestinal cell proliferation and renewal, exert a vital effect on repairing injured intestinal epithelial cells and keeping homeostasis. Intestinal stem cell-regulated intestinal epithelial balance is closely controlled and modulated by interlinked developmental loops that maintain cell proliferation and differentiation processes in balance. Some conservative signaling pathways, including the Wnt, Notch, hedgehog, and bone morphogenetic protein (BMP) loops, have been proved to modulate intestinal health in poultry. Meanwhile, studies have revealed the importance of the Hippo pathway in gastrointestinal tract physiology by regulating intestinal stem cells. Moreover, crosstalk between Hippo and other signaling pathways provides tight, yet versatile, regulation of tissue homeostasis. In this review, we summarize studies on the role of the Hippo pathway in the intestine in these physiological processes and the underlying mechanisms responsible via interacting with these signaling pathways and discuss future research directions and potential therapeutic strategies targeting Hippo signaling in intestinal disease. A comprehensive understanding of how these signaling pathways regulate stem cell proliferation, differentiation, and self-renewal will help to understand the regulation of intestinal homeostasis. In addition, it has the capacity for creative ways to govern intestinal damage, enteritis, and associated disorders induced by different factors. Full article

Phosphorus is one of the most abundant minerals in the body and plays a critical role in numerous cellular and metabolic processes. Most of the phosphate is deposited in bones, 14% is present in soft tissues as various organic phosphates, and only 1% is found in extracellular space, mainly as inorganic phosphate. The plasma inorganic phosphate concentration is closely maintained between 2.5 and 4.5 mg/dL by intertwined interactions between fibroblast growth factor 23 (FGF-23), parathyroid hormone (PTH), and vitamin D, which tightly regulate the phosphate trafficking across the gastrointestinal tract, kidneys, and bones. Disruption of the strict hemostatic control of phosphate balance can lead to altered cellular and organ functions that are associated with high morbidity and mortality. In the past three decades, there has been a steady increase in the prevalence of kidney failure (KF) among populations. Individuals with KF have unacceptably high mortality, and well over half of deaths are related to cardiovascular disease. Abnormal phosphate metabolism is one of the major factors that is independently associated with vascular calcification and cardiovascular mortality in KF. In early stages of CKD, adaptive processes involving FGF-23, PTH, and vitamin D occur in response to dietary phosphate load to maintain plasma phosphate level in the normal range. However, as the CKD progresses, these adaptive events are unable to overcome phosphate retention from continued dietary phosphate intake and overt hyperphosphatemia ensues. As these hormonal imbalances and the associated adverse consequences are driven by the underlying hyperphosphatemic state in KF, it appears logical to strictly control serum phosphate. Conventional dialysis is inadequate in removing phosphate and most patients require dietary restrictions and pharmacologic interventions to manage hyperphosphatemia. However, diet control comes with many challenges with adherence and may place patients at risk for inadequate protein intake and malnutrition. Phosphate binders help to reduce phosphate levels but come with a sizable pill burden and high financial costs and are associated with poor adherence and psychosocial issues. Additionally, long-term use of binders may increase the risk of calcium, lanthanum, or iron overload or promote gastrointestinal side effects that exacerbate malnutrition and affect quality of life. Given the aforesaid challenges with phosphorus binders, novel therapies targeting small intestinal phosphate absorption pathways have been investigated. Recently, tenapanor, an agent that blocks paracellular absorption of phosphate via inhibition of enteric sodium–hydrogen exchanger-3 (NHE3) was approved for the treatment of hyperphosphatemia in KF. While various clinical tools are now available to manage hyperphosphatemia, there is a lack of convincing clinical data to demonstrate improvement in outcomes in KF with the lowering of phosphorus level. Conceivably, deleterious effects associated with hyperphosphatemia could be attributable to disruptions in phosphorus-sensing mechanisms and hormonal imbalance thereof. Further exploration of mechanisms that precisely control phosphorus sensing and regulation may facilitate development of strategies to diminish the deleterious effects of phosphorus load and improve overall outcomes in KF. Full article

