A neutral polysaccharide from the pulp of Trichosanthes kirilowii Maxim mitigates constipation through microbiota-dependent activation of brain-gut axis.

Flushing is a common clinical symptom characterised by transient cutaneous vasodilation and erythema, frequently accompanied by a sensation of heat. Although often benign, it may signal endocrine, neuroendocrine, autonomic, inflammatory, pharmacologic, or neoplastic disorders. To provide an integrated review of the neuroendocrine and vascular mechanisms underlying flushing and to propose a structured, clinically applicable diagnostic approach based on symptom patterns and pathophysiological pathways. A narrative review of the literature was conducted, focusing on thermoregulatory physiology, neuroendocrine signalling, vascular control, and clinical conditions associated with flushing. Evidence from experimental, observational, and clinical studies was synthesised to develop a mechanistic framework and a stepwise diagnostic algorithm integrating clinical features and targeted laboratory evaluation. Flushing arises from disruption of central thermoregulatory integration involving hypothalamic nuclei, peripheral sensory pathways, and vasoactive mediators, including oestrogens, serotonin, catecholamines, vasoactive intestinal peptide, prostaglandins, substance P, and histamine. Neurotransmitters help modulate the vascular response, which is further influenced by endothelial function and autonomic tone. Flushing is a multifactorial symptom reflecting integrated neuroendocrine and vascular dysregulation rather than an isolated cutaneous phenomenon. Recognising the distinction between wet and dry flushing and applying a mechanism-based diagnostic framework may improve diagnostic accuracy and facilitate earlier identification of clinically important underlying disorders.

All-optical electrophysiology reveals behavior-dependent dynamics of excitation and inhibition in the hippocampus.

Detecting statistical regularities in sound and responding to violations of these patterns, termed deviance detection, is a core function of the auditory system. In the human brain, studies have shown that deviance responses are enhanced in regular compared with random auditory contexts, but the underlying neuronal circuit mechanisms remain unclear. Here, we examined how inhibitory neurons contribute to context-dependent deviance responses in the mouse auditory cortex (AC). Using two-photon calcium imaging in AC of awake head-fixed male and female mice, we recorded neuronal activity during presentation of spectrotemporally rich moving ripple sounds, with deviant ripples embedded in either regular or random ripple sequences. AC neurons exhibited stronger responses to deviant sounds in regular contexts compared with random ones. To identify circuit mechanisms, we selectively inactivated parvalbumin (PV), somatostatin (SST), or vasoactive intestinal polypeptide (VIP) inhibitory neurons during the deviant stimulus presentation. Inactivation of PV and SST neurons broadly increased deviance responses in both contexts. In contrast, VIP inactivation selectively reduced responses to deviant stimuli in the regular, but not random, context, decreasing the context-dependent deviance signal enhancement. At the population level, inactivating all three neuronal subtypes increased detectability of the deviant stimulus, but the effects were context-dependent only for VIP inactivation. These findings reveal the distinct role of VIP neurons in modulating deviance signals based on context regularity, identifying a specific inhibitory neuron type that is critical for context-sensitive auditory processing and predictive coding.

