Vasoactive Intestinal Peptide Secretion Research Articles

Microglia cells treated with synthetic vasoactive intestinal peptide or transduced with LentiVIP protect neuronal cells against degeneration.

A common pathological hallmark of neurodegenerative disorders is neuronal cell death, accompanied by neuroinflammation and oxidative stress. The vasoactive intestinal peptide (VIP) is a pleiotropic peptide that combines neuroprotective and immunomodulatory actions. The gene therapy field shows long-term promise for treating a wide range of neurodegenerative diseases (ND). In this study, we aimed to investigate the in vitro efficacy of transduction of microglia using lentiviral gene therapy vectors encoding VIP (LentiVIP). Additionally, we tested the protective effects of the secretome derived from LentiVIP-infected "immortalized human" microglia HMC3 cells, and cells treated with Synthetic VIP (SynVIP), against toxin-induced neurodegeneration. First, LentiVIP, which stably expresses VIP, was generated and purified. VIP secretion in microglial conditioned media (MG CM) for LentiVIP-infected HMC3 microglia cells was confirmed. Microglia cells were activated with lipopolysaccharide, and groups were formed as follows: 1) Control, 2) SynVIP-treated, or 3) LentiVIP-transduced. These MG CM were applied on an in vitro neurodegenerative model formed by differentiated (d)-SH-SY5Y cells. Then, cell survival analysis and apoptotic nuclear staining, besides measurement of oxidative/inflammatory parameters in CM of cells were performed. Activated MG CM reduced survival rates of both control and toxin-applied (d)-SH-SY5Y cells, whereas LentiVIP-infected MG CM and SynVIP-treated ones exhibited better survival rates. These findings were supported by apoptotic nuclear evaluations of (d)-SH-SY5Y cells, alongside oxidative/inflammatory parameters in their CM. LentiVIP seems worthy of further studies for the treatment of ND because of the potential of gene therapy to treat diseases effectively with a single injection.

Bidirectional regulation effect of rhubarb as laxative and astringent by metabolomics studies

Ethnopharmacological relevanceRhubarb, a prominent traditional Chinese medicine, has been employed as a potent laxative for centuries and garnered particular popularity among the youth owing to its notable efficacy in weight management. Historical records indicated that rhubarb initially exhibited robust laxative properties, but extended and consistent usage may lead to an astringent response in the later stage of long-term use. In contrast, steamed pieces of rhubarb (SR), preparing through the process of steaming with wine, have demonstrated a gentle laxative effect with no reported adverse effects. Aim of the studyOur study was designed to explore the intricate mechanisms underlying laxative and astringent properties of rhubarb through metabolomics research. Materials and methodsIn this investigation, we employed a serum metabolomics approach utilizing the UPLC-Q-Extractive-Orbitrap-MS method to delve into the contrasting laxative and astringent effects of rhubarb, as well as to unravel the mechanisms of underpinning its bidirectional regulatory influence. To commence, we assessed alterations in Evacuation Index (EI) values, intestinal hormone levels, and colon histopathology in mice to gauge rhubarb's laxative and astringent effects. Subsequently, metabolomics methodology was employed for cluster analysis through Principal Component Analysis (PCA) and biomarker identification via Orthogonal Partial Least Squares-Discriminant Analysis (OPLS-DA). Then, we delved into the distinctions in characteristic biomarkers, metabolic pathways, their association with pathological changes, and correlation heatmap for biomarkers between raw pieces of rhubarb (RR) and SR to gain insights into the potential mechanisms behind rhubarb's bidirectional regulatory effects. ResultsOur findings revealed that RR exhibited a laxative effect in the early stage and transitioned to an astringent effect in the later stage, as indicated by the EI values. In contrast, SR consistently demonstrated a mild laxative effect. Biochemical indexes and histopathological assessments unveiled that RR triggered its astringent effect by inhibiting secretion of motilin (MTL), promoting secretion of vasoactive intestinal peptide (VIP) and epinephrine (EPI), and inducing onset of inflammation. Furthermore, serum metabolomics analysis identified 59 discriminative biomarkers modulated by RR and SR. Through comprehensive analysis, we elucidated the in vivo transformation relationships among multiple endogenous metabolites. Notably, our results underscored the down-regulation of certain phosphatidylcholines (PCs), amino acids, acylcarnitines, and up-regulation of lysophosphatidylcholines (LysoPCs) played pivotal roles in the onset of gut dysfunction, intestinal inflammation, gut barrier damage, and gastrointestinal motility disorder upon prolonging RR administration, ultimately contributing to its astringent effect. Additionally, our correlation analysis elucidated that anthraquinones, stilbenes, and phenylbutanones were the pharmacodynamic material basis responsible for inducing the astringent effect of RR. ConclusionThis study provides valuable insights into the bidirectional regulatory effects of rhubarb and sheds light on its underlying mechanisms through a comprehensive metabolomics approach.

