Vasoactive Intestinal Peptide (VIP) and VIP Receptors-Elucidation of Structure and Function for Therapeutic Applications

Vasoactive intestinal peptide (VIP) is a 28-amino acid polypeptide first isolated from swine duodenum. VIP is a neurotransmitter that is extensively distributed in tissues. According to published reports, VPAC1 and VPAC2 act as VIP receptors and are widely present in the central nervous system and peripheral tissues. VIP exerts diverse actions on the cardiovascular system, pancreas, digestive tract, respiratory system, and urological system. Recent reports indicated that VIP has immunological and neuroprotective effects and also affects cell growth. While primary investigations for developing therapeutic applications for various pathological conditions and diseases are underway, the structure and function of VIP should be analyzed in more detail.

Vasoactive intestinal polypeptide (VIP) corrects chronic inflammatory response syndrome (CIRS) acquired following exposure to water-damaged buildings

Exposure in water-damaged buildings (WDB) to airborne bioaerosols including metabolic products of toxigenic fungi, bacteria and actinomycetes;and inflammagens, can lead to a persistent innate immune inflammatory illness. This illness, termed a chronic inflammatory response syndrome (CIRS-WDB), is systemic with symptoms acquired from multiple organ systems. Treatment of CIRS-WDB has progressed rapidly as a better understanding of the inflammatory pathophysiology has led to targeted, sequential therapies. The fundamental basis of uncontrolled innate immune responses, the humoral deficiency of regulatory neuropeptides melanocyte stimulating hormone (MSH) or vasoactive intestinal polypeptide (VIP), seen in over 98% of pa tients, has not consistently responded to any treatment modality. Use of replacement VIP has been attempted anecdotally;VIP replacement therapies show promise in short term studies but longer therapies have not been attempted. Here we report an open label trial of 20 patients with refractory CIRS-WDB illness who took replacement VIP in a nasal spray for at least 18 months with confirmation of durable efficacy and absence of significant side effects. These 20 patients were similar in symptoms and lab find- ings to three previously published cohorts in- volving 1829 patients and 169 controls. Dosage of VIP was titrated downwards from four to zero doses a day to determine minimum effective dose, and retitrated upwards for maximum improvement over time. The trial showed that VIP therapy safely 1) reduced refractory symptoms to equal controls;2) corrected inflammatory parameters C4a, TGF beta-1, VEGF, MMP9;3) corrected estradiol, testosterone and 25-OH Vitamin D;4) returned pulmonary artery systolic pressure (PASP) during exercise to normal;and 5) enhanced quality of life in 100% of trial patients. Subsequent identification of correction of T-regulatory cell levels supports the potential role of VIP in both innate and adaptive immune function.

Differences and significance of motilin,vasoactive intestinal peptide and gastrin in blood and gallbladder tissues of patients with gallstones

BACKGROUND: The disorders of gallbladder motility may play an important role in the formation of gallstones. Many neural and hormonal factors and their interactions regulate gallbladder motility and bile flow into the duodenum. Further study in these factors may help to reveal the etiology of gallbladder diseases. This study was undertaken to assess the relationship of the levels of motilin, vasoactive intestinal peptide (VIP) and gastrin in blood and gallbladder tissues with the formation of cholelithiasis. METHODS: The levels of motilin, gastrin and VIP in blood and gallbladder tissues of 36 patients with gallbladder stones, 14 patients with gallbladder polyps, 10 healthy volunteers and 10 patients with common bile duct stones were measured by radioimmunoassay. RESULTS: The level of motilin in plasma and gallbladder tissues of the gallbladder stone group was higher than that of the control and gallbladder polyp groups (P<0.05). The levels of plasma VIP and serum gastrin were much higher than those of the other three groups (P<0.01). The level of VIP in gallbladder tissues was higher than that of the control and gallbladder polyp groups (P<0.01). CONCLUSIONS: The abnormal excretion of hormonal factors is closely related to gallstone formation. The high level of VIP in gallbladder tissues may be an important cause of gallbladder hypomotility. The abnormal level of serum gastrin may be related to the gastrointestinal symptoms of patients with gallstones.

