Vasoactive Intestinal Peptide Concentrations Research Articles

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

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

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

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

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

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

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

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

Dietary supplementation with pyrroloquinoline quinone promotes growth, relieves weaning stress, and regulates metabolism of piglets compared with adding zinc oxide

Hindered growth often occurs because of psychological and environmental stress during the weaning period of piglets. This study aimed to compare the effects of growth performance, diarrhea indices, digestibility of nutrients, antioxidant capacity, neurotransmitters levels and metabolism of weaned pigs fed diets supplemented with pyrroloquinoline quinone (PQQ) and zinc oxide (ZnO). Pigs weaned at d 28 (n = 108) were fed with three different diets including: the basal diet (CTRL group), the basal diet supplemented with 3.0 mg/kg PQQ (PQQ group) and the basal diet containing 1,600 mg/kg ZnO (ZNO group). During the first 14 d, weaned pigs fed the diet supplemented with PQQ and ZnO decreased feed to gain ratio and diarrhea rate (P < 0.01). Compared with the CTRL group, average daily gain was increased in weaned pigs in the PQQ group from d 15 to 28 (P = 0.03). Compared with the CTRL group, pigs fed PQQ and ZnO supplemented diets showed improved apparent total tract digestibility (ATTD) of nutrients (P ≤ 0.05). During the overall experimental period, the concentration of malondialdehyde was decreased in plasma of pigs in the PQQ and ZNO groups compared with the CTRL group (P < 0.05). At d 28, the concentration of vasoactive intestinal peptide (VIP) and calcitonin gene-related peptide (CGRP) was lower in plasma of weaned pigs in the PQQ and ZNO groups compared with the CTRL group (P < 0.05). There was no difference between the PQQ and ZNO group in growth performance, ATTD of nutrition, antioxidant capacity and neurotransmitters levels. PQQ increased 3-methoxy-4-hydroxymandelate (P < 0.05) compared with the CTRL group. According to metabolomic analysis, erucamide, formononetin and 3-methyl-L-histidine were up-regulated in the PQQ group (P < 0.05). Compared with the CTRL group, aloesin and dibutyl adipate were down-regulated in the PQQ group (P < 0.05). In conclusion, similar to ZnO, PQQ improves growth performance, digestibility of nutrients, antioxidant capacity, neuromodulation and metabolism of weaned pigs. Thus, like ZnO, PQQ can be effectively applied in weaned pigs.

Brain-bacteria-gut axis and oxidative stress mediated by intestinal mucosal microbiota might be an important mechanism for constipation in mice.

Intestinal microbiota disorder was associated with constipation. This study investigated the microbiota-gut-brain axis and oxidative stress mediated by intestinal mucosal microbiota in mice with spleen deficiency constipation. The Kunming mice were randomly divided into the control (MC) group and the constipation (MM) group. The spleen deficiency constipation model was established by gavage with Folium sennae decoction and controlled diet and water intake. The body weight, spleen and thymus index, 5-Hydroxytryptamine (5-HT) and Superoxide Dismutase (SOD) content were significantly lower in the MM group than the MC group, the content of vasoactive intestinal peptide (VIP) and malondialdehyde (MDA) content were significantly higher than the MC group. The Alpha diversity of intestinal mucosal bacteria was not changed but beta diversity was changed in mice with spleen deficiency constipation. Compared to the MC group, the relative abundance of Proteobacteria was an upward trend and the Firmicutes/Bacteroidota (F/B) value was a downward trend in the MM group. There was a significant difference in the characteristic microbiota between the two groups. In the MM group, Brevinema, Akkermansia, Parasutterella, Faecalibaculum, Aeromonas, Sphingobium, Actinobacillus, and other pathogenic bacteria were enriched. Meanwhile, there was a certain relationship between the microbiota and gastrointestinal neuropeptide and oxidative stress indicators. The community structure of intestinal mucosal bacteria in mice with spleen deficiency constipation was changed, which was characterized by the reduction of F/B value and enrichment of Proteobacteria. Microbiota-gut-brain axis may be important for spleen deficiency constipation.

