Vasoactive Intestinal Peptide Levels Research Articles

Pretreatment with Lactobacillus fermentum XY18 Relieves Gastric Injury Induced by HCl/Ethanol in Mice via Antioxidant and Anti-Inflammatory Mechanisms.

AimLactobacillus fermentum XY18 (LF-XY18) is a bacterial strain with satisfactory antioxidant properties in vitro that we previously isolated from Xinjiang yogurt. This article will explore the preventive effect of LF-XY18 on acute gastric injury and provide the basis for the innovative development and application of lactic acid bacteria (LAB).MethodsKunming mice underwent gastric injury induced by hydrochloric acid and ethanol. LF-XY18 isolated from yogurt in Xinyuan County in the Yili region of Xinjiang was subsequently administered intragastrically to mice for 2 weeks to explore the mechanism of LF-XY18 in preventing gastric injury via its antioxidant effects.ResultsThere was decreased gastric juice volume, gastric injury area, and formation of gastric mucosal lesions in the LF-XY18 mice as compared to those in the control mice, while LF-XY18 prevented the decrease in the gastric juice pH value in mice. Compared with the gastric injury model group mice, LF-XY18 reduced the serum levels of motilin, substance P, interleukin-6, interleukin-12, tumor necrosis factor-α, and interferon-γ but increased the serum levels of somatostatin and vasoactive intestinal peptide. The activities of superoxide dismutase, glutathione peroxidase, glutathione, and nitric oxide were increased in the gastric tissue of the LF-XY18 mice compared with the control mice, but malondialdehyde activity was decreased in the LF-XY18 mice. Quantitative polymerase chain reaction analysis illustrated that in the gastric tissue of LF-XY18 mice, the messenger RNA (mRNA) expression of occludin, epidermal growth factor (EGF), EGF receptor, vascular EGF, inhibitor kappa-B-α, neuronal nitric oxide synthase, endothelial nitric oxide synthase, cuprozinc superoxide dismutase, manganese superoxide dismutase, and catalase was stronger than that in the control mice, but the mRNA expression of activated B cells (NF-κB), inducible nitric oxide synthase, and cyclooxygenase-2 was weaker than in the control mice.ConclusionThese results indicate that LF-XY18 has a potential role in the prevention of gastric injury through antioxidant effects, and a high concentration (1.0 × 109 CFU/kg b.w.) of LF-XY18 has a stronger anti-gastric injury effect than a low concentration (1.0 × 108 CFU/kg b.w.).

Effects of intradermal needle therapy plus pinaverium bromide on gastrointestinal hormone levels in irritable bowel syndrome-diarrhea patients

To observe the clinical efficacy difference in treating irritable bowel syndrome-diarrhea (IBS-D) of liver-qi stagnation and spleen-deficiency pattern with different treatment protocols, and the effects on serum levels of 5-hydroxytryptamine (5-HT), substance P (SP) and vasoactive intestinal peptide (VIP), for unveiling the mechanism of intradermal needle therapy plus pinaverium bromide in treating IBS-D. A total of 123 IBS-D patients were divided into an observation group, a Western medication group and an integrated Western and Chinese medication group using the random number table method, with 41 cases in each group. The Western medication group was given oral pinaverium bromide, 50 mg each time and 3 times a day. The integrated Western and Chinese medication group was given additional Chinese herbal medicine Tong Xie Yao Fang, one dose each day. The observation group was given additional intradermal needle therapy on the basis of the Western medication group. The whole intervention lasted for 6 weeks. Before and after treatment, the scores of gastrointestinal symptoms, traditional Chinese medicine (TCM) symptoms, irritable bowel syndrome (IBS) symptom severity scale (IBS-SSS) and IBS quality of life (IBS-QOL) questionnaire, as well as the serum levels of 5-HT, SP and VIP were observed. The clinical efficacy was estimated. The total effective rate was 92.7% in the observation group, 68.3% in the Western medication group and 78.1% in the integrated Western and Chinese medication group. The total effective rate was higher in the observation group than in the other two groups, and higher in the integrated Western and Chinese medication group than in the Western medication group, showing statistical significance (all P<0.05). After treatment, the scores of gastrointestinal symptoms, TCM symptoms and IBS-SSS showed significant decreases in the three groups, presenting statistical significance compared with the baseline (all P<0.05); the scores of gastrointestinal symptoms, TCM symptoms and IBS-SSS were notably lower in the observation group than in the other two groups (all P<0.05), and lower in the integrated Western and Chinese medication group than in the Western medication group (all P<0.05). After treatment, the eight component scores of IBS-QOL showed significant increases in the three groups compared with the baseline (all P<0.05); the eight component scores in IBS-QOL were significantly higher in the observation group than in the other two groups (all P<0.05), and higher in the integrated Western and Chinese medication group than in the Western medication group (all P<0.05). After treatment, the serum levels of 5-HT, SP and VIP decreased markedly in the three groups compared with the baseline (all P<0.05); the serum levels of 5-HT, SP and VIP were significantly lower in the observation group than in the other two groups (all P<0.05), and lower in the integrated Western and Chinese medication group than in the Western medication group (P<0.05). Treatment with intradermal needle therapy plus pinaverium bromide results in significant improvements in the gastrointestinal symptoms and quality of life in patients with IBS-D of liver-qi stagnation and spleen deficiency pattern, and effectively regulates the gastrointestinal hormone production.

