Gastric Sensitivity Research Articles

Effects of corticotropin-releasing hormone on gastric electrical activity and sensorimotor function in healthy volunteers: a double-blinded crossover study.

Biopsychosocial factors are associated with disorders of gut-brain interaction (DGBI) and exacerbate gastrointestinal symptoms. The mechanisms underlying pathophysiological alterations of stress remain unclear. Corticotropin-releasing hormone (CRH) is a central regulator of the hormonal stress response and has diverse impact on different organ systems. The aim of the present study was to investigate the effects of peripheral CRH infusion on meal-related gastrointestinal symptoms, gastric electrical activity, and gastric sensorimotor function in healthy volunteers (HVs). In a randomized, double-blinded, placebo-controlled, crossover study, we evaluated the effects of CRH on gastric motility and sensitivity. HVs were randomized to receive either peripheral-administered CRH (100 µg bolus + 1 µg/kg/h) or placebo (saline), followed by at least a 7-day washout period and assignment to the opposite treatment. Tests encompassed saliva samples, gastric-emptying (GE) testing, body surface gastric mapping (BSGM, Gastric Alimetry; Alimetry) to assess gastric myoelectrical activity with real-time symptom profiling, and a gastric barostat study to assess gastric sensitivity to distention and accommodation. Twenty HVs [13 women, mean age 29.2 ± 5.3 yr, body mass index (BMI) 23.3 ± 3.8 kg/m2] completed GE tests, of which 18 also underwent BSGM measurements during the GE tests. The GE half-time decreased significantly after CRH exposure (65.2 ± 17.4 vs. 78.8 ± 24.5 min, P = 0.02) with significantly increased gastric amplitude [49.7 (34.7-55.6) vs. 31.7 (25.7-51.0) µV, P < 0.01], saliva cortisol levels, and postprandial symptom severity. Eleven HVs also underwent gastric barostat studies on a separate day. However, the thresholds for discomfort during isobaric distensions, gastric compliance, and accommodation did not differ between CRH and placebo.NEW & NOTEWORTHY In healthy volunteers, peripheral corticotropin-releasing hormone (CRH) infusion accelerates gastric-emptying rate and increases postprandial gastric response, accompanied by a rise in symptoms, but does not alter gastric sensitivity or meal-induced accommodation. These findings underscore a significant link between stress and dyspeptic symptoms, with CRH playing a pivotal role in mediating these effects.

Targeting Ubiquitin-specific Protease 5 Overcomes Chemoresistance via Negatively Regulating p53 in Gastric Cancer.

Resistance to chemotherapy is a major obstacle in the clinical management of gastric cancer, and the mechanisms underlying chemoresistance remain largely unknown. This study aimed to investigate the involvement of ubiquitin-specific protease 5 (USP5), a deubiquitinating enzyme, in gastric cancer chemoresistance Methods: USP5 expression was analyzed in fifty paired gastric cancer and adjacent normal tissues, chemo-sensitive and chemo-resistant gastric cancer lines using quantitative ELISA. The role of USP5 was determined using loss-of-function and gainof- function methods. USP5-mediated downstream effectors were analyzed using biochemical methods focusing on p53. USP5 expression was comparable in tumors and normal in the majority of the cohort. Following chemotherapy treatment, USP5 expression significantly increased in gastric cancer cells, while p53 levels remained unaltered. Overexpression of USP5 amplified growth and migration while decreasing apoptosis induced by serum withdrawal across multiple gastric cancer cell lines. Conversely, USP5 knockdown effectively heightened gastric cancer sensitivity to paclitaxel and 5-FU treatments, particularly targeting chemo-resistant gastric cancer cells by inhibiting proliferation and migration and inducing apoptosis. Additionally, USP5 knockdown increased levels of p53 but not MDM2, increased p53 activity and increased transcription of p53 target genes. In contrast, USP5 overexpression decreased the level and activity of p53 and inhibited transcription of p53 target genes. The anti-proliferative, anti-migratory, and pro-apoptotic effects of USP5 were significantly diminished upon p53 depletion, highlighting the interplay between p53 and USP5 in regulating gastric cancer cell activities. Additionally, USP5 inhibition suppressed chemo-resistant gastric cancer cell migration via suppressing epithelial-mesenchymal transition (EMT) and RhoA activity. Targeting USP5 inhibition has emerged as a promising alternative therapeutic approach to overcoming chemoresistance in gastric cancer. Additionally, our study sheds light on the novel role of USP5 as a regulator of p53 in gastric cancer.

