Search Results (147)

This study focuses on the issue of whether orally administered zinc (gluconate) (26 mg BID) can induce the remodeling of gastrointestinal barrier function and reduce passive leak across the human intestinal mucosal barrier in situ. Increased transmucosal leak has been implicated in diseases as diverse and seemingly unconnected as Inflammatory Bowel Disease (IBD), Celiac Disease, Autism Spectrum Disorders and Alzheimer’s Dementia. Our current investigation represents the first patient-based study to examine the effect of zinc on gastrointestinal epithelial tight junctions and gastrointestinal barrier leak in otherwise healthy test subjects. Using independent test subject groups for each endpoint, three separate molecular analyses indicated that zinc treatment can achieve a positive outcome: (1) RNA-seq analyses of intestinal biopsies showed salutary patterns of gene transcription changes dealing with not only transcripts of junctional proteins but also transcripts mitigating the proinflammatory state, as well as dedifferentiation (both modulators of tight junction permeability); (2) Western immunoblot analyses of intestinal tissue indicated that tight junctional protein expression was being modified by the administered zinc, most notably Claudin-2 and Tricellulin; (3) zinc treatment induced a reduction in serum levels of a functional marker of passive intestinal leak, namely the GI microbiome metabolite D-Lactate. The data collectively suggest that orally administered zinc can induce remodeling of the intestinal epithelial barrier, resulting in the reduction in GI barrier leak. The overall safety and economy of supplement levels of zinc suggest that this micronutrient could be efficacious as an adjuvant therapy to reduce the condition known as leaky gut, and possibly therefore be protective regarding diseases postulated to involve leaky gut. Full article

MRGPRX2 (Mas-related G protein-coupled receptor member X2) is implicated in mast cell (MC)-driven disorders due to its ability to bind diverse ligands, which may be G-protein-biased or balanced, with the latter activating both G-proteins and the β-arrestin pathway. Icatibant, a peptide drug, produces injection-site reactions in most patients and is used experimentally to probe MRGPRX2 function in skin tests. While reported to be G-protein-biased, it is unknown how skin MCs respond to icatibant, although these are the primary target cells during therapy. We therefore compared responses to icatibant with those induced by the balanced agonist substance P (SP) in skin MCs. Degranulation and desensitization were assessed via β-hexosaminidase release, receptor internalization by flow cytometry, and downstream signaling by immunoblotting. Skin MCs degranulated in response to SP and icatibant, relying on Gi proteins and calcium channels; Gq and PI3K (Phosphoinositide 3-kinase) contributed more strongly to exocytosis following icatibant, while JNK (c-Jun n-terminal kinase) was more relevant for SP. Both agonists activated ERK, PI3K/AKT, and (weakly) p38. Surprisingly, and in contrast to the LAD2 (Laboratory of Allergic Diseases 2 mast cell line) MC line, icatibant was at least as potent as SP in eliciting MRGPRX2 internalization and (cross-)desensitization in skin MCs. These findings suggest that icatibant functions differently in primary versus transformed MCs, acting as a fully balanced ligand in the former by triggering not only degranulation but also receptor internalization and desensitization. Therefore, not only the ligand but also the MRGPRX2-expressing cell plays a decisive role in whether a ligand is balanced or biased. These findings are relevant to our understanding of icatibant’s clinical effects on edema and itch. Full article