A comparative study of vestibular improvement and gastrointestinal effect of betahistine and gastrodin in mice

Betahistine and gastrodin are the first-line medications for vestibular disorders in clinical practice, nevertheless, their amelioration effects on vestibular dysfunctions still lack direct comparison and their unexpected extra-vestibular effects remain elusive. Recent clinical studies have indicated that both of them may have effects on the gastrointestinal (GI) tract. Therefore, we purposed to systematically compare both vestibular and GI effects induced by betahistine and gastrodin and tried to elucidate the mechanisms underlying their GI effects. Our results showed that betahistine and gastrodin indeed had similar therapeutic effects on vestibular-associated motor dysfunction induced by unilateral labyrinthectomy. However, betahistine reduced total GI motility with gastric hypomotility and colonic hypermotility, whereas gastrodin did not influence total GI motility with only slight colonic hypermotility. In addition, betahistine, at normal dosages, induced a slight injury of gastric mucosa. These GI effects may be due to the different effects of betahistine and gastrodin on substance P and vasoactive intestinal peptide secretion in stomach and/or colon, and agonistic/anatgonistic effects of betahistine on histamine H1 and H3 receptors expressed in GI mucosal cells and H3 receptors distributed on nerves within the myenteric and submucosal plexuses. Furthermore, treatment of betahistine and gastrodin had potential effects on gut microbiota composition, which could lead to changes in host-microbiota homeostasis in turn. These results demonstrate that gastrodin has a consistent improvement effect on vestibular functions compared with betahistine but less effect on GI functions and gut microbiota, suggesting that gastrodin may be more suitable for vestibular disease patients with GI dysfunction.

Vasoactive intestinal peptide secreting tumour: An overview.

Vasoactive intestinal peptide (VIP) secreting tumour (VIPoma) is a rare functional neuroendocrine tumour that typically arises from pancreatic islet cells. These present as sporadic, solitary pancreatic neoplasias with an estimated incidence of one in ten million individuals per year. Only around 5% of VIPomas are associated with multiple endocrine neoplasia type I syndrome. Excessive VIP secretion produces a clinical syndrome characterized by refractory watery diarrhoea, hypokalemia and metabolic acidosis. These coupled with elevated plasma levels of VIP are diagnostic. The majority of VIPomas are malignant and have already metastasized at the time of diagnosis (60%). Metastases occur most frequently in the liver, or regional lymph nodes, lungs, kidneys and bones. Some reports of skin metastases have been documented. Complete surgical resection continues to be the only potentially curative treatment. However, when the neoplasia cannot be excised completely, surgical debulking may provide palliative benefit. Other palliative options have included recently the peptide receptor radionuclide therapy which has shown to be effective and well-tolerated. This article will review all aspects of pancreatic VIPomas highlighting aspects such as clinical presentation, diagnosis and management.

Protective effect of α-asarone and β-asarone on Aβ -induced inflammatory response in PC12 cells and its.

