Vasoactive Intestinal Peptide Levels Research Articles

Increased Vasoactive Intestinal Peptide (VIP) in polycystic ovary syndrome patients undergoing IVF.

Polycystic ovary syndrome (PCOS) is a common multifactorial and polygenic disorder of the endocrine system, affecting up to 20% of women in reproductive age with a still unknown etiology. Follicular fluid (FF) represents an environment for the normal development of follicles rich in metabolites, hormones and neurotransmitters, but in some instances of PCOS the composition can be different. Vasoactive intestinal peptide (VIP) is an endogenous autonomic neuropeptide involved in follicular atresia, granulosa cell physiology and steroidogenesis. ELISA assays were performed to measure VIP and estradiol levels in human follicular fluids, while AMH, FSH, LH, estradiol and progesterone in the plasma were quantified by chemiluminescence. UHPLC/QTOF was used to perform the untargeted metabolomic analysis. Our ELISA and metabolomic results show: i) an increased concentration of VIP in follicular fluid of PCOS patients (n=9) of about 30% with respect to control group (n=10) (132 ± 28 pg/ml versus 103 ± 26 pg/ml, p=0,03) in women undergoing in vitro fertilization (IVF), ii) a linear positive correlation (p=0.05, r=0.45) between VIP concentration and serum Anti-Müllerian Hormone (AMH) concentration and iii) a linear negative correlation between VIP and noradrenaline metabolism. No correlation between VIP and estradiol (E2) concentration in follicular fluid was found. A negative correlation was found between VIP and noradrenaline metabolite 3,4-dihydroxyphenylglycolaldehyde (DOPGAL) in follicular fluids. VIP concentration in follicular fluids was increased in PCOS patients and a correlation was found with noradrenaline metabolism indicating a possible dysregulation of the sympathetic reflex in the ovarian follicles. The functional role of VIP as noradrenergic modulator in ovarian physiology and PCOS pathophysiology was discussed.

Unveiling the gut microbiota and metabolite profiles in guinea pigs with form deprivation myopia through 16S rRNA gene sequencing and untargeted metabolomics

AimThe aim of this study was to confirm the presence of the form deprivation myopia (FDM) guinea pig eye-gut axis and investigate the relationship between serum vasoactive intestinal peptide (VIP), lipopolysaccharides (LPS), specific gut microbiota and their metabolites. Method20 specific-pathogen-free (SPF) guinea pigs were divided into the FDM and the control(Con) group. Following model induction, serum levels of VIP and LPS were quantified. A combination of 16S ribosomal ribosomal Ribonucleic Acid (rRNA) gene sequencing, non-targeted metabolomics and bioinformatics analysis were employed to identify disparities in gut microbiota and metabolites between the two groups of guinea pigs. ResultCompared to the control group, FDM guinea pigs exhibited a significant trend towards myopia, along with significantly elevated concentrations of LPS and VIP (p < 0.0001). Furthermore, Ruminococcus_albus emerged as the predominant bacterial community enriched in FDM (p < 0.05), and demonstrated positive correlations with 10 metabolites, including l-Glutamic acid, Additionally, Ruminococcus_albus exhibited positive correlations with VIP and LPS levels (p < 0.05). ConclusionThe findings suggest that the Ruminococcus_Albus and glutamate metabolic pathways play a significant role in myopia development, leading to concurrent alterations in serum VIP and LPS levels in FDM guinea pigs. This underscores the potential of specific gut microbiota and their metabolites as pivotal biomarkers involved in the pathogenesis of myopia.

Preventive effect of kiwi berry (Actinidia arguta) on loperamide-induced constipation

Constipation is a common intestinal disease. Kiwi berries can effectively prevent constipation. However, studies have yet to be done to determine how kiwi berries prevent constipation. For 2 weeks, mice in this study were continually orally gavaged with kiwi berry, loperamide, or a combination of the two. This study found that the kiwi group's feces had more water than the constipated mice. In addition, kiwi berries can speed up gastrointestinal transit (GI), shorten the time it takes to pass the first dark stool, and dramatically enhance body weight gain. In the interstitial cells of Cajal (ICC) cells and colon tissues, alterations in the protein expression of vasoactive intestinal peptide (VIP), cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), and aquaporin-3 (AQP3) were found. At 3, 6, and 12 h of ICC cells and mouse colon, the kiwi group’s VIP, cAMP, PKA, and AQP3 protein expression levels were lower than those of the constipated mice. The kiwi berry can decrease the Firmicutes to Bacteroidetes ratio and boost the diversity and quantity of gut microbiota. By influencing the gut microbiota and VIP-cAMP-PKA-AQP3 signaling pathway, kiwi berries prevent constipation.

Effects of the Neuropeptides Pituitary Adenylate Cyclase Activating Polypeptide and Vasoactive Intestinal Peptide in Male Fertility.