Acute pancreatitis (AP) is a common gastrointestinal condition characterized by inflammation of the pancreas. AP treatment is highly challenging due to the long hospital stays, higher medical expenses, and multiple complications. Traditional Chinese medicine has been used in China for thousands of years and is clinically proven to be a safe and effective treatment strategy for pancreatitis. To investigate whether a da-yuan-yin (DYY) decoction ameliorates inflammatory injury in severe pancreatitis. The severe acute pancreatitis (SAP) model was established by retrograde injection of 5% sodium taurocholate into the bile duct of male Sprague-Dawley rats. We detected the intestinal mucosal barrier function and intestinal immune function, and analyzed the changes of gut flora using the 16S rRNA gene testing. Cell damage was more serious in SAP than that of DYY+SAP. The expression of myeloperoxidase and EGF-like module-containing mucin-like hormone receptor-like 1 in SAP was significantly higher than in DYY+SAP. Serum endotoxin, d-lactate, intestinal fatty acid-binding protein, interleukin (IL)-1β, and IL-10 of SAP and DYY+SAP were significantly increased. Plasma vasoactive intestinal peptide (VIP) was significantly reduced in both SAP and DYY+SAP; plasma VIP in DYY+SAP was significantly lower than in SAP. Levels of CD3+, CD4+, and CD8+ cells from ileal Peyer's patches in SAP and DYY+SAP were decreased; the levels of CD3+, CD4+, and CD8+ cells of DYY+SAP were significantly higher than in SAP. Species difference analysis showed significant differences among the top 10 most relatively abundant species in the sham operation (SO), SAP, and DYY+SAP at each taxonomic level (phylum, class, order, family, and genus). Clustered heat map analysis showed differences in species at the genus level among the SO, SAP, and DYY+SAP. At the phylum level, there were differences in the expression levels of proteobacteria and bactroidota between the SO and SAP, but not among other groups. The DYY decoction may reduce tissue injury, protect the intestinal mucosal barrier, enhance intestinal immune function, and help prevent intestinal dysbiosis in ascitic fluid and stool specimens.

Vasoactive intestinal peptide attenuates form-deprivation myopia in guinea pigs by suppressing the Wnt/β-catenin pathway along the retina-choroid-scleral axis.

BACKGROUND Laparoscopic anterior resection for colorectal cancer often necessitates a temporary protective stoma to mitigate anastomotic-leak risk, yet stoma reversal is frequently delayed by postoperative ileus. Western medicine offers limited pro-motility options, while traditional Chinese medicine (TCM) has shown promise within enhanced-recovery protocols. Modified Da-Cheng-Qi decoction (mDCQD), a purgative- and qi-moving formula, has demonstrated intestinal motility benefits, but its specific impact on stoma-reversal timing remains unexamined. We undertook a retrospective study to determine whether mDCQD accelerates stoma closure and reduces postoperative ileus after laparoscopic colorectal resection with protective stoma. AIM To investigate the effect of mDCQD on stoma reversal time and incidence of postoperative ileus after laparoscopic anterior resection for colorectal cancer. METHODS A retrospective analysis was conducted on 283 patients who underwent laparoscopic anterior resection for colorectal cancer with prophylactic stoma at our hospital from January 2022 to August 2024. According to whether mDCQD was used postoperatively, patients were divided into observation group (132 cases) and control group (151 cases). The control group received conventional treatment postoperatively, while the observation group received oral mDCQD (raw rhubarb 12 g, mirabilite 10 g, immature bitter orange 15 g, magnolia bark 15 g, radish seed 15 g, aucklandia root 10 g, areca seed 10 g, cannabis seed 15 g) starting from postoperative day 2-3 (the day of gastric tube removal) in addition to conventional treatment, twice daily, 150 mL each time, continued until anal gas passage and defecation. Observation indicators included stoma reversal time, incidence of postoperative ileus, time to first anal gas passage, time to first defecation, time to bowel sound recovery, TCM symptom scores, quality of life scores European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30), gastrointestinal hormone levels [motilin (MTL), gastrin (GAS), vasoactive intestinal peptide (VIP)], and inflammatory and nutritional indicators [C-reactive protein (CRP), procalcitonin (PCT), albumin (ALB), prealbumin (PA)]. Kaplan-Meier method and Cox proportional hazards regression model were used to analyze factors affecting stoma reversal time. RESULTS The stoma reversal time in the observation group was 118.5 ± 23.7 days, shorter than 142.8 ± 28.4 days in the control group (t = 7.623, P < 0.001). The incidence of postoperative ileus in the observation group was 6.1% (8/132), lower than 18.5% (28/151) in the control group (χ 2 = 10.245, P = 0.001). The time to first anal gas passage (52.3 ± 10.8 hours vs 68.7 ± 14.2 hours), time to first defecation (78.6 ± 15.3 hours vs 96.4 ± 18.7 hours), and time to bowel sound recovery (38.2 ± 8.5 hours vs 51.6 ± 11.3 hours) in the observation group were all shorter than those in the control group (P < 0.001). On postoperative days 5 and 7, TCM symptom scores in the observation group were lower than those in the control group (P < 0.001). At 3 months after stoma surgery, the EORTC QLQ-C30 overall health status score in the observation group was 68.5 ± 11.7 points, higher than 62.3 ± 13.2 points in the control group (t = 4.19, P < 0.001). On postoperative days 5 and 7, MTL and GAS levels in the observation group were higher than those in the control group, while VIP levels were lower (P < 0.001); CRP and PCT levels in the observation group were lower than those in the control group, while ALB and PA levels were higher (P < 0.05). Multivariate Cox regression analysis showed that the use of mDCQD was an independent factor for shortening stoma reversal time (hazard ratio = 2.147, 95% confidence interval: 1.658-2.781, P < 0.001). CONCLUSION mDCQD can shorten stoma reversal time after laparoscopic anterior resection for colorectal cancer, reduce the incidence of postoperative ileus, promote intestinal function recovery, and improve patients’ quality of life. It is a safe and effective integrated traditional Chinese and Western medicine treatment method.