Does multiple gastric aspirate collection increase sensitivity of M. tuberculosis detection in children with pulmonary tuberculosis?

This study aims to investigate the sensitivity of microscopy, culture and polymerase chain reaction on three gastric aspirates (GAs) in the microbiological confirmation of active pulmonary tuberculosis (TB) and to identify possible changes in sensitivity derived from the collection of a different number of aspirates. Children with clinical and radiological diagnoses of active pulmonary TB who underwent three GAs between March 2007 and June 2019 were retrospectively evaluated. Clinical, radiological, and microbiological data were collected. The sensitivity of microbiological tests on GAs was calculated. Moreover, differences in sensitivity according to age and radiological pattern were investigated. Overall, 156 children with active pulmonary TB were enrolled with a median age of 51.5 (IQR: 25.2–113.2) months. Microbiological investigations on the first GA showed a sensitivity of 34% (95%CI 26.7, 42), the cumulative sensitivity of first and second GAs was 40.4% (95%CI 32.7, 48.5) and of the three GAs was 47.4% (95%CI 39.8, 55.2). The collection of three GAs leads to an overall increase in sensitivity of the first GA by 13.4% (95%CI 2.8, 24.1%; p=0.014). Moreover, the increase in sensitivity was significantly higher in children ≤ 4 years of age and in those with uncomplicated TB (p=0.008).Conclusions: Performing a higher number of GAs increases the sensitivity of microbiological confirmation of active pulmonary TB, particularly in children ≤ 4 years and with an uncomplicated radiological pattern.What is known:• The diagnosis of paediatric tuberculosis is a challenge for paediatricians• Despite their low sensitivity gastric aspirates represent the standard sample for microbiological confirmation of active pulmonary tuberculosis in children• Most international guidelines recommend performing three sequential gastric aspirates on three consecutive daysWhat is new:• A significant increase in global sensitivity by 13.4% was found by the collection of three gastric aspirates compared to the first one• Performing a higher number of gastric aspirates increases the sensitivity of microbiological confirmation, particularly in children ≤ 4 years and with an uncomplicated radiological pattern

Lower gastric sensitivity in quiescent inflammatory bowel disease than in irritable bowel syndrome

ObjectiveVisceral hypersensitivity is considered a key symptom in inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS), both of which seriously affect health-related quality of life (HrQoL). Previous findings are mostly based on invasive procedures that may interfere with the assessment of visceral perception. The current study, therefore, investigates whether IBD and IBS are characterized by altered perception of ‘natural’ gastric distensions (‘interoception’). MethodsTwenty IBD patients in remission (13 Crohn's disease, 7 ulcerative colitis), 12 IBS patients, and 20/12 matched healthy control (HC) individuals, respectively, underwent the water load test, in which they could drink ad libitum until the subjective thresholds of satiation (stage 1) and fullness (stage 2) were reached. Gastric motility was assessed using electrogastrography. ResultsIBD patients drank significantly more water until satiation than IBS patients, whereas no differences between patients and HC groups were observed. Electrogastrographic patterns were comparable between groups, suggesting no pathologies in gastric motility in IBD or IBS. The amount of water consumed until satiation negatively correlated with HrQoL related to bowel symptoms in IBD patients, but was positively associated with emotional well-being in IBS patients. ConclusionOur findings implicate relative gastric hypersensitivity in IBS, and relative hyposensitivity in IBD patients, which are both related to specific HrQoL aspects.

Pitongshu Alleviates the Adverse Symptoms in Rats with Functional Dyspepsia Through Regulating Visceral Hypersensitivity Caused by 5-HT Overexpression.