Shengmai Yin formula modulates the gut microbiota of spleen-deficiency rats

BackgroundSpleen-deficiency syndrome, an important pathological change in traditional Chinese medicine, has been proven to attribute to intestinal dysbacteriosis. Shengmai Yin (SMY), a classic formula for replenishing qi and restoring pulse, is a common medicine for critical emergencies in traditional Chinese Medicine. Interestingly, our previous study established a spleen-deficiency rat model and verified the potency of SMY formula in curing spleen-deficiency rats. Our goal herein was to explore whether SMY can modulate the composition of intestinal flora and alleviate spleen-deficiency in rats.MethodsThis experiment was randomly divided into three groups, namely the normal control group (NC), model control group (MC), and the Shengmai Yin group (SMY). After the treatment, the weight and symptom indexes of the rats were recorded, histological changes in the colon were observed, levels of serum D-xylose, gastrin (GAS), and vasoactive intestinal peptide (VIP) were measured, and gut microbiota profiling was conducted by 16S rRNA sequencing.ResultsThe body mass of the spleen-deficiency model rats significantly decreased compared with that of the NC group, and SMY treatment significantly increased body mass compared with the MC group (P < 0.01). Colon histopathology revealed that SMY treatment alleviated colonic mucosal damage in spleen-deficiency rats. The serum levels of D-xylose and gastrin (GAS) were significant increased by SMY (P < 0.05, P < 0.01), and vasoactive intestinal peptide (VIP) was reduced by SMY (P < 0.01) compared with MC. Furthermore, alpha diversity was significantly decreased in the model rats compared to the normal rats (P < 0.05) and increased with SMY treatment (P < 0.01). The most abundant phyla were Firmicutes and Bacteroidetes, followed by Proteobacteria, Verrucomicrobia, and Actinobacteria. At the genus level, there was a lower relative abundance of Lactobacillus, Bacteroides, Akkermasia, and Allobaculum, and a higher relative abundance of Lachnospiraceae NK4A 136 group, Ruminococcaceae UCG-014, and Sphingomonas in the MC group. The relative abundance of Actinobacteria, Alistipes, Bifidobacterium, Bifidobacterium, Bifidobacteriaceae, Lachnospiraceae NK4A136group, Lactobacillus, Lactobacillaceae, Bacilli, Verrucomicrobiae, and Akkermansia were significantly abundant in the treatment groups, and thus may be singled out as potential biomarkers for SMY in the treatment of spleen deficiency. In addition, analysis on the correlation between species and physicochemical indexes showed that the abundance of Parasutterella was negatively correlated with the change in GAS, and positively correlated with the change in VIP (P < 0.01).ConclusionOur findings have provided preliminary evidence that modulating the gut microbiota may play a role in the treatment of spleen deficiency with SMY. However, further studies are needed to clarify the mechanism by which SMY regulation of related gut microbiota occurs.

Role of Substance P in the Pathophysiology of Inflammatory Bowel Disease and Its Correlation With the Degree of Inflammation.

Inflammatory bowel disease (IBD) is a multi-factorial, chronic inflammation of the gastrointestinal tract, containing ulcerative colitis (UC) and Crohn's disease (CD). In UC, inflammation and sores are confined morphologically and microscopically to the mucosa, the innermost surface of the colon and the rectum. Although, in CD, the infection is granulomatous and transmural, affecting the entire gastrointestinal tract from the mouth to the anus, with the skip area in-between. A Neuropeptide, substance P (SP), which acts as a neurotransmitter and as a neuromodulator, plays a vital role in the brain-gut axis under stress. Owing to the pro-inflammatory effects of SP, neuropeptide dysregulation induces inflammation in the intestine. There are variations in the distribution of substance P immunoreactive fibres in the various intestinal layers. The highest concentration of SP is in the mucosa and the lowest concentration in the lamina propria of the intestinal muscular membrane. Reduced vasoactive intestinal peptide (VIP) levels and elevated SP levels observed in the colonic mucosa of IBD by using immunohistochemistry and immunoassay. This literature review aims to find out the correlations between the level of substance P (SP) and disease activity. We conducted a literature review on IBD, SP, and we searched PubMed and Google Scholar for relevant articles in English. The result of the study supports a positive relationship between the level of substance P (SP) and disease activity, with increased concentration of substance p in the colon and rectum of CD and UC patients. It is concluded that patients with active CD, along with inflammatory changes, had elevated plasma SP levels and immunoreactivity of SP in the colon than those seen in control and inactive cases. These alterations are more prevalent in ulcerative colitis than Crohn's disease and are more prevalent in the moderately infected area than the least affected area of the intestine.