Objective: This study aimed to investigate the therapeutic effects and underlying mechanisms of Tiaozang Shumi Mixture for treating chronic constipation. Methods: Network pharmacology identified active components of Tiaozang Shumi Mixture and their targets via the Traditional Chinese Medicine Systems Pharmacology (TCMSP). Core targets were screened through protein–protein interaction (PPI) network analysis using STRING and Cytoscape. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed with Database for Annotation, Visualization, and Integrated Discovery (DAVID), and molecular docking of core components with targets was validated using AutoDock and PyMOL. In animal studies, 60 male C57 mice were randomly divided into normal control, model, positive control, and low-, medium-, and high-dose Tiaozang Shumi Mixture groups. Results: A total of 151 active compounds and 924 potential targets were obtained through comprehensive database screening and target mapping, yielding 298 potential therapeutic targets and six core targets. In comparison to the model group, Tiaozang Shumi Mixture significantly reduced the time to first black stool, increased defecation frequency and fecal water content, and enhanced small intestinal propulsion in the animal model ( p < 0.01). The mixture ameliorated colonic histopathological injury, elevated serum 5-hydroxytryptamine (5-HT) concentrations, and reduced vasoactive intestinal peptide (VIP), nitric oxide (NO), and aquaporin-3 (AQP3) expression levels ( p < 0.05), whereas gastrin levels demonstrated no significant difference. Conclusion: Tiaozang Shumi Mixture effectively improved constipation symptoms in mice. The underlying mechanism may involve modulation of the PI3K-Akt signaling pathway and regulation of 5-HT, VIP, NO, and AQP3 expression, thereby promoting intestinal motility.

In nasopharyngeal carcinoma, mitochondria often function abnormally. However, the precise signals that cause excessive mitochondrial division are still undefined. Levels of the neuropeptide Vasoactive Intestinal Peptide are altered in NPC tissues. How VIP influences the metabolic behavior of cancer cells is not well established. Our experiments utilized established NPC cell lines. We tested how physiological concentrations (10-100 nM) of VIP exposure affect survival and mitochondrial integrity. Morphology was analyzed using fluorescence staining. We measured functional outputs, including reactive oxygen species, ATP levels, and membrane potential. Immunoblotting and activity assays helped trace the involved molecular events. Both genetic knockdown and a highly selective pharmacological inhibitor confirmed the proposed mechanism. To address pathway generality, experiments were repeated in an additional NPC line (NPC‑TW02). Receptor identity was probed using siRNA against VPAC1 and VPAC2. Selectivity for cancer cells was tested in normal nasopharyngeal epithelial NP69 cells. Administering VIP at 10-100 nM increased oxidative stress within mitochondria in a concentration-dependent manner. The transmembrane potential collapsed. Activity of the electron transport chain's Complex IV was suppressed, and cellular ATP content diminished. These failures led to pronounced mitochondrial fragmentation. VIP treatment (100 nM) rapidly activated the kinase PKCδ. PKCδ then phosphorylated the fission protein Drp1 at serine 616, causing Drp1 to accumulate at mitochondria. When we applied the compound Rottlerin to inhibit PKCδ, it effectively blocked Drp1 modification and recruitment. Consequently, mitochondrial fragmentation was prevented and energy metabolism recovered. These findings were confirmed in NPC‑TW02 cells. VPAC1 silencing, but not VPAC2 silencing, blocked VIP effects in C666-1 cells. Normal NP69 cells showed no significant response to VIP under the tested conditions. This work defines a previously unrecognized VIP-PKCδ-Drp1 pathway that operates at physiologically relevant VIP concentrations and controls mitochondrial division and fitness in NPC cells. This signaling axis highlights a specific metabolic weak point in these tumors. Our results suggest PKCδ could be investigated as a candidate target for therapies designed to correct mitochondrial dysfunction in nasopharyngeal carcinoma.