Role of tear vasoactive intestinal peptide on dry eyes after laser keratorefractive surgery

BackgroundTo explore the changes in vasoactive intestinal peptide (VIP) concentration in tears post laser-assisted sub-epithelial keratomileusis (LASEK) and femtosecond laser-assisted in situ keratomileusis (FS-LASIK) surgeries and related factors, possible association between postoperative dry eye symptoms and VIP concentration in tears, and factors influencing dry eye symptoms after different periods post LASEK and FS-LASIK surgeries.MethodsIn this prospective, non-randomized, longitudinal cohort study, 23 and 22 subjects were recruited and underwent LASEK and FS-LASIK, respectively. After conducting an intact ophthalmic examination and collecting relevant surgical data, all subjects were examined for VIP concentration in their tears using ELISAs, tear-film breakup time, ocular staining and ocular surface disease index questionnaire before surgery and 1 day, 1 week, and 1 month post-surgery.ResultsTear VIP concentration increased significantly after both LASEK and FS-LASIK, with the highest concentration observed 1 week post-surgery (P ≤ 0.05). Tear VIP concentration correlated negatively with corneal ablation depth (AD). The extent of dry eyes was related to the operation method employed and postoperative recovery period. In FS-LASIK and LASEK subjects, dry eyes were mainly affected by the basic ocular surface status before surgery, and VIP concentration. Furthermore, in LASEK subjects, dry eyes were negatively correlated with AD.ConclusionVIP was stimulated and mobilized as an emergency protection post-refractive surgery and a trauma model affected by AD. It can indirectly indicate the inevitable relationship between postoperative dry eye and nerve injury. Elevated post-surgery tear VIP relieves dry eye symptoms, showing its neuroimmune role in regulating adverse injury stimulation. The present study provides a solution to the pathogenesis of postoperative dry eyes.Trial registrationThe trial registration number: 2021JS22. Date of registration: 10 May 2021.

Research on the mechanism of prednisone in the treatment of ITP via VIP/PACAP-mediated intestinal immune dysfunction

RationaleImmune thrombocytopenia (ITP) is thought to be a result of immune dysfunction, which is treated by glucocorticoids such as prednisone. Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP) have immunomodulatory properties, but their role in intestinal immune control is unclear. The major goal of this study was to look at the effects of prednisone on platelet, VIP, and PACAP levels in ITP mice, as well as the regulatory system that controls intestinal immunity.MethodsEighteen BALB/c mice were randomly divided into three groups: blank control group, model control group, and prednisone group, with six mice in each group. The ITP animal model control group and the prednisone group were injected with anti-platelet serum (APS) to replicate the ITP animal model. The prednisone group began prednisone intervention on the 8th day. Platelet count was dynamically measured before APS injection, on the 4th day of injection, on the 1st day of administration, on the 4th day of administration, and at the end of the experiment. After the experiment, the expression of p53 protein in mouse mesenteric lymph node lymphocytes was detected by immunohistochemistry. The changes in lymphocyte apoptosis rate in mouse mesenteric lymph nodes were detected by in situ terminal transferase labeling (TUNEL). The contents of VIP and PACAP in the mouse brain, colon, and serum were detected by enzyme-linked immunosorbent assay (ELISA). The contents of IFN-γ, IL-4, IL-10, IL-17A in the mouse spleen were detected by ELISA.Results①Changes of peripheral platelet count: there was no significant difference in platelet count among the three groups before modeling; on the 4th day, the platelet count decreased in the model control group and prednisone group; on the 8th day, the number of platelets in model control group and prednisone group was at the lowest level; on the 12th day, the platelet count in prednisone group recovered significantly; on the 15th day, the platelet count in prednisone group continued to rise. ②Changes of VIP, PACAP: compared with the blank control group, VIP and PACAP in the model control group decreased significantly in the brain, colon, and serum. Compared with the model control group, the levels of VIP and PACAP in the brain, colon, and serum in the prednisone group were increased except for serum PACAP. ③Changes of mesenteric lymphocytes: the expression of p53 protein in the mesenteric lymph nodes of model control group mice was significantly higher than that of blank control group mice. After prednisone intervention, the expression of p53 protein decreased significantly.④Changes of cytokines in spleen: compared with blank control group, IFN- γ, IL-17A increased and IL-4 and IL-10 decreased in model control group. After prednisone intervention, IFN- γ, IL-17A was down-regulated and IL-4 and IL-10 were upregulated.ConclusionsPrednisone-upregulated VIP and PACAP levels decreased P53 protein expression and apoptosis rate in mesenteric lymph node lymphocytes and affected cytokine expression in ITP model mice. Therefore, we speculate that the regulation of intestinal immune function may be a potential mechanism of prednisone in treating ITP.

