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The peristaltic reflex has been a central concept in gastrointestinal motility; however, evidence was published recently suggesting that post‐stimulus responses that follow inhibitory neural responses provide the main propulsive force in colonic motility. This new concept was based on experiments on proximal colon where enteric inhibitory neural inputs are mainly nitrergic. However, the nature of inhibitory neural inputs changes from proximal to distal colon where purinergic inhibitory regulation dominates. In spite of the transition from nitrergic to purinergic regulation, post‐stimulus responses and propulsive contractions were both blocked by antagonists of a conductance (ANO1) exclusive to interstitial cells of Cajal (ICC). How purinergic neurotransmission, transduced by PDGFRα+ cells, can influence ANO1 in ICC is unknown. We compared neural responses in proximal and distal colon. Post‐stimulus responses were blocked by inhibition of nitrergic neurotransmission in proximal colon, but P2Y1 receptor antagonists were more effective in distal colon. Ca2+ entry through voltage‐dependent channels (CaV3) enhances Ca2+ release in ICC. Thus, we reasoned that hyperpolarization caused by purinergic responses in PDGFRα+ cells, which are electrically coupled to ICC, might decrease inactivation of CaV3 channels and activate Ca2+ entry into ICC via anode‐break upon cessation of inhibitory responses. Post‐stimulus responses in distal colon were blocked by MRS2500 (P2Y1 receptor antagonist), apamin (SK channel antagonist) and NNC55‐0396 (CaV3 antagonist). These compounds also blocked propagating contractions in mid and distal colon. These data provide the first clear demonstration that integration of functions in the smooth muscle–ICC–PDGFRα+ cell (SIP) syncytium generates a major motility behaviour. Key points: Propagating propulsive contractions initiated by the enteric nervous system are a major motility behaviour in the colon. A major component of contractions, necessary for propulsive contractions, occurs at cessation of enteric inhibitory neurotransmission (post‐stimulus response) and is generated by interstitial cells of Cajal (ICC), which are electrically coupled to smooth muscle cells.The nature of enteric inhibitory neurotransmission shifts from proximal colon, where it is predominantly due to nitric oxide, to distal colon, where it is predominantly due to purine neurotransmitters.Different cells transduce nitric oxide and purines in the colon. ICC transduce nitric oxide, but another type of interstitial cell, PDGFRα+ cells, transduces input from purinergic neurons.However, the post‐stimulus responses in proximal and distal colon are still generated in ICC.This paper explores how integrated behaviours of ICC, PDGFRα+ cells and smooth muscle cells accomplish propulsive motility in the colon. [ABSTRACT FROM AUTHOR]

Abstract Introduction Hirschsprung’s disease (HD) is a neurogenic intestinal disorder attributed to incomplete neural crest cell migration during fetal intestinal development, leading to an aganglionic segment of the colon and functional obstruction. Associated malformations like intestinal atresia, hydronephrosis, and imperforate anus can accompany Hirschsprung’s disease. this study aims to evaluate the efficacy of Calretinin and Cajal cells (CD34 and CD117) immunohistochemical staining in improving HD diagnosis. Methods The study involved 70 pediatric patients suspected of Hirschsprung’s disease. Clinical, histopathological, and immunohistochemical analyses were conducted, focusing on calretinin, CD34, and CD117 markers to identify ganglion cells and Cajal cells. Data were statistically analyzed using SPSS software. Results In the examination of the samples, the calretinin marker exhibited a consistent accuracy of 100% in diagnosing Hirschsprung’s disease (with sensitivity and specificity both at 100%). Regarding the markers for Cajal cells in cases of Hirschsprung’s disease, an irregularity in the arrangement of Cajal cells was observed, which was absent in normal cases. These markers also demonstrated a specificity and sensitivity of 100% in diagnosing the disease. Conclusion Hirschsprung’s disease remains a complex condition with multifaceted pathophysiological mechanisms. Calretinin immunohistochemical staining offers enhanced diagnostic accuracy, while the debate surrounding ICC distribution underscores the need for advanced diagnostic techniques. Further research is warranted to unravel the intricacies of Hirschsprung’s disease and its associated complications.

Abstract Background Gastrointestinal mesenchymal stromal tumors (GISTs) are a group of intramural tumors that exhibit a wide range of morphologies. Dysfunction or loss of interstitial cells of Cajal (ICCs) is correlated with the disorders of gastrointestinal motility. At present, the characterization and molecular mechanisms underlying the role of ICCs in GIST are still not clear. Methods The GSE162115 dataset from Gene Expression Omnibus database was processed using Seurat package for quality control, data normalization, and cell clustering. Differential expression and functional enrichment analyses were performed using the FindAllMarkers function and clusterProfiler package. Cellular heterogeneity was assessed by CytoTRACE and potential regulatory mechanisms of ICCs in GISTs were investigated using SCENIC. Cellular communication was inferred and analyzed applying the CellChat package. Results Eight clusters were identified based on 34,861 cells. Intra-tumor samples had a higher proportion of ICCs than peri-tumor. ICCs were related to cell cycle and glycolytic activity in intra-tumor samples, while those in peri-tumor samples were involved in immune response. Further analysis identified four ICC subgroups (subcluster 1–4), of which subcluster 3 showed the most typical stem cell properties and interacted with the rest of the cells through the MIF-CD74 (CD44) protein. Conclusion This study analyzed the heterogeneity and stem cell properties of ICCs in GISTs, revealing the molecular mechanisms and potential therapeutic targets for GISTs.