Plasma levels of vasoactive neuropeptides in pediatric patients with migraine during attack and attack-free periods

Increasing evidence suggests that vasoactive neuropeptides such as pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38), substance P, calcitonin gene-related peptide, and vasoactive intestinal peptide are involved in the pathophysiology of migraine in adults, but their role in pediatric migraineurs remains unclear. We prospectively investigated plasma levels of these vasoactive neuropeptides in pediatric migraine patients without aura and compared the results with those of age-matched healthy controls. Thirty-eight children aged 6-18 years with migraine without aura and 20 age-matched control subjects were included in the study. Neuropeptides in plasma samples from the controls, and in either the ictal or interictal periods in pediatric migraine without aura, were measured using ELISA. PACAP-38 and vasoactive intestinal peptide levels in both ictal and interictal plasma were higher in the patients with pediatric migraine without aura than in the controls (p < 0.001), although calcitonin gene-related peptide and substance P levels remained unchanged. Otherwise, no significant difference was determined between ictal and interictal periods in terms of all neuropeptide levels. This study demonstrates increased plasma PACAP-38 and vasoactive intestinal peptide levels, but not calcitonin gene-related peptide and substance P levels, in pediatric patients with migraine during both attack and attack-free periods. The study findings suggest that PACAP-38 and vasoactive intestinal peptide may be implicated in the pathophysiology of migraine, particularly in pediatric migraineurs.

Preventive effect of Lactobacillus plantarum HFY09 on HCl/ethanol-induced gastric injury in mice

The aim of this study was to investigate the effect of Lactobacillus plantarum HFY09 on gastric injury induced by HCl/ethanol in Kunming mice. The results showed that HFY09-H inhibited any increases in gastric juice volume, maintained the normal pH value of gastric acid, and reduced the damage caused to the gastric mucosa and gastric wall, the inhibition rate on the injury area reaches 63.70%. Compared with the negative control group, HFY09 increased the levels of serum somatostatin (SS) and vasoactive intestinal peptide (VIP), and also decreased the levels of substance P (SP), endothelin-1 (ET-1), interleukin-6 (IL-6), interleukin-12 (IL-12), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ). In addition, real time fluorescent quantitative PCR (Q-PCR) also confirmed that high-dose HFY09 (109 CFU/kg/day) upregulated the mRNA expression of copper/zinc superoxide dismutase (Cu/Zn-SOD), manganese superoxide dismutase (Mn-SOD), catalase (CAT), endothelial nitric oxide synthase (eNOS), and neuronal nitric oxide synthase (nNOS), and downregulated the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). At the same time, the results of the HFY09 treatment group were similar to those of the ranitidine treatment group. These results indicate that HFY09 can prevent gastric injury induced by HCl/ethanol in vivo. Therefore, HFY09 may play a potential role in the treatment of gastric diseases.

Abstract 5571: Turning up the heat on pancreatic ductal adenocarcinoma via inhibiting vasoactive intestinal peptide signaling

Abstract Pancreatic ductal adenocarcinoma (PDAC) constitutes more than 90% of all pancreatic cancers and has a 5-year survival rate of only 5-7%. A dense stroma, an immunosuppressive tumor microenvironment (TME) and scarce tumor infiltrating T cells, contribute toward the poor responsiveness of PDAC to conventional and FDA-approved checkpoint therapies. In this study, we show that vasoactive intestinal peptide (VIP) signaling is a novel immune checkpoint pathway in PDAC, which when inhibited in combination with anti-PD1 checkpoint inhibitor, significantly decreases tumor burden and enhances T cell infiltration in mouse models of PDAC. VIP is a 28-amino acid neuropeptide secreted at the nerve terminals, pancreas and the GI tract, and is commonly associated with regulating gut motility and blood pressure. Interestingly, VIP is also secreted by immune cells and is known to have immunosuppressive properties such as decreasing T cell proliferation and polarizing T cells towards Th2 phenotype. Intriguingly, according to the cancer genome atlas (TCGA), human exocrine pancreatic cancers expresses the highest level of VIP mRNA expression when compared to other solid malignancies. Similarly, we have generated preliminary data that shows enhanced VIP levels both systemically and locally in mouse models of PDAC and in human PDAC patients. Thus, taking all this into consideration, we hypothesized that enhanced VIP signaling is a potential mechanism of immune escape in PDAC and that inhibiting VIP signaling either alone or in combination with checkpoint inhibitors would significantly enhance treatment response in mouse models of PDAC. We tested the effect of inhibiting VIP signaling by using a VIP receptor antagonist (VIPR antagonist) in orthotopic mouse models of PDAC, where luciferase transfected KPC cells (mouse PDAC cell line), were implanted in the tail of the pancreas. Mice were then treated with VIPR antagonist and/or anti-PD1 seven days after tumor implantation. Our results showed that the combination treatment significantly reduced tumor burden and growth rate, as well as, enhanced the infiltration of both CD4+ and CD8+ T cells into the tumor microenvironment (as per immunohistochemistry of tumor tissues). Furthermore, analysis of tumor infiltrating T cells via Nanostring analysis showed that the combination treatment also significantly enhanced levels of IFN gamma and TNF alpha secreting T cells and costimulatory and effector molecules, including CD27 and FasL. In summary, we have identified that VIP signaling is a novel and targetable immune checkpoint pathway in PDAC, which when inhibited in combination with checkpoint inhibitors, significantly improves treatment response in mouse PDAC models. As the VIP sequence is conserved across different species including mouse and human, and since we have observed VIPR antagonists stimulate proliferation of human T cells, there is an increased potential for clinical translation of VIPR antagonists in the treatment of human PDAC. Citation Format: Sruthi Ravindranathan, Brandon Ware, Mohammad Zaidi, Jingru Zhu, Rohan K. Dhamsania, Shuhua Wang, Yiwen Li, Ishani H. Rao, Susan N. Thomas, Gregory B. Lesinski, Bassel El-Rayes, Edmund K. Waller. Turning up the heat on pancreatic ductal adenocarcinoma via inhibiting vasoactive intestinal peptide signaling [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5571.