The human gastrointestinal tract is estimated to be populated by 38 trillion bacteria from almost 1000 different species. The dominant phyla are Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria. However, the diversity and amount of gut microbiota depends on various factors. The importance of gut microbiota is increasingly noticed due to the influence of bacteria on energy homeostasis, the immune system, general health, and metabolism. Bariatric surgery is the mainstay treatment for patients with obesity. Two of the most common mechanisms are reducing gastric volume and decreasing ghrelin secretion. This literature review aims to depict the diverse impact of different bariatric procedures on gut microbiota. The original research papers were collected from the PubMed, Cochrane, and Elsevier databases. This literature review is focused on human studies. However, several references include animal models, specifically rats and germ-free mice. The findings suggest that bariatric surgery causes changes in the diversity of gut microbiota. However, the specificity of the changes depends on the type of bariatric surgery. The Firmicutes/Bacteroidetes ratio is elevated in the groups of patients with obesity compared to lean individuals. Bariatric surgery lowers the ratios impact on metabolism and energy absorption. Gut microbiota produces short-chain fatty acids, of which butyrate is responsible for strengthening the gut barrier, and acetate is correlated with fat deposition and lipogenesis. Moreover, changes in short-chain fatty acids influence insulin resistance and inflammation. In conclusion, bariatric surgery impacts gut microbiota, resulting in metabolic changes in patients, and the need for further study regarding long-term microbiota alterations post-operation is notable. Full article

In this study, we synthesized a novel trimethoprim derivative, 4-(((2-amino-5-(3,4,5-trimethoxybenzyl) pyrimidine-4-yl)imino)methyl)benzene-1,3-diol (HD), by the reaction of trimethoprim with 2,4-dihydroxybenzaldehyde. We then prepared metal complexes of this derivative with Cu(II), Co(II), Ni(II), Ag(I), and Zn(II) and functionalized them with ZnO and Au nanoparticles. Their structures were confirmed through ¹H NMR, mass spectrometry, FTIR, conductivity, thermal analysis, magnetic susceptibility, X-ray diffraction, UV-Vis spectroscopy, and TEM, revealing octahedral geometries for all complexes. Surface features were investigated using density functional theory (DFT) analysis. Pharmacokinetic parameters and target enzymes for HD and its complexes were computed using the SwissADME web tool, with the BOILED-Egg model indicating that HD and its Cu complex should be passively permeable via the blood-brain barrier and highly absorbed by the gastrointestinal tract (GIT), unlike the Ni, Co, Ag, and Zn complexes, which are predicted to show low GIT absorption. Molecular docking studies with the Caspase-3 enzyme (PDB code: 3GJQ) using the AutoDock 4.2 software demonstrated binding energies of −7.66, −8.36, −9.05, −8.62, −6.90, and −7.81 kcal/mol for HD and the Cu, Co, Ni, Ag, and Zn complexes, respectively, compared to −6.54 and −4.63 kcal/mol for TMP and 5-FU (5-fluorouracil), indicating a potential superior anticancer potential of the novel compounds. The anticancer activities of these complexes were evaluated using the MTT assay. The IC₅₀ values for 5-FU, TMP, HD, Cu-HD, HD@ZnONPs, Cu-HD@ZnONPs, HD@AuNPs, and Cu-HD@AuNPs were found to be 32.53, 80.76, 114.7, 61.66, 77, 53.13, 55.06, and 50.81 µg/mL, respectively. Notably, all derivatives exhibited higher activity against the HepG-2 cancer cell line than TMP, except for HD, which showed similar effectiveness to TMP. Real-time PCR analysis revealed that the Au-HD@AuNPs and Cu-HD@AuNPs significantly increased caspase-3 inhibition by 4.35- and 4.5-fold and P53 expression by 3.05- and 3.41-fold, respectively, indicating enhanced pro-apoptotic gene expression and apoptosis induction in HepG2 cells. Our findings demonstrate that these novel derivatives possess significant anticancer properties, with some complexes showing superior activity compared to standard drugs such as 5-Fluorouracil (5-FU) and Trimethoprim (TMP). This study highlights the potential of these nanocomposites as promising candidates for cancer therapy. Full article

Nanotechnology refers to the science that modulates molecules to the nanoscale dimension. Nanomedicine, i.e., the utilization of nanotechnology for diagnosing and treating several disorders, is a subject of ongoing research. The concept behind nanomedicine in diabetes mellitus (DM) treatment stems from the need to ameliorate absorption and distribution of antidiabetic therapies in order to overcome barriers, namely the pH throughout the gastrointestinal tract, the gut microbiota, the temperature/heat and the difficulties in the incorporation of drugs into the cells. Thus, the scope of nanomedicine is particularly challenging and demanding, considering the fact that the human body is a perpetually changing entity in order to achieve homeostasis. In this review, we will delve into various nanoparticles that are being studied in terms of antidiabetic treatment, their pros and cons and the expanding knowledge in this field. Despite the fact that nanomedicine seems to be very promising, there are still many gaps in our understanding of how the human body addresses its utilization. Moreover, its high costs, along with an as-yet unclear safety profile, remain a significant barrier to widespread adoption. In this review, we will describe both phytochemicals and chemical compounds that nanomedicine seeks to exploit in order to pave the way for a more efficacious and comprehensive management of diabetes mellitus. Full article