Background: Hypercholesterolemia induces cholelithiasis and dysfunction of gallbladder motility. Interstitial cells of Cajal (ICCs) contribute to gallbladder motility. Emodin modulates the contractility of the gallbladder muscle; however, the underlying mechanism is unknown. Aim: This study aimed to explore the effects of emodin on gallbladder ICCs with cholelithiasis in a guinea pig model. Methods: Animals were randomly divided into a healthy control group and three study groups. All study groups received a high-cholesterol diet (HCD) for 8 weeks. Subsequently, they were randomly assigned to either the HCD group or one of the emodin treatment groups lasting 4 or 8 weeks. Total cholesterol (TC) and triglycerides (TG) were measured to determine changes in serum lipid levels. Immunohistochemistry was performed to detect the morphology and number of ICCs. TUNEL assays were performed to detect ICC apoptosis. Transmission electron microscopy was employed to observe ICC structure. Western blotting and real-time polymerase chain reaction were used to detect changes in stem cell factor (SCF)/c-kit pathway expression. Results: Serum TC and TG were higher in all study groups. In cases of cholelithiasis, the SCF/c-kit pathway was downregulated, the number of gallbladder ICCs decreased, apoptosis increased, and the ICC network structure was damaged. After emodin treatment, the SCF/c-kit pathway was upregulated, the number of gallbladder ICCs increased, apoptosis decreased, and the ICC network structure recovered. Conclusion: Cholelithiasis downregulates the SCF/c-kit pathway and damages gallbladder ICCs. Emodin upregulates the SCF/c-kit pathway and increases gallbladder ICCs, contributing to recovery from gallbladder motility disorders. [ABSTRACT FROM AUTHOR]

Background: Gastrointestinal mesenchymal stromal tumors (GISTs) are a group of intramural tumors that exhibit a wide range of morphologies. Dysfunction or loss of interstitial cells of Cajal (ICCs) is correlated with the disorders of gastrointestinal motility. At present, the characterization and molecular mechanisms underlying the role of ICCs in GIST are still not clear. Methods: The GSE162115 dataset from Gene Expression Omnibus database was processed using Seurat package for quality control, data normalization, and cell clustering. Differential expression and functional enrichment analyses were performed using the FindAllMarkers function and clusterProfiler package. Cellular heterogeneity was assessed by CytoTRACE and potential regulatory mechanisms of ICCs in GISTs were investigated using SCENIC. Cellular communication was inferred and analyzed applying the CellChat package. Results: Eight clusters were identified based on 34,861 cells. Intra-tumor samples had a higher proportion of ICCs than peri-tumor. ICCs were related to cell cycle and glycolytic activity in intra-tumor samples, while those in peri-tumor samples were involved in immune response. Further analysis identified four ICC subgroups (subcluster 1–4), of which subcluster 3 showed the most typical stem cell properties and interacted with the rest of the cells through the MIF-CD74 (CD44) protein. Conclusion: This study analyzed the heterogeneity and stem cell properties of ICCs in GISTs, revealing the molecular mechanisms and potential therapeutic targets for GISTs. [ABSTRACT FROM AUTHOR]

Rhythmic electrical events, termed slow waves, govern the timing and amplitude of phasic contractions of the gastric musculature. Extracellular multielectrode measurement of gastric slow waves can be a biomarker for phenotypes of motility dysfunction. However, a gastric slow-wave conduction pathway for the rat, a common animal model, is unestablished. In this study, the validity of extracellular recording was demonstrated in vitro with simultaneous intracellular and extracellular recordings and by pharmacological inhibition of slow waves. The conduction pathway was determined by in vivo extracellular recordings while considering the effect of motion. Slow-wave characteristics [means (SD)] varied regionally having higher amplitude in the antrum than the distal corpus [1.03 (0.12) mV vs. 0.75 (0.31) mV; n ¼ 7; P ¼ 0.025 paired t test] and faster propagation near the greater curvature than the lesser curvature [1.00 (0.14) mm·s-1 vs. 0.74 (0.14) mm·s-1 ; n ¼ 9 GC, 7 LC; P ¼ 0.003 unpaired t test]. Notably, in some subjects, separate wavefronts propagated near the lesser and greater curvatures with a loosely coupled region occurring in the area near the distal corpus midline at the interface of the two wavefronts. This region had either the greater or lesser curvature wavefront propagating through it in a time-varying manner. The conduction pattern suggests that slow waves in the rat stomach form annular wavefronts in the antrum and not the corpus. This study has implications for interpretation of the relationship between slow waves, the interstitial cells of Cajal network structure, smooth muscles, and gastric motility. NEW & NOTEWORTHY Mapping of rat gastric slow waves showed regional variations in their organization. In some subjects, separate wavefronts propagated near the lesser and greater curvatures with a loosely coupled region near the midline, between the wavefronts, having a varying slow-wave origin. Furthermore, simultaneous intracellular and extracellular recordings were concordant and independent of movement artifacts, indicating that extracellular recordings can be interpreted in terms of their intracellular counterparts when intracellular recording is not possible [ABSTRACT FROM AUTHOR]

Few biomarkers support the diagnosis and treatment of disorders of gut-brain interaction (DGBI), although gastroduodenal junction (GDJ) electromechanical coupling is a target for novel interventions. Rhythmic "slow waves," generated by interstitial cells of Cajal (ICC), and myogenic "spikes" are bioelectrical mechanisms underpinning motility. In this study, simultaneous in vivo high-resolution electrophysiological and impedance planimetry measurements were paired with immunohistochemistry to elucidate GDJ electromechanical coupling. Following ethical approval, the GDJ of anaesthetized pigs (n = 12) was exposed. Anatomically specific, high-resolution electrode arrays (256 electrodes) were applied to the serosa. EndoFLIP catheters (16 electrodes; Medtronic, MN) were positioned luminally to estimate diameter. Postmortem tissue samples were stained with Masson's trichrome and Ano1 to quantify musculature and ICC. Electrical mapping captured slow waves (n = 512) and spikes (n = 1,071). Contractions paralleled electrical patterns. Localized slow waves and spikes preceded rhythmic contractions of the antrum and nonrhythmic contractions of the duodenum. Slow-wave and spike amplitudes were correlated in the antrum (r = 0.74, P < 0.001) and duodenum (r = 0.42, P < 0.001). Slow-wave and contractile amplitudes were correlated in the antrum (r = 0.48, P < 0.001) and duodenum (r = 0.35, P < 0.001). Distinct longitudinal and circular muscle layers of the antrum and duodenum had a total thickness of (2.8 ± 0.9) mm and (0.4 ± 0.1) mm, respectively. At the pylorus, muscle layers merged and thickened to (3.5 ± 1.6) mm. Pyloric myenteric ICC covered less area (1.5 ± 1.1%) compared with the antrum (4.2 ± 3.0%) and duodenum (5.3 ± 2.8%). Further characterization of electromechanical coupling and ICC biopsies may generate DGBI biomarkers. NEW & NOTEWORTHY: This study applies electrical mapping, impedance planimetry, and histological techniques to the gastroduodenal junction to elucidate electromechanical coupling in vivo. Contractions of the terminal antrum and pyloric sphincter were associated with gastric slow waves. In the duodenum, bursts of spike activity triggered oscillating contractions. The relative sparsity of myenteric interstitial cells of Cajal in the pylorus, compared with the adjacent antrum and duodenum, is hypothesized to prevent coupling between antral and duodenal slow waves. [ABSTRACT FROM AUTHOR]