Vasoactive intestinal peptide axis is dysfunctional in patients with Graves\u2019 disease

Vasoactive intestinal peptide (VIP) is a neuropeptide with potent immunoregulatory properties. Reduced serum VIP levels and alterations in VIP receptors/signaling on immune cells have been associated with different inflammatory/autoimmune diseases. However, its role in autoimmune thyroid diseases (AITD) remains unknown. This study examined the interrelationship between VIP system, autoimmune background and thyroid hormones in peripheral immune cells in patients with AITD. Only Graves’ disease (GD) patients showed significantly lower serum VIP levels when compared to healthy subjects and to Hashimoto’s thyroiditis patients. Serum VIP levels were lower at the onset of GD, showing a significant negative correlation with thyroid hormone levels. The expression of VIP receptors, VPAC1 and VPAC2, was significantly upregulated in peripheral blood mononuclear cells (PBMC) from GD patients. There was an impairment of VIP signalling in these patients, probably attributable to a dysfunction of VPAC1 with preservation of VPAC2. The correlation between VPAC1 and thyroid hormone receptor expression in PBMC from healthy subjects was lost in GD patients. In summary, the VIP system is altered in peripheral immune cells of GD patients and this finding is associated with different thyroid hormone receptor patterns, showing a dynamic inter-regulation and a prominent role of VIP in this setting.

Gut microbiota is involved in the alleviation of loperamide-induced constipation by honey supplementation in mice.

Constipation is one of the most common functional gastrointestinal disorders accompanied with intestinal dysbiosis. Laxatives for constipation usually have side effects. Bee honey is a natural food with unique composition, antimicrobial properties, and bifidogenic effect. In order to assess whether honey can ameliorate loperamide‐induced constipation in BALB/c mice through the alteration of the gut microbiota, the present study was undertaken. Mice were given Jarrah honey (7.5 g/kg body weight) by gavage once per day for 5 days. Fecal water content, intestinal transit rate together with the colon concentrations of substance P (SP), vasoactive intestinal peptide (VIP), and serotonin (5‐hydroxytryptamine; 5‐HT) were evaluated. Furthermore, we determined the effect of honey treatment on gut microbiota in mice using stool genomic 16S rRNA sequencing. As a result, honey showed an obvious improvement in fecal water content and alleviated constipation by modulating the microbial composition of the microbiota, and this was highly associated with a proportional decrease in gut Desulfovibrio. In addition, we found that the colon level of neurotransmitters SP and VIP was significantly related to microbial variations. Our results indicate that gut microbiota is involved in the alleviation of loperamide‐induced constipation by honey supplementation in mice, and it could be considered as an evaluating parameter in constipation therapy strategies.

Physical Therapy as an Adjuvant Treatment for the Prevention and Treatment of Cancer.