Behavioral trade-offs, such as between territorial aggression and parental care, require coordination among neural and genetic mechanisms that influence opposing phenotypes. In some systems, including the white-throated sparrow, this coordination has been proposed to be mediated in part by chromosomal inversions that bind together multiple genes associated with alternative strategies. Here, we demonstrate that opposing components of a life-history trade-off can be linked, via alternative alleles inside a chromosomal rearrangement, to a single pleiotropic gene. In white-throated sparrows, a species with polymorphic aggressive and parental behavior, the gene encoding the neuromodulator vasoactive intestinal peptide (VIP) lies within an inversion-based supergene. Working with a free-living population, we found that VIP expression in a pro-aggression cell population in the anterior hypothalamus positively predicted territorial singing, whereas expression in a pro-parental cell population in the infundibular nucleus positively predicted parental provisioning. Expression in these two regions was negatively correlated, consistent with opposing behavioral roles. Allele-specific analyses revealed stronger expression bias toward the supergene-associated allele in the anterior hypothalamus than in the infundibular nucleus. These findings suggest that chromosomal inversions can support opposing behavioral phenotypes not only by linking multiple genes, but also by driving regulatory divergence of individual genes that organize behavioral trade-offs.

The aim of this study was to investigate the effects of acupuncture on a rat model of chronic migraine (CM) and explore the underlying mechanism of action from the perspective of the gut-brain axis. A total of 24 male Sprague-Dawley (SD) rats were randomly allocated into control, model and acupuncture groups (n = 8 each). The CM model was established by intraperitoneal injection of nitroglycerin (NTG). Acupuncture was administered at GV20 and bilateral PC6/LR3/ST36 for rats in the acupuncture group once a day for 9 days. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of 5-hydroxytryptamine (5-HT), calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP) in plasma. A combination of 16S rDNA sequencing and liquid chromatography-mass spectrometry (LC-MS) metabolomics was adopted to investigate the role of the gut-brain axis in migraine chronification and the effect of acupuncture on CM. Acupuncture treatment significantly attenuated hyperalgesia in CM model rats and regulated serum levels of brain-gut peptides, including 5-HT, CGRP and VIP. Furthermore, the gut microbial community structure and metabolic profile changed in CM rats and acupuncture impacted the changes. Notably, acupuncture modulated 10 gut microbial genera and 13 fecal metabolites. These findings suggest that the gut-brain axis may play an important role in the chronification of migraine, and the regulation of gut microbiota and metabolites may be one of the mechanisms underlying the analgesic effect of acupuncture in CM.