To investigate effects of α-asarone and β-asarone on induced PC12 cell injury and related mechanisms. Aβ toxic injury cell model was induced by Aβ in PC12 cells. PC12 cells were divided into blank control group, model control group, α-asarone group (0.5, 1.0, β-asarone group (6.3, 12.5, vasoactive intestinal peptide (VIP) group, and VIP antagonist control group. Cell survival rate was detected by CCK-8 kit; cell apoptosis rate was detected by flow cytometry. The levels of inflammatory cytokines interleukin (IL)-1, , tumor necrosis factor (TNF)-α, oxidation-related inducible nitric oxide synthase (iNOS), nitric oxide (NO), apoptosis factors caspase-3 and p53 were detected by ELISA method. The expressions of C-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38MAPK) were detected by Western blotting. Compared with model control group, cell survival rates of group, β-asarone group and VIP group increased; the cell apoptosis rate decreased; levels of apoptosis-related factors caspase-3, p53, inflammatory factors IL-1, TNF-α decreased; IL-10 level increased; levels of oxidization-related factors iNOS and NO decreased; the expression of JNK and p38MAPK protein decreased (all <0.05). After VIP antagonist intervention, the survival rate of β-asarone group decreased; apoptosis rate increased; apoptosis related factors caspase-3, p53, inflammatory factors IL-1, TNF-α increased; IL-10 decreased; oxidation related factors iNOS and NO increased; the expression of JNK and p38MAPK protein increased (all <0.05); while there were no significant changes in these indicators of α-asarone group (all >0.05). α-asarone and β-asarone have protective effects on PC12 cell injury induced by Aβ. β-asarone may inhibit inflammatory factors and oxidation-related factors through promoting VIP secretion, regulating JNK/MAPK pathway, and reducing PC12 cell apoptosis; however, the effect of α-asarone may be not related to VIP secretion.

Chronic Diarrhea and Weight Loss in an 18-month-old Boy.

Chronic Diarrhea and Weight Loss in an 18-month-old Boy.

Disrupted local innervation results in less VIP expression in CF mice tissues

Vasoactive Intestinal Peptide (VIP) is the major physiological agonist of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) chloride channel activity. VIP functions as a neuromodulator and neurotransmitter secreted by neurons innervating all exocrine glands. VIP is also a potent vasodilator and bronchodilator that regulates exocrine gland secretions, contributing to local innate defense by stimulating the movement of water and chloride transport across intestinal and tracheobronchial epithelia. Previous human studies have shown that the rich intrinsic neuronal networks for VIP secretion around exocrine glands could be lost in tissues from patients with cystic fibrosis. Our research has since confirmed, in vitro and in vivo, the need for chronic VIP exposure to maintain functional CFTR chloride channels at the cell surface of airways and intestinal epithelium, as well as normal exocrine tissues morphology [1]. The goal of the present study was to examine changes in VIP in the lung, duodenum and sweat glands of 8- and 17-weeks old F508del/F508del mice and to investigate VIPergic innervation in the small intestine of CF mice, before important signs of the disease development. Our data show that a low amount of VIP is found in CF tissues prior to tissue damage. Moreover, we found a specific reduction in VIPergic and cholinergic innervation of the small intestine. The general innervation of the primary and secondary myenteric plexus was lost in CF tissues, with the presence of enlarged ganglionic cells in the tertiary layer. We propose that low amount of VIP in CF tissues is due to a reduction in VIPergic and cholinergic innervation and represents an early defect that constitutes an aggravating factor for CF disease progression.

VIP and muscarinic synergistic mucin secretion by salivary mucous cells is mediated by enhanced PKC activity via VIP-induced release of an intracellular Ca2+ pool

Mucin secretion by salivary mucous glands is mediated predominantly by parasympathetic acetylcholine activation of cholinergic muscarinic receptors via increased intracellular free calcium ([Ca2+]i) and activation of conventional protein kinase C isozymes (cPKC). However, the parasympathetic co-neurotransmitter, vasoactive intestinal peptide (VIP), also initiates secretion, but to a lesser extent. In the present study, cross talk between VIP- and muscarinic-induced mucin secretion was investigated using isolated rat sublingual tubuloacini. VIP-induced secretion is mediated by cAMP-activated protein kinase A (PKA), independently of increased [Ca2+]i. Synergistic secretion between VIP and the muscarinic agonist, carbachol, was demonstrated but only with submaximal carbachol. Carbachol has no effect on cAMP ± VIP. Instead, PKA activated by VIP releases Ca2+ from an intracellular pool maintained by the sarco/endoplasmic reticulum Ca2+-ATPase pump. Calcium release was independent of phospholipase C activity. The resultant sustained [Ca2+]i increase is additive to submaximal, but not maximal carbachol-induced [Ca2+]i. Synergistic mucin secretion was mimicked by VIP plus either phorbol 12-myristate 13-acetate or 0.01μM thapsigargin, and blocked by the PKC inhibitor, Gö6976. VIP-induced Ca2+ release also promoted store-operated Ca2+ entry. Synergism is therefore driven by VIP-mediated [Ca2+]i augmenting cPKC activity to enhance muscarinic mucin secretion. Additional data suggest ryanodine receptors control VIP/PKA-mediated Ca2+ release from a Ca2+ pool also responsive to maximal carbachol. A working model of muscarinic and VIP control of mucous cell exocrine secretion is presented. Results are discussed in relation to synergistic mechanisms in other secretory cells, and the physiological and therapeutic significance of VIP/muscarinic synergism controlling salivary mucous cell exocrine secretion.