Background Purpose The incidence of constipation increases among the elderly (>65 years), while abdominal pain decreases. Causes include changes in lifestyle (e.g., diet and reduced exercise), disease and medications affecting gastrointestinal functions. Degenerative changes may also occur within the colo‐rectum. However, most evidence is from rodents, animals with relatively high rates of metabolism and accelerated aging, with considerable variation in time course. In humans, cellular and non‐cellular changes in the aging intestine are poorly investigated.To examine all available studies which reported the effects of aging on cellular and tissue functions of human isolated colon, noting the region studied, sex and age of tissue donors and study size. The focus on human colon reflects the ability to access full‐thickness tissue over a wide age range, compared with other gastrointestinal regions. Details are important because of natural human variability.We found age‐related changes within the muscle, in the enteric and nociceptor innervation, and in the submucosa. Some involve all regions of colon, but the ascending colon appears more vulnerable. Changes can be cell‐ and sublayer‐dependent. Mechanisms are unclear but may include development of “senescent‐like” and associated inflammaging, perhaps associated with increased mucosal permeability to harmful luminal contents.In summary, reduced nociceptor innervation can explain diminished abdominal pain among the elderly. Degenerative changes within the colon wall may have little impact on symptoms and colonic functions, because of high “functional reserve,” but are likely to facilitate the development of constipation during age‐related challenges (e.g., lifestyle, disease, and medications), now operating against a reduced functional reserve. [ABSTRACT FROM AUTHOR]

Background. The aim of the research was to determine the ultrastructure of the cells of the muscle wall of the mice gallbladder under the influence of ursodeoxycholic acid. Materials and methods. The animals were divided into 2 groups: experimental (n = 17) — mice which received ursodeoxycholic acid at a dose of 100.0 mg/kg and control (n = 13) — intact ones (distilled water). Histological and ultrastructural analyses of gallbladder wall samples of mice were performed. Results. Mitotic figures of myocytes in the wall of the gallbladder bottom (1.794 ± 0.103 %) and body (1.607 ± 0.095 %) in the experimental group of mice were significantly more frequent compared to the controls (0.946 ± 0.058 % and 0.873 ± 0.061 %) (p

Introduction: Etiopathogenesis and the symptomatology of ureteropelvic junction obstruction (UPJO) in the pediatric population has not yet been definitely clarified, suggesting a multifactorial nature of the condition. The aim was to analyze the association between the number of Interstitial Cells of Cajal (ICCs), as well as P2X3 receptors in ureteropelvic junction (UPJ) and the pain response in pediatric patients with hydronephrosis. Methods: 50 patients with congenital hydronephrosis underwent open or laparoscopic pyeloplasty at one of two departments of pediatric surgery and urology in Poland. Patients were divided into two groups according to the pain symptoms before surgery. A total of 50 samples of UPJ were obtained intraoperatively and underwent histopathological and immunohistochemical (IHC) analysis. Quantitative assessment of ICCs was based on the number of CD117(+) cells of adequate morphology in the subepithelial layer and the muscularis propria. Expression of P2X3 receptors was evaluated as the intensity of IHC staining. Results: Patients with hydronephrosis and accompanying pain were on average 60 months older (77 vs. 17 months) than children with asymptomatic hydronephrosis (p = 0.017). Symptomatic children revealed higher numbers of ICCs in both the subepithelial layer and in the lamina muscularis propria. In particular, symptomatic patients aged 2 years or more exhibited significantly higher numbers of ICCs in the subepithelial layer. Significant differences in the distribution of ICCs between the subepithelial layer and the lamina muscularis propria were observed in both groups. Expression of P2X3 receptors was limited to the urothelium and the muscle layer and correlated between these structures. There was no relationship between pain response and the expression of P2X3 receptors. Conclusions: ICCs and P2X3 receptors may participate in the pathogenesis of UPJO and in the modulation of pain response to a dilatation of the pyelocaliceal system. Explanation of the role of ICCs and P2X3 receptors in propagation of ureteral peristaltic wave and the modulation of pain stimuli requires further studies. [ABSTRACT FROM AUTHOR]

Diabetic gastroparesis (DGP) is a common complication of diabetes mellitus, marked by gastrointestinal motility disorder, a delayed gastric emptying present in the absence of mechanical obstruction. Clinical manifestations include postprandial fullness and epigastric discomfort, bloating, nausea, and vomiting. DGP may significantly affect the quality of life and productivity of patients. Research on the relationship between gastrointestinal dynamics and DGP has received much attention because of the increasing prevalence of DGP. Gastrointestinal motility disorders are closely related to a variety of factors including the absence and destruction of interstitial cells of Cajal, abnormalities in the neuro-endocrine system and hormone levels. Therefore, this study will review recent literature on the mechanisms of DGP and gastrointestinal motility disorders as well as the development of prokinetic treatment of gastrointestinal motility disorders in order to give future research directions and identify treatment strategies for DGP. [ABSTRACT FROM AUTHOR]

We examined the localization of the 5-hydroxytryptamine (5-HT) receptor and its effects on mouse colonic interstitial cells of Cajal (ICCs) using electrophysiological techniques. Treatment with 5-HT increased the pacemaker activity in colonic ICCs with depolarization of membrane potentials in a dose-dependent manner. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blockers blocked pacemaker activity and 5-HT-induced effects. Moreover, an adenylate cyclase inhibitor inhibited 5-HT-induced effects, and cell-permeable 8-bromo-cAMP increased the pacemaker activity. Various agonists of the 5-HT receptor subtype were working in colonic ICCs, including the 5-HT4 receptor. In small intestinal ICCs, 5-HT depolarized the membrane potentials transiently. Adenylate cyclase inhibitors or HCN blockers did not show any influence on 5-HT-induced effects. Anoctamin-1 (ANO1) or T-type Ca2+ channel blockers inhibited the pacemaker activity of colonic ICCs and blocked 5-HT-induced effects. A tyrosine protein kinase inhibitor inhibited pacemaker activity in colonic ICCs under controlled conditions but did not show any influence on 5-HT-induced effects. Among mitogen-activated protein kinase (MAPK) inhibitors, a p38 MAPK inhibitor inhibited 5-HT-induced effects on colonic ICCs. Thus, 5-HT's effect on pacemaker activity in small intestinal and colonic ICCs has excitatory but variable patterns. ANO1, T-type Ca2+, and HCN channels are involved in 5-HT-induced effects, and MAPKs are involved in 5-HT effects in colonic ICCs. [ABSTRACT FROM AUTHOR]