Repeated UV exposure, air pollution, and toxins promote skin oxidative stress. ROS destroy macromolecules, changing cellular mechanisms and signaling cascades. Inflammation and injury to skin cells degrade function and accelerate aging, causing wrinkles, firmness loss, and dermatological disorders. Gymnema inodorum (GI) contains phytochemical antioxidants such polyphenols and triterpenoids that lower ROS and strengthen skin. GI extracts (GIEs) have never been examined for their effects on dermal skin fibroblasts’ oxidative stress and intracellular cytoprotective mechanisms. In this study, GIEs were prepared as a water extract (GIE0) and ethanol extracts with concentrations ranging from 20% to 95% v/v (GIE20, GIE40, GIE60, GIE80, and GIE95). These extracts were assessed for phytochemical content, antioxidant capacity, and free radical scavenging efficacy. The results were compared to a commercially available native Gymnema extract (NGE) obtained from Gymnema sylvestre. During principal component analysis (PCA), the most effective extracts were identified and subsequently evaluated for their ability to mitigate oxidative stress in fibroblasts. Cytoprotective effects of GIE and NGE against H₂O₂-induced human dermal fibroblast injury were investigated by cell viability, intracellular ROS production, and signaling pathways. GIE0, GIE80, GIE95, and NGE were the best antioxidants. By preserving ROS balance and redox homeostasis, GIE and NGE reduce fibroblast inflammation and oxidative stress-induced damage. Decreased ROS levels reduce MAPK/AP-1/NF-κB and PI3K/AKT/NF-κB signaling pathways, diminishing inflammatory cytokines. In conclusion, GIE and NGE have antioxidant and anti-inflammatory capabilities that can reduce H₂O₂-induced fibroblast oxidative stress and damage, thereby preventing skin aging and targeting cancer-associated fibroblasts. Full article

Oxytocin (OT), traditionally associated with reproduction and social bonding, has emerged as a key modulator of gastrointestinal (GI) physiology and appetite regulation behavior through its actions within the gut–brain axis. Central to this regulation are vagal oxytocin receptors (VORs), which are located along vagal afferent and efferent fibers and within brainstem nuclei such as the nucleus tractus solitarius and dorsal motor nucleus of the vagus. This review presents a comprehensive synthesis of current knowledge on the anatomical distribution, molecular signaling, developmental plasticity, and functional roles of VORs in the regulation of GI motility, satiety, and energy homeostasis. We highlight how VORs integrate hormonal, microbial, and stress-related cues and interact with other neuropeptidergic systems including GLP-1, CCK, and nesfatin-1. Recent advances in spatial transcriptomics, single-nucleus RNA sequencing, chemogenetics, and optogenetics are discussed as transformative tools for mapping and manipulating VOR-expressing circuits. Particular attention is given to sex differences, translational challenges, and the limited understanding of VOR function in humans. This article proposes VORs as promising therapeutic targets in dysphagia, obesity, and functional GI disorders. We outline future research priorities, emphasizing the need for integrative, cross-species approaches to clarify VOR signaling and guide the development of targeted, personalized interventions. Full article

The ability of the neuropeptide oxytocin to affect glial cell function is receiving increasing attention. We previously reported that oxytocin at a low nanomolar concentration could inhibit both astrocytic Ca²⁺ signals and glutamate release. Here, we investigate the ability of oxytocin receptors to couple both inhibitory and stimulatory pathways in astrocytes, as already reported in neurons. We assessed the effects of oxytocin at concentrations ranging from low to high in the nanomolar range on intracellular Ca²⁺ signals and on the glutamate release in astrocyte processes freshly prepared from the striatum of adult rats. Our main findings are as follows: oxytocin could induce dual responses in astrocyte processes, namely the inhibition and facilitation of both Ca²⁺ signals and glutamate release; the inhibitory and the facilitatory response appeared dependent on activation of the G_i and the G_q pathway, respectively; both inhibitory and facilitatory responses were evoked at the same nanomolar oxytocin concentrations; and the biased agonists atosiban and carbetocin could duplicate oxytocin’s inhibitory and facilitatory response, respectively. In conclusion, due to the coupling of striatal astrocytic oxytocin receptors to different transduction pathways and the dual effects on Ca²⁺ signals and glutamate release, oxytocin could also play a crucial role in neuron–astrocyte bi-directional communication through a subtle regulation of striatal glutamatergic synapses. Therefore, astrocytic oxytocin receptors may offer pharmacological targets to regulate glutamatergic striatal transmission, which is potentially useful in neuropsychiatric disorders and in neurodegenerative diseases. Full article