The aim of the study was to explore the efficacy as well as the mechanism of action of Pitongshu (PTS) on rats with functional dyspepsia (FD) induced by iodoacetamide gavage and tail clamping. The bioactive components of PTS were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), whereas the potential targets of PTS were obtained from the Similarity Ensemble Approach (SEA), TCMSP, and Swiss Target Prediction Database. The disease targets were obtained from the DisGeNET database, whereas Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using the R Software. The method of iodoacetamide gavage combined with tail clamping was used to establish the FD rat model in this study. Body weight, food intake, gastrointestinal motility, gastric acidity and secretion, and the mechanical pain threshold of rats were measured. The open-field test was also performed. The stomach and duodenum were histologically observed. The levels of serotonin (5-HT), Calcitonin Gene-Related Peptide (CGRP), Motilin (MTL), and Gastrin (GAS) in gastric tissues were detected by ELISA. A total of 139 bioactive components and 17 potential targets of PTS were identified through a network pharmacology approach. The results of GO and KEGG enrichment analyses indicated that PTS could reduce the 5-HT secretion of gastric tissues through the serotonergic synaptic pathway and alleviate the symptoms of FD, indicating that PTS plays a therapeutic role. The results of animal experiments showed that PTS could increase body weight and food intake, improve autonomous activity, and decrease gastric acidity and secretion in FD rats. Furthermore, gastric sensitivity increased in FD rats, and PTS treatment could significantly decrease it. The results of ELISA showed that the overexpression of 5-HT and CGRP was decreased after PTS treatment in FD rats. Lastly, PTS could significantly improve gastrointestinal motility, as well as the levels of GAS and MTL in FD rats. PTS may reduce 5-HT secretion by regulating the serotonergic synaptic pathway, thereby reducing visceral sensitivity and alleviating the symptoms of FD.

Bakteri Asam Laktat Kandidat Probiotik dari Susu Kuda Bima

Awareness of the role of healthy food has led to increased public interest in healthy food that has additional functions than as energy fulfillment. One form of the healthy foods is food that contains probiotics, so this study aims to select lactic acid bacteria from milk as probiotic candidates. Lactic acid bacteria isolates from goat, horse and buffalo milk in Indonesia were studied to find the best probiotic candidates out of 100 isolates. Parameters which are measured in this study included resistance to gastric acid, bile salts, aggregation, autoaggregation abilities, and sensitivity to antibiotics. One isolate from bima horse’s milk has the potency as a probiotic candidate. The bacterial isolate from Bima horse’s milk has the character of being resistant to acids, and bile salts, sensitive to the two antibiotics tested and can aggregate with Salmonella Thypimurium. From molecular identification, the selected Bima horse’s milk isolate has similarities with Lacticaseibacillus rhamnosus strain MG5511.

Perinatal high-fat diet exposure alters oxytocin and corticotropin releasing factor inputs onto vagal neurocircuits controlling gastric motility.

Perinatal high-fat diet (pHFD) exposure alters the development of vagal neurocircuits that control gastrointestinal (GI) motility and reduce stress resiliency in offspring. Descending oxytocin (OXT; prototypical anti-stress peptide) and corticotropin releasing factor (CRF; prototypical stress peptide) inputs from the paraventricular nucleus (PVN) of the hypothalamus to the dorsal motor nucleus of the vagus (DMV) modulate the GI stress response. How these descending inputs, and their associated changes to GI motility and stress responses, are altered following pHFD exposure are, however, unknown. The present study used retrograde neuronal tracing experiments, cerebrospinal fluid extraction, in vivo recordings of gastric tone, motility and gastric emptying rates, and in vitro electrophysiological recordings from brainstem slice preparations to investigate the hypothesis that pHFD alters descending PVN-DMV inputs and dysregulates vagal brain-gut responses to stress. Compared to controls, rats exposed to pHFD had slower gastric emptying rates and did not respond to acute stress with the expected delay in gastric emptying. Neuronal tracing experiments demonstrated that pHFD reduced the number of PVNOXT neurons that project to the DMV, but increased PVNCRF neurons. Both in vitro electrophysiology recordings of DMV neurons and in vivo recordings of gastric motility and tone demonstrated that, following pHFD, PVNCRF -DMV projections were tonically active, and that pharmacological antagonism of brainstem CRF1 receptors restored the appropriate gastric response to brainstem OXT application. These results suggest that pHFD exposure disrupts descending PVN-DMV inputs, leading to a dysregulated vagal brain-gut response to stress. KEY POINTS: Maternal high-fat diet exposure is associated with gastric dysregulation and stress sensitivity in offspring. The present study demonstrates that perinatal high-fat diet exposure downregulates hypothalamic-vagal oxytocin (OXT) inputs but upregulates hypothalamic-vagal corticotropin releasing factor (CRF) inputs. Both in vitro and in vivo studies demonstrated that, following perinatal high-fat diet, CRF receptors were tonically active at NTS-DMV synapses, and that pharmacological antagonism of these receptors restored the appropriate gastric response to OXT. The current study suggests that perinatal high-fat diet exposure disrupts descending PVN-DMV inputs, leading to a dysregulated vagal brain-gut response to stress.

Examination of the two-step water load test as a measure of gastric interoception and associations with eating and weight/shape concerns in a nonclinical sample.