Artificial gastrointestinal tract models have become essential tools in veterinary medicine, providing alternatives to in vivo studies, which are labor-intensive, costly, and under certain circumstances even ethically challenging. These in vitro models facilitate the study of digestion, enable disease and host–pathogen interaction modeling, and allow for the investigation of nutrient absorption, microbiota, and pharmacokinetics. Considering the One Health concept, the application of gastrointestinal tract systems in investigations for animals can clearly reflect human health, and thus, it is pointing to the relevance of the adaptation of already existing models and the development of new models to meet the needs of veterinary and animal farming practices. This review explores and compares the various types of gastrointestinal tract models, including static and dynamic systems, and their applications across different animal species. Specific technical and methodological considerations are discussed for core animal-developed and -tested artificial systems and their integration with common ‘omics’ techniques. Dynamic models, such as RUSITEC and PolyFermS, more accurately simulate in vivo processes, including peristalsis, enzymatic activity, and microbial fermentation. The studies employing tools for ‘omics’ approaches have been conducted with more understanding analysis and comprehensive discussion and results. Full article

Among medicinal plants, the Panax genus (family: Araliaceae) includes plant species widely recognized for their multi-faceted pharmacological attributes. The triterpenoids, designated as ginsenosides, are increasingly recognized as drug-like molecules in cancer therapies due to their therapeutic role in restricting tumor invasion, proliferation, metastasis, apoptosis, and drug resistance reversal in tumor cells. In the nanobiotechnological era, nano-delivery systems provide feasible solutions to address bottlenecks associated with traditional drug delivery methods (low bioavailability, instability in the gastrointestinal tract, high dosage requirements, side effects, poor absorption, and incomplete drug utilization in the body). The dedicated efforts for precise and effective treatment have directed the development of ginsenoside-based nano-delivery systems to achieve potent anticancer efficacies and address the limitations in ginseng pharmacokinetics, facilitating drug development trials. Studies into ginseng pharmacokinetics showed a remarkable prolonged clearance and free drug levels of ~15% (ginsenoside RB1 nanoparticles) in mice (compared to only ~5% for ginsenosides) and better antitumor efficacies, demonstrating key success in ginseng biotechnology for drug development. Delving into the nanobiotechnological interventions in ginseng-derived therapeutics, this study summarizes current advances and achievements, particularly in cancer treatment, tackles existing gaps, focuses on feasible solutions, and examines prospects of translational success. Full article

Vitamin B12 is the common name for a group of cobalamins, which are cobalt corrines. Cobalamins are water-soluble B vitamins. Vitamin B12, as a coenzyme of various enzymes, is an essential component of many key metabolic processes in the body. Vitamin B12 deficiency causes dysfunction of various organs and systems in the body, including the central nervous system. Humans, like other animals, are unable to synthesize cobalamin. This vitamin must be supplied with a balanced diet. The only valuable dietary sources of cobalamin are foods of animal origin, especially offal (e.g., liver). Vegan and vegetarian diets are deficient in vitamin B12. People who follow this nutritional model require systematic cobalamin supplementation, usually in oral form. Other causes of cobalamin deficiency are various pathogenetic processes, in the course of which any of the stages of the complicated process of absorption of this vitamin from the gastrointestinal tract are impaired. Disorders of intestinal absorption of vitamin B12 require systematic supplementation of cobalamin parenterally (usually by intramuscular or subcutaneous injections) for the rest of life. Supplementary therapy with vitamin B12 may cause various adverse reactions, among which hypersensitivity reactions of various spectrums and intensity of symptoms are possible. According to available data, hypersensitivity to cobalamin is more likely after intramuscular or subcutaneous administration than in oral form. It also seems that long-term administration of cobalamin predisposes to allergy to vitamin B12, regardless of its chemical form. Although hypersensitivity to cobalamin is rather rare, it can also be of great clinical importance. This is due to the fact that vitamin B12 deficiency affects a significant part of the population, especially the elderly and those with chronic diseases that impair its absorption. In addition, supplementary therapy with cobalamin is long-term (usually lifelong) and there is no alternative form of treatment. For these reasons, solutions are sought that will allow for the safe continuation of treatment supplementing cobalamin deficiency. Various cyanocobalamin desensitization protocols are proposed, differing in duration, the dynamics of gradual dose increase, or the method of injection (intramuscular or subcutaneous). An analysis of available data in this field suggests that desensitization with cyanocobalamin seems to be an effective way to obtain tolerance to vitamin B12, allowing for long-term supplementation of this vitamin regardless of the chemical form, dose size, frequency, or route of administration. Full article