Osteoprotective effects of the neuropeptide VIP: insights from triple cultures of human osteocytes, osteoblasts, and osteoclasts.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory decline, cognitive impairment, and behavioral changes, ultimately leading to a loss of independence and reduced quality of life. Although understanding of the molecular basis of AD has advanced, effective disease-modifying therapies remain scarce. Neuropeptides are small protein-like signaling molecules that regulate diverse physiological processes, including mood, memory, and neuronal function. Growing evidence indicates that neuropeptides are promising therapeutic candidates for AD, particularly through modulation of neuroinflammation, synaptic plasticity, and amyloid-beta (Aβ) aggregation. Preclinical AD models show that neuroprotective neuropeptides, such as neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating peptide (PACAP), exert neuroprotective effects, enhance memory, and attenuate cognitive decline. This review summarizes current research on neuropeptide-based therapies for AD, detailing their molecular mechanisms, therapeutic actions, and the barriers to their clinical translation. We specifically highlight neuropeptides whose clinical potential in AD remains comparatively underrecognized, discuss strategies for optimizing their delivery and overcoming pharmacokinetic limitations, and outline future perspectives for integrating neuropeptide-based interventions into AD therapy.

Constipation has emerged as an important public health concern, and novel therapeutic approaches, such as those, are attracting increasing attention. However, the effects and mechanisms of Bifidobacterium breve and lacto-N-neotetraose (LNnT) in relieving constipation remain incompletely understood. Moreover, the potential synergistic effects of B. breve and LNnT in alleviating constipation are still unclear. In this study, we used 4-wk-old female BALB/c mice (n = 60), which were randomly assigned to normal control (NC) group, model control (MC) group, LNnT group, B. breve group, and B. breve+LNnT group. We evaluated the effects of B. breve+LNnT on defecation performance and intestinal mucus secretion. We also analyzed gut microbiota composition and metabolic functions. Additionally, an independent cohort of 45 mice was used to assess the effect of gut microbiota and microbiota-derived metabolites on constipation. The results demonstrated that B. breve+LNnT increased the gastrointestinal transit rate and fecal water content while reducing whole-gut transit time. It also elevated serum concentrations of gastrin (GAS) and motilin (MLT) while decreasing those of vasoactive intestinal peptide (VIP) and nitric oxide (NO). Mice receiving B. breve+LNnT showed increased intestinal mucus content, a more organized mucus layer structure, and higher expression of mucus-related genes (Muc2, Agr2, Muc1, Muc4, Muc13). Additionally, B. breve+LNnT increased gut microbiota diversity and enriched potentially beneficial microbiota, including Ruminococcus, Bifidobacterium, Tyzzerella, and Roseburia. Consistently, levels of the acetate and propionate were elevated in the B. breve+LNnT group. Correlation analysis indicated positive associations between these microbiota and acetate. Finally, we explored the role of gut microbiota, acetate, and propionate in constipation. We found that the alleviation of constipation by B. breve+LNnT depended on the presence of gut microbiota and was associated with microbiota-derived acetate.

Altered responsiveness to photic stimuli contribute to circadian disruption in cystic fibrosis.

Serotonergic and glutamatergic mechanisms converge in ketamine's rapid responses.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with diverse genetic and environmental origins, yet whether these factors converge on common molecular pathways remains unclear. This study identifies dysregulation of the Notch signaling pathway as a shared mechanism in both hereditary and nonhereditary ASD models. Aberrant histone deacetylase 3-mediated epigenetic regulation of Notch signaling during embryonic forebrain development disrupts the specification of vasoactive intestinal peptide (VIP + ) GABAergic interneuron subtypes (VIP-INs), which originate in the caudal ganglionic eminence (CGE). CGE-specific ablation of Notch1/2 genes in ASD models restores the loss of VIP-INs, normalizes maladaptive excitatory and inhibitory balance, and selectively improves social behaviors. A single antenatal dose of a γ-secretase inhibitor ameliorates multiple ASD-associated neuronal, behavioral, and transcriptomic changes in adult models. The study indicates a strong convergence of ASD-related factors on Notch signaling dysregulation and establishes this pathway as a promising therapeutic target for developmental and behavioral deficits in ASD.