Effects of electroacupuncture at "Zhongliao" and "Xialiao" on serotonin signaling system and short-chain fatty acids in slow transit constipation rats

To observe the effect of electroacupuncture (EA) at "Zhongliao" (BL33) and "Xialiao" (BL34) on the 5-hydroxytryptamine (5-HT) signaling system in colon tissue and short-chain fatty acids in feces of rats with slow transit constipation (STC), so as to explore the underlying mechanisms of EA in the treatment of STC. A total of 32 SD rats were randomly divided into normal, model, drug control and EA groups, with 8 rats in each group. The STC model was established by intragastric administration of loperamide for 14 days. The EA stimulation (2 Hz/15 Hz) was performed at bilateral BL33 and BL34 for 30 min, once a day for 14 days. The first black stool de-fecation time and fecal water content were detected after treatment. The expressions of 5-hydroxytryptamine 4 receptor (5-HT4R), tryptophan hydroxylase 1 (TPH1) and 5-HT transporter (SERT) in colon tissues were detected by Western blot. The contents of substance P (SP) and vasoactive intestinal peptide (VIP) in serum were detected by ELISA. The contents of 5-HT in colon tissue and short chain fatty acid (SCFA) in feces were detected by mass spectrometry. Compared with the normal group, the fecal water content, the expressions of 5-HT, 5-HT4R, TPH1 and SERT in colon tissue, the content of serum SP were significantly decreased (P<0.05), the first black stool de-fecation time, and the content of serum VIP was significantly increased (P<0.05), the contents of SCFA in feces were significantly decreased except isobutyric acid (P<0.05) in the model group. Compared with the model group, the fecal water content, the expressions of 5-HT, 5-HT4R, TPH1 and SERT in colon tissues, the contents of acetic acid and butyrate in feces were significantly increased (P<0.05) in the EA and drug control groups, the first black stool defecation time was decreased (P<0.05) in the EA and drug control groups, and the content of serum SP was increased and the content of serum VIP was decreased (P<0.05) in the EA group. Compared with the drug control group, the content of serum VIP was significantly decreased (P<0.05), and the expressions of TPH1 and SERT in colon tissue were significantly increased (P<0.05) in the EA group. EA at BL33 and BL34 can promote intestinal motility by intervening multiple links of 5-HT signaling system in treating STC.

Intervention Effects of Okra Extract on Brain-Gut Peptides and Intestinal Microorganisms in Sleep Deprivation Rats.

Objective Okra, possessing various bioactive components, is used to treat different diseases. This study sought to estimate the intervention effects of okra extract (OE) on brain-gut peptides (BGPs) and intestinal microorganisms in sleep deprivation (SD) rats. Methods SD rat models were established using the modified multiple platform method and then treated with normal saline, diazepam tablets, or different doses of OE. Body weight and average daily water consumption of rats were recorded. Depressive behaviors of rats were assessed by the open field test and sucrose preference test. Serum levels of noradrenaline, melatonin, inflammatory factors (IL-1β/IL-6/TNF-α/IL-4/IL-10), and BGP indexes, including gastrin (GAS), motilin (MTL), 5-hydroxytryptamine (5-HT), cholecystokinin (CCK), and vasoactive intestinal peptide (VIP) were measured by ELISA. Additionally, the DNA relative contents of representative intestinal microorganisms in the collected rat feces were determined using RT-qPCR. Results SD decreased body weight and average daily water consumption and induced depressive behaviors as well as stress and inflammatory responses in rats. SD rats exhibited lowered GAS, MTL, 5-HT, and VIP but elevated CCK and showed diminished DNA relative contents of Bacteroidetes and probiotics (Bifidobacteria and Lactobacilli) but increased Clostridium perfringens. OE at different doses ameliorated the depressive behaviors and mitigated the stress and inflammatory responses in SD rats, raised the serum contents of GAS, MTL, 5-HT, and VIP, reduced CCK level, elevated the DNA relative contents of Bacteroidetes and probiotics, but diminished Clostridium perfringens. OE exhibited similar intervention effects to diazepam tablets (positive control). Conclusion OE exerts intervention effects on BGPs and intestinal microorganisms in SD rats.