Transplanted Vasoactive Intestinal Peptide-Secreting Donor Plasmacytoid Dendritic Cells Migrate to Lymphoid Organs and GvHD Target Organs

Introduction: Donor plasmacytoid dendritic cells (pDCs) have important roles in the pathogenesis of graft versus host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Vasoactive intestinal peptide (VIP), a potent anti-inflammatory neuropeptide with pleiotropic effects, has shown promise in managing GvHD through induction of regulatory dendritic cells (Chorny, Blood 2006) and regulatory T cells (Delgado, JLB 2005). Our previous data showed that transplantation of hematopoietic stem cells (HSC) lacking VIP expression in enhanced Th1 polarization and antiviral immunity (Li, JI 2011). Whether VIP produced by pDCs plays a key role in preventing GvHD is the focus of the current study. Method: A reductive allo-HSCT model was established by transplanting purified populations of 5 x 103 hematopoietic stem cells (HSC), 5 x 104 pDCs and 106 T cells from B6 (H-2Kb) to MHC mismatched B10.BR (H-2Kk) recipients. Mice received either VIP knockout pDCs (experimental group) or wild-type pDCs (control). Survival and clinical GvHD scores were monitored for at least 60 days. Serum pro-inflammatory cytokines were measured by luminex on day 3 and day 8. Additional recipients were transplanted for interim analyses of GvHD pathology in histological sections of small intestine and colon on day 8 and day 15. To investigate pDC migration and proliferation status, 5 x 104 luciferase-expressing pDCs, together with 5 x 103 WT B6 HSC, were transplanted to MHC mismatched Balb/c (H2kd) recipients. Bioluminescent imaging was performed on day 14. We used mice carrying an eGFP reporter linked to a VIP promoter to measure VIP production by donor cells in vivo. The construct has the eGFP reporter gene, followed by a polyadenylation sequence, inserted into BAC clone RP23-25A8 at the initiating ATG codon of the first coding exon of the VIP gene, so that eGFP expression is driven by the regulatory sequences of the BAC gene. The BAC is inserted randomly in the genome. We used serial breeding to establish the eGFP-VIP reporter in B6 mice. Bone marrow pDCs were sorted from transgenic eGFP-VIP B6 mice and used in transplant experiments, allowing VIP gene activity from donor-derived pDCs to be detected as GFP expression using confocal microscopy. Results: Compared to recipients of WT pDCs, recipients of VIP-KO pDCs have a significantly lower survival rate with increased GvHD clinical score (Figure 1; *p&lt;0.05). Transplant recipients of VIP-KO donor pDC had higher serum pro-inflammatory cytokine levels on day 3 and day 8 respectively. (Figure 2). At 2 weeks post-transplant donor pDCs migrated primarily to the spleen, with limited presence of donor pDCs in the gastrointestinal tract and lung (Figure 3). Compared to mice transplanted with WT pDCs, recipients of VIP-KO pDCs had increased donor T cell migration to the lung and paw, which are chronic GvHD target organs after two weeks. (Figure 4; *p&lt;0.05). When stimulated with IFN-g, eGFP-VIP transgenic pDCs have activation of the VIP gene promoter in vitro, as detected using eGFP (Figure 5). Confocal microscopy data showed that pDCs have activated the VIP promoter and secreted more VIP following stimulation by IFN-g, consistent with VIP up-regulation by the inflammatory mileu in allo-transplant recipients. Conclusions: These data show that lack of VIP secretion by donor pDCs resulted in lower survival rates and higher GvHD scores in allo-BMT recipients. Recipients of VIP KO donor pDC had increased donor T cell proliferation in GvHD target organs and increased GvHD clinical signs. The major site of donor pDCs migration in recipients is spleen, suggesting that pDCs may interact with other lymphoid cells, such as T cells, inducing a more tolerogenic environment. Donor pDCs were also found, to a lesser extent, in the lung and gastrointestinal tract, which are both GvHD target organs. Thus, pDCs may protect recipients from GvHD by limiting the activity of alloreactive T cells at these sites. The mechanism by which VIP-secreting donor pDCs regulate GvHD will be discussed. Disclosures Waller: Amgen: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Other: Travel expenses, Research Funding; Cerus Corporation: Other: Stock, Patents &amp; Royalties; Chimerix: Other: Stock; Cambium Oncology: Patents &amp; Royalties: Patents, royalties or other intellectual property ; Kalytera: Consultancy.