Background and Objectives: The neuroendocrine system plays a crucial role in regulating various bodily functions, including reproduction, with evidence suggesting its significant involvement in male fertility and sperm development. Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP) are expressed in both male and female reproductive tissues, influencing penile erection and regulating steroidogenesis in males. Therefore, our study aimed to compare the protein levels of VIP and PACAP in seminal plasma between healthy controls and sub-fertile patients. Additionally, we sought to correlate the levels of these biomarkers with clinical, functional, and laboratory findings in the participants. Materials and Methods: The study included a total of 163 male participants for analysis. The participants were further stratified into subgroups of fertile and sub-fertile men of four subgroups according to the 2021 WHO guidelines. Seminal plasma concentrations of the neuropeptides VIP and PACAP were measured using human enzyme-linked immunosorbent assay technique. Results: The findings showed statistically significant differences in total sperm count, sperm concentration, total motility, and vitality (p < 0.001) between the fertile group and the sub-fertile group. Specifically, significant differences found between healthy males and oligoasthenospermic patients (p = 0.002), and between asthenospermic and oligoasthenospermic patients (p = 0.039). An ROC analysis showed associated sensitivity and specificity values of 62.2% and 55.6%, respectively, to PACAP seminal levels differentiated between sub-fertile patients from fertile males (p = 0.028). No significant difference in seminal levels of VIP was found between the sub-fertile and fertile groups. Conclusions: Previous research leads to the point of PACAP active involvement in spermatogenesis. In accordance to our study, in human semen samples, we have seen a significance change in PACAP levels amongst patients with low sperm count or with both low sperm count and low motility, hinting at its contribution and acting as a possible factor in this complex process. Thus, alterations in the levels or actions of these neuropeptides have been associated with certain reproductive disorders in males.

Activation of ASIC3/ERK pathway by paeoniflorin improves intestinal fluid metabolism and visceral sensitivity in slow transit constipated rats.

Slow transit constipation (STC) is one of the most common gastrointestinal disorders in children and adults worldwide. Paeoniflorin (PF), a monoterpene glycoside compound extracted from the dried root of Paeonia lactiflora, has been found to alleviate STC, but the mechanisms of its effect remain unclear. The present study aimed to investigate the effects and mechanisms of PF on intestinal fluid metabolism and visceral sensitization in rats with compound diphenoxylate-induced STC. Based on the evaluation of the laxative effect, the abdominal withdrawal reflex test, enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction, western blot, and immunohistochemistry were used to detect the visceral sensitivity, fluid metabolism-related proteins, and acid-sensitive ion channel 3/extracellular signal-regulated kinase (ASIC3/ERK) pathway-related molecules. PF treatment not only attenuated compound diphenoxylate-induced constipation symptoms and colonic pathological damage in rats but also ameliorated colonic fluid metabolic disorders and visceral sensitization abnormalities, as manifested by increased colonic goblet cell counts and mucin2 protein expression, decreased aquaporin3 protein expression, improved abdominal withdrawal reflex scores, reduced visceral pain threshold, upregulated serum 5-hydroxytryptamine, and downregulated vasoactive intestinal peptide levels. Furthermore, PF activated the colonic ASIC3/ERK pathway in STC rats, and ASIC3 inhibition partially counteracted PF's modulatory effects on intestinal fluid and visceral sensation. In conclusion, PF alleviated impaired intestinal fluid metabolism and abnormal visceral sensitization in STC rats and thus relieved their symptoms through activation of the ASIC3/ERK pathway.

Sex-Dependent Effects of Chronic Circadian Disruption in AβPP/PS1 Mice.

Chronic disruption of the circadian timing system, often reflected as a loss of restful sleep, also includes myriad other pathophysiological effects. The current study examined how chronic circadian disruption (CD) could contribute to pathology and rate of progression in the AβPP/PS1 mouse model of Alzheimer's disease (AD). A chronic CD was imposed until animals reached 6 or 12 months of age in AβPP/PS1 and C57BL/6J control mice. Home cage activity was monitored for a period of 3-4 weeks prior to the endpoint along with a single timepoint measure of glucose sensitivity. To assess long term effects of CD on the AD phenotype, animals were re-entrained to a no disruption (ND) schedule just prior to the endpoint, after which a Morris water maze (MWM) was used to assess spatial learning and memory. Dampening of nighttime activity levels occurred in disrupted animals, and female animals demonstrated a greater adaptability to CD. Diminished arginine vasopressin (AVP) and vasoactive intestinal peptide (VIP) levels in the suprachiasmatic nucleus (SCN) of 12-month male AβPP/PS1 exposed to the CD paradigm were observed, potentially accounting for the diminished re-entrainment response. Similarly, CD worsened performance in the MWM in 12-month male AβPP/PS1 animals, whereas no effect was seen in females. Collectively, these findings show that exposure to chronic CD impairs circadian behavioral patterns and cognitive phenotypes of AβPP/PS1 mouse model in a sex-dependent manner.