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

Background: Gastrointestinal (GI) symptoms, often reported by individuals with autism spectrum disorders (ASD), may impair functionality and exacerbate behavioral symptoms. Gut dysbiosis has been identified as a potential environmental factor influencing these symptoms through gut-brain axis dysregulation. Fecal microbiota transplantation (FMT) is a promising therapeutic strategy with potential to alleviate symptoms. This review systematically evaluates the efficacy and safety of FMT in GI and ASD-related symptoms. Methods: This systematic review followed PRISMA 2020 guidelines and was registered in PROSPERO. The review included clinical trials on FMT in children and adolescents with ASD, published up to October 2024. The bias assessments were performed using Cochrane tools. Outcomes focused on changes in GI and ASD-related symptoms using scales selected by the authors. Results: This systematic review included two RCTs and seven before-and-after studies. Improvements in GI and ASD-related outcomes were reported in all before-and-after studies, whereas the results of RCTs were inconsistent. The before-and-after studies showed a high risk of bias, while the RCTs demonstrated a low risk. Conclusions: Although many studies have been conducted, the methodological limitations of some and contradictory findings of others make it difficult to draw clear conclusions about the effectiveness of FMT in children with ASD. Variations in intervention protocols underscore the importance of establishing standardized FMT procedures in future rigorously designed trials. Full article

Background: Lysosomal storage disorders (LSDs) are rare inherited metabolic diseases characterized by defects in lysosomal enzyme function or membrane transport. These defects lead to substrate accumulation and multisystemic manifestations. This review focuses on gastrointestinal (GI) involvement in LSDs, which is a significant but often overlooked aspect of these disorders. Methods: A comprehensive literature review was conducted to examine the pathophysiology, clinical presentation, diagnosis and management of GI manifestations in several LSDs, including Fabry disease, Gaucher disease, Pompe disease, Niemann–Pick disease type C, mucopolysaccharidoses and Wolman disease. Results: The pathogenesis of GI involvement in LSDs varies and encompasses substrate accumulation in enterocytes, mesenteric lymphadenopathy, mass effects, smooth muscle dysfunction, vasculopathy, neuropathy, inflammation and alterations to the microbiota. Clinical presentations range from non-specific symptoms, such as abdominal pain, diarrhea and malabsorption, to more severe complications, such as protein-losing enteropathy and inflammatory bowel disease. Diagnosis often requires a high level of suspicion, as GI symptoms may precede the diagnosis of the underlying LSD or be misattributed to more common conditions. Management strategies include disease-specific treatments, such as enzyme replacement therapy or substrate reduction therapy, as well as supportive care and targeted interventions for specific GI complications. Conclusions: This review highlights the importance of recognizing and properly managing GI manifestations in LSDs to improve patient outcomes and quality of life. It also emphasizes the need for further research to develop more effective treatments for life-threatening GI complications associated with these rare genetic disorders. Full article

With the rapid development of urban motorized transportation, the narrow and aging streets in historical and cultural districts can no longer meet modern traffic demands. The development of pedestrian systems and the improvement in street walkability have become important issues in the preservation and renewal of these districts. Although walkability research has established a relatively systematic theoretical framework and technical methods, current studies predominantly focus on modern urban roads due to limited attention to the unique characteristics of streets within historical and cultural districts. As a mixed-use area integrating residential, commercial, and tourism functions, the former Russian concession in Hankou features diverse street types and a rich spatial texture, making it a representative case for walkability research in historical districts. This study aimed to construct a walkability evaluation framework suited to the characteristics of such districts. First, relevant literature was reviewed and combined with the actual conditions of streets in the study area to select evaluation indicators and reconstruct the framework. Second, based on multi-source data, a comprehensive evaluation was conducted using spatial syntax, semantic segmentation, and GIS spatial analysis. The results show that streets with high walkability scores are mainly concentrated in the core tourism area and are strongly associated with the distribution of historical buildings. Finally, based on the evaluation results, three groups of representative streets were compared to analyze differences in pedestrian environments. Key issues such as low spatial quality and functional disorder were identified, and targeted optimization strategies are proposed. The findings provide useful references for the future preservation and sustainable renewal of historical and cultural districts. Full article