Renal cell carcinoma (RCC) is a common urologic malignancy with limited treatment options. The neuropeptide vasoactive intestinal peptide (VIP) regulates diverse biological processes by binding to VPAC1 and VPAC2 receptors, but its role in RCC remains unclear. The proliferation of RCC Caki-1 cells was evaluated using the Cell Counting Kit-8 (CCK-8), while lactate dehydrogenase (LDH) and γ-glutamyl transpeptidase (γ-GPT) release were measured using commercial kits. Reactive oxygen species (ROS) levels were analyzed via dihydroethidium (DHE) staining. Superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels were quantified using commercial assay kits. Autophagy was assessed through monodansylcadaverine (MDC) staining, and the expression levels of related mRNAs and proteins were quantified by RT-PCR and Western blotting, respectively. VIP treatment (0-50 μM) exhibited dose-dependent cytotoxic effects, including reduced cell viability, increased LDH and γ-GPT release, and induction of oxidative stress as evidenced by elevated ROS and MDA levels with concomitant decrease in SOD2 activity. At concentrations of 5-10 μM, VIP induced autophagic responses characterized by enhanced MDC staining, increased microtubule-associated protein 1 light chain 3 (LC3)-II/LC3-I ratio, upregulated Beclin1 expression, and accelerated p62 degradation. Mechanistically, VIP-mediated autophagy was associated with sirtuin 3 (SIRT3) downregulation and increased Ac-FOXO1 levels, with SIRT3 overexpression effectively counteracting the VIP-induced autophagic effects. Our findings demonstrate that VIP induces both cytotoxic effects and autophagy in VPAC1-expressing RCC cells through modulation of the SIRT3/FOXO1 signaling pathway, highlighting its potential therapeutic value for renal cell carcinoma.

Chronic pain exhibits circadian rhythms in humans, but the mechanisms underlying such rhythmicity remain unclear. Here, we found daily oscillations in the nociceptive thresholds in a mouse model of neuropathic pain, driven by a rhythmic circuit from the master clock in the hypothalamus to the descending analgesia system. In the daytime (resting phase), higher vasoactive intestinal peptide (VIP) neuronal activity in suprachiasmatic nucleus (SCNVIP) activates a signaling pathway involving the paraventricular nucleus (PVN) and the ventrolateral periaqueductal gray (vlPAG), ultimately increasing nociceptive sensitivity. At night (active phase), reduced SCNVIP neuronal activity decreases pain sensitivity through this polysynaptic circuit. This study identified a circuit for regulating pain rhythmicity that might be targeted to improve chronic pain management.

Refractory allergic rhinitis (RAR) encompasses distinct immune-inflammatory endotypes, notably neurogenic and eosinophilic phenotypes, which may differentially respond to surgical intervention such as posterior nasal neurectomy (PNN). Identifying prognostic biomarkers to guide patient selection remains an unmet clinical need. In this retrospective cohort study, 92 patients with moderate-to-severe RAR undergoing endoscopic PNN were stratified by 1-year outcome (effective: ≥50% improvement in Total Nasal Symptom Score [TNSS]). Preoperative serum levels of neuropeptides (Substance P, SP; Vasoactive Intestinal Peptide, VIP) were measured. Postoperative histopathological tissue eosinophil (TEos) counts (cells/HPF) from resected nasal mucosa were analyzed. Patients were categorized into Low-TEos (<10/HPF) and High-TEos (≥10/HPF) groups. The overall effective rate was 88.0%. The effective group exhibited significantly higher preoperative SP (56.4±12.1 vs. 38.2±9.5 pg/mL, P<0.001) and lower TEos counts (6.5±3.2 vs. 18.4±6.7 cells/HPF, P<0.001). Low TEos count strongly correlated with greater TNSS improvement (r=-0.62, P<0.001). Multivariate analysis identified High-TEos as an independent risk factor for poor outcome (OR=4.25, 95% CI: 1.56-11.58, P=0.005). ROC analysis confirmed TEos as a robust prognostic predictor (AUC=0.845, cutoff 11.5 cells/HPF). High tissue eosinophilia defines an immune-endotypic subset of RAR with attenuated response to PNN, whereas a neurogenic-dominant profile (high SP, low TEos) predicts excellent surgical prognosis. TEos count serves as a clinically actionable histopathological prognostic biomarker, facilitating personalized surgical management through immune-endotype stratification.