Effect of Kvass on Improving Functional Dyspepsia in Rats.

Functional dyspepsia (FD) is a common digestive system disease, and probiotics in the treatment of FD have a good curative effect. Patients with gastrointestinal diseases often show a poor response to traditional drug treatments and suffer from adverse reactions. Kvass can be used as a functional drink without side effects to improve the symptoms of FD patients. The results showed that compared with those of the model group, the body weight and food intake of the treatment group were significantly increased (P < 0.05), and the gastric residual rate of the treatment group was significantly decreased (P < 0.05); the amount of pepsin in the treatment group was significantly higher than that in the model group (P < 0.05); a high dose of Kvass could increase the contents of ghrelin, motilin (MTL), and gastrin (GAS) in the plasma and decrease the contents of vasoactive intestinal peptide (VIP) in the plasma; the contents of ghrelin, MTL, and GAS in the gastric antrum were also increased in the high-dose group. Kvass beverage can significantly improve the gastrointestinal function of rats, which may be because it can improve the contents of ghrelin, MTL, GAS, and VIP in both the serum and gastric antrum by regulating the expression of short-chain fatty acids in the colon.

Correlation between slow transit constipation and spleen deficiency, and gut microbiota: a pilot study.

To investigate the effect of slow transit constipation (STC) and spleen deficiency on gut microbiota, and the mechanism underlying the action that the positive drug Maren Runchang (MR) alleviates STC. STC was induced, using the cathartic method of Senna and the hunger-fullness disorder method, in ICR mice; one group of model mice was treated with MR (6.24 g/kg). The changes in the general condition, fecal parameters, D-xylose content in the serum, intestinal propulsion rate, and histopathology of the colon were assessed after STC induction in the control, model, and MR groups. Fecal microbiota transplantation (FMT) was performed from STC mice into pseudo germ-free mice. Changes in the contents of substance P (SP), vasoactive intestinal peptide (VIP), and gut microbiota in STC mice and pseudo germ-free mice were assessed after FMT. Compared with the control group, the model mice showed the following results: the time of the first black stool was significantly longer ( 0.01), the number and weight of black stools were significantly reduced within 6 h ( 0.05), the D-xylose content in the serum was significantly reduced ( < 0.05), the intestinal propulsion rate decreased ( < 0.01), the content of VIP in colon tissue significantly increased ( < 0.05), and SP content in the colon tissue significantly decreased ( < 0.01); moreover, the colon showed significant inflame-mation and injury. Furthermore, the abundance of Firmicutes was increased, the abundance of Bacteroides decreased, and the abundance of decreased, while the abundance of the conditional pathogenic bacteria and Klebsiella increased. However, after treatment with MR, the time of the first black stool decreased (0.01), the number of black stools within 6 h increased, and the intestinal propulsion rate increased ( < 0.05). Moreover, the content of D-xylose in the serum and the content of VIP in colon tissue significantly decreased ( < 0.05), the content of SP in colon tissue significantly increased ( < 0.01), and colon inflammation significantly improved. Additionally, the abundance of Firmicutes decreased, and the abundance of Bacteroides increased. The abundance of increased, and the abundance of decreased. In the model + FMT group, compared with control + FMT group, the content of VIP in colon tissue decreased ( < 0.05), the content of SP in colon tissue significantly increased ( < 0.01), and the abundance of probiotics, such as , decreased. In the MR + FMT group, compared with the model + FMT group, the content of VIP in colon tissue increased, the content of SP in colon tissue significantly decreased ( < 0.01), and the abundance of probiotics increased. STC mice with spleen deficiency show a decreased abundance of beneficial bacteria, such as , and an increased abundance of the conditional pathogenic bacteria . Furthermore, the mechanism of action of MR in treating STC may involve the regulation of intestinal movement, reduction of intestinal inflammation, elevation of intestinal absorption, and regulation of gut microbiota.