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.

Predictors of Recurrence in Vasoactive Intestinal Peptide Secreting Tumors of Pancreas

Predictors of Recurrence in Vasoactive Intestinal Peptide Secreting Tumors of Pancreas

Diagnostic and Management Challenges in Vasoactive Intestinal Peptide Secreting Tumors: A Series of 15 Patients.

Vasoactive intestinal peptide-secreting tumors (VIPomas) are rare functioning neuroendocrine tumors often characterized by a difficult-to-control secretory syndrome and high potential to develop metastases. We hereby present the characteristics of 15 cases of VIPomas and provide a recent literature review. This was a retrospective data analysis of 15 patients with VIPoma from 3 different centers and literature research through PubMed database during the last 10 years. Fifteen patients with VIPomas (9 with hepatic metastases at diagnosis) with watery diarrhea and raised VIP levels were studied. Ten patients (67%) had grade 2 tumors, 6 of 15 had localized disease and underwent potentially curative surgery, whereas the remaining 9 received multiple systemic therapies; 3 patients died during follow-up. The median overall survival was 71 months (range, 41-154 months). Patients who were treated with curative surgery (n = 7) had longer median overall survival compared with patients who were treated with other therapeutic modalities (44 vs 33 months). The management of VIPomas is challenging requiring the application of multiple treatment modalities. Patients who underwent surgical treatment with curative intent appear to have higher survival rate. Central registration and larger prospective studies are required to evaluate the effect of currently employed therapies in these patients.

VPAC1 couples with TRPV4 channel to promote calcium-dependent gastric cancer progression via a novel autocrine mechanism.

Although VPAC1 and its ligand vasoactive intestinal peptide (VIP) are important in gastrointestinal physiology, their involvements in progression of gastrointestinal tumor have not been explored. Here, we found that higher expression of VIP/VPAC1 was observed in gastric cancer compared to the adjacent normal tissues. The increased expression of VIP/VPAC1 in gastric cancer correlated positively with invasion, tumor stage, lymph node, distant metastases, and poor survival. Moreover, high expression of VIP and VPAC1, advanced tumor stage and distant metastasis were independent prognostic factors. VPAC1 activation by VIP markedly induced TRPV4-mediated Ca2+ entry, and eventually promoted gastric cancer progression in a Ca2+ signaling-dependent manner. Inhibition of VPAC1 and its signaling pathway could block the progressive responses. VPAC1/TRPV4/Ca2+ signaling in turn enhanced the expression and secretion of VIP in gastric cancer cells, enforcing a positive feedback regulation mechanism. Taken together, our study demonstrate that VPAC1 is significantly overexpressed in gastric cancer and VPAC1/TRPV4/Ca2+ signaling axis could enforce a positive feedback regulation in gastric cancer progression. VIP/VPAC1 may serve as potential prognostic markers and therapeutic targets for gastric cancer.

Effect of intracanal medicaments on matrix metalloproteinase-9 and vasoactive intestinal peptide secretion in periapical lesions of re-treated canals: a randomized controlled clinical study.