The current study extended research examining the validity of the two-step Water Load Test (WLT-II), an objective, laboratory-based measure of gastric interoception, by investigating the validity of the WLT-II in a nonclinical sample and testing its contribution to the prediction of eating and weight/shape concerns. Participants (n = 129, 73.6% cisgender female, M = 20.13 years old) completed the WLT-II Questionnaire and two-step WLT-II, as well as self-report measures of eating and weight/shape concerns (Eating Disorder Examination Questionnaire; EDE-Q) and interoception (Multidimensional Assessment of Interoceptive Awareness-2; Intuitive Eating Scale-2 Reliance on Hunger and Satiety), in the lab at a large southeastern university. Data analysis included repeated measures ANOVA, correlations, and a series of hierarchical linear regressions. Participants reported considerably more discomfort after the "maximum fullness" trial compared to the "satiation" trial. The WLT-II's objective measure of gastric interoception (sat_%) was not significantly correlated with the self-report measures of interoception and did not predict EDE-Q Dietary Restraint, Eating Shame, or Weight/Shape Concerns. Unexpectedly, greater gastric sensitivity was associated with less EDE-Q Preoccupation/Restriction. Exploratory analyses suggested a possible nonlinear association. These results support the validity of the WLT-II in its ability to create, measure, and distinguish between the states of satiation and maximum fullness. However, results also suggest additional work is needed to better understand what the WLT-II's sat_% measure is capturing, as well as investigate potential nonlinear associations of the WLT-II with disordered eating. Interoception, or the processing of internal body signals, shows important links to disordered eating. Despite the clear relevance of gastric interoception to disordered eating-such as the ability to detect satiety signals-existing research has relied on general, self-report measures of interoception. This study examined the utility of a laboratory-based measure of gastric interoception. Results suggested mixed support for its validity and utility for predicting eating and weight/shape concerns in a nonclinical population.

VPS35 promotes cell proliferation via EGFR recycling and enhances EGFR inhibitors response in gastric cancer.

Vacuolar protein sorting-associated protein 35 (VPS35) is a core component of the retromer complex which mediates intracellular protein transport. It is well known that dysfunctional VPS35 functions in the accumulation of pathogenic proteins. In our previous study, VPS35 was found to be a potential gene related to poor prognosis in gastric cancer. However, the biological functions of VPS35 in gastric cancer remain unclear. Cell viability assays were performed to examine whether VPS35 affected cell proliferation. Immunoprecipitation and biotin assays showed that VPS35 bound to epidermal growth factor receptor (EGFR) in the cytoplasm and recycled it to the cell surface. Patient-derived xenografts and organoids were used to evaluate the effect of VPS35 on the response of gastric cancer to EGFR inhibitors. VPS35 expression levels were upregulated in tumour tissues and correlated with local tumour invasion and poor survival in patients with gastric cancer. VPS35 promoted cell proliferation and increased tumour growth. Mechanistically, VPS35 selectively bound to endocytosed EGFR in early endosomes and recycled it back to the cell surface, leading to the downstream activation of the ERK1/2 pathway. We also found that high VPS35 expression levels increased the sensitivity of the xenograft and organoid models to EGFR inhibitors. VPS35 promotes cell proliferation by recycling EGFR to the cell surface, amplifying the network of receptor trafficking. VPS35 expression levels are positively correlated with gastric cancer sensitivity to EGFR inhibitors, which offers a potential method to stratify patients for EGFR inhibitor utilisation. National Natural Science Foundation of China.

6-Phosphogluconate dehydrogenase inhibition arrests growth and induces apoptosis in gastric cancer via AMPK activation and oxidative stress.

Poor outcomes in advanced gastric cancer necessitate alternative therapeutic strategies. 6-Phosphogluconate dehydrogenase (6-PGDH), an enzyme that catalyzes the decarboxylation step in the oxidative pentose phosphate pathway, has been identified as a promising therapeutic target in many cancers. In this study, we systematically investigated the expression and function of 6-PGDH in gastric cancer. We found that 6-PGDH expression and activity were aberrantly elevated in gastric cancer tissues compared to their adjacent normal tissues. 6-PGDH knockdown using two independent shRNAs resulted in minimal 6-PGDH levels and activity, decreased growth, and enhanced gastric cancer cell sensitivity to 5-flurorouracil. However, 6-PGDH knockdown did not affect the cancer cells. Mechanistic studies showed that 6-PGDH inhibition disrupted lipid biosynthesis and redox homeostasis in gastric cancer, inhibited growth, and induced apoptosis. Notably, the in vitro findings were validated using an in vivo gastric cancer xenograft mouse model. This study established that 6-PGDH is broadly elevated in gastric cancer patients and that 6-PGDH inhibition can sensitize gastric cancer cells in response to chemotherapy.