Cisplatin is an antimitotic drug able to cause acute and chronic gastrointestinal side effects. Acute side effects are attributable to mucositis while chronic ones are due to neuropathy. Cisplatin has also antibiotic properties inducing dysbiosis which enhances the inflammatory response, worsening local damage. Thus, a treatment aimed at protecting the microbiota could prevent or reduce the toxicity of chemotherapy. Furthermore, since a healthy microbiota enhances the effects of some chemotherapeutic drugs, prebiotics could also improve this drug effectiveness. We investigated whether chronic cisplatin administration determined morphological and functional alterations in mouse proximal colon and whether a diet enriched in prebiotics had protective effects. The results showed that cisplatin caused lack of weight gain, increase in kaolin intake, decrease in stool production and mucus secretion. Prebiotics prevented increases in kaolin intake, changes in stool production and mucus secretion, but had no effect on the lack of weight gain. Moreover, cisplatin determined a reduction in amplitude of spontaneous muscular contractions and of Connexin (Cx)43 expression in the interstitial cells of Cajal, changes that were partially prevented by prebiotics. In conclusion, the present study shows that daily administration of prebiotics, likely protecting the microbiota, prevents most of the colonic cisplatin‐induced alterations. [ABSTRACT FROM AUTHOR]

Abstract Disorders of gastrointestinal motility are the major physiologic problem in chagasic megacolon. The contraction mechanism is complex and controlled by different cell types such as enteric neurons, smooth muscle, telocytes, and an important pacemaker of the intestine, the interstitial cells of Cajal (ICCs). The role of ICCs in the progression of acute and chronic Chagas disease remains unclear. In the present work, we investigate the aspects of ICCs in a long-term model of Chagas disease that mimics the pathological aspects of human megacolon. Different subsets of ICCs isolated from Auerbach’s myenteric plexuses and muscle layers of control and Trypanosoma cruzi infected animals were determined by analysis of CD117, CD44, and CD34 expression by flow cytometer. Compared with the respective controls, the results showed a reduced frequency of mature ICCs in the acute phase and three months after infection. These results demonstrate for the first time the phenotypic distribution of ICCs associated with functional dysfunction in a murine model of chagasic megacolon. This murine model proved valuable for studying the profile of ICCs as an integrative system in the gut and as a platform for understanding the mechanism of chagasic megacolon development.

ObjectiveThe significance of interstitial cells of Cajal (ICC) in the gastrointestinal tract has garnered increasing attention. In recent years, approximately 80 articles on ICC have been published annually in various journals. However, no bibliometric study has specifically focused on the literature related to ICC. Therefore, we conducted a comprehensive bibliometric analysis of ICC to reveal dynamic scientific developments, assisting researchers in exploring hotspots and emerging trends while gaining a global perspective.MethodsWe conducted a literature search in the Web of Science Core Collection (WoSCC) from January 1, 2013, to December 31, 2023, to identify relevant literature on ICC. We employed bibliometric software, namely VOSviewer and CiteSpace, to analyze various aspects including annual publication output, collaborations, research hotspots, current status, and development trends in this domain.ResultsA total of 891 English papers were published in 359 journals by 928 institutions from 57 countries/regions. According to the keyword analysis of the literature, researchers mainly focused on “c-Kit,” “expression,” “smooth muscle,” and “nitric oxide” related to ICC over the past 11 years. However, with “SIP syncytium,” “ANO1,” “enteric neurons,” “gastrointestinal stromal tumors (GIST),” and “functional dyspepsia (FD),” there has been a growing interest in the relationship between ANO1, SIP syncytium, and ICC, as well as the role of ICC in the treatment of GIST and FD.ConclusionBibliometric analysis has revealed the current status of ICC research. The association between ANO1, SIP syncytium, enteric neurons and ICC, as well as the role of ICC in the treatment of GIST versus FD has become the focus of current research. However, further research and collaboration on a global scale are still needed. Our analysis is particularly valuable to researchers in gastroenterology, oncology, and cell biology, providing insights that can guide future research directions.

The main function of interstitial cells of Cajal (ICCs) is to regulate gastrointestinal peristalsis by acting as a “pacemaker” cell by generating spontaneous slow electrical waves. In 2005, electron microscopy revealed a cell type similar to ICCs (ICC-like) outside the gastrointestinal tract, with contractile activity and c-Kit+ immunohistochemistry shared with ICCs. Among the locations where ICC-like cells have been observed, it is in the uterus where they have a significant functional and pathophysiological role. These cells are involved in obstetric phenomena of contractile action, such as ascending sperm transport, embryo implantation, pregnancy, delivery, and the expulsion of menstrual debris. Within the pathophysiology related to these cells, we find obstetric alterations such as recurrent miscarriages, premature deliveries, abolition of uterine contractions, and failures of embryo implantation, in addition to other common conditions in the fertile age, such as endometriosis and leiomyoma.

Diabetic gastroenteropathy is a common complication in diabetes mellitus. Disturbance of interstitial cells of Cajal (ICC) distribution plays a significant role in the development of intestinal motility dysfunction. The aim of this study was to investigate the alterations of the intramuscular and myenteric ICC in the small intestine of rats with diabetes mellitus. Male Wistar rats were used and diabetes was induced by streptozotocinnicotinamide (STZ-NA) application. The small intestine specimens were exposed to c-Kit antibody to investigate the ICC. Morphological changes of the cells were quantified by the numerical areal density of intramuscular ICC, and the ICC score of myenteric ICC. Results showed loss of ICC and their network in the small intestine in the diabetic group. In conclusion, a statistically significant decrease in the number of intramuscular ICC and myenteric ICC was observed in all examined parts of the small intestine in rats with diabetes mellitus. Diabetes mellitus significantly changes the microenvironment of ICC and most likely the reduced signaling by insulin affects ICC and causes their loss. [ABSTRACT FROM AUTHOR]