The aim of this study was to evaluate the effect of calcium hydroxide (Ca[OH]2) and chlorhexidine (CHX) gel on matrix metalloproteinase-9 (MMP-9) and vasoactive intestinal peptide (VIP) secretion in periapical lesions. A total of 60 patients were randomly divided into two groups that were to receive different medications. Pre-and post-treatment samples were collected from the interstitial fluid of periapical lesions using sterile paper points. VIP and MMP-9 levels were measured by enzyme-linked immunosorbent assay kits, and the data were statistically analyzed. Gender and smoking habits had no effect on the pre- and post-treatment VIP and MMPs levels. Intragroup analyses revealed that in the Ca(OH)2 group, the post-treatment VIP level was found to be significantly higher than the pre-treatment VIP level. In the CHX group, the post-treatment MMP-9 level was significantly higher than the pre-treatment MMP-9 level. According to the results of the present study, the type of the medication affected the amount of periapical VIP and MMP-9 secretion. VIP is a neuropeptide that promotes new bone formation. Thus, intracanal Ca(OH)2 medication may accelerate the repair process of bone tissue.

Malignant-functioning neuroendocrine tumors of the pancreas: A survival analysis

Malignant-functioning pancreatic neuroendocrine tumors (mFpNETs) are rare. Research analyzing the presentation, biological behavior, and patient outcomes of these tumors is limited. We used the Surveillance, Epidemiology, and End Results database to identify patients with malignant insulinomas, gastrinomas, glucagonomas, vasoactive intestinal peptide secreting tumors (VIPomas), somastatinomas, and mixed islet cell tumors (MICTs). The primary endpoint of this study was to identify factors affecting survival. We identified 401 patients with mFpNETs. Between histologic subtypes, there were significant differences in sex and age, and in tumor size, grade, location, and stage. Median survival time for insulinomas was 12.7 years; gastrinomas, 10.2 years; glucagonomas, 7.7 years; VIPomas, 7.9 years; and MICTs, 3.4 years. Multivariable analysis showed that histology (insulinoma, gastrinoma, and VIPoma; P = .009), absence of distant metastases (P = .002), age < 50 years (P = .001), surgical intervention (P = .001), and stage I/II disease (P = .011) were independently associated with prolonged survival. Subgroup analysis demonstrated that removal of the primary tumor in stage IV mFpNETs was associated with significantly prolonged survival (P = .01). mFpNETs are rare tumors that commonly present at an advanced stage despite hormonal secretion. Primary tumor resection is associated with longer survival in stages I-III as well as stage IV tumors.

Rapid octreotide separation from synthetic peptide crude mixtures by chromatography on poly(styrene–co-divinylbenzene)-based reversed phases

Octreotide, a disulfide-cyclized eight amino acids long analogue of somatostatin, has been used to treat the symptoms associated with metastatic carcinoid tumors (flushing and diarrhea), and vasoactive intestinal peptide secreting adenomas (watery diarrhea). As composed by D-amino acids, C-terminal alcohol, and disulfide bond, octreotide can be only prepared using chemistry synthesis method, which increases difficulty of the traditional reversed-phase separation. In this paper, we report a very fast separation of octreotide from synthetic peptide crude mixtures on a poly(styrene co-divinylbenzene) (PSt)-based reversed phases prepared by a quick membrane emulsification process. In general, fourier-transformed infrared resonance (FT-IR) spectroscopy, reversed-phase high performance liquid chromatography (HPLC) combined with electrospray ionisation mass spectrometry (ESI-MS), and nuclear magnetic resonance (NMR) spectroscopy are routinely used for analyses of resultant peptides. Under the optimized conditions, the octreotide is purified from 42.89% to 99.99%. Consequently, the poly(styrene co-divinylbenzene)-based phase can provide more flexibility to improve separation efficiency for the octreotide from the synthetic peptide crude mixtures. (C) 2015 Elsevier B.V. All rights reserved.

Nöroblastomlu Bir Olguda VİP İlişkili Diyarenin Yönetimi

Watery diarrhea associated with hypokalemia and achlorhydria (WDHA) syndrome is commonly caused by vasoactive intestinal peptide (VIP) secreting tumors in adults and generally associated with neural crest tumors in pediatric population. VIP secretion is associated with neuroblastic cell differentiation. Octreotide treatment can be a choice for diarrhea in such cases. However, its benefit is controversial and surgery is usually needed. A 14-month-old female with diagnosis of inoperable undifferantiated intraabdominal neuroblastoma who developed chronic diarrhea at first year of chemotherapy is reported. Octreotide treatment was used to control diarrhea. Because of the failure of octreotide treatment, debulking surgery was performed and diarrhea subsided after the surgery.