The prevalence of cancer has been increasing. In cancer patients, quality of life and physical abilities are often impaired. Exercise is aimed at improving patient physical fitness and the symptoms associated with cancer and its treatment. During exercise, muscle cells release substances, referred to as myokines, that have a protective effect against oncological diseases. Regular exercise can influence the levels of cytokines IL-2, IL-6, IL-8, and TNF-&#945;. Reductions in the risk of developing an oncological disease by performing physical activity can be explained by several mechanisms, which can be divided into direct and indirect mechanisms. People with increased physical activity tend to have more optimal BMI values and a lower incidence of intraabdominal obesity. Other direct mechanisms include the effect of exercise on the levels of insulin-like growth factor and vasoactive intestinal peptide. Epigenetic effects of exercise are also an important mechanism. Additionally, exercise also affects oxidative and antioxidant pathways, energy metabolism, and insulin sensitivity. Optimal physical activity reduces the risk of cancer and leads to improvements in cardiovascular health in cancer patients. It also optimizes of BMI values. In cancer patients, regular exercise also improves muscle strength and significantly affects quality of life. Exercise is an important therapeutic option for reducing the fatigue associated with cancer and can benefit patients by improving their condition in the preoperative and postoperative periods. Exercise also reduces the risk of complications associated with surgery and reduces the risk of injury. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.

Ganjiang granule regulates cecal microflora and serum biochemical components in a rat model of constipation-predominant irritable bowel syndrome

Abstract Objective To investigate the effects of Ganjiang granule (GG) on cecal microflora and serum biochemical components in rats with constipation-predominant irritable bowel syndrome (IBS–C). Methods Twenty-four Sprague–Dawley rats were randomly divided into four groups: control, model, GG, and probiotics. Rats in the model, GG, and probiotics groups received 3 °C tap water intragastrically; rats in the GG group were treated with GG; rats in the probiotics group were treated with probiotics. For all rats, enzyme-linked immunosorbent assay and colorimetry were used to assess serum biochemical components related to gastrointestinal function; 16S rRNA high-throughput sequencing was used to analyze the cecal microflora. Results The serum level of 5-hydroxytryptamine (HT) was higher in the model group than in the control group (Z = −2.082, P = .037). The model group exhibited changes in cecal microflora: the relative abundances of Lactobacillus decreased (Z = −2.882, P = .004) and Dorea increased (t = −3.030, P = .023), compared with the control group. The GG and probiotics groups exhibited normal serum levels of 5-HT. The GG and probiotics groups exhibited improved serum levels of gastrin; the probiotics group exhibited an improved serum level of vasoactive intestinal peptide. Compared with the model group, The GG group exhibited greater relative abundance of Ruminococcus (Z = −2.402, P = .016); the probiotics group exhibited greater relative abundance of SMB53 (Z = −2.823, P = .005) and lower relative abundances of Desulfovibrio (Z = −2.823, P = .005) and Facklamia (Z = −2.608, P = .009). Conclusion The effects of GG on IBS-C may be related to regulation of the serum level of 5-HT, as well as elevated relative abundance of beneficial bacteria in cecal microflora.

Soluble Dietary Fiber Reduces Feeding Intolerance in Severe Acute Pancreatitis: A Randomized Study.

Feeding intolerance of enteral nutrition (EN) frequently occurs in patients with severe acute pancreatitis (SAP) because of intestinal motility disorders. Soluble dietary fiber (SDF) modulates the intestinal motility. The present study examined whether SDF can improve intestinal motility and permeability, and thereby reduce feeding intolerance, in patients with SAP. This study was a single-blind, randomized, controlled, single-center trial. Forty-nine patients with SAP were included. The control and SDF groups received the same EN solution via a nasojejunal tube. The SDF group additionally received 20-g/d polydextrose. The primary outcome was the time to reach the energy goal. Follow-up was continued for 28 days after admission or until discharge from the hospital. Among 49 randomized patients, 46 patients (n=22, control group; n=24, SDF group) were included in the intent-to-treat analysis. The time to reach the energy goal was 7.00 (6.00, 8.25) days and 5.00 (4.25, 6.00) days in the control and SDF groups, respectively (P<0.001). The rates of feeding intolerance were significantly reduced in the SDF group (59.09% vs 25.00%, P<.05). SDF was associated with decreases in the incidence of abdominal distension (72.73% vs 29.17%, P<.01), diarrhea (40.91% vs 8.33%, P<.05), and constipation (72.73% vs 12.50%, P<.001). The time to first flatus and first defecation were significantly shorter in the SDF group (P<.001). The intestinal mucosal barrier function and levels of gastrointestinal hormone were improved by SDF, as evidenced by significantly reduced blood levels of diamine oxidase, D-lactic acid, endotoxin, and vasoactive intestinal peptide (P<.05). SDF shortens the time to reach the energy goal during EN and improves intestinal permeability and motility disorders, thus reducing the incidence of feeding intolerance in SAP patients.

Pituitary adenylate cyclase activating polypeptide concentrations in the sheep mammary gland, milk, and in the lamb blood plasma after suckling.