The Gain-of-Function R222S Variant in Scn11a Contributes to Visceral Hyperalgesia and Intestinal Dysmotility in Scn11a R222S/R222S Mice.

BackgroundThe SCN11A gene encodes the α-subunit of the Nav1. 9 channel, which is a regulator of primary sensory neuron excitability. Nav1.9 channels play a key role in somatalgia. Humans with the gain-of-function mutation R222S in SCN11A exhibit familial episodic pain. As already known, R222S knock-in mice carrying a mutation orthologous to the human R222S variant demonstrate somatic hyperalgesia. This study investigated whether Scn11aR222S/R222S mice developed visceral hyperalgesia and intestinal dysmotility.MethodsWe generated Scn11aR222S/R222S mice using the CRISPR/Cas9 system. The somatic pain threshold in Scn11aR222S/R222S mice was assessed by Hargreaves' test and formalin test. The excitability of dorsal root ganglia (DRG) neurons was assessed by whole-cell patch-clamp recording. Visceralgia was tested using the abdominal withdrawal reflex (AWR), acetic acid-induced writhing, and formalin-induced visceral nociception tests. Intestinal motility was detected by a mechanical recording of the intestinal segment and a carbon powder propelling test. The excitability of the enteric nervous system (ENS) could influence gut neurotransmitters. Gut neurotransmitters participate in regulating intestinal motility and secretory function. Therefore, vasoactive intestinal peptide (VIP) and substance P (SP) were measured in intestinal tissues.ResultsThe R222S mutation induced hyperexcitability of dorsal root ganglion neurons in Scn11aR222S/R222S mice. Scn11aR222S/R222S mice exhibited somatic hyperalgesia. In addition, Scn11aR222S/R222S mice showed lower visceralgia thresholds and slowed intestinal movements when compared with wild-type controls. Moreover, Scn11aR222S/R222S mice had lower SP and VIP concentrations in intestinal tissues.ConclusionsThese results indicated that Scn11aR222S/R222S mice showed visceral hyperalgesia and intestinal dysmotility.

Pyrroloquinoline Quinone Regulates Enteric Neurochemical Plasticity of Weaned Rats Challenged With Lipopolysaccharide.

The enteric nervous system (ENS) is important for the intestinal barrier to defend and regulate inflammation in the intestine. The aim of this study was to investigate the effect of pyrroloquinoline quinone (PQQ) on regulating neuropeptide secretion by ENS neurons of rats challenged with lipopolysaccharide (LPS) to create enteritis. Thirty Sprague Dawley rats were divided into five groups, namely, basal (CTRL), basal plus LPS challenge (LPS), basal with 2.5 mg/kg b.w./day of PQQ plus challenge with LPS (PQQ 2.5), basal with 5.0 mg/kg b.w./day PQQ plus challenge with LPS (PQQ 5), and basal with 10.0 mg/kg b.w./day PQQ plus challenge with LPS (PQQ 10). After treatment with basal diet or PQQ for 14 days, rats were challenged with LPS except for the CTRL group. Rats were euthanized 6 h after the LPS challenge. Rats showed an increased average daily gain in PQQ treatment groups (P < 0.05). Compared with the LPS group, PQQ 5 and PQQ 10 rats showed increased villus height and villus height/crypt depth of jejunum (P < 0.05). In PQQ treatment groups, concentrations of IL-1β and TNF-α in serum and intestine of rats were decreased, and IL-10 concentration was increased in serum compared with the LPS group (P < 0.05). Compared with the LPS group, the concentration of neuropeptide Y (NPY), nerve growth factor (NGF), vasoactive intestinal peptide (VIP), substance P (SP), calcitonin gene-related peptide (CGRP), and brain-derived neurotropic factor (BDNF) in serum were decreased in PQQ treatment groups (P < 0.05). Compared with the LPS group, ileal mRNA levels of BDNF, NPY, and NGF were decreased in PQQ treatment groups (P < 0.05). Jejunal concentrations of SP, CGRP, VIP, BDNF, NPY, and NGF were decreased in PQQ treatment groups compared with the LPS group (P < 0.05). Compared with the LPS group, phosphor-protein kinase B (p-Akt)/Akt levels in jejunum and colon were decreased in PQQ treatment groups (P < 0.05). In conclusion, daily treatment with PQQ improved daily gain, jejunal morphology, immune responses. PQQ-regulated enteric neurochemical plasticity of ENS via the Akt signaling pathway of weaned rats suffering from enteritis.