Correlation between vasoactive intestinal peptide and expression of NKG2D, adaptor protein 10 and extracellular signal-regulated kinase in inflammatory cells of gastric adenocarcinoma

Objective To investigate the expression of NKG2D and related signaling molecules adaptor protein(DAP10) and extracellular signal-regulated kinase(ERK) in the inflammatory cells of gastric adenocarcinoma and para-carcinoma tissues,the effects of vasoactive intestinal peptide(VIP) on the expression of NKG2D,DAP10 and ERK in natural killer(NK) cells of healthy volunteers.Methods The expression of NKG2D,DAP10 and ERK in the inflammatory cells of 36 gastric adenocarcinoma and para-carcinoma tissues were detected by immunohistochemistry.The peripheral blood NK cells of healthy volunteers were isolated and purified with CDC method.The expressions of NKG2D,DAP10 and ERK in NK cells were determined by immunocytochemistry and reverse transcription-polymerase chain reaction(RT-PCR) methods before and after VIP intervention.The ttest was used for comparison between two groups and rank transformation nonparametric test (Kruskal-Wallis H test) for count data analysis.Results The expression levels of NKG2D,DAP10 and ERK in the inflammatory cells of gastric adenocarcinoma were significantly lower than those of para-carcinoma tissues (H=30.640,24.910,20.320,all P＜0.01).The expression levels of NKG2D,DAP10 and ERK were much lower in poorly differentiated gastric adenocarcinoma (H =4.049,11.830,8.118),at stage Ⅲ-Ⅳ (H=4.275,11.560,7.686),and the expression levels of NKG2D,ERK were lower with lymph nodes metastasis (H=6.513,6.064,all P＜0.05).The expression levels of NKG2D,DAP10 and ERK in gastric adenocarcinoma tissues and inflammatory cells were not correlated with gender,age and the location of lesions (all P＞0.05).The expression levels of NKG2D,DAP10 and ERK in NK cells was decreased after VIP intervention (protein:H=12.438,4.798,13.745,mRNA:F=337.640,638.579,1055.015,all P＜0.05).Conclusion Gastric adenocarcinoma may downregulate the expression of NKG2D,DAP10 and ERK in NK cells through VIP secretion,which may be involved in the immune escape of gastric cancer. Key words: Vasoactive intestinal peptide; Killer cells, natural; Stomach neoplasms; Adenocarcinoma; DAP10 protein; Mitogen-activated protein kinases ; Tumor escape

Correlation between gastrointestinal hormones and anxiety-depressive states in irritable bowel syndrome

The aim of this study was to investigate the mechanism(s) of action of gastrointestinal hormones in the pathogenesis of irritable bowel syndrome (IBS), and the correlation between gastrointestinal hormones and psychological factors. Patients with IBS were divided into IBS with normal emotional state ratings and IBS in anxiety-depressive states groups. The two groups were then subdivided into IBS-constipation predominant (IBS-C) and IBS-diarrhea predominant (IBS-D) groups. Non-IBS patients with normal depression and anxiety ratings were recruited as controls. The serum concentrations of somatostatin (SS) and vasoactive intestinal peptide (VIP) were measured by radioimmunoassay, and the expression of SS and VIP in the colonic mucosa was detected by immunohistochemistry and radioimmunoassay. The anxiety-depression scores of patients with IBS were significantly different from those of the control group (P<0.05). The expression levels of SS and VIP in the serum and colonic mucosa of the patients with IBS were higher compared with those of the control group. Furthermore, the expression level of SS in the IBS-C group demonstrated a significantly larger increase than that in the IBS-D group (P<0.05); however, there was no significant difference in the expression of VIP between the IBS-C and IBS-D groups (P>0.05). In addition, the expression levels of SS and VIP in the IBS groups with normal emotional state ratings were notably different from those in the IBS groups in anxiety-depressive states (P<0.05). Anxiety-depressive states may lead to changes in the secretion of SS and VIP, and subsequently to changes in gastrointestinal motility and function.