Pituitary adenylate cyclase activating polypeptide (PACAP) is involved in development and reproduction. We previously described elevated PACAP levels in the milk compared to the plasma, and the presence of its specific PAC1 receptor in the mammary gland. This study aimed to determine PACAP and vasoactive intestinal peptide (VIP) levels in female suckling lambs compared to ewe plasma and mammary gland, as well as their age-dependent alterations. mRNA expressions of PACAP, VIP, PAC1 receptor and brain-derived neurotrophic factor (BDNF) were quantified in the milk whey and mammary gland. PACAP38-like immunoreactivity (PACAP38-LI) was measured in plasma, milk whey and mammary gland by radioimmunoassay, VIP-LI by enzyme-linked immunoassay. PACAP38-LI was 5, 6 times higher in the milk compared to the plasma of lactating sheep. It significantly increased in the lamb plasma 1 h, but returned to basal level 2 h after suckling. However, VIP mRNA was not present in the mammary gland, we detected the VIP protein in the milk whey. BDNF mRNA significantly decreased with age to approximately 60% and 25% in the 3- and 10-year-old sheep respectively, compared to the 3-month-old lambs. No differences were found between mammary and jugular vein plasma PACAP and VIP concentrations, or during the daily cycle. We propose a rapid absorption of PACAP38 from the milk and/or its release in suckling lambs. PACAP accumulated in the milk might be synthesized in the mammary gland or secreted from the plasma of the mothers. PACAP is suggested to have differentiation/proliferation promoting and immunomodulatory effects in the newborns and/or a local function in the mammary gland.

Effect of moxibustion on respiratory function and cutaneous histamine and neuropeptide contents of "Feishu" (BL13) in asthmatic rats

To observe the effect of moxibustion on respiratory function and contents of histamine and neuropeptides in skin tissue of "Feishu" (BL13) in asthmatic rats, so as to explore its mechanisms underlying improvement of asthma. Thirty-six SD rats were randomly divided into normal control, model and moxibustion groups, with 12 rats in each group. The asthma model was established by subcutaneous injection (at the back and groin, 0.5 mL) and i．p. injection (1 mL)of mixture solution of ovalbumin (OVA), Aluminium Hydroxide gel and 0.9% sodium chloride solution, and repeated nasal drip of 1% OVA. Moxibustion was applied to bilateral BL13 for 15 min, once daily for 14 days. The inspiratory and expiratory resistance, and pulmonary ventilation compliance were detected by using a small animal pulmonary function tester under anesthesia. The contents of histamine, vasoactive intestinal peptide (VIP), substance P (SP) and calcitonin gene-related peptide (CGRP) in the local skin tissue of the left BL13 were assayed by using enzyme-linked immunosorbent assay (ELISA). After modeling, the inspiratory and expiratory resistance were significantly increased (P<0.01), and the lung ventilation compliance was significantly decreased in the model group relevant to the normal control group (P<0.01). Outcomes of ELISA showed that the content of VIP was significantly lower (P<0.01), and those of histamine, SP and CGRP in the skin of left BL13 were significantly increased in the model group relevant to the normal control group (P<0.01). Following the intervention, the inspiratory and expiratory resis-tance, cutaneous histamine, SP and CGRP contents were significantly decreased (P<0.01), while the lung ventilation compliance and cutaneous VIP level were significantly increased in the moxibustion group in contrast to the model group (P<0.01, P<0.05). Moxibustion of BL13 can improve pulmonary function in asthma rats, which may be related to changes of levels of histamine and neuropeptides as VIP, SP and CGRP in the local skin tissues of BL13.

Neuropeptide regulation of secretion and inflammation in human airway gland serous cells.

Airway submucosal gland serous cells are sites of expression of the cystic fibrosis transmembrane conductance regulator (CFTR) and are important for fluid secretion in conducting airways. To elucidate how neuropeptides regulate serous cells, we tested if human nasal turbinate serous cells secrete bicarbonate (HCO3 -), important for mucus polymerisation and antimicrobial peptide function, during stimulation with cAMP-elevating vasoactive intestinal peptide (VIP) and if this requires CFTR. Serous cells stimulated with VIP exhibited a ∼15-20% cAMP-dependent decrease in cell volume and a ∼0.15 unit decrease in intracellular pH (pHi), reflecting activation of Cl- and HCO3 - secretion, respectively. HCO3 - secretion was directly dependent on CFTR and was absent in cells from CF patients. In contrast, neuropeptide Y (NPY) reduced VIP-evoked cAMP increases, CFTR activation, and Cl-/HCO3 - secretion. Culture of primary serous cells in a model that maintained a serous phenotype confirmed the activating and inhibiting effects of VIP and NPY, respectively, on fluid and HCO3 - secretion. Moreover, VIP enhanced antimicrobial peptide secretion and antimicrobial efficacy of secretions while NPY reduced antimicrobial efficacy. In contrast, NPY enhanced cytokine release while VIP reduced cytokine release through a mechanism requiring CFTR. As levels of VIP and NPY are up-regulated in diseases like allergy, asthma, and chronic rhinosinusitis, the balance of these two peptides in the airway may control mucus rheology and inflammatory responses in serous cells. Furthermore, the loss of CFTR conductance in serous cells may contribute to CF pathophysiology by increasing serous cells inflammatory responses in addition to directly impairing Cl- and HCO3 - secretion.