Role of vasoactive intestinal peptide and nitric oxide in the modulation of electroacupucture on gastric motility in stressed rats

AIM: To investigate the effects and mechanisms of vasoactive intestinal peptide (VIP) and nitric oxide (NO) in the modulation of electroacupucture (EA) on gastric motility in restrained-cold stressed rats. METHODS: An animal model of gastric motility disorder was established by restrained-cold stress. Gastric myoelectric activities were recorded by electrogastroent erography (EGG). VIP and NO concentrations in plasma and gastric mucosal and bulb tissues were detected by radioimmunoassay (RIA). VIP expression in the gastric walls was assayed using avidin-biotin-peroxidase complex (ABC) and image analysis. RESULTS: In cold restrained stressed rats, EGG was disordered and irregular. The frequency and amplitude of gastric motility were higher than that in control group (P < 0.01). VIP and NO contents of plasma, gastric mucosal and bulb tissues were obviously decreased (P < 0.01). Following EA at “Zusanli” (ST36), the frequency and amplitude of gastric motility were obviously lowered (P < 0.01), while the levels of VIP and NO in plasma, gastric mucosal and bulb tissues increased strikingly (P < 0.01, P < 0.05) and expression of VIP in antral smooth muscle was elevated significantly (P < 0.01) in comparison with those of model group. CONCLUSION: VIP and NO participate in the modulatory effect of EA on gastric motility. EA at “Zusanli” acupoint (ST36) can improve gastric motility of the stressed rats by increasing the levels of VIP and NO.

Recombinant expressed vasoactive intestinal peptide analogue ameliorates TNBS-induced colitis in rats

AIM To investigate the modulatory effect of recombinantexpressed vasoactive intestinal peptide(VIP) analogue(rVIPa) on trinitrobenzene sulfonic acid(TNBS)-induced colitis in rats. METHODS Forty-eight rats were randomized into six groups: normal control group(Control), model control group(TNBS), ethanol treatment group(ETOH), and VIP treatment groups with different dosage(rVIPa_(1nmol), rVIPa_(2nmol), rVIPa_(4nmol)). Diarrhea and bloody stool were observed. Colonic damage was evaluated histologically. The levels of tumor necrosis factor-α( TNF-α), interleukin-10(Il-10), myeloperoxidase(MPO) and endotoxin in colonic tissue and serum were determined by enzyme-linked immunosorbent assay(ElISA). The expression of occludin, ZO-1, Toll-like receptor 4(TlR4),and nuclear factor-kappa B p65(NF-κBp65), IκBα, and p-IκBα were detected by Western blot. RESULTS Administration with 2 nmol rVIPa prevented TNBSinduced necrosis, hyperemia, swelling, inflammation, etc., pathologic changes observed in the inner surface of colon in experimental rats. Moreover, rVIPa significantly decreased colonic TNF-α level(P < 0.001), MPO activity(P < 0.001) and serum endotoxin level(P < 0.01), and remarkably increased colonic Il-10 content(P < 0.001) in rats with TNBS-induced colitis. Furthermore, compared to the TNBS-induced colitis group, 2 nmol rVIPa treatment up-regulated the levels of occludin(P < 0.05) and ZO-1(P < 0.05), NF-κB p65(P < 0.01) and IκBα(P < 0.001), and down-regulated the levels of TlR4. CONCLUSION rVIPa ameliorates TNBS-induced colonic injury and inflammation and effectively protected the intestinal mucosal barrier function in rats. The mechanism may be related to TlR4/NF-κB-mediated signaling pathway. rVIPa could be used as a new alternative therapy for intestinal inflammatory disorders.

Vasoactive intestinal peptide,a promising agent for myopia?

AIM： To investigate the role of vasoactive intestinal peptide（VIP） in form-deprivation myopia（FDM）.METHODS： FDM was created in three groups of eight chicks by placing a translucent diffuser on their right eyes.Intravitreal injections of saline and VIP were applied once a day into the occluded eyes of groups 2 and 3,respectively.Retinoscopy and axial length（AL） measurements were performed on the first and 8^th days of diffuser wear.The retina mR NA levels of the VIP receptors and the ZENK protein in right eyes of the three groups and left eyes of the first group on day 8 were determined using real time polymerase chain reaction（PCR）.RESULTS： The median final refraction（D） in right eyes were-13.75（-16.00,-12.00）,-11.50（-12.50,-7.50）,and-1.50（-4.75,-0.75） in groups 1,2,and 3,respectively（P〈0.001）.The median AL（mm） in right eyes were 10.65（10.00,11.10）,9.90（9.70,10.00）,and 9.20（9.15,9.25） in groups 1,2,and 3,respectively（P〈0.001）.The median delta-delta cycle threshold（CT） values for the VIP2 receptors were 1.07（0.82,1.43）,1.22（0.98,1.65）,0.29（0.22,0.45） in right eyes of groups 1,2,and 3,and 1.18（0.90,1.37） in left eyes of group 1,respectively（P=0.001）.The median delta-delta CT values for the ZENK protein were 1.07（0.63,5.03）,3.55（2.20,5.55）,undetectable in right eyes of groups 1,2,and 3 and 1.89（0.21,4.73） in left eyes of group 1,respectively（P=0.001）.CONCLUSION： VIP has potential inhibitory effects in the development of FDM.