Multi-slice spiral computed tomography in differential diagnosis of gastric stromal tumors and benign gastric polyps, and gastric stromal tumor risk stratification assessment.

BACKGROUNDThe biological characteristics of gastric stromal tumors are complex, and their incidence has increased in recent years. Gastric stromal tumors (GST) have potential malignant tendencies, and the probability of transformation into malignant tumors is as high as 20%-30%.AIMTo investigate the value of multi-slice spiral computed tomography (MSCT) in the differential diagnosis of GST and benign gastric polyps, and GST risk stratification assessment.METHODSWe included 64 patients with GST (GST group) and 60 with benign gastric polyps (control group), confirmed by pathological examination after surgery in PLA General Hospital, from January 2016 to June 2021. The differences in the MSCT imaging characteristic parameters and enhanced CT values between the two groups before surgery were compared. According to the National Institutes of Health’s standard, GST is divided into low- and high-risk groups for MSCT imaging characteristic parameters and enhanced CT values.RESULTSThe incidences of extraluminal growth, blurred boundaries, and ulceration in the GST group were significantly higher than those in the control group (P < 0.05). The CT values and enhanced peak CT values in the arterial phase in the CST group were higher than those in the control group (P < 0.05). The MSCT differential diagnosis of GST and gastric polyp sensitivity, specificity, misdiagnosis rate, missed diagnosis rate, and areas under the curve (AUCs) were 73.44 %, 83.33%, 26.56%, 16.67%, 0.784, respectively. The receiver operating characteristic curves were plotted with the arterial CT value and enhanced peak CT value, with a statistical difference. The results showed that the sensitivity, specificity, misdiagnosis rate, missed diagnosis rate, and AUC value of arterial CT in the differential diagnosis of GST and gastric polyps were 80.18%, 62.20%, 19.82%, 37.80%, and 0.710, respectively. The sensitivity, specificity, misdiagnosis rate, missed diagnosis rate, and AUC value of the enhanced peak CT value in the differential diagnosis of GST and gastric polyps were 67.63%, 60.40%, 32.37%, 39.60%, and 0.710, respectively. The incidence of blurred lesion boundaries and ulceration in the high-risk group was significantly higher than that in the low-risk group (P < 0.05). The arterial phase and enhanced peak CT values in the high-risk group were significantly higher than those in the low-risk group (P < 0.05).CONCLUSIONPresurgical MSCT examination has important value in the differential diagnosis of GST and gastric benign polyps and can effectively evaluate the risk grade of GST patients.

Association of FLG mutation with tumor mutation load and clinical outcomes in patients with gastric cancer.

Background: Stomach adenocarcinoma (STAD) is one of the most frequently diagnosed cancers in the world with a poor prognosis due to genetic heterogeneity. The present study aimed to explore potential prognostic predictors and therapeutic targets that can be used for STAD treatment. Methods: We collected relevant data of STAD patients from the Cancer Genome Atlas (TCGA), including somatic mutation, transcriptome, and survival data. We performed a series of analyses such as tumor mutational burden (TMB), immune infiltration, and copy number variation (CNV) analysis to evaluate the potential mechanism of filaggrin (FLG) mutation in gastric cancer. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and gene set enrichment analysis (GSEA) were performed for annotation of differentially expressed genes (DEGs). The STRING online database was used to construct the protein–protein interaction (PPI) and ceRNA network and hub genes were identified. Univariate and multivariate Cox regression analyses were used to determine the effect of selected DEGs on tumor prognosis. Results: The FLG-mutant group (FLG-MT) showed a higher mutation load and immunogenicity in gastric cancer. GO and KEGG analyses identified and ranked unique biologic processes and immune-related pathway maps that correlated with the FLG-mutant target. GSEA analysis showed that several tumorigenesis and metastasis-related pathways were indeed enriched in FLG-mutant tumor tissue. Both cell cycle–related pathways and the DNA damage and repair associated pathways were also enriched in the FLG-MT group. The FLG mutations resulted in increased gastric cancer sensitivity to 24 chemotherapeutic drugs. The ceRNA network was established using Cytoscape and the PPI network was established in the STRING database. The results of the prognostic information further demonstrated that the OS and DFS were significantly higher in FLG mutation carriers, and the FLG gene mutation might be a protective factor. Conclusion: The multiple molecular mechanisms of the FLG gene in STAD are worthy of further investigation and may reveal novel therapeutic targets and biomarkers for STAD treatment.