Enhanced Contractive Tension and Upregulated Muscarinic Receptor 2/3 in Colorectum Contribute to Constipation in 6-Hydroxydopamine-Induced Parkinson's Disease Rats.

Constipation and defecatory dysfunctions are frequent symptoms in patients with Parkinson’s disease (PD). The pathology of Lewy bodies in colonic and rectal cholinergic neurons suggests that cholinergic pathways are involved in colorectal dysmotility in PD. However, the underlying mechanism is unclear. The aim of the present study is to examine the effect of central dopaminergic denervation in rats, induced by injection 6-hydroxydopamine into the bilateral substania nigra (6-OHDA rats), on colorectal contractive activity, content of acetylcholine (ACh), vasoactive intestinal peptide (VIP) and expression of neural nitric oxide synthase (nNOS) and muscarinic receptor (MR). Strain gauge force transducers combined with electrical field stimulation (EFS), gut transit time, immunohistochemistry, ELISA, western blot and ultraperformance liquid chromatography tandem mass spectrometry were used in this study. The 6-OHDA rats exhibited outlet obstruction constipation characterized by prolonged transit time, enhanced contractive tension and fecal retention in colorectum. Pretreatment with tetrodotoxin significantly increased the colorectal motility. EFS-induced cholinergic contractions were diminished in the colorectum. Bethanechol chloride promoted colorectal motility in a dose-dependent manner, and much stronger reactivity of bethanechol chloride was observed in 6-OHDA rats. The ACh, VIP and protein expression of nNOS was decreased, but M2R and M3R were notably upregulated in colorectal muscularis externa. Moreover, the number of cholinergic neurons was reduced in sacral parasympathetic nucleus (SPN) of 6-OHDA rats. In conclusion, central nigrostriatal dopaminergic denervation is associated with decreased cholinergic neurons in SPN, decreased ACh, VIP content, and nNOS expression and upregulated M2R and M3R in colorectum, resulting in colorectal dysmotility, which contributes to outlet obstruction constipation. The study provides new insights into the mechanism of constipation and potential therapeutic targets for constipation in PD patients.

Вплив факторів запалення на показники вегетативного тонусу в дітей із рекурентними захворюваннями респіраторного тракту

Серед дітей шкільного віку хвороби органів дихання посідають перше місце в структурі загальної захворюваності, їх поширеність становить понад 60 %. Здебільшого часті епізоди респіраторної патології призводять до формування рекурентних форм, що є вагомою причиною відсутності активних ігор і прогулянок на свіжому повітрі, пропусків школи і збільшення проведеного часу за засобами масової комунікації й електронними іграми, що, зі свого боку, призводить до формування гіподинамії і підвищення психоемоційного напруження, надаючи негативний вплив на функціонування регуляторних систем дитячого організму. Рекурентні захворювання респіраторного тракту (гострі респіраторні захворювання — ГРЗ) сприяють напрузі нейроендокринноімунної регуляції, приводячи до дисбалансу нейропептидів — медіаторів нейрогенного запалення. Метою даної роботи є вивчення показників нейрогенного запалення в школярів молодших класів із рекурентною патологією респіраторного тракту. Під час виконання роботи виявлено підвищення вмісту субстанції Р у сироватці крові в школярів із рекурентними ГРЗ, що мало статистично вірогідні відмінності з показниками умовно здорових дітей (р &lt; 0,05). Установлено, що перевищення концентрації субстанції Р підвищує ризик розвитку повторних захворювань. Доведено, що в дітей із рекурентними ГРЗ за рахунок підвищення сироваткового вмісту КСМ NO, які мають прозапальну спрямованість, посилюється активність нейрогенного запалення. Виявлено, що вірогідне зниження вмісту ВІП як протизапального трансмітера в дітей із рекурентними ГРЗ не в змозі пригнічувати активність нейрогенного запалення, приводячи до його надмірної стимуляції.