The Role of Biomarkers Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) and Vasoactive Intestinal Peptide (VIP) in Chronic and Episodic Migraines: A Meta-Analysis

Background. Migraine is a neurological disorder that results in disability accumulation, and there are no blood-based markers for indicating migraine susceptibility. Here, we aimed to evaluate the possible biomarker role of neuropeptides, vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating polypeptide (PACAP) in chronic (CM) and episodic migraine (EM). Method. PubMed, medRxiv, and Google Scholar databases were searched up to the 7th of September 2022 using the search syntax to define all relevant articles addressing the plasma and serum levels of VIP and PACAP in migraineurs and controls. Concerning bias assessment, the risk of bias in nonrandomized studies-I (ROBINS-I) was assessed. Also, the standardized mean difference (SMD) was measured with a random effects model. Results. Five case-control studies with 503 migraine cases were included. CM patients had elevated VIP levels compared to controls (SMD=0.44, 95% CI 0.25-0.62, p&lt;0.00001). In contrast, PACAP levels were lower in EM patients (SMD=−0.30, 95% CI -0.48 to -0.11, p=0.002). Overall, migraine cases had higher VIP levels (SMD=0.25, 95% CI 0.11-0.39, p=0.0006) but lower PACAP levels (SMD=−0.16, 95% CI -0.30 to -0.03, p=0.020) than controls. Conclusion. The results support the role of VIP and PACAP neuropeptides in migraine pathophysiology. CM patients have significantly higher serum VIP levels, while EM patients have lower serum PACAP levels compared to controls. Further studies should confirm these findings.

The rhizomes of Atractylodes macrocephala relieve loperamide-induced constipation in rats by regulation of tryptophan metabolism

Ethnopharmacological relevanceConstipation is one of the most prevalent gastrointestinal tract diseases that seriously affects health-related quality of human life and requires effective treatments without side effect. The rhizome of Atractylodes macrocephala Koidz. (Compositae), called Atractylodes Macrocephala Rhizome (AMR), a commonly used traditional Chinese medicine, has been used to relieve the clinical symptoms of patients with constipation. Aim of the studyTo reveal the dose-dependent laxative effect and potential mechanism of AMR on loperamide-induced slow transit constipation (STC) rats. Materials and methodsLoperamide-induced constipation rat model was established and the dose-dependent laxative effect of AMR was investigated. Untargeted metabolomics based on an UPLC-Q/TOF-MS technique combined with western blot analysis was used to explain the potential mechanism of AMR relieve loperamide-induced constipation in rats. ResultsThe results showed that medium dose of AMR (AMR-M, 4.32 g raw herb/kg) and high dose of AMR (AMR-H, 8.64 g raw herb/kg) treatments significantly increased the fecal water content, Bristol score, gastrointestinal transit rate, and recovered the damaged colon tissues of constipated rats, but low dose of AMR (AMR-L, 2.16 g raw herb/kg) did not show laxative effect. Both AMR-M and AMR-H treatments also remarkably reduced the serum levels of vasoactive intestinal peptide (VIP), somatostatin (SS) and dopamine (DA), and increased the levels of motilin (MTL), gastrin (GAS) and 5-hydroxytryptamine (5-HT). Urine metabolomics revealed that constipation development was mainly ascribed to the perturbed tryptophan metabolism, and AMR-M and AMR-H markedly corrected the abnormal levels of five urine tryptophan metabolites, namely 4,6-dihydroxyquinoline, indole, 4,8-dihydroxyquinoline, 5-hydroxytryptamine, and kynurenic acid. Additionally, western blot analysis confirmed that the abnormal expression of rate-limiting enzyme involving in tryptophan metabolism, including tryptophan hydroxylase (TPH), monoamine oxidase (MAO) and indoleamine-2,3-dioxygenase (IDO) in the colon of constipated rats, were mediated by AMR-M and AMR-H. Conclusions: The findings provide insight into the mechanisms of STC and AMR could be developed as new therapeutic agent for prevention or healing of constipation.

Therapeutic effects of curcumin on constipation-predominant irritable bowel syndrome is associated with modulating gut microbiota and neurotransmitters.

Constipation-predominant irritable bowel syndrome (IBS-C) is a functional bowel disease that affects 10-20% of the population worldwide. Curcumin (CUR) is widely used in traditional Chinese medicine to treat IBS, but its mechanism of action needs further investigation. In this study, we used mosapride (MOS) as a positive control to evaluate the changes in gut microbiota in IBS-C rat models after treatment with CUR or MOS by analyzing 16S rDNA variation. In addition, we used enzyme immunoassay kits and immunohistochemical analysis to investigate whether CUR or MOS influenced serotonin (5-HT), substance P (SP), and vasoactive intestinal peptide (VIP) levels in the serum and colon of IBS-C rats. The study showed that rats supplemented with CUR showed significantly increased fecal weight, fecal water content, small intestine transit rate and significantly decreased serum levels of 5-HT, VIP and SP compared to the IBS group (p < 0.05). In addition, treatment with CUR changed the relative abundance of Blautia, Sutterella, Acetanaerobacterium and Ruminococcus2 in the gut microbiota. This study showed that the efficacy of CUR on IBS-C was possibly by modulating the microbiota and lowering the serum levels of HT, SP, and VIP.