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The Xiao Chengqi (XCQ) formula is a newly constituted traditional Chinese medicine prescription in the treatment of intestinal motility deficiency and is effective in patients with slow transit constipation (STC). XCQ formula was reconstructed based on a "Chengqi" decoction. Astragali Radix, Angelicae Sinensis Radix, and cooked ground Salviae Miltiorrhizae Radix et Rhizoma were added to the prescription to enhance. An STC rat model was constructed and treated with the formula to understand the detailed mechanism by which XCQ promotes intestinal peristalsis. The effects of the XCQ formula on intestinal microflora and metabolic levels and the possible molecular mechanism of its regulation were explored using 16S rDNA sequencing, metabolomics sequencing, and tissue RNA sequencing. The results showed a significant decrease in the abundance of Roseburia spp. in the feces of STC rats, a significant decrease in the content of butyl aminobenzene (BAB) in feces, and an increase in the number of interstitial cells of Cajal (ICC) in the colon of STC rats. Furthermore, in vitro and in vivo experiments revealed that BAB could activate IL-21R on the ICC surface, upregulate the phosphorylation of the downstream molecules STAT3 and ERK, and inhibit loperamide-induced ICC apoptosis. Therefore, the XCQ formula can improve the defecation status of patients with STC by protecting ICC activity, promoting the colonization of Roseburia spp. to promote peristalsis, and increasing the BAB content after metabolism. [ABSTRACT FROM AUTHOR]

The article discusses advancements in gastric electrophysiology research, particularly focusing on the use of body surface gastric mapping (BSGM) technology as an alternative to legacy electrogastrography (EGG). The authors highlight the clinical benefits of BSGM in identifying patients with gastric neuromuscular disorders and exploring new physiological phenotypes. Additionally, the study examines the effects of exogenous hormonal contraception on gastric electrophysiology, suggesting a potential role for progesterone in regulating gastric frequency. Overall, the authors express optimism about the future clinical applications of high-resolution EGG technology. [Extracted from the article]

Effective and widely available strategies are needed to diagnose colonic motility dysfunction. We investigated whether ultrasonography could generate spatiotemporal maps combined with motor pattern frequency analysis, to become a noninvasive method to characterize human colon motor patterns. Abdominal colonic ultrasonography was performed on healthy subjects (N = 7), focusing on the detailed recording of spontaneous haustral activities. We developed image segmentation and frequency analysis software to analyze the motor patterns captured. Ultrasonography recordings of the ascending, transverse, and descending colon identified three distinct rhythmic motor patterns: the 1 cycle/min and the 3 cycles/min cyclic motor pattern were seen throughout the whole colon, whereas the 12 cycles/min cyclic motor pattern was identified in the ascending colon. The rhythmic motor patterns of the human colon that are associated with interstitial cells of Cajal-associated pacemaking activity can be accurately identified and quantified using ultrasound. [ABSTRACT FROM AUTHOR]

Gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms, believed to originate from the interstitial cells of Cajal (ICC), often caused by overexpression of tyrosine kinase receptors (TKR) KIT or PDGFRA. Here, we present evidence that the embryonic stem cell factor FOXD3, first identified as ‘Genesis’ and involved in both gastrointestinal and neural crest cell development, is implicated in GIST pathogenesis; its involvement is investigated both in vitro and in zebrafish and a mouse model of FOXD3 deficiency. Samples from a total of 58 patients with wild-type GISTs were used for molecular analyses, including Sanger sequencing, comparative genomic hybridization, and methylation analysis. Immunohistochemistry and western blot evaluation were used to assess FOXD3 expression. Additionally, we conducted in vitro functional studies in tissue samples and in transfected cells to confirm the pathogenicity of the identified genetic variants. Germline partially inactivating FOXD3 sequence variants (p.R54H and p.Ala88_Gly91del) were found in patients with isolated GISTs. Chromosome 1p loss was the most frequent chromosomal abnormality identified in tumors. In vitro experiments demonstrate the impairment of FOXD3 in the presence of those variants. Animal studies showed disruption of the GI neural network and changes in the number and distribution in the ICC. FOXD3 suppresses KIT expression in human cells; its inactivation led to an increase in ICC in zebrafish, as well as mice, providing evidence for a functional link between FOXD3 defects and KIT overexpression leading to GIST formation. [ABSTRACT FROM AUTHOR]

Neurointestinal diseases result from dysregulated interactions between the nervous system and the gastrointestinal (GI) tract, leading to conditions such as Hirschsprung's disease and irritable bowel syndrome. These disorders affect many people, significantly diminishing their quality of life and overall health. Central to GI motility are the interstitial cells of Cajal (ICC), which play a key role in muscle contractions and neuromuscular transmission. This review highlights the role of ICC in neurointestinal diseases, revealing their association with various GI ailments. Understanding the functions of the ICC could lead to innovative perspectives on the modulation of GI motility and introduce new therapeutic paradigms. These insights have the potential to enhance efforts to combat neurointestinal diseases and may lead to interventions that could alleviate or even reverse these conditions. [ABSTRACT FROM AUTHOR]

The enteric nervous system (ENS) is organized into two plexuses—submucosal and myenteric—which regulate smooth muscle contraction, secretion, and blood flow along the gastrointestinal tract under the influence of the rest of the autonomic nervous system (ANS). Interstitial cells of Cajal (ICCs) are mainly located in the submucosa between the two muscle layers and at the intramuscular level. They communicate with neurons of the enteric nerve plexuses and smooth muscle fibers and generate slow waves that contribute to the control of gastrointestinal motility. They are also involved in enteric neurotransmission and exhibit mechanoreceptor activity. A close relationship appears to exist between oxidative stress and gastrointestinal diseases, in which ICCs can play a prominent role. Thus, gastrointestinal motility disorders in patients with neurological diseases may have a common ENS and central nervous system (CNS) nexus. In fact, the deleterious effects of free radicals could affect the fine interactions between ICCs and the ENS, as well as between the ENS and the CNS. In this review, we discuss possible disturbances in enteric neurotransmission and ICC function that may cause anomalous motility in the gut.