Roles of sphincter of Oddi motility and serum vasoactive intestinal peptide,gastrin and cholecystokinin octapeptide

AIM: To investigate roles of sphincter of Oddi (SO) motility played in pigment gallbladder stone formation in model of guinea pigs.

Research advances of vasoactive intestinal peptide in the pathogenesis of ulcerative colitis by regulating interleukin-10 expression in regulatory B cells

Ulcerative colitis(UC)is a chronic relapsed intestinal disease with an increasing incidence around the world.The pathophysiology of UC remains unclear.However,the role of the interaction between the enteric nervous system and the immune system in the pathogenesis of UC has been the focus of attention and has become a research hotspot.Vasoactive intestinal peptide(VIP)is a kind of endogenous neuropeptide with regulatory activity on intestinal immunity.It has been shown to regulate immune disorders in animal and human experiments and has become an effective anti-inflammatory and immune modulator that affects the innate immune system and adaptive immune system.Regulatory B cells(Bregs)are a new group of B cells that negatively regulate the immunity and have received extensive attention in immune circles.Bregs can regulate immune tolerance by producing interleukin(IL)-10,IL-35,and transforming growth factor-β,suppressing autoimmune diseases or excessive inflammatory responses.The secretion of IL-10 by Bregs induces the development of T helper(Th)0 and Th2 cells.It also induces Th2 cytokines and inhibits Th1 cytokines,thereby inhibiting Th1 cells and the Th1/Th2 balance.With further clarity on the mechanism of the regulation of IL-10 expression by VIP in Bregs in colitis patients,we believe that Bregs can provide a novel strategy for the clinical treatment of UC.Thus,we aim to review the current literature on this evolving topic.

Effect of vasoactive intestinal peptide on the wound healing of alkali-burned corneas

AIM： To study the effect of vasoactive intestinal peptide （VIP） on wound healing in experimental alkali burns of the cornea. METHODS： Twenty-seven albino rabbits, weighing 3.2 -0.75 kg were used. Alkali burns were induced on corneas by applying 10 mm Whatman paper No：50 soaked in 1 mol/L NaOH. They have further classified into 5 groups as follows： 1） control group given no treatment （n=5）; 2） VIP given subconjunctivally （n=6）; 3） VIP injected into anterior chamber （n=6）; 4） NaCI 0.9% given subconjunctivally （n=5）; 5） NaCI 0.9% given into the anterior chamber （n=5）. All treatment protocols except control group were followed by topical eye drops composed of VIP at two hourly intervals for one week from 8 a.mo to 6 p.m, RESULTS： VIP treated groups of rabbits with alkali burns were found to have better wound healing findings histo-pathologically when compared to those of control group who have received no treatment on day 30. No differences were observed between groups in respect to degree of polymorphonuclear leukocytes （PMNL） infiltration and degree of loss of amorphous substrate on day 15. However, PMNL infiltration and degree of loss of amorphous substrate were lower in Groups 2 and 3 when compared to that of control group on day 30 （P〈0.05）. CONCLUSION： We have shown that VIP has positive effects on alkali induced corneal burns. VIP may inhibit PMNL migration to cornea through an immunomodulatory effect. Inhibition of PMNL migration might reduce the release of collagenaees and this might prevent the extracellular amorphous substance loss.