Early Plasma Levels of IL7 and IL15 Predict Response to Chimeric Antigen Receptor T Cell Therapy (CAR-T) in Large B-Cell Lymphoma (LBCL) Patients

Introduction Anti-CD19 chimeric antigen receptor T cells (CAR-T) have rapidly shifted the treatment paradigm for relapsed/refractory large B-cell lymphoma (LBCL) but produce durable complete response (CR) in only 30-40% of patients. In addition, CAR-T-mediated toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) remain a major concern. To investigate the relationships of circulating cytokines and chemokines on CAR-T outcomes, we applied specialized comprehensive cytokine panels to peripheral blood samples serially collected from LBCL patients undergoing treatment with anti-CD19 CAR-T cells. Methods LBCL patients were consented to our IRB-approved study and longitudinally followed for sample collection at pre-specified timepoints: prior to lymphodepleting chemotherapy (LD chemo), day 0 (day of [and prior to] CAR-T infusion), and days 3, 7, 10, 14, 21, and 90. MSD R-PLEX and U-PLEX assays were used to detect 47 cytokines and chemokines in plasma; vasoactive intestinal peptide (VIP) levels were quantified via a VIP-specific enzyme immunoassay. Mann-Whitney U test, Spearman's correlation coefficient, and a LASSO (least absolute shrinkage and selection operator) model were utilized to identify key cytokines contributing to critical clinical outcomes. Results Peri-CAR-T blood samples were collected from 24 LBCL patients, including one patient who received 2 infusions of an investigational allogeneic anti-CD19 product; all other patients received commercially available products, each associated with their distinct LD chemo dosing regimens. With median follow-up of 11.2 months, 54% patients achieved CR as best response, 50% experienced CRS (maximum Grade 2 in 25%), and 29% experienced ICANS (Grade ≥3 in 8%). Most cytokines demonstrated characteristic peak patterns over time that were not dependent on whether cytokines were produced by hematopoietic cells ( Table). Among most cytokines with peak values at Day 0, the mean percentage change from Pre-LD Chemo to Day 0 increased as chemo intensity increased (i.e., fludarabine dose from 25 to 30 mg/m 2, and cyclophosphamide dose from 250 to 500 mg/m 2). Notably, levels of the non-hematopoietic cytokines IL7 and IL15 were highest at day 0, reflecting effects of LD chemo. Using statistical models to filter relevant values, we developed a signature of 14 key cytokines that could be used to predict clinical response at 3 months. Half of these were stromal-produced cytokines from early timepoints: Cytokines positively correlated with CR or partial response (PR) included IL7 at Day 0 (Mann-Whitney U p&amp;lt;0.001) and Day 7 (p=0.044), and IL15 at Day 0 (p=0.016). Negatively correlated cytokines included IL4 at Day 3 (p=0.041), IL10 at Day 7 (p=0.027), CCL19 at Day 10 (p=0.017), and MIP1α at Day 14 (p=0.03). Intriguingly, several Type 1 T helper cell (Th1)-related cytokines with peaks at Day 3 or Day 7 (e.g., IL2, IFN-γ, TNF-α, and IL18) were not associated with response. Strong associations of timepoint-specific cytokine levels with patient outcomes are exemplified in the Figure: all patients achieving CR had IL7 levels above average on Day 0, while most patients (9/10) who failed to achieve CR had IL7 levels below average on Day 0. This same striking pattern was observed for IL15 at Day 0. Similar analyses gauged which timepoint-specific cytokines were associated with CRS and ICANS. Of 14 values associated with CRS, 13 were from Day 3 or later, likely reflecting sequelae of CRS rather than representing predictive biomarkers. Pre-LD Chemo CCL18 was the exception, positively correlated with CRS (p=0.035). Only 5 cytokine values were associated with development of ICANS, 3 from Day 10 or later; IL7 at Day 0 (p=0.011) and Day 3 (p&amp;lt;0.001) was positively correlated with ICANS . Conclusions Comprehensive cytokine profiling revealed that early measurements of several stromal-produced cytokines can predict response in LBCL patients who receive CAR-T-most notably IL7 and IL15 levels on Day 0, prior to CAR-T infusion. Conversely, few early cytokine measurements were helpful in predicting CRS and ICANS, limited to CCL18 and IL7. Analyses are ongoing to characterize associations of patient characteristics, product differences, and circulating immune cell subsets with changes in cytokine profile over time. Further studies are warranted to validate our findings in a larger data set.

