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Sensory neurons sense pathogenic infiltration to drive innate immune responses, but their role in humoral immunity is unclear. Here, using mouse models of Streptococcus pneumoniae infection and Alternaria alternata asthma, we show that sensory neurons are required for B cell recruitment and antibody production. In response to S. pneumoniae, sensory neuron depletion increases bacterial burden and reduces B cell numbers, IgG release, and neutrophil stimulation. Meanwhile, during A. alternata-induced airway inflammation, sensory neuron depletion decreases B cell population sizes, IgE levels, and asthmatic characteristics. Mechanistically, during bacterial infection, sensory neurons preferentially release vasoactive intestinal polypeptide (VIP). In response to asthma, sensory neurons release substance P. Administration of VIP into sensory neuron-depleted mice suppresses bacterial burden, while VIPR1 deficiency increases infection. Similarly, exogenous substance P delivery aggravates asthma in sensory neuron-depleted mice, while substance P deficiency ameliorates asthma. Our data, thus demonstrate that sensory neurons release select neuropeptides which target B cells dependent on the immunogen.

The pig is an important translational model for studying intestinal physiology and disorders for its many homologies with humans, including the organization of the enteric nervous system (ENS), the major regulator of gastrointestinal functions. This study focused on the quantification and neurochemical characterization of substance P (SP) neurons in the pig ascending (AC) and descending colon (DC) in wholemount preparations of the inner submucosal plexus (ISP), outer submucosal plexus (OSP), and myenteric plexus (MP). We used antibodies for the pan-neuronal marker HuCD, and choline acetyltransferase (ChAT) and neuronal nitric oxide synthase (nNOS), markers for excitatory and inhibitory transmitters, for multiple labeling immunofluorescence and high-resolution confocal microscopy. The highest density of SP immunoreactive (IR) neurons was in the ISP (222/mm2 in the AC, 166/mm2 in the DC), where they make up about a third of HuCD-IR neurons, compared to the OSP and MP (19-22% and 13-17%, respectively, P

Key points Intrinsic cardiac neurons (ICNs) play a crucial role in the proper functioning of the heart; yet a paucity of data pertaining to human ICNs exist. We took a multidisciplinary approach to complete a detailed cellular comparison of the structure and function of ICNs from mice, pigs and humans. Immunohistochemistry of whole and sectioned ganglia, transmission electron microscopy, intracellular microelectrode recording and dye filling for quantitative morphometry were used to define the neurophysiology, histochemistry and ultrastructure of these neurons across species. The densely packed, smaller ICNs of mouse lacked dendrites, formed axosomatic connections and had high synaptic efficacy constituting an obligatory synapse. At pig ICNs, a convergence of subthreshold cholinergic inputs onto extensive dendritic arbors supported greater summation and integration of synaptic input. Human ICNs were tonically firing, with synaptic stimulation evoking large suprathreshold EPSPs like mouse, and subthreshold potentials like pig. Ultrastructural examination of synaptic terminals revealed conserved architecture, yet small clear vesicles were larger in pigs and humans. The presence and localization of ganglionic neuropeptides was distinct, with abundant vasoactive intestinal polypeptide observed in human but not pig or mouse ganglia, and little substance P or calcitonin gene‐related peptide in pig ganglia. Action potential waveforms were similar, but human ICNs had larger after‐hyperpolarizations. Intrinsic excitability differed; 95% of human neurons were tonic, all pig neurons were phasic, and both phasic and tonic phenotypes were observed in mouse. In combination, this publicly accessible, multimodal atlas of ICNs from mice, pigs and humans identifies similarities and differences in the evolution of ICNs. Intrinsic cardiac neurons (ICNs) are essential to the regulation of cardiac function. We investigated the neurochemistry, morphology, ultrastructure, membrane physiology and synaptic transmission of ICNs from donated human hearts in parallel with identical studies of ICNs from mice and pigs to create a publicly accessible cellular atlas detailing the structure and function of these neurons across species. In addition to presenting foundational data on human ICNs, this comparative study identifies both conserved and derived attributes of these neurons within mammals. The findings have significant implications for understanding the regulation of cardiac autonomic function in humans and may greatly influence strategies for neuromodulation in conditions such as atrial fibrillation and heart failure. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental Approach Key Results Conclusions and Implications Opioid drugs are potent analgesics that carry the risk of respiratory side effects due to actions on μ‐opioid receptors (MORs) in brainstem regions that control respiration. Substance P is encoded by the Tac1 gene and is expressed in neurons regulating breathing, nociception, and locomotion. Tac1‐positive cells also express MORs in brainstem regions mediating opioid‐induced respiratory depression. We determined the role of Tac1‐positive cells in mediating the respiratory effects of opioid drugs.In situ hybridization was used to determine Oprm1 mRNA expression (gene encoding MORs) in Tac1‐positive cells in regions regulating respiratory depression by opioid drugs. Conditional knockout mice lacking functional MORs in Tac1‐positive cells were produced and the respiratory and locomotor responses to the opioid analgesic fentanyl were assessed using whole‐body plethysmography. A tail immersion assay was used to assess the antinociceptive response to fentanyl.Oprm1 mRNA was highly expressed (>80%) in subpopulations of Tac1‐positive cells in the preBötzinger Complex, nucleus tractus solitarius, and Kölliker–Fuse/lateral parabrachial region. Conditionally knocking out MORs in Tac1‐positive cells abolished the effects of fentanyl on respiratory rate, relative tidal volume, and relative minute ventilation compared with control mice. Importantly, the antinociceptive response of fentanyl was eliminated in mice lacking functional MORs in Tac1‐positive cells, whereas locomotor effects induced by fentanyl were preserved.Our findings suggest that Tac1‐positive cells mediate the respiratory depressive and antinociceptive effects of the opioid fentanyl, providing important insights for the development of pain therapies with reduced risk of respiratory side effects. [ABSTRACT FROM AUTHOR]