Динаміка показників нейровегетативної регуляції в дітей із рекурентними захворюваннями респіраторного тракту і зниженим функціональним резервом міокарда після реабілітаційної програми

Актуальність. Останнім часом проблеми з рівнем дитячого здоров’я викликають побоювання з боку як медичної, так і педагогічної громадськості. Інтенсивна програма шкільної освіти, високе інфекційне навантаження на організм молодшого школяра і підвищений інтерес до засобів масової електронної комунікації — все це призводить до напруження функціонування вегетативної нервової системи (ВНС) і, як результат, зниження функціонального резерву міокарда. У зв’язку з цим було запропоновано проведення оздоровчих літніх заходів, метою яких було надати відновлюваний вплив на функціонування ВНС і стан функціонального резерву міокарда молодшого школяра. Мета роботи: проаналізувати клінічну ефективність реабілітаційної програми в дітей із рекурентними захворюваннями респіраторного тракту і зниженим функціональним резервом міокарда. Матеріали та методи. 30 дітям раннього шкільного віку проведена протягом 1 літнього місяця реабілітаційна програма. Здійснена оцінка клінічної ефективності реабілітаційної програми за даними стану ВНС, показників активності регуляторних систем (ПАРС), рівнів концентрації нейротрансмітерів у сироватці крові. Проведено оцінку функціонального резерву міокарда. Результати. За підсумками реабілітаційної програми отримані вірогідні результати поліпшення функціонування ВНС: знизилися прояви симпатикотонії і зменшилася реєстрація порушеного ПАРС і зривів процесів адаптації (p &lt; 0,05). Звертають на себе увагу статистично значуще зниження сироваткової концентрації субстанції Р і кінцевих стабільних метаболітів NO (KCM NO) і підвищення сироваткової концентрації вазоактивного інтестинального пептиду. Дана позитивна динаміка супроводжувалася значним зниженням реєстрації симпатикотонії, ригідного ритму, порушеного ПАРС, зриву процесів адаптації (p &lt; 0,05). Проведена річна реабілітаційна програма привела до поліпшення результатів проби Руф’є на 4 бали порівняно з показниками наприкінці навчального року. Висновки. Здійснення реабілітаційної програми в дітей із рекурентними захворюваннями респіраторного тракту і зниженим функціональним резервом міокарда поліпшило показники функціонального стану ВНС і ПАРС. Поліпшення функціонального стану ВНС і ПАРС супроводжувалося: зниженням рівня концентрації субстанції Р, КСМ NO в сироватці крові та підвищенням вазоактивного інтестинального пептиду. Проведення оздоровчого курсу в дітей із рекурентними гострими респіраторними захворюваннями та зниженим функціональним резервом міокарда дозволило знизити показник проби Руф’є на 4 бали, що свідчить про підвищення функціонального резерву міокарда.

Neurotransmitter serum levels in children with recurrent upper respiratory tract infections