Effect of intracolonic volume on gastric sensory-motor responses in constipation-predominant irritable bowel syndrome.

Interaction between gut stimuli may induce symptom overlap in patients with functional gastrointestinal disorders. The aim is to determine the effect of increased volumes of colonic contents on gastric sensory/motor responses and satiety in patients with constipation-predominant irritable bowel syndrome (IBS-C) and overlapping dyspeptic symptoms, and a cohort of healthy subjects. In 15 patients with IBS-C and 10 healthy subjects, the effect of real versus sham colonic filling with gas (1080 ml) on gastric sensitivity (measured by stepwise distensions of the stomach), gastric compliance, abdominal perception, and nutrient drink tolerance was studied on separate days. In healthy subjects, colonic gas filling induced an increment in gastric sensitivity to distension (mean score 2.0 ± 0.2 before, and 3.0 ± 0.4 after; p=0.038). In IBS, basal sensitivity was greater and remained unchanged after colonic gas filling (score 4.0 ± 0.1 and 3.8 ± 0.3, respectively; p < 0.001 vs. basal in health). Colonic gas infusion induced abdominal symptoms that were significantly greater in IBS-C (score 2.6 ± 0.1) than in health (score 1.7 ± 0.4; p=0.027), with minor changes in gastric tone, and no changes in gastric compliance in both groups. Colonic filling produced a profound reduction in nutrient drink tolerance in IBS (791 ± 87 ml sham filling, 491 ± 58 ml gas filling; p < 0.001) but only a minor reduction in health (940 ± 70 ml sham filling, 860 ± 94 ml gas filling; p=0.223). The volume of the colonic contents modulates satiety in patients with IBS-C, due to a general visceral pan-hypersensitivity. These effects should be considered in the choice of treatment for constipation in these patients.

Transcutaneous auricular vagus nerve stimulation promotes gastric motility by up-rgulating α7nAChR and suppressing NF-κB p65 expression in duodenum in rats with functional dyspepsia

To study the effect of transcutaneous auricular vagus nerve stimulation (taVNS) on gastric sensitivity and motility in rats with functional dyspepsia (FD), so as to explore its underlying mechanism in improving FD. A total of 48 young SD rats were randomly divided into control (n=10), model (n=9), taVNS (n=9), subdiaphragmatic vagus nerve stimulation (SDVNS, n=9) and sham SDVNS (n=7) groups. The FD model was established by gavage of 0.1% iodoa-cetamide+2% glucose, once daily for 6 days. Rats in the taVNS group received taVNS (0.5 mA) of optopoint "Heart" and "Stomach" for 30 min, once daily for 14 days, while rats in the SDVNS group received subdiaphragmatic vagus nerve stimulation through the implanted electrode, and those of the sham SDVNS group received only application of the same electrodes without electrical stimulation. Electromyogram (EMG) of the cervical trapezius muscle (reflecting gastric sensitivity) was recorded before and after intragastric expansion via an air ballon and the gastric emptying rate was calculated for assessing the gastric motility. The contents of acetylcholine (ACh), nicotinic acetylcholine receptor α7 subunit (α7nAChR), interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in the duodenum tissue were detected by enzyme-linked immunosorbent assay (ELISA). The expression of nuclear factor kappa B (NF-κB) p65 in the duodenum tissue was determined by Western blot. In comparison with the control group, the EMG change rate at intragastric pressure levels of 40, 60 and 80 mm Hg, expression of NF-κB p65 protein, and contents of IL-6, IL-1β and TNF-α were significantly increased (P<0.05,P<0.01, P<0.001), while the gastric emptying rate, ACh and α7nAChR contents considerably decreased (P<0.05, P<0.001) in the model group. After interventions, the EMG change rate, contents of IL-6, IL-1β and TNF-α, and expression of NF-κB p65 were notably decreased (P<0.05, P<0.01, P<0.001), and the gastric emptying rate, ACh and α7nAChR contents obviously increased (P<0.05, P<0.001) in both taVNS and SDVNS groups relevant to the model group. In comparison with the sham SDVNS group, the EMG change rate, contents of IL-6, IL-1β and TNF-α, and expression of NF-κB p65 were notably decreased (P<0.01, P<0.05,P<0.001), and the gastric emptying rate, ACh and α7nAChR contents obviously increased (P<0.01, P<0.001) in the both SDVNS and taVNS groups. taVNS can reduce gastric sensitivity and promote gastric emptying in FD model rats, which may be closely related to its functions in up-regulating ACh and α7nAChR contents and inhibiting the activation of NF-κB p65 signaling in the duodenum.