Targeting the Insulin-Like Growth Factor Pathway in Estrogen Receptor–Positive Breast Cancer: A Bumpy Start With an Uncertain Future

During the last decade, we have made significant advances in the field of endocrine therapy for patients with hormone receptor (HR)positive early-stage breast cancer. The first report from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trialists in 2000 introduced the use of anastrozole in the adjuvant setting as an alternative to tamoxifen for women with HR-positive disease who were postmenopausal. Since that time, additional trials have demonstrated the benefit of all three aromatase inhibitors, either as initial endocrine therapy after surgery, as sequential therapy after 2 to 3 years of tamoxifen, or as extended adjuvant therapy after 5 years of tamoxifen. Despite these substantial gains, approximately one third of women with HRpositive early-stage disease will relapse, and the majority of these women will die from distant metastatic disease (MBC). Molecular cross talk between the estrogen receptor (ER) and growth factor receptor signaling pathways likely contributes to de novo or acquired resistance to endocrine therapy. In addition to classic ER activation by ligand binding (estrogen), a subset of the ER pool may initiate alternative cellular signaling by direct interaction with components of growth factor signaling pathways. As one example, upregulation of the human epidermal growth factor receptor 2 (HER2) pathway leads to ligand-independent phosphorylation of the ER and increased downstream signaling despite ongoing antiestrogen therapy. To counteract these resistance mechanisms, clinical trials that have combined endocrine therapy with anti-HER2 therapy (trastuzumab and lapatinib) have been performed in MBC and demonstrated increased clinical activity in patients with ER-positive, HER2-positive disease compared with endocrine therapy alone. However, definitive conclusions that support the beneficial effects of dual-targeted therapy are limited by the design of these trials, given that single-agent anti-HER2 therapy was not tested in these studies. In a similar fashion, other growth factor signaling pathways, such as the insulin-like growth factor (IGF) pathway, can activate ER signaling and contribute to resistance to endocrine therapy (Fig 1). The IGF system is composed of four related receptors (insulin receptor [IR], type 1 IGF receptor [IGF1R], and hybrid receptors between the IR and IGF1R), three ligands (IGF-1, IGF-2, and insulin), and six binding proteins (IGFBP-1 to IGFBP-6). There is a growing body of preclinical evidence that breast tumors express insulin and IGF-1 receptors, and that these receptors activate the phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase signaling pathways. Inhibition of the IGF1R pathway in combination with letrozole synergistically inhibited proliferation and induced apoptosis in breast cancer cells. In addition, there is increasing evidence that women with early-stage breast cancer and hyperinsulinemia or elevated fasting C-peptide levels have a worse prognosis. Taken together, these findings support the hypothesis that dual targeting of the IGF1R and ER pathways is a rational strategy to prevent or delay the onset of endocrine resistance. In the article that accompanies this editorial, Pritchard et al report a randomized, open-label, phase III trial that compared 5 years of tamoxifen treatment with or without 2 years of long-acting–release octreotide as adjuvant therapy in 667 postmenopausal women with HR-positive early-stage breast cancer (NCIC Clinical Trials Group study MA.14, A Randomized Trial of Tamoxifen Therapy Versus Combined Tamoxifen and Octreotide LAR Therapy in the Adjuvant Treatment of Breast Cancer in Postmenopausal Women). Long-acting–release octreotide is a long-acting somatostatin analog that binds to somatostatin receptors, inhibiting secretion of pituitary and gastroenteropancreatic hormones including growth hormone, insulin, glucagon, cholecystokinin, and vasoactive intestinal peptide (Fig 1). Octreotide is commonly used in the clinic for a myriad of indications including the treatment of hormone-secreting tumors in the pituitary, the control of symptoms such as diarrhea and flushing in patients with metastatic carcinoid and vasoactive intestinal peptide–secreting tumors, and the treatment of diarrhea associated with AIDS, chemotherapy, and graft-versus-host disease. Octreotide was one of the first IGF-1 targeting agents available in the 1990s, and was chosen for this trial, which was initiated in 1996, on the basis of small MBC studies that showed antitumor activity and greater suppression of IGF-1 with octreotide plus tamoxifen compared with tamoxifen alone. In the MA.14 trial, the duration of octreotide was shortened from 5 to 2 years after a substantial rise was noted in the incidence of symptomatic gallbladder disease. As hypothesized by the study investigators, patients who were treated with octreotide plus tamoxifen had a greater reduction in IGF-1 levels compared with patients who were treated with tamoxifen alone. However, after a median follow-up of JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L S