Role of vasoactive intestinal peptide in Aspergillus fumigatus-infected cornea

AIM： To investigate the anti-inflammatory role of vasoactive intestinal peptide（VIP） in Aspergillus fumigatus（A. fumigatus） ketatitis.METHODS： Expression of VIP was tested by polymerase chain reaction（PCR） in C57BL/6 and BALB/c normal and A. fumigatus infected corneas. C57BL/6 mice were pretreated with recombinant（r） VIP, while BALB/c mice were pretreated with VIP antagonist, and then infected with A. fumigatus. Clinical score was recorded. Expression of pro-and anti-inflammatory cytokines, toll-like receptor 4（TLR4）, lectin-like oxidized low-density lipoprotein receptor 1（LOX-1）, and neutrophil infiltration were tested by PCR, enzyme-linked immunosorbent assay（ELISA）, and myeloperoxidase（MPO） assay.RESULTS： VIP mR NA expression in BALB/c cornea was higher than C57BL/6 cornea at 1 and 3 d post infection（p.i.）. rV IP treatment of C57BL/6 mice showed alleviated disease and down-regulated expression of interleukin-1β（IL-1β） and tumor necrosis factor-α（TNF-α）, while IL-10 expression was up-regulated. Neutrophil infiltration and TLR4, IL-17 expression were decreased after rVIP treatment, while LOX-1 expression was up-regulated in C57BL/6. VIP antagonist pretreatment showed increased disease and higher IL-1β, TNF-α, TLR4, IL-17 and MPO levels, while IL-10 and LOX-1 levels were down-regulated in BALB/c mice.CONCLUSION： rVIP alleviate disease response of C57BL/6 mice. VIP antagonist resulted in worsened disease of BALB/c mice. VIP proposed anti-inflammatory role in A. fumigatus keratitis.

Octreotide reverses shock due to vasoactive intestinal peptide-secreting adrenal pheochromocytoma: A case report and review of literature

Vasoactive intestinal peptide-producing tumors （VIP-oma） usually originate in the pancreas and are chara-cterized by diarrhea, hypokalemia, and achlorhydria （WDHA syndrome）. In adults, nonpancreatic VIPoma is very rare. Herein, we report an unusual case of VIP-producing pheochromocytoma marked by persistent shock, fushing, and watery diarrhea and high sensitivity to octreotide. A 53-year-old woman was hospitalized for sudden-onset hypertension with convulsions, which then rapidly evolved to persistent shock, fushing, and watery diarrhea. Abdominal computed tomography indicated a left adrenal mass, accompanied by bleeding;and marked elevations of both plasma catecholamine and VIP concentrations were documented via laboratory testing. Surprisingly, all clinical symptoms responded swiftly to octreotide treatment. Once surgically treated, hormonal levels normalized in this patient, and the clinical symptoms dissipated. Postoperative pathological and immunohistopathological studies confrmed a VIP-secreting pheochromocytoma with strong, diffuse positivity for somatostatin receptor type 2. During a 6-mo follow-up period, she seemed in good health andwas symptom-free.

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.

Effect of vasoactive intestinal peptide on proliferation of hepatoma cells

It has been found that vasoactive intestinal peptide (VIP) stimulates the growth ofseveral kinds of tumor cells.There is no report so far about the effect of VIP on the growth ofhepatoma cells.Using the tetrazolium colorimetric assay (MTT assay) and cell countingmethod,it was investigated that the effect of VIP on the growth of a cultured rat hepatomaFSK-7902 cells.The results showed that VIP stimulated the proliferation of the rat hepatomacells obviously.The addition of 1μmol/L VIP caused a significant increase in the number of thecultured rat hepatoma cells on 3rd day and maximal increase occured on 4th day and 5th day ( P【0.01).The growth promoting effect was greater as the concentration of VIP increased.Thelowest effective concentration of VIP was 0.5μmol/L.Exposure to VIP for 12 h followed by re-moval of the peptide resulted in sustained growth for several days.

EFFECTSOFVASOACTIVEINTESTINALPEPTIDEONACTIVITIESOFSUCCINICDEHYDROGENASEANDALKALINEPHOSPHATASEINRATHEPATOMACELLS

Using cytochemical method,microspectrophotometry and image analysis,effects of va-soactive intestinal peptide(VIP)on activities of succinic dehydrogenase(SDH)and alkalinephosphatase(ALP)in rat hepatoma cells were studied in vitro.The results showed that thehepatoma cell expressed potent positive reactions of SDH and ALP,the positive positionswere located at the cell membranes and/or cytoplasm.Having been treated with VIP,ALPdecreased obviously in activity(P【0. 01,compared with hepatoma cells untreated by VIP).The sites of ALP activty were chiefly located at the cell membranes,particularly at the cell-cell contacts.Cultured rat hepatoma cells had intensive SDH activity in their cytoplasm.Compared with untreated eclls,there was no marked difference in the intensity of SDH activ-ity in VIP-treated hepatoma cells(P】0.05).