The Efficacy of Budesonide, Levocabastine, and Their Combination in Treatment of Vasomotor Rhinitis

Introduction: Relevant studies have demonstrated that glucocorticoids and antihistamines, such as budesonide and azelastine, are effective in the treatment of vasomotor rhinitis, with their combined use being more effective than that of a single drug. The aim of this study was to assess the improvement in the symptoms of patients following the combined administration of these drugs. Methods: We conducted a single-center randomized study on 42 patients. Participants were randomly treated with budesonide, levocabastine hydrochloride, or their combination for 2 weeks. The visual analog scale (VAS) score and levels of eosinophil cationic protein (ECP), histamine (HA), leukotriene B4 (LTB4), and vasoactive intestinal peptide (VIP) in nasal secretions were evaluated before and after treatment. Results: The symptoms of patients were improved in all 3 treatment groups compared with those before treatment. Following combined treatment, the improvement in symptoms of nasal obstruction, runny nose, nasal itching, and sneezing was much greater than those in the groups treated with budesonide or levocabastine hydrochloride alone (p = 0.04, 0.004, 0.005, 0.004, respectively). The decreased levels of these inflammatory mediators were significantly different between the different treatment groups. Conclusions: Budesonide or levocabastine hydrochloride alone improved the nasal symptoms of patients with vasomotor rhinitis and reduced the levels of ECP, HA, LTB4, and VIP in nasal secretions. However, their combination improved the symptoms of patients more significantly than each drug alone.

Clinical Efficacy and Mechanism of Transcutaneous Neuromodulation on Functional Dyspepsia.

Prokinetics and proton pump inhibitors are first-line drugs for functional dyspepsia (FD) patients. However, no available treatment is effective for most FD patients, and the pathogenesis is still unclear. The purpose of this study was to investigate the therapeutic effect of transcutaneous neuromodulation (TN) on FD and its potential mechanisms. Fifty-seven FD patients were enrolled in the study and randomly divided into 3 groups (TN Neiguan (PC6) group, TN Zusanli (ST36) group, and sham TN group) that received corresponding treatment respectively for 4 weeks. Then, all the patients enrolled received TN PC6 combined with ST36 treatment for another 4 weeks. Dyspepsia symptom questionnaire, Medical outcomes study item short form health survey (SF-36), Hospital Anxiety and Depression Scale were used to assess the severity of symptoms. Gastric accommodation, gastric emptying rate, and related parameters of electrogastrogram were used to assess the pathophysiological mechanism of FD. The possible gastrointestinal hormonal mechanism involved was assessed by detecting serum ghrelin, neuropeptide Y, and vasoactive intestinal peptide. The possible duodenal inflammation mechanism involved was assessed by detecting duodenal mucosa. TN treatment reduced the dyspepsia symptom score ( P <0.05) and improved the quality of life. After TN treatment, the gastric accommodation ( P <0.01), the gastric emptying rate ( P <0.01), and the percentages of preprandial ( P <0.05) and postprandial ( P <0.05) gastric slow waves (GSW) were increased. The proportions of preprandial ( P <0.05) and postprandial ( P <0.05) gastric electrical rhythm disorder were reduced. The double acupoint combination therapy further enhanced the therapeutic effect of single acupoint. In addition, the levels of ghrelin ( P <0.001) and neuropeptide Y ( P <0.001) were significantly increased, the level of vasoactive intestinal peptide ( P <0.001) was significantly decreased, and the total number of mast cells ( P <0.001) in the duodenal bulb was significantly decreased after double acupoints combination therapy. TN treatment significantly improves the dyspepsia symptoms of FD patients and their quality of life. TN treatment increases the percentage of normal GSW, reduces the proportion of gastric electrical rhythm disorder, and improves the gastric accommodation and gastric emptying rate. The therapeutic effect of TN may be caused by regulating gastrointestinal hormone secretion and alleviating local inflammatory responses in duodenum. In addition, the improvement of TN on GSW was closely related to the decrease of bradygastria.

Stool-softening effect and action mechanism of free anthraquinones extracted from Rheum palmatum L. on water deficit-induced constipation in rats

Ethnopharmacological relevanceIn traditional Chinese herbal medicine, rhubarb is said to remove accumulation with purgation, clearing heat, and discharging fire. Modern pharmacology has shown that rhubarb extract has a purgative effect when given to experimental animals in an appropriate dose. However, the active components and their mechanism of action are still not clearly defined. Aim of the studyThe current research aimed to evaluate the synergistic stool-softening effects and explore the action mechanism of rhubarb free anthraquinones (RhA) and their monomers on constipation in rats. Materials and methodsA rat model of water deficit-induced constipation was established to induce constipation, and these rats were treated with RhA and its monomers. ELISA, histopathology, immunohistochemistry, qPCR and Western blotting based on network pharmacology and molecular docking were conducted to explore the possible mechanism of action of RhA and its monomers. ResultsRhA, aloe-emodin, rhein, and chrysophanol showed stool-softening activity, and the combination of aloe-emodin and rhein had the strongest softening effect on faecal pellets. Aloe-emodin, rhein, and chrysophanol significantly increased the serum levels of vasoactive intestinal peptide (VIP), motilin (MTL), and substance P (SP), upregulated the expression of VIP, cyclase-associated protein 1 (CAP1), protein kinase A (PKA), cystic fibrosis transmembrane conductance regulator (CFTR), aquaporin 3 (AQP3), aquaporin 4 (AQP4), and aquaporin 8 (AQP8), decreased the expression of epithelial sodium channel (ENaC) and Na+/H+ exchanger 3 (NHE3), and reduced the colonic tissue concentration of Na+-K+-ATPase in the constipated rats. Osmolality of colonic fluid in model rats treated by RhA, aloe-emodin, rhein, and chrysophanol was increased. ConclusionAloe-emodin, rhein, and chrysophanol were the stool-softening components of the RhA extract, and there were certain drug-interactions between the components. RhA upregulated VIP expression, activated the cyclic adenosine monophosphate protein kinase A (cAMP/PKA) pathway, and further stimulated CFTR expression while inhibiting NHE3 and ENaC expression, resulting in a hypertonic state in the colonic lumen. Water transport could then be driven by an osmotic gradient, which in turn led to the upregulation of AQP3, AQP4, and AQP8 expression. In addition, RhA likely improved gastrointestinal motility by increasing serum VIP, SP, and MTL concentrations, thus promoting faecal excretion.