Gastroparesis is defined by delayed gastric emptying in the absence of mechanical obstruction of the stomach. Patients experience symptoms of nausea, vomiting, abdominal pain, fullness, and early satiety. The recognition of the disorder has progressed due to availability of gastric emptying scintigraphy and advancements made in understanding its pathophysiology and treatment options. The clinical presentation and treatment of gastroparesis overlap with a more commonly recognized disorder of gut-brain interaction, functional dyspepsia. Recent studies have reenergized the discussion whether these two are separate entities or perhaps reflect a spectrum of gastroduodenal neuromuscular disorders. The societal guidelines conflict on the utility of gastric emptying scintigraphy in assessment of patients with upper gastrointestinal symptoms. A better appraisal of similarities and differences between gastroparesis and functional dyspepsia will allow targeted treatment for these disorders. This is particularly important as specific pharmacological and endoscopic treatment options are being developed for gastroparesis which are unlikely to be helpful for functional dyspepsia. This review makes the case for considering these disorders in a spectrum where identification of both would most ideally position us toward providing the optimal clinical care.

Background and Aims: Smooth muscle cells (SMCs), interstitial cells of Cajal (ICCs), and platelet-derived growth factor receptor alpha (PDGFRα+) cells (PαCs) form a functional syncytium in the bowel known as the “SIP syncytium.” The SIP syncytium works in concert with the enteric nervous system (ENS) to coordinate bowel motility. However, our understanding of individual cell types that form this syncytium and how they interact with each other remains limited, with no prior single-cell RNAseq analyses focused on human SIP syncytium cells. Methods: We analyzed single-nucleus RNA sequencing data from 10,749 human colon SIP syncytium cells (5572 SMC, 372 ICC, and 4805 PαC nuclei) derived from 15 individuals. Results: Consistent with critical contractile and pacemaker functions and with known enteric nervous system interactions, SIP syncytium cell types express many ion channels, including mechanosensitive channels in ICCs and PαCs. PαCs also prominently express extracellular matrix–associated genes and the inhibitory neurotransmitter receptor for vasoactive intestinal peptide (VIPR2), a novel finding. We identified 2 PαC clusters that differ in the expression of many ion channels and transcriptional regulators. Interestingly, SIP syncytium cells co-express 6 transcription factors (FOS, MEIS1, MEIS2, PBX1, SCMH1, and ZBTB16) that may be part of a combinatorial signature that specifies these cells. Bowel region–specific differences in SIP syncytium gene expression may correlate with regional differences in function, with right (ascending) colon SMCs and PαCs expressing more transcriptional regulators and ion channels than SMCs and PαCs in left (sigmoid) colon. Conclusion: These studies provide new insights into SIP syncytium biology that may be valuable for understanding bowel motility disorders and lead to future investigation of highlighted genes and pathways.

Background & Aims: Impaired gastric motor function in the elderly causes reduced food intake leading to frailty and sarcopenia. We previously found that aging-related impaired gastric compliance was mainly owing to depletion of interstitial cells of Cajal (ICC), pacemaker cells, and neuromodulator cells. These changes were associated with reduced food intake. Transformation-related protein 53–induced suppression of extracellular signal-regulated protein kinase (ERK)1/2 in ICC stem cell (ICC-SC) cell-cycle arrest is a key process for ICC depletion and gastric dysfunction during aging. Here, we investigated whether insulin-like growth factor 1 (IGF1), which can activate ERK in gastric smooth muscles and invariably is reduced with age, could mitigate ICC-SC/ICC loss and gastric dysfunction in klotho mice, a model of accelerated aging. Methods: Klotho mice were treated with the stable IGF1 analog LONG R3 recombinant human (rh) IGF1 (150 μg/kg intraperitoneally twice daily for 3 weeks). Gastric ICC/ICC-SC and signaling pathways were studied by flow cytometry, Western blot, and immunohistochemistry. Gastric compliance was assessed in ex vivo systems. Transformation-related protein 53 was induced with nutlin 3a and ERK1/2 signaling was activated by rhIGF-1 in the ICC-SC line. Results: LONG R3 rhIGF1 treatment prevented reduced ERK1/2 phosphorylation and gastric ICC/ICC-SC decrease. LONG R3 rhIGF1 also mitigated the reduced food intake and impaired body weight gain. Improved gastric function by LONG R3 rhIGF1 was verified by in vivo systems. In ICC-SC cultures, rhIGF1 mitigated nutlin 3a–induced reduced ERK1/2 phosphorylation and cell growth arrest. Conclusions: IGF1 can mitigate age-related ICC/ICC-SC loss by activating ERK1/2 signaling, leading to improved gastric compliance and increased food intake in klotho mice.

Diabetic peristalsis disorders are common complications in diabetes mellitus type 2. Disturbance of interstitial cells of Cajal (ICC) caused by metabolic changes in diabetes could explain the symptoms of diabetic gastroenteropathy. Although heterogenous interstitial cell types represent only 5% of the cell population of the muscle layer in the gastrointestinal tract (GIT), they are important for conducting electrical signals and regulating muscle excitability. The aim of this study was to investigate the alterations of the myenteric and intramuscular ICCs in the gaster of rats with diabetes mellitus type 2 (DMT2), as well as determine their distribution in relation to smooth muscle cells and enteric nerve structures. Male Wistar rats were used and DT2 was induced by streptozotocin-nicotinamide (STZ-NA) application. The stomach specimens were exposed to type III transmembrane tyrosine kinase (c-KIT), neurofilament (NF-M) protein and desmin antibodies to investigate the ICC, enteric neurons and smooth muscle cells. Morphological changes of the cells were quantified by the numerical areal density of intramuscular ICC, the ICC score of myenteric ICC and the volume density of nerve fibers. In conclusion, a statistically significant decrease in the number of intramuscular ICC and myenteric ICC without nerve fiber loss were observed in all stomach regions in rats with STZ-NA-induced DMT2.