Characterization of the Active Components of Aurantii fructus Causing Dry Mouth by Analysis of Aquaporin 5 Expression

Aurantii fructus, the dried immature fruit of Citrus aurantium L., Rutaceae, or its cultivated variants, has been used in traditional Chinese medicine for thousands of years. Unprocessed Aurantii fructus can trigger various side effects, collectively known as “zao”. Dry mouth is the obvious symptom. Fengyan pieces, a processed product of Aurantii fructus, can relieve dry mouth but does not affect its efficacy. In order to analyze this mechanism, the effect on the gastrointestinal tract was characterized by measuring the levels of gastrin, a vasoactive intestinal peptide, in rat serum. Chemical analysis of Aurantii fructus pieces (raw product) and Fengyan pieces was performed by ultra-performance liquid chromatography-mass spectrometry (quadrupole time-of-flight) in combination with chemometrics methods to dereplicate the characteristic components. Aquaporin 5 expression in human submandibular gland cells was measured to validate the effect of the identified components. The results showed that serum gastrin content was different between the different dose groups, and Fengyan pieces showed lower levels of serum vasoactive intestinal peptide than Aurantii fructus pieces. 3,5,6,7,8,3′,4′-Heptamethoxyflavone was the distinctive component, and it has most effectively downregulated aquaporin 5 expression in the submandibular glands of mice. It also reduced aquaporin 5 mRNA and protein expression in human submandibular gland cells. Collectively, these results suggest that processing did not affect the efficacy of Fengyan pieces, but did relieve dry mouth and that 3,5,6,7,8,3′,4′-heptamethoxyflavone was the Aurantii fructus component responsible for dry mouth. This study provides a new scientific basis for reduction of the dry mouth effects of Aurantii fructus from processing.

Maillard Reaction Products of Stir Fried Hordei Fructus Germinatus Are Important for Its Efficacy in Treating Functional Dyspepsia.

Hordei Fructus Germinatus (HFG) has been used as a traditional medicine to treat functional dyspepsia (FD) in China. Stir fried HFG (F-HFG) containing Maillard reaction products (MRPs) is used more widely than the raw HFG (R-HFG). However, the exact mechanisms in its functionality remain unclear. This article investigated the effect of R-HFG, F-HFG, and MRPs on brain-gut peptides, gut microbiota, and digestive enzymes using an FD animal mode. After administration of R-HFG, F-HFG, and MRPs, higher mRNA expression level of gastrin (GAS) and lower mRNA expression level of vasoactive intestinal peptide (VIP) were exhibited in F-HFG and MRPs rats than R-HFG rats (P < .05). Furthermore, compared with the R-HFG group, the contents of motilin (MTL) and GAS showed an upward tendency, whereas the contents of VIP and chokcystokinin (CCK) showed a downward tendency in the F-HFG group. In addition, bacterial communities in the control, F-HFG, and MRPs groups clustered closely to one another, and bacterial communities in the model and recovery groups clustered together, whereas the bacterial communities in the R-HFG group were clustered into a category. Moreover, there were no apparent differences in brain-gut peptides and gut microbiota between the F-HFG and MRPs groups. However, after the oral administration of R-HFG, F-HFG, and MRPs, the level of digestive enzyme did not show a significant change as compared with the recovery group. These results indicated that the stronger effect of F-HFG could be attributed to the MRPs produced during stir frying, and MRPs possessed the effect of regulating brain-gut peptides and gut microbiota.

Zhujie Hewei Granules Ameliorated Reflux Esophagitis in Rats.

Background Gastroesophageal reflux disease (GERDs) is a common chronic digestive system disease, in which the symptoms of reflux esophagitis (RE) seriously affect the quality of life. Aims We aimed to study the therapeutic effect of Zhujie Hewei granules (ZHG) on reflux esophagitis in model rats. Materials and Methods A rat model of RE was established with the steps of half pylorus ligation, cardiotomy, and hydrochloric acid perfusion. The rats in treatment groups were orally administered with 1.30, 2.60, or 5.20 g/kg ZHG once daily for 28 days. Histopathological changes of the esophagus were observed with hematoxylin-eosin staining. The content of total bilirubin and pH in gastric juice was determined. Esophageal mucosal injury was assessed by macroscopic observation scores, mucosal injury index scores, and esophageal inflammation scores. The levels of gastrin (GAS), motilin (MTL), and vasoactive intestinal peptide (VIP) in serum were evaluated by using ELISA kits. Results After treatment with ZHG, the body weight of RE rats tended to increase drastically, the macroscopic observation scores of the esophagus mucous membrane decreased (P < 0.05), the mucosal injury index scores decreased (P < 0.05), the gastric pH values increased (P < 0.05), and the levels of serum MTL and VIP decreased (P < 0.05). In addition, the high dose of the ZHG-treated group showed lower serum GAS (P < 0.05), while the high and middle doses of the ZHG-treated groups showed lower esophageal inflammation scores (P < 0.05). Conclusions ZHG was effective in treating RE in rats due using mechanisms including improving the pH value of gastric contents, decreasing the gastrointestinal hormones (including GAS, MTL, and VIP), and improving the inflammatory damage.