RELAXANT EFFECTS OF VASOACTIVE INTESTINAL PEPTIDE ON PULMONARY ARTERY IN CHRONICALLY HYPOXIC RATS

The object of this study is to investigate the effect of VIP on pulmonary artery of chronically hypoxic rats. It was shown that chronic hypoxia depressed significantly pulmonary artery relaxation induced by VIP as compared with those of control (P<0. 001). The vascular relaxation of both groups was correlated with concentration of VIP. In addition, the relaxant effect of VIP on pulmonary arteries in rats was endothelium─independent, and was not prevented by indomethacin or nordihydroguaiaretic acid, but was abolished completely by methylene blue. These results suggest that the lower relaxation of pulmonary artery in rats might not be due to the endothelial injury caused by chronic hypoxia, and chronic hypoxia may inhibit directly the soluble guanylate cyclase in vascular smooth muscle cells invloved in synthesis of cGMP and thus reduced the sensitivity and reactivity of pulmonary artery to VIP.

THE AUTOCRINE REGULATORY EFFECT OF VASOACTVE INTESTINAL PEPTIDE ON THE GROWTH OF HUMAN PANCREATIC CARCINOMA CELLS

In the present study, the effects of VIP on the growth of two human pancreatic carcinoma cell lines PU-PAN-l and PANC-I were determined using tritiated thymidine incorporation. VIP receptors. intracellular cAMP and polyamines were investigated. The results indicated that VIP at a concentration of 10-8 mol/L to 10-7 mol/L can significantly stimulate the growth of PU-PAN-I cells but not PANC-1 cells. This effect is dose-dependent and abolished by VIP receptor antagonist, [4-C1-Phe6 . Leu17] VIP, suggesting VIP receptors in PU-PAN-I cells may mediate this effect. VIP can markedly elevate the levels of intracellular cAMP and polyamines in PU-PAN-I cells.indicating that the growth-promoting effect stimulated by VIP may be via a rapid increase in the biosyntheses of cAMP and polyamines. In addition, the VIP-antibody inhibited the growth of PU-PAN-I cells in serum-free culture mediurn. The results above suggested that VIP has an autocrine regulatory effect on this pancreatic carcinoma cell line (PU-PAN-1).

温中和胃汤联合耳穴压豆对脾胃虚寒型慢性胃炎患者治疗疗效及对血清VIP、MTL水平的影响

目的 温中和胃汤联合耳穴压豆对脾胃虚寒型慢性胃炎(CG)患者的治疗疗效及对血清VIP、MTL水平的影响。方法 选取2021年1月—2022年5月该院接收的脾胃虚寒型CG患者90例,采用随机数字表法分为观察组47例和对照组43例。所有患者均行常规治疗,同时对照组给予耳穴压豆治疗,观察组在对照组基础上联合温中和胃汤治疗。对比两组的治疗疗效、中医证候评分、不良反应发生情况。治疗前后,检测两组患者外周血胃肠功能指标[胃动素(MTL)、血管活性肽(VIP)]以及炎症指标[白细胞介素-1β(IL-1β)以及白细胞介素-6(IL-6)]表达水平。在患者停药3个月后,对其进行为期半年的跟踪随访调查,记录其复发情况。结果 观察组、对照组治疗总有效率分别为93.62%、76.74%,不良反应总共发生率分别为17.02%、9.30%,6个月内复发率分别为0.00%、13.95%。,观察组治疗总有效率较高、6个月复发率较低(P<0.05),两组不良反应发生率无差异(P>0.05)。治疗后中医证候对比,观察组胃隐痛、喜温喜按、劳累/受凉后症状加重和泛吐清水评分低于对照组(P<0.05),两组神疲倦怠、舌淡胖评分无差异(P>0.05)。治疗后,观察组血清MTL高于对照组(P<0.05),VIP、IL-1β低于对照组(P<0.05),两组IL-6浓度无差异(P>0.05)。结论 温中和胃汤联合耳穴压豆可有效提高脾胃虚寒型CG治疗疗效,降低VIP和IL-1β表达,同时提高MTL表达水平,降低短期内复发率。