Background/Aims The interstitial cells of Cajal (ICC) are pacemaker cells in the gastrointestinal (GI) tract. We examined whether the activity of ICC could be stimulated to control colonic contractions. An optogenetics-based mouse model in which the light-sensitive protein channelrhodopsin-2 (ChR2) was expressed was used to accomplish cell specific, direct stimulation of ICC. Methods An inducible site-specific Cre-loxP recombination system was used to generate KitCreERT2/+;ROSAChR2(H134R)/tdTomato/+ mice in which ChR2(H134R), a variant of ChR2, was genetically expressed in ICC after tamoxifen administration. Genotyping and immunofluorescence analysis were performed to confirm gene fusion and expression. Isometric force recordings were performed to measure changes in contractions in the colonic muscle strips. Results ChR2 was specifically expressed in Kit-labeled ICC. The isometric force recordings showed that the contractions of the colonic muscle strips changed under 470 nm blue light. Light stimulation evoked premature low-frequency and high amplitude (LFHA) contractions and enhanced the frequency of the LFHA contractions. The light-evoked contractions were blocked by T16Ainh-A01, an antagonist of anoctamin 1 channels that are expressed selectively in ICC in colonic muscles. Conclusions Our study demonstrates a potentially feasible approach to stimulate the activity of ICC by optogenetics. The colonic motor patterns of muscle strips, especially LFHA contractions, can be regulated by 470 nm light via ChR2, which is expressed in ICC. [ABSTRACT FROM AUTHOR]

Background One of the most frequent urological abnormalities in pediatric urology and the most frequent cause of hydronephrosis in the pediatric age group is uteropelvic junction obstruction (UPJO). Although its etiology has been the subject of several investigations, it is still unknown. Objective Comparing the quantitative changes in the interstitial cells of Cajal (ICC) between specimens with UPJO and specimens without hydronephrosis using light microscopy and correlating these changes to the etiology of the disease. Methods Patients with UPJO and patients without obstruction were compared immunohistochemically with c-kit (CD117) between February 2020 and February 2022 at Ain Shams University Hospital to quantify the ICC, which is situated close to the circular muscle layer and parallel to the muscle cells. Results Light microscopic analysis revealed that the control group's Cajal cell density was much higher than the number of cells in the patients with UPJ blockage. Conclusion Our research found that the mean density of the ICC was lower in UPJO patients compared with controls, indicating that the absence of the ICC may contribute to the pathogenesis of UPJO. [ABSTRACT FROM AUTHOR]

Although being the most common type of mesenchymal tumors of the digestive tract, gastrointestinal stromal tumors are considered to be rare. The incidence is under 15 cases per million which are usually diagnosed by mistake. Several risk factors were identified and analyzed in the recent years showing a lower survival rate overall. Interstitial cells of Cajal are considered to be involved in the pathologic process. Because GISTs are known to be refractory to conventional chemotherapy and radiotherapy, the surgical approach is the treatment of choice. We present a case of a 74-year-old patient found with GIST, who presented non-specific gastrointestinal symptoms. The case required a multidisciplinary team to develop a diagnostic and management strategy. [ABSTRACT FROM AUTHOR]

BackgroundInositol 1,4,5-trisphosphate receptors (IP3Rs) are a family of intracellular Ca2+ release channels located on the membrane of endoplasmic reticulum, which have been shown to play critical roles in various cellular and physiological functions. However, their function in regulating gastrointestinal (GI) tract motility in vivo remains unknown. Here, we investigated the physiological function of IP3R1 in the GI tract using genetically engineered mouse models.MethodsPdgfrb-Cre mice were bred with homozygous Itpr1 floxed (Itpr1f/f) mice to generate conditional IP3R1 knockout (pcR1KO) mice. Cell lineage tracing was used to determine where Pdgfrb-Cre-mediated gene deletion occurred in the GI tract. Isometric tension recording was used to measure the effects of IP3R1 deletion on muscle contraction.ResultsIn the mouse GI tract, Itpr1 gene deletion by Pdgfrb-Cre occurred in smooth muscle cells, enteric neurons, and interstitial cells of Cajal. pcR1KO mice developed impaired GI motility, with prolonged whole-gut transit time and abdominal distention. pcR1KO mice also exhibited lethality as early as 8 weeks of age and 50% of pcR1KO mice were dead by 40 weeks after birth. The frequency of spontaneous contractions in colonic circular muscles was dramatically decreased and the amplitude of spontaneous contractions was increased in pcR1KO mice. Deletion of IP3R1 in the GI tract also reduced the contractile response to the muscarinic agonist, carbachol, as well as to electrical field stimulation. However, KCl-induced contraction and expression of smooth muscle-specific contractile genes were not significantly altered in pcR1KO mice.ConclusionsHere, we provided a novel mouse model for impaired GI motility and demonstrated that IP3R1 plays a critical role in regulating physiological function of GI tract in vivo.

Background/Aims Interstitial cells of Cajal (ICC) are specialized gastrointestinal (GI) pacemaker cells required for normal GI motility. Dysfunctions in ICC have been reported in patients with GI motility disorders, such as gastroparesis, who exhibit debilitating symptoms and greatly reduced quality of life. While the proteins, calcium-activated chloride channel anoctamin-1 (ANO1) and the receptor tyrosine kinase (KIT), are known to be expressed by human ICC, relatively little is known about the broad molecular circuitry underpinning human ICC functions. The present study therefore investigates the transcriptome and proteome of ANO1-expressing, KITlow/CD45– /CD11B– ICC obtained from primary human gastric tissue. Methods Excess human gastric tissue resections were obtained from sleeve gastrectomy patients. ICC were purified using fluorescence-activated cell sorting (FACSorting). Then, ICC were characterized by using immunofluorescence, real-time polymerase chain reaction, RNA)sequencing and mass spectrometry. Results Compared to unsorted cells, real-time polymerase chain reaction showed the KITlow/CD45– /CD11B– ICC had: a 9-fold (P < 0.05) increase in ANO1 expression; unchanged KIT expression; and reduced expression for genes associated with hematopoietic cells (CD68, > 10-fold, P < 0.001) and smooth muscle cells (DES, > 4-fold, P < 0.05). RNA-sequencing and gene ontology analyses of the KITlow/ CD45– /CD11B– cells revealed a transcriptional profile consistent with ICC function. Similarly, mass spectrometry analyses of the KITlow/ CD45– /CD11B– cells presented a proteomic profile consistent with ICC activities. STRING-based protein interaction analyses using the RNA-sequencing and proteomic datasets predicted protein networks consistent with ICC-associated pacemaker activity and ion transport. Conclusion These new and complementary datasets provide a valuable molecular framework for further understanding how ICC pacemaker activity regulates smooth muscle contraction in both normal GI tissue and GI motility disorders. [ABSTRACT FROM AUTHOR]