Effects of ticagrelor, empagliflozin and tamoxifen against experimentally-induced vascular reactivity defects in rats in vivo and in vitro.

In the current investigation, the effects of the P2Y12 blocker ticagrelor, the sodium/glucose transporter-2-inhibitor empagliflozin, and the selective estrogen receptor modulator tamoxifen were examined against rheumatoid arthritis (RA)/diabetes mellitus (DM)-co-morbidity-induced defects in vascular reactivity. After model setting, rats were allocated into a normal control, an RA/DM-co-morbidity, and three treatment groups receiving ticagrelor, empagliflozin and tamoxifen. Aorta tissue was isolated for enzyme-linked immunosorbent assay (ELISA) and western blot estimation of the pro-inflammatory molecules angiotensin-II (Ang-II) and endothelin-1 (ET-1), the adhesion molecules P-selectin and vascular cell adhesion molecule-1 (VCAM-1), the energy preserving molecule adenosine-5'-monophosphate-activated protein kinase (AMPK), and the anti-inflammatory molecule vasoactive intestinal peptide (VIP). Estimations of endothelial nitric oxide synthase (eNOS) and matrix metalloproteinase (MMP)-2 were performed immunohistochemically, together with histopathological examination using hematoxylin and eosin and Masson trichrome staining. An in vitro study on rat aortic strips was conducted to assess aorta vasorelaxation. Ticagrelor, empagliflozin and tamoxifen significantly increased aorta tissue AMPK and eNOS and decreased Ang-II, ET-1, P-selectin, VCAM-1 and VIP levels compared with RA/DM-co-morbidity, coupled with improved acetylcholine vasorelaxation in vitro. Ticagrelor, empagliflozin and tamoxifen may correct vascular reactivity defects, where modulation of vascular AMPK, eNOS, Ang-II, ET-1, P-selectin, VCAM-1 and MMP-2 underline their protective effects.

1408 A Tail of Acute Diarrhea

INTRODUCTION: VIPomas are neuroendocrine neoplasms arising from the pancreas in 90% of the cases reported, while the remaining 10% occur in other tissues of neural crest origin. The symptoms found are secondary to an excessive secretion of vasoactive intestinal peptide (VIP) including profuse watery diarrhea, dehydration, hypokalemia and hypoclorhydria. VIPomas are classically slow-growing, and previously reported cases consistently describe chronic diarrhea and a slowly progressing constellation of associated symptoms. We present a case of acute onset of secretory diarrhea secondary to a VIPoma. CASE DESCRIPTION/METHODS: The patient is a 62 y/o F with PMHx of HTN who presented to the ED w/complaints of abdominal pain, diarrhea, nausea and vomiting for approximately 3 days. Patient reported she was having 5-6 episodes of large volume, pale colored diarrhea. She denied any weight loss, change in diet, recent travel, blood in the stool, foul smell or bulky stool. She was initially found to be hypotensive BP 85/45, MAP 58, HR 88. Labs revealed K+ 3.1 meq/L, HCO3 was 16 meq/L, she had an AGMA measured at 15, and AKI with BUN: Cr 52:3.60 mg/dl respectively. On exam of the stool she was noted to have a stool osmolar gap of -14. Given no obvious underlying cause for these findings she underwent CT A/P which revealed a 7.8 × 6 cm mass contiguous w/both body/tail of the pancreas and posterior wall of the stomach, with no other sites of metastasis. EUS/FNA was done and pathology returned as NET type 1. VIP levels were subsequently sent and were elevated at 1385.8 pg/mL. She was started on octreotide 50 mcg TID with significant improvement in her diarrhea. She underwent surgery with distal pancreatectomy and splenectomy. Pathology confirmed the presence of a grade 2, stage T3 well differentiated NET. She had an uneventful recovery and was discharged home. She continues to be asymptomatic several weeks after surgery. DISCUSSION: Pancreatic VIPoma was first described in 1958 by Verner and Morrison in a patient with chronic refractory diarrhea and hypokalemia. VIPoma is very rare with an estimated incidence of 0.05-0.2 cases per million people. Acute diarrhea resulting from a VIPoma is rare event in an already rare malignancy. Our patient presented with acute secretory diarrhea proven by a stool osmolar gap less than 50, which resulted in acute kidney injury. Her diarrhea, secondary to VIPoma responded well to octreotide. VIPomas are classically rare tumors, but our specific case presents an even more rare presentation.