Aged black tea alleviates constipation in mice by modulating intestinal neurotransmitters and decreasing AQP3 and AQP9 expression

Background: Black tea is fully fermented tea with abundant functional components that benefit the gastrointestinal tract. But whether black tea extract relieves constipation is unknown. Therefore, we used loperamide to induce constipation in mice to assess the therapeutical effect of extracts from aged black tea with different storage times.&#x0D; Design: Sixty-three C57BL/6J male mice were randomly divided into Control group (Con), Model group (Mod), Positive group (Pos), aged 6 years group (15Y), aged 4 years group (17Y), aged 2 years group (19Y), and unaged group (21Y). Mice were given loperamide (20 mg/kg, twice a day) to induce constipation for 10 days, and black tea extracts (500 mg/kg) were intragastrically given for 7 days while continuing modeling.&#x0D; Results: The results showed that black tea extracts relieved constipation symptoms by improving defecation weight, fecal water content, and gastrointestinal transit rate. Black tea extracts can also protect colon tissue, regulate serum neurotransmitters, increase the levels of excitatory neurotransmitters motilin (MTL) and substance P (SP), and decrease the levels of inhibitory neurotransmitters vasoactive intestinal peptide (VIP) and nitric oxide (NO). Immunohistochemistry (IHC) showed that black tea extracts were able to reduce AQP3 and AQP9 expression in the colon of constipated mice. In addition, Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) showed that black tea extracts could decrease AQP3 and AQP9 mRNA expression. The relief effect of aged black tea (15Y) with the longest storage was better than that of other years, which may be due to the role of active ingredients such as thearubigins (TRs), soluble sugar, tea polysaccharide (TPS), gallic acid (GA), and catechin gallate (CG) in aged black tea.&#x0D; Conclusions: Based on these results, we believe that regular consumption of black tea is effective in relieving constipation, and that black tea is more effective in relieving constipation as the storage time increases.

SAT610 Multiple Endocrine Neoplasia Type 1 - The First Reported Case In An Indigenous Australian

Abstract Disclosure: E. Mignone: None. K. Neal: None. Background: Multiple Endocrine Neoplasia type 1 (MEN1) is a rare and under recognised syndrome. It has not been previously reported in Indigenous Australians for this reason. Clinical Case: A 48-year-old Indigenous Australian female was consulted on by an inpatient endocrine team in March 2020 for persistent hypercalcaemia on a background of a parathyroidectomy in 2011 for primary hyperparathyroidism (PHPTH). She was admitted to a remote Australian hospital for investigation and management of acute on chronic abdominal pain. Relevant medical history included a parathyroidectomy at age 40, multiple PE/DVT, MI, AF, CTEPH, right heart failure, HTLV-1 and recurrent abdominal pain presumed secondary to GORD. Gastroscopy from 2013 revealed chronic gastritis with hundreds of gastric polyps discovered on subsequent gastroscopy in 2015. The young age of PHPTH combined with her chronic gastritis and polyps prompted neuroendocrine tumour (NET) screening, including MEN1. At time of consult in 2020, laboratory studies were consistent with recurrence of PHPTH with a corrected calcium of 2.9 mmol/L (2.15-2.57mmol/L), serum PTH level 31.5 pmol/L (1-7pmol/L), vitamin D level 30 nmol/L, 24-hour urinary calcium variable between low and high. NET markers were markedly elevated with a gastrin level of 14042 ng/L (&amp;lt;100 ng/L), pancreatic polypeptide 2905 pmol/L (&amp;lt;55 pmol/L), urine 5HIAA ratio 8 mmol/L (&amp;lt;4 mmol/L), vasoactive intestinal peptide and glucagon levels normal. Pituitary studies, serum calcitonin, plasma metanephrines and PTH related protein levels were within normal limits. A CT of the abdomen showed thickened gastric folds, and persistent liver and IVC lesions from 2018. A diagnosis of Zollinger Ellison Syndrome (ZES) was made. Eventually, genetic testing was positive for a rare heterozygous variant of c.207dupC in exon 2 of MEN1 gene. A 68-gallium-DOTATATE PET/CT showed multiple avid pancreatic, gastric, nodal and liver lesions with high somatostatin receptor expression, suggestive of a neuroendocrine malignancy. Treatment was based largely on symptom control due to poor overall prognosis from underlying cardiorespiratory comorbidities. Abdominal pain from ZES was managed with a high dose PPI, H2 receptor antagonist and subcutaneous somatostatin analogue were trialled. Hypercalcaemia was treated with IV bisphosphonate therapy. Calcimimetic analogues were considered however patient declined. Genetic counselling was attempted however many cultural and logistical barriers were identified and family declined further testing. Unfortunately, our patient died in 2021 from presumed multifactorial respiratory failure. Conclusion: High index of suspicion is required to diagnose MEN1. This is particularly true within the Indigenous Australian population, with no prior documented cases reported. Presentation: Saturday, June 17, 2023