Multi-targeting regulation of auricular vagus nerve stimulation on gastric hypersensitivity and gastric dysmotility in a rodent model of functional dyspepsia

Background: Evidences have shown the auricular vagus nerve stimulation (aVNS) is effective for functional dyspepsia (FD) recently. This study aimed to observe the mechanism of aVNS on facilitatory mediators of the inflammation in a rat model of functional dyspepsia. Methods: Thirty-six 5 d-old male Sprague Dawley rats were randomly divided into control groups (n = 12), model group (n = 12), aVNS group (n = 6) and sham-aVNS group (n = 6). Except for the control rats, all other rats were treated with iodoacetamide gavage. After the model was developed successfully, rats in aVNS group and sham-aVNS group received aVNS and sham-aVNS respectively, 30 min/1 time per day for 14 consecutive days. The control group and model group received no intervention. Gastric sensitivity after 1-week of intervention and gastric emptying after 2-week of intervention were adopted to assess the effect of aVNS. Brain-gut peptides, facilitatory mediators of the inflammation in serum were tested by ELISA, and α7 nicotinic acetylcholine receptor (α7-nAchR) in antrum tissue were tested by Immunohistochemistry to explore the mechanism of aVNS. Results: Compared with the control group, the gastric sensitivity was increased, gastric emptying decreased, and there was no structural damage in the gastric antrum in the model group. aVNS reduced visceral hypersensitivity and improved gastric emptying but not sham-aVNS. cholecystokinin, glucagon-like peptide-1, peptide, tumor necrosis factorα and interleukin 6 were all increased, while ghrelin and α7-nAchR decreased in model rats (P &lt; 0.01 for all, compared with the control group). aVNS can normalize them. Conclusion: The aVNS can decrease the gastric sensitivity and increase gastric emptying, the mechanism was related to its regulation of brain-gut peptides and facilitatory mediators of the inflammation. The ameliorating effect was related to cholinergic mechanism.

Adapting a two-stage water load test to measure gastric sensitivity over time

Van Dyck et al. [8] developed a two-stage protocol to estimate interoceptive (gastric) sensitivity independently of stomach volume. They provided no foreknowledge of the second stage (reaching stomach fullness), following the initial stage (drinking until satiated), therefore preventing longitudinal research. The current study provided foreknowledge. Despite this, within-subject variation over time was found, with increases for satiation (p < 0.050) and% satiation (p < 0.000), and decreases regarding fullness (p < 0.000). Some participants expressed trepidation at baseline, hence foreknowledge may have encouraged avoidance of premature fullness. Future longitudinal studies should consider using one baseline to acclimatise, followed by a true baseline.

Electroacupuncture Regulates TRPV1 through PAR2/PKC Pathway to Alleviate Visceral Hypersensitivity in FD Rats.

Visceral hypersensitivity (VH) is the predominant pathogenesis of functional dyspepsia (FD). Duodenal hypersensitivity along with nausea further reduces the comfort level in gastric balloon dilatation and inhibits gastric receptive relaxation. The potential mechanism behind electroacupuncture- (EA-) mediated alleviation of VH has not been elucidated. In an FD rat model with tail clamping stress, iodine acetamide (IA) induced VH. The rats were treated with EA with or without PAR2 antagonist FSLLRY-NH2, and the body weight, gastric sensitivity, compliance, and gastrointestinal motility were determined. Mast cells and activated degranulation were stained with toluidine blue (TB) staining and visualized under a transmission electron microscope (TEM). Immunofluorescence was used to detect the expression of PAR2, PKC, and TRPV1 in the duodenum and dorsal root ganglion (DRG) and that of CGRP, SP in DRG, and c-fos in the spinal cord. EA alone and EA + antagonist enhanced the gastrointestinal motility but diminished the expression of TRPV1, CGRP, SP, and c-fos-downstream of PAR2/PKC pathway and alleviated VH in FD rats. However, there was no obvious superposition effect between the antagonists and EA + antagonists. The effect of EA alone was better than that of antagonists and EA + antagonists 2 alone. EA-induced amelioration of VH in FD rats was mediated by TRPV1 regulation through PAR2/PKC pathway. This protective mechanism involved several pathways and included several targets.

Role of Neuromodulators for the Management of Post-Gastric-Fundoplication Dyspepsia: A Retrospective Series.