Background: Anorectal Manometry (ARM) plays a crucial role in diagnosing potential motility disorders of anorectum in pediatric gastroenterology. Despite its prevalence, the predictive utility of ARM in guiding therapeutic response remains poorly characterized. Objectives: This study aims to evaluate the effectiveness of ARM in predicting therapeutic responses among children with functional constipation. Methods: A retrospective chart review was conducted at two tertiary centers examining pediatric patients who underwent ARM between January 2018 and July 2022. Key ARM parameters were analyzed, including anal resting pressure, recto-anal inhibitory reflex (RAIR), first rectal sensation, and bear-down maneuver (BDM). Therapeutic responses were assessed post-ARM, with success defined as an increase in bowel movement frequency and/or a decrease in fecal incontinence. In addition, we also intended to evaluate the eventual need for surgical intervention as another outcome. Results: The study included 327 patients, with a median age of 8.2 years. The overall therapeutic response rate was 40.7%, with stimulant laxatives showing a 48% response. Notably, lower anal resting pressures and delayed rectal sensations were associated with better therapeutic outcomes. Abnormal BDM correlated with a lack of response to therapies, while the presence of abnormal RAIR was linked to a higher eventual need for surgical intervention. Conclusions: ARM is instrumental in predicting therapeutic responses in pediatric patients with functional constipation. In addition to diagnosing HD, ARM could be an instrumental tool in identifying patients with dyssynergic defecation for early intervention with targeted therapy in age-appropriate patients. Full article

Gastroenterology faces significant challenges due to the global burden of gastrointestinal (GI) diseases, driven by socio-economic disparities and their wide-ranging impact on health and healthcare systems. Advances in molecularly imprinted polymers (MIPs) offer promising opportunities for developing non-invasive, cost-effective diagnostic tools that enhance the accuracy and accessibility of GI disease detection. This research explores the potential of MIP-based sensors in revolutionizing gastrointestinal diagnostics and improving early detection and disease management. Biomarkers are vital in diagnosing, monitoring, and personalizing disease treatment, particularly in gastroenterology, where advancements like MIPs offer highly selective and non-invasive diagnostic solutions. MIPs mimic natural recognition mechanisms, providing stability and sensitivity even in complex biological environments, making them ideal for early disease detection and real-time monitoring. Their integration with advanced technologies, including conducting polymers, enhances their functionality, enabling rapid, point-of-care diagnostics for gastrointestinal disorders. Despite regulatory approval and scalability challenges, ongoing innovations promise to revolutionize diagnostics and improve patient outcomes through precise approaches. Full article

Background: Upper gastrointestinal (GI) motility disorders, such as gastroparesis and functional dyspepsia (FD), contribute significantly to morbidity, especially in populations at risk for type 2 diabetes. However, the prevalence and clinical manifestations of these disorders in India, and associated gastric dysrhythmias, are not well studied within this population. Methods: This retrospective, cross-sectional study analyzed 3689 patients who underwent electrogastrography with water load satiety test (EGGWLST) testing across multiple motility clinics in India. The prevalence of gastroparesis and FD-like symptoms, symptom severity, and their association with diabetes and other comorbidities were evaluated. Symptom severity was assessed using the Gastroparesis Cardinal Symptom Index (GCSI). EGGWLST findings were documented, including the gastric myoelectric activity threshold (GMAT) scores. Results: The study population had a mean age of 43.18 years. GCSI scores indicated that patients had symptoms that were mild (55%), moderate (33%), and severe (8%). Compared with the non-diabetic population, diabetic subjects had significantly higher rates of early satiety (56% vs. 45%, p < 0.0001), bloating (73% vs. 67%, p = 0.005), and reflux (28% vs. 24%, p = 0.029). WLST data analysis revealed that significantly more diabetic subjects ingested <350 mL (16% vs. 12%, p = 0.000016). EGG analysis revealed gastric dysthymias in one-third (65%) of patients. Significantly more diabetic subjects (22% vs. 18% p = 0.015) had a GMAT score >0.59. Conclusions: Upper GI motility disorders are prevalent in India, particularly among diabetic patients. EGG is a valuable tool for characterizing these disorders, and may help in personalizing therapeutic approaches. Further research is required to optimize treatment strategies. Full article