The Different Ways Multi-Strain Probiotics with Different Ratios of Bifidobacterium and Lactobacillus Relieve Constipation Induced by Loperamide in Mice.

Constipation is currently one of the most common gastrointestinal disorders, and its causes are diverse. Multi-strain probiotics are often considered a more effective treatment than single-strain probiotics. In this study, a constipation model was constructed using loperamide hydrochloride to evaluate the ability of a multi-strain probiotic combination of four different ratios of Bifidobacterium and Lactobacillus to regulate intestinal flora, relieve constipation, and explore the initial mechanism in mice. After four weeks of probiotic intervention, BM1, BM2, and PB2 effectively relieved constipation; however, the pathways involved were different. The Bifidobacteria-dominated formulations BM1 and BM2 mainly changed the composition and structure of the intestinal flora and significantly decreased the relative abundance of Tyzzerella, Enterorhabdus, Faecalibaculum, Gordonibacter, and Mucispirillum in stool; increased the relative abundance of Parabacteroides and the content of short-chain fatty acids (SCFAs) in stool; restored motilin (MTL) and vasoactive intestinal peptide (VIP) levels; and downregulated interleukin 6 (IL-6) and IL-8 levels in serum. This repaired the inflammatory response caused by constipation. Finally, it promoted peristalsis of the gastrointestinal tract, increasing stool water content, and relieving constipation. While Lactobacillus-dominated formula PB2 mainly restored the levels of serum neurotransmitters (MTL, SP (substance P), VIP and PYY (Peptide YY)) and inflammatory factors (IL-1, IL-6 and IL-8), it significantly decreased the relative abundance of Tyzzerella, Enterorhabdus, Faecalibaculum, Gordonibacter and Mucispirillum in stool; it then increased acetic acid content, thereby reducing the level of inflammation and changing stool properties and gastrointestinal motility.

Effects of Lactiplantibacillus plantarum GUANKE on Diphenoxylate-Induced Slow Transit Constipation and Gut Microbiota in Mice.

Slow transit constipation (STC) is a prevalent gastrointestinal condition with slow transit, and some probiotics can effectively relieve constipation, but the exact mechanisms have not been fully understood. In this study, we evaluate the impact of Lactiplantibacillus plantarum GUANKE (GUANKE) on diphenoxylate-induced slow transit constipation and speculate on the underlying mechanisms in a mouse model. Administration of L. plantarum GUANKE alleviated constipation indexes, including defecation time, fecal output and water content, and gastrointestinal transit ratio. In addition, GUANKE restored the protein expression of constipation-related intestinal factors (aquaporins (AQPs) and interstitial Cajal cells (ICCs)) in colon tissues measured using immunofluorescence staining; regulated the neurotransmitters and hormones, such as increased levels of 5-hydroxytryptamine, substance P, and motilin; and decreased levels of vasoactive intestinal peptide and nitric oxide in serum, as measured by an ELISA. 16S rRNA and correlation analysis of feces indicated that GUANKE administration effectively reduced constipation-induced Prevotella enrichment and suggested a potential contribution of Prevotella to diphenoxylate-induced STC in mice. GUANKE had no effect on short-chain fatty acids (SCFAs) in cecum content. This study revealed that GUANKE may alleviate constipation in mice through regulating intestinal neurotransmitter and hormone release and altering specific bacterial taxa, rather than by affecting SCFAs and the diversity of microbiota in the gut. Further research is needed to confirm if the findings observed in this study will be consistent in other animal studies or clinical trials.