Of all the organ systems in the body, the gastrointestinal tract is the most complicated in terms of the numbers of structures involved, each with different functions, and the numbers and types of signaling molecules utilized. The digestion of food and absorption of nutrients, electrolytes, and water occurs in a hostile luminal environment that contains a large and diverse microbiota. At the core of regulatory control of the digestive and defensive functions of the gastrointestinal tract is the enteric nervous system (ENS), a complex system of neurons and glia in the gut wall. In this review, we discuss 1) the intrinsic neural control of gut functions involved in digestion and 2) how the ENS interacts with the immune system, gut microbiota, and epithelium to maintain mucosal defense and barrier function. We highlight developments that have revolutionized our understanding of the physiology and pathophysiology of enteric neural control. These include a new understanding of the molecular architecture of the ENS, the organization and function of enteric motor circuits, and the roles of enteric glia. We explore the transduction of luminal stimuli by enteroendocrine cells, the regulation of intestinal barrier function by enteric neurons and glia, local immune control by the ENS, and the role of the gut microbiota in regulating the structure and function of the ENS. Multifunctional enteric neurons work together with enteric glial cells, macrophages, interstitial cells, and enteroendocrine cells integrating an array of signals to initiate outputs that are precisely regulated in space and time to control digestion and intestinal homeostasis. [ABSTRACT FROM AUTHOR]

Aims and Objectives: This study aims to study the variation in the expression of CD117-positive interstitial cells of Cajal-like cells (ICC-LC) across the upper urinary tract region in children presenting with pelvic-ureteric junction obstruction (PUJO) and its association with renal functional and sonological parameters of patients. Materials and Methods: A prospective observational study was done on 20 children with congenital PUJO who underwent dismembered pyeloplasty. All children underwent renal sonography (anteroposterior pelvic diameter [APPD], pelvicalyceal ratio [P/C ratio], Mid polar renal parenchymal diameter [MPPD]) and functional imaging scan (LLEC scan or DTPA scan). Three specimens were taken intraoperatively from above PUJ, at the level of PUJ, and below PUJ. Those were examined immunohistochemically using CD117 to count ICC-LC using standard criteria. Variation in the expression of CD117-positive ICC-LC was correlated with the abovestated parameters. Results: The number of CD117-positive ICC-LC showed a continuous decreasing trend above downward. P/C ratio and APPD showed a parallel trend with ICC-LC distribution, whereas split renal function (SRF) showed an inverse relationship with the expression of ICC-LC. Children with lesser severity of obstruction (APPD <30 mm and SRF >40%) showed a uniform decreasing trend in the number of CD117-positive ICC-LC across PUJ. Children with more severe obstruction (APPD >30 mm and SRF <40%) showed a decrease in the expression of ICC-LC up to the level of PUJO followed by a sudden relatively increased expression of ICC-LC below the obstruction. Conclusion: The expression of ICC-LC shows a uniformly decreasing trend across obstruction when the severity of obstruction is less. Resurgence in the number of ICC-LC below PUJ in subjects with severe obstruction hints at the emergence of a new pacemaker area below severely blocked PUJ akin to that seen in complete heart block patients and deserves early attention. [ABSTRACT FROM AUTHOR]

Objective To investigate the expression levels of scf and c-kit under the regulation of Dahuang Lingxian prescription and the possible mechanism of its effect on gallbladder dynamics, and to provide a theoretical basis for Dahuang Lingxian prescription in preventing the development and recurrence of cholesterol gallstone. Methods A total of 45 specific pathogen-free healthy male guinea pigs were randomly divided into normal group, model group, and traditional Chinese medicine (TCM) group. The guinea pigs in the normal group were fed with normal diet, and those in the model group and the TCM group were fed with high-fat lithogenic diet. After 8 weeks of feeding, 5 guinea pigs were randomly selected from each group, and successful modeling was determined if gallstone was observed with the naked eye in more than 4 guinea pigs. After successful modeling, the guinea pigs in the TCM group were given Dahuang Lingxian prescription by gavage, and those in the model group were given an equal volume of normal saline by gavage. After 8 consecutive weeks of administration by gavage, gallbladder tissue samples were collected, and HE staining was used to observe the pathological changes of gallbladder tissue; Western blot was used to measure the expression level of tumor necrosis factor-α (TNF-α) in gallbladder tissue; immunohistochemistry was used to measure the protein expression levels of scf and c-kit in gallbladder smooth muscle tissue. A one-way analysis of variance was used for comparison of normally distributed continuous data between multiple groups, and the least significant difference multiple comparison method was used for further comparison between two groups. Results HE staining showed marked inflammation of gallbladder tissue in the model group, and compared with the model group, the TCM group had a significantly lower degree of inflammation. Western blot showed that the model group had the highest expression level of TNF-α in gallbladder tissue, followed by the TCM group and the normal group (P < 0.05); immunohistochemistry showed that compared with the model group, the normal group and the TCM group had significantly higher protein expression levels of scf and c-kit in gallbladder smooth muscle tissue (P < 0.05). Conclusion Dahuang Lingxian prescription can enhance the dynamic function of the gallbladder, possibly by upregulating the scf/c-kit signaling pathway in interstitial cells of Cajal in gallbladder. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate if the density of interstitial cells of Cajal (ICC) in the ureteropelvic junction (UPJ) influences the outcomes of pyeloplasty in adults. Methods: Twenty-three patients with the diagnosis of ureteropelvic junction obstruction (UPJO) that underwent laparoscopic dismembered pyeloplasty were included. ICC density was measured using immunohistochemistry reaction for c-KIT expression in the resected UPJ segment. Pyeloplasty outcome was evaluated by patient self-report pain, urinary outflow using DTPA renogram and hydronephrosis assessment using ultrasound (US) at 12 months of follow-up. A logistic regression analysis was performed to assess the association of pyeloplasty outcomes and ICC density. Results: Low, moderate, and high ICC density were present in 17.4%, 30.4%, and 52.2% of the patients, respectively. Complete pain resolution was observed in 100%, 85.7%, and 75% of patients with low, moderate and high ICC density, respectively (p = 0.791). DTPA renogram improved in 75%, 85.7%, and 91.7% of patients with low, moderate and high ICC density, respectively (p = 0.739). Hydronephrosis improved in 25%, 85.7%, and 91.7% of patients with low, moderate and high ICC density, respectively (p = 0.032). Conclusions: Patients with high ICC density have a significant amelioration of hydronephrosis after pyeloplasty. However, ICC density is not associated with functional outcomes. [ABSTRACT FROM AUTHOR]