Background. Schoolchildren are prone to frequent respiratory tract diseases. In the structure of general morbidity, this pathology ranks first. Its prevalence is more than 60 %, which leads to frequent school absenteeism, lack of active games and outdoor walks. So, there is an increase in the amount of time that a child spent on means of mass electronic communication and electronic games, resulting in high affection and addiction, forming hypodynamia, which in aggregate has a negative impact on the regulatory systems functioning. Recurrent upper respiratory tract infections (URTI) contribute to the strain of neuro-endocrine-immune regulation, causing an imbalance of neuropeptides — mediators of neurogenic inflammation. The purpose of this work is to study the neurogenic inflammation parameters in schoolchildren with functional disorders of the cardiovascular system and recurrent respiratory tract diseases. Materials and methods. We surveyed 130 children with URTI aged 6 to 9 years in the somatic well-being period. The analysis of the contents of vasoactive intestinal peptide (VIP), substance P and final stable metabolites of nitric oxide (FSM NO) in serum was carried out. An increase in substance P level in children with recurrent URTI was found, which had statistically significant differences with the healthy children indices (p &lt; 0.05). Results. It has been found that high concentration of substance P increases the risk of recurrent URTI. It has been proved that in children with recurrent URTI due to increased FSM NO serum content that has a pro-inflammatory orientation, there is an increased neurogenic inflammation activity. It was found that the reliable reduction in the content of VIP as an anti-inflammatory transmitter in children with recurrent URTI can not suppress the activity of neurogenic inflammation, resulting in its excessive stimulation. Conclusions. Children with recurrent URTI in the somatic well-being period have increased serum levels of substance Р and FSM NO. In the somatic well-being period in schoolchildren with recurrent URTI, a decrease in the concentration of anti-inflammatory neuropeptide VIP is observed.

Inulin and isomalto-oligosaccharide alleviate constipation and improve reproductive performance by modulating motility-related hormones, short-chain fatty acids, and feces microflora in pregnant sows.

Constipation in gestating and lactating sows is common and the inclusion of dietary fiber may help to alleviate this problem. We investigated the effects of inulin (INU) and isomalto-oligosaccharide (IMO), two sources of soluble dietary fiber, on gastrointestinal motility-related hormones, short-chain fatty acids (SCFA), fecal microflora, and reproductive performance in pregnant sows. On day 64 of gestation, 30 sows were randomly divided into three groups and fed as follows: a basal diet, a basal diet with 0.5% INU, and a basal diet with 0.5% IMO. We found that INU and IMO significantly modulated the levels of gastrointestinal motility-related hormones, as evidenced by an increase in substance P (P < 0.05), and a decrease in the vasoactive intestinal peptide concentrations (P < 0.05), indicating the capacity of INU and IMO to alleviate constipation. Furthermore, IMO enhanced the concentrations of acetic, propionic, isobutyric, butyric, isovaleric, and valeric acids in the feces (P < 0.05). High-throughput sequencing showed that IMO and INU increased the fecal microflora α- and β-diversity (P < 0.05). Methanobrevibacter was more abundant (P < 0.05), whereas the richness of Turicibacter was lower in the INU and IMO groups than in the control group (P < 0.05). In addition, IMO significantly increased litter size (P < 0.05). Overall, our findings indicate that INU and IMO can relieve constipation, optimize intestinal flora, and promote reproductive performance in pregnant sows.

VIP reduction in the pancreas of F508del homozygous CF mice and early signs of Cystic Fibrosis Related Diabetes (CFRD)

Vasoactive intestinal peptide (VIP), a 28-amino acid neuropeptide with potent anti-inflammatory, bronchodilatory and immunomodulatory functions, is secreted by intrinsic neurons innervating all exocrine glands, including the pancreas, in which it exerts a regulatory function in the secretion of insulin and glucagon. Cystic fibrosis-related diabetes (CFRD) is the most common co-morbidity associated with cystic fibrosis (CF), impacting approximately 50% of adult patients. We recently demonstrated a 50% reduction of VIP abundance in the lungs, duodenum and sweat glands of C57Bl/6 CF mice homozygous for the F508del-CFTR disease-causing mutation. VIP deficiency resulted from a reduction in VIPergic and cholinergic innervation, starting before signs of CF disease were observed. As VIP functions as a neuromodulator with insulinotropic effect on pancreatic beta cells, we sought to study changes in VIP in the pancreas of CF mice. Our goal was to examine VIP content and VIPergic innervation in the pancreas of 8- and 17-week-old F508del-CFTR homozygous mice and to determine whether changes in VIP levels would contribute to CFRD development. Our data showed that a decreased amount of VIP and reduced innervation are found in CF mice pancreas, and that these mice also exhibited reduced insulin secretion, up-regulation of glucagon production and high random blood glucose levels compared to same-age wild-type mice. We propose that low level of VIP, due to reduced innervation of the CF pancreas and starting at an early disease stage, contributes to changes in insulin and glucagon secretion that can lead to CFRD development.