Oral suspension of thaliporphine alter the functional dyspepsia in gastroduodenal lesions rats via gastrointestinal hormones and brain-gut peptides

Functional dyspepsia (FD), also known as nonulcer dyspepsia, is distinguished by epigastric burning or pain, nausea, a feeling of being overly full, and bloating. Thaliporphine an alkaloid exhibited the protective effect against the inflammatory reaction and oxidative stress. Our aim to scrutinized the therapeutic potential of thaliporphine against FD in rats. Sprague-Dawley (SD) rats were randomised into six groups at random, and the FD model was created using irregular tail clamp stimulation over 14 days (except from rats in the control group). The normal and model group rats got menstruum and thaliporphine oral administration for 14 days after the FD rat models were effectively established. The body weight, food and water intake were estimated. The level of plasma gastrin (GAS), motilin (MTL), vasoactive intestinal peptide (VIP), somatostatin (SS), calcitonin gene-related peptide (CGRP), acetylcholine (AChE), antioxidant, cytokines and inflammatory parameters were estimated. Thaliporphine treated group rats exhibited the increased body weight and food intake, which was suppressed during the FD. Thaliporphine significantly increased the rate of intestinal propulsion and gastric emptying in addition to changing the levels of leptin, CGRP, MLT, SS, and VIP. Thaliporphine significantly (P &lt;0.001) reduced the level of AChE in serum and boosted the level in stomach and hypothalamus. Thaliporphine significantly changed the cytokine and inflammatory parameter levels. Treatment with thaliporphine improves gut peptide levels, controls the peripheral and central nervous systems, and restores levels of gastrointestinal hormones, all of which point to the drug’s potential for protecting against FD.

Vasoactive intestinal polypeptide level in gastroesophageal reflux disease before and after surgical treatment

From year to year, wide spread of gastroesophageal reflux disease (GERD) is attracting greater attention of specialists in the field of this pathology diagnosis and treatment. In-depth studies on etiological and pathogenetic factors in the GERD development are being conducted. Of particular interest is the role of humoral factors, one of which is vasoactive intestinal peptide (VIP). There are currently no data on the dynamics of this hormone during surgical treatment of GERD. The aim of the study was to examine the dynamics of plasma VIP during surgical treatment of GERD and its influence on the lower esophageal sphincter (LES) function. Materials and methods. Surgical treatment in the Nissen modification was performed for 35 patients with GERD. There were 26 women (74.3 %), men – 9 (25.7 %). mean age – 55.3 ± 11.3 years. Comparison group – 20 apparently healthy individuals: women – 14 (70.0 %); men – 6 (30.0 %), mean age – 56.7 ± 10.6 years. VIP was measured in venous blood plasma by an enzyme immunoassay (Vasoactive intestinal peptide ELISA, S-1201, BCM Diagnostics) using an immunoenzyme complex ImmunoChem-2100 (USA). The sampling of the studied samples in the main group was carried out before the operation and 2–3 months post-surgery. Results. In the main group before the surgery, the level of VIP was 3.1 ± 1.1 ng/ml, after the surgery – 2.2 ± 1.0 ng/ml. In the comparison group, VIP was determined at the level of 2.1 ± 1.1 ng/ml. In GERD before the surgery, the VIP level was statistically different from the indicators in the comparison group and from postoperative values. After surgical treatment, VIP values were decreased to the level of apparently healthy individuals. There was a positive correlation between the VIP level and acid exposure time (AET), the total number of refluxes, the number of reflux events longer than 5 minutes, the maximum duration of refluxes and the degree of esophageal inflammation. Conclusions. In the surgical treatment of GERD, the statistically significant decrease in the VIP level to that of apparently healthy individuals is determined. The moderate positive correlation between the levels of VIP, AET, the average number of refluxes, the number of reflux events longer than 5 minutes, and the maximum duration of refluxes confirms the inhibitory effect of VIP on LES tone. The relationship between the degree of esophageal inflammation and the VIP level confirms the indirect, through the action of VIP, inhibitory effect of the esophagitis severity on the LES tone.

Evaluation of serum VIP and aCGRP during pulmonary exacerbation in cystic fibrosis: A longitudinal pilot study of patients undergoing antibiotic therapy.

Objective monitoring of improvement during treatment of pulmonary exacerbation can be difficulty in children when pulmonary function testing cannot be obtained. Thus, the identification of predictive biomarkers to determine the efficacy of drug treatments is of high priority. The major aim of the current study was to investigate the serum levels of vasoactive intestinal peptide (VIP) and alpha calcitonin gene related peptide (aCGRP) of cystic fibrosis pediatric patients during pulmonary exacerbation and post-antibiotic therapy, and possible associations of their levels with different clinicopathological parameters. 21 patients with cystic fibrosis were recruited at onset of pulmonary exacerbation. Serum was collected at time of admission, three days post-antibiotic therapy, and two weeks post-antibiotic therapy (end of antibiotic therapy). Serum VIP and aCGRP levels were measured using ELISA. Overall least square means of serum aCGRP level but not VIP changed from time of exacerbation to completion of antibiotic therapy (p = 0.005). Serum VIP was significantly associated with the presence of diabetes mellitus (p = 0.026) and other comorbidities (p = 0.013), and with type of antibiotic therapy (p = 0.019). Serum aCGRP level was significantly associated with type of antibiotic therapy (p = 0.012) and positive Staphylococcus aureus microbiology test (p = 0.046). This study could only show significant changes in serum aCGRP levels following treatment of pulmonary exacerbations. Future studies with larger sample size are required to investigate the clinical importance of VIP and aCGRP in cystic fibrosis patients.