EFFECT OF ERYTHROMYCIN ON GASTRIC DYSMOTILITY AND NEUROENDOCRINE PEPTIDES IN RATS WITH DIABETES MELLITUS

Objective To investigate the effect of erythromycin on the contractive activity of the isolated gastric antrum smooth muscle and somatostatin （SS）, vasoactive intestinal peptide （VIP）, motilin （MTL）, and substance P （SP） in plasma and isolated gastric antrum tissue of diabetes mellitus （DM） rat models. Methods Thirty male Sprague-Dawley rats were divided into three groups： control group （n = 10）, DM group （n = 10）, and erythromycin group （DM models with erythromycin treatment, n = 10）. A single dose of streptozotocin （100 mg/kg, dissolved in 0. I mol/L citric acid buffer, pH4.5） was injected intraperitoneally. After 48 to 72 hours, rats with blood glucose above 16.7 mmol/L and urine glucose level to be （＋＋＋ ） to （＋＋＋＋） over one week were considered successful DM models. The resting tension, mean contractile amplitude and fi＇equency of spontaneous change in isolated longitudinal and circular gastric antrum smooth muscle strips were measured. SS, VIP, MTL, and SP levels in plasma and gastric antrum tissue were measured using radioimmunoassay. Results （1） In the isolated gastric antrum smooth muscle strips, the gastric motility parameters were lower in DM group than those in control group except circular smooth muscle contractile amplitude and longitudinal smooth muscle contractile fi＇equency. The gastric motility parameters were significantly strengthened in erythromycin group, compared with DM group except longitudinal smooth muscle resting tension （P 〈 0.01 ）. （2） Plasma SS, VIP, and MTL concentrations in DM group were higher than those in control （P 〈 0.05）, while the SP level decreased （P 〈 0.05）. In the gastric antrum, SS of DM group was significantly higher than that of control group （P 〈 0.01 ）, while SP and MTL levels were lower than those of control group （P 〈 0.05 and P 〈 0.01, respectively）. However, the level of VIP in gastric antrum tissue did not change among three groups. The plasma level of SS in erythromycin group was higher than that of DM group （P 〈 0.05）. （3） The blood glucose was lower in erythromycin group than DM group （P 〈 0.01 ）. Conclusions Erythromycin has direct effects on contractive activity of gastric smooth muscle in diabetic rats, but there are few effects on neuroendocrine peptides. Gastric-motility disorders in diabetic rats have a correlation with the changes of neuroendocrine peptide levels in plasma and gastric antrum tissue.

Effect of Vasocation Intestinal Peptide on Immune Privilege of the Rat Testis

Objective To study the effect of vasocation intestinal peptide （VIP） on immune privilege of the rat testis. Methods The UU infected SD rats and Leydig cells were intervened by VIP, the secretion of TGF-β and the expression of FasL in rat Leydig cells were compared between VIP-intervened group and control group to test the effect of VIP on immune privilege of the rat testis in vitro and in vivo. Results In vitro, the secretion of TGF-β in Leydig cells could be increased by low dosage of VIP while inhibitited by high dosage of VIP; expression of FasL mRNA in Leydig cells could be decreased by VIP In vivo, increased expression of TGF-β mRNA and decreased FasL mRNA were observed in VIP group in 2-3 weeks after infected by UU. In addition, the apoptosis of Jurkat cells mediated by Leydig cells could be prevented by VIP Conclusion When Leydig cells or testis infected by UU, VIP could regulate the immune function of rat Leydig cells and participate in the regulation of immune privilege of testis through the regulation of TGF-β secretion and FasL expression pattern of Leydig cells.

Potential PET Ligands for Imaging of Cerebral VPAC and PAC Receptors: Are Non-Peptide Small Molecules Superior to Peptide Compounds?

Pituitary adenylate cyclase activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) have been known for decades to mediate neuroendocrine and vasodilative actions via G-protein-coupled receptors of Class B. These are targets of imaging probes for positron emission tomography (PET) or single photon emission tomography (SPECT) in tumor diagnostics and tumor grading. However, they play only a subordinate role in the development of tracers for brain imaging. Difficulties in development of non-peptide ligands typical for cerebral receptors of PACAP and VIP are shared by all members of Class B receptor family. Essential landmarks have been confirmed for understanding of structural details of Class B receptor molecular signalling during the last five years. High relevance in the explanation of problems in ligand development for these receptors is admitted to the large N-terminal?ectodomain markedly different from Class A receptor binding sites and poorly suitable as orthosteric binding sites for the most small-molecule compounds. The present study is focused on the recently available receptor ligands for PAC1, VPAC1 and VPAC2 receptors as well as potential small-molecule lead structures suitable for use in PET or SPECT. Recently, biaryl, cyanothiophene and pentanamide structures with affinities in nM-range have been proposed as non-peptide ligands at VPAC1 and VPAC2 receptors. However, most of these ligands have been classified as non-competitive related to the orthosteric binding site of endogenous peptide ligands of VPAC receptors. For PAC1 receptors have been identified hydrazide compounds for which an inhibitory and potentially competitive mechanism of receptor binding has been postulated based on molecular docking studies.