Post-fundoplication dyspepsia is a common complication of gastric fundoplication surgeries. This can be attributable to the loss of fundal relaxation, decreased gastric accommodation, and/or alterations in gastric motility and sensitivity following fundoplication. The role of neuromodulators in the management of such symptoms is unknown. We retrospectively assessed the efficacy of neuromodulators such as tricyclic antidepressants, buspirone, and mirtazapine for the management of post-fundoplication dyspepsia.

Effects of transcutaneous auricular vagus nerve stimulation on autonomic nervous function in rats with functional dyspepsia

To observe the effect of transcutaneous auricular vagus nerve stimulation (taVNS) on the autonomic nerve function in a rat model of functional dyspepsia (FD), so as to explore the mechanism of taVNS underlying regulation of FD. SD rats were randomly divided into normal control group(n=8) and FD model group(n=26).The FD model was replicated with iodoacetamide gavage. The FD model rats were randomly divided into model, taVNS, sham-taVNS and Zusanli(ST36) groups, with 6 rats in each group. Rats in the taVNS group received electrical stimulation of auricular concha,while the sham-taVNS group received no electrical stimulation and rats in the ST36 group received stimulation at ST36 for 30 min once daily for 14 consecutive days. Cervical trapezius electromyography score and abdominal withdrawal reflex (AWR) score were used to evaluate gastric sensitivity. Histopathological changes of the gastric antrum tissue were observed under microscope after H.E. staining. Autonomic nerve function in rats was recorded and assessed by heart rate variability(HRV). The content of acetylcholine (Ach) and the expression of Ach receptor M3R in gastric antrum was detect by ELISA and Western blot, separately. Compared with the normal control group, the cervical trapezius electromyography and AWR scores of the model group increased (P<0.01, P<0.001), and there was no erosion in the gastric antral mucosa and muscle layer. The high-frequency power (HF) in HRV decreased (P<0.05), the ratio of low-frequency power/high-frequency power (LF/HF) increased (P<0.001), and the Ach content and its receptor M3R expression in gastric antrum tissue decreased (P<0.05). Following interventions, the cervical trapezius electromyography and AWR scores decreased (P<0.01,P<0.001, P<0.05), HF in HRV increased and LF/HF decreased(P<0.01，P<0.05,P<0.001), and the content of Ach in gastric antrum tissue and the expression of its receptor M3R increased (P<0.01, P<0.05) in both taVNS and ST36 groups relevant to the model group. taVNS can increase the activity of the vagus nerve and regulate the balance of the autonomic nerve function, which may be one of the mechanisms of taVNS in reducing the gastric sensitivity of rats with FD. In regulating the vagus nerve function, taVNS and acupuncture at ST36 acupoint have the similar effects.

ST6Gal1 targets the ectodomain of ErbB2 in a site-specific manner and regulates gastric cancer cell sensitivity to trastuzumab

The clinical performance of the therapeutic monoclonal antibody trastuzumab in the treatment of ErbB2-positive unresectable gastric cancer (GC) is severely hampered by the emergence of molecular resistance. Trastuzumab’s target epitope is localized within the extracellular domain of the oncogenic cell surface receptor tyrosine kinase (RTK) ErbB2, which is known to undergo extensive N-linked glycosylation. However, the site-specific glycan repertoire of ErbB2, as well as the detailed molecular mechanisms through which specific aberrant glycan signatures functionally impact the malignant features of ErbB2-addicted GC cells, including the acquisition of trastuzumab resistance, remain elusive. Here, we demonstrate that ErbB2 is modified with both α2,6- and α2,3-sialylated glycan structures in GC clinical specimens. In-depth mass spectrometry-based glycomic and glycoproteomic analysis of ErbB2’s ectodomain disclosed a site-specific glycosylation profile in GC cells, in which the ST6Gal1 sialyltransferase specifically targets ErbB2 N-glycosylation sites occurring within the receptor’s trastuzumab-binding domain. Abrogation of ST6Gal1 expression reshaped the cellular and ErbB2-specific glycomes, expanded the cellular half-life of the ErbB2 receptor, and sensitized ErbB2-dependent GC cells to trastuzumab-induced cytotoxicity through the stabilization of ErbB dimers at the cell membrane, and the decreased activation of both ErbB2 and EGFR RTKs. Overall, our data demonstrates that ST6Gal1-mediated aberrant α2,6-sialylation actively tunes the resistance of ErbB2-driven GC cells to trastuzumab.