Background/Objectives: Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder affecting women of reproductive age. It is associated with glucose intolerance, insulin resistance and diabetes mellitus. The oral glucose tolerance test (OGTT) is commonly employed to detect glucose intolerance, but it can be inconvenient and time-consuming. We aimed to evaluate the precision of haemoglobin A1c (HbA1c) and other serum markers in predicting abnormal glucose tolerance (AGT). Methods: This diagnostic study involved 121 PCOS women who attended the Gynaecologic Endocrinology Unit at Siriraj Hospital. Patients underwent assessments for weight, height, waist circumference, modified Ferriman–Gallwey score and acanthosis nigricans. Blood samples were collected to measure fasting glucose and insulin levels after a 75-gram oral OGTT, fasting insulin level, HbA1c, lipid profile, androgen profile and complete blood count. Homeostasis model assessment of insulin resistance (HOMA-IR), homeostasis model assessment of beta-cell function (HOMA-β), quantitative insulin sensitivity check index (QUICKI) and fasting glucose-to-insulin ratio (G/I ratio) were calculated. The sensitivity, specificity and accuracy of these serum markers were compared. Results: The prevalence of AGT was 24.8%. The area under the receiver operating characteristic curve for HbA1c in detecting AGT was 0.656, while HOMA-IR, HOMA-β, QUICKI and the G/I ratio had values of 0.817, 0.737, 0.817 and 0.77, respectively. The G/I ratio cut-off point of 6% demonstrated a sensitivity of 73.3%, specificity of 74.7%, positive predictive value of 48.9%, negative predictive value of 89.5% and accuracy of 74.4%. Conclusions: The G/I ratio is the most accurate compared to other serum markers in detecting AGT among Thai women with PCOS. Full article

Conditions like diabetes mellitus (DM), cancer, infections, inflammation, cardiovascular diseases (CVDs), and gastrointestinal (GI) disorders continue to have a major global impact on mortality and morbidity. Medicinal plants have been used since ancient times in ethnomedicine (e.g., Ayurveda, Unani, Traditional Chinese Medicine, and European Traditional Medicine) for the treatment of a wide range of disorders. Plants are a rich source of diverse phytoconstituents with antidiabetic, anticancer, antimicrobial, antihypertensive, antioxidant, antihyperlipidemic, cardioprotective, immunomodulatory, and/or anti-inflammatory activities. This review focuses on the 35 plants most commonly reported for the treatment of these major disorders, with a particular emphasis on their traditional uses, phytoconstituent contents, pharmacological properties, and modes of action. Active phytomolecules with therapeutic potential include cucurbitane triterpenoids, diosgenin, and limonoids (azadiradione and gedunin), which exhibit antidiabetic properties, with cucurbitane triterpenoids specifically activating Glucose Transporter Type 4 (GLUT4) translocation. Capsaicin and curcumin demonstrate anticancer activity by deactivating NF-κB and arresting the cell cycle in the G2 phase. Antimicrobial activities have been observed for piperine, reserpine, berberine, dictamnine, chelerythrine, and allitridin, with the latter two triggering bacterial cell lysis. Quercetin, catechin, and genistein exhibit anti-inflammatory properties, with genistein specifically suppressing CD8+ cytotoxic T cell function. Ginsenoside Rg1 and ginsenoside Rg3 demonstrate potential for treating cardiovascular diseases, with ginsenoside Rg1 activating PPARα promoter, and the PI3K/Akt pathway. In contrast, ternatin, tannins, and quercitrin exhibit potential in gastrointestinal disorders, with quercitrin regulating arachidonic acid metabolism by suppressing cyclooxygenase (COX) and lipoxygenase activity. Further studies are warranted to fully investigate the clinical therapeutic benefits of these plants and their phytoconstituents, as well as to elucidate their underlying molecular mechanisms of action. Full article