The operation of the retina, like other brain circuits, is under modulatory control. One coordinator of changes in retinal function is dopamine, a neuromodulator released in a light-dependent way to adjust vision on a diurnal cycle. Here, we demonstrate that substance P is a similarly powerful retinal modulator that interacts with the dopamine system. By imaging glutamatergic synaptic transmission in larval zebrafish, we find that substance P decreases the contrast sensitivity of ON and OFF visual channels up to 8-fold, with suppression of visual signals being strongest through the "transient" pathway responding to higher frequencies. These actions are exerted in the morning, in large part by suppressing the amplification of visual signals by dopamine, but substance P is almost completely inactive in the afternoon. Modulation of retinal gain is accompanied by changes in patterns of vesicle release at the synapses of bipolar cells: increased gain shifts coding of stimulus strength from the rate of release events to their amplitude generated by a process of multivesicular release (MVR). Together, these actions of substance P reduce the flow of visual information, measured in bits, ∼3-fold. Thus, whereas dopamine "pushes" the retina to transmit information at higher rates in the afternoon, substance P acts in antiphase to suppress dopamine signaling and "pull down" information transmission in the morning. • Substance P (SP) decreases gain of zebrafish retina and blocks transient pathway • SP acts in the morning and suppresses signal amplification by dopamine • SP adjusts the way vesicles encode stimulus strength at bipolar cell synapses • SP and dopamine interact to adjust diurnal flow of visual information José Moya-Díaz et al. demonstrate that substance P is a powerful retinal modulator that interacts with the dopamine system. While dopamine "pushes" the retina to transmit visual signals at high gain in the afternoon, substance P acts in antiphase to suppress dopamine signaling and "pull down" information transmission in the morning. [ABSTRACT FROM AUTHOR]

Microplastic is an environmental hazard to which both animals and humans are exposed. Current reports show that it can cause inflammation, including in the gastrointestinal tract. To examine the impact on the ileum, 15 eight-week-old gilts (five individuals/group) were exposed to PET microplastics (7.6 µm–416.9 µm) at a dose of 0.1 g/day or 1 g/day for 28 days. The collected ileum fragments were investigated for the cytokine concentrations (IL-1β, IL-6, IL-8, IL-10, and TNF-α; ELISA test), neuron populations (cocaine and amphetamine-regulated transcript, galanin, neuronal nitric oxide synthase, substance P, vesicular acetylcholine transporter, and vasoactive intestinal peptide; immunofluorescence staining), and morphometric parameters (histological analysis). Under the influence of MP-PET, there was a reduction in the populations of CART- and GAL-positive neurons in the submucosal plexuses and of nNOS-, VAChT-, and VIP-positive neurons in all the plexuses. In contrast, there was an increase in GAL-positive neurons in the myenteric plexus and SP-positive neurons in all the plexuses. The concentrations of IL-1β, IL-6, IL-8, IL-10, and TNF-α did not undergo statistically significant changes under the influence of the low or high dose of MP-PET. The changes in the histological structure exclusively concerned the thinning of the mucosa and the muscularis externa. The results support the thesis that MP-PET is not neutral to the ileal cells. [ABSTRACT FROM AUTHOR]

Introduction: Because MRGPRX2 is now recognized as the mast cell receptor for basic secretagogues, there is currently a tremendous interest in whetherMRGRPX2 could play an important role in various pruritic dermatoses such as chronic spontaneous urticaria. Therefore, we sought to identify new potent and selective antagonists to pharmacologically characterize the biological role of MRGPRX2. Methods: Various relevant in vitro, ex vivo, and in vivo model systems were used to investigate the role of MRGPRX2. This included the study of freshly isolated human skin mast cells and human basophils as well as an ex vivo human skin microdialysis preparation. The additivity of MRGPRX2 and FceR1-mediated degranulation was also investigated. Human MRGPRX2 knock-in mice were generated to interrogate pharmacokinetic/pharmacodynamic relationships because both antagonists studied were shown to be human specific. Results: Two novel and structurally distinct MRGPRX2 antagonists were identified with one, Compound B, being orally active and demonstrating high potency in blocking Substance P-mediated degranulation using freshly isolated human skin mast cells with half maximal inhibitory concentration (IC50) at 0.42 nM. Compound B also potently blocked Substance P-stimulated histamine release from resident mast cells in a human skin explant setup as well as blocking itch in an established behavioral scratching model using MRGPRX2 knock-in mice. Unlike human mast cells, Substance P failed to elicit a functional response in human basophils. Conclusion: These data fully support the investigation of MRGPRX2 receptor antagonists in mast cell-driven allergic skin disorders such as chronic spontaneous urticaria. [ABSTRACT FROM AUTHOR]

Introduction: Allergic asthma has been linked to the activation of mast cells (MCs) by the neuropeptide substance P (SP), but the mechanism underlying this neuroimmune interaction is unknown. Substance P produced from cutaneous nociceptors activates MCs via Mas-related G-protein-coupled receptor B2 (MrgprB2) to enhance type 2 immune response in experimental atopic dermatitis in mice. We recently showed that the adapter protein β-arrestin2 (β-arr2) contributes to MrgprB2-mediated MC chemotaxis. The goals of this study were to determine if MrgprB2 facilitates neuroimmune interaction in IgE (FcεRI)-mediated allergic airway inflammation (AAI) and to assess if this response is modulated by β-arr2. Methods: Wild-type (WT), MrgprB2−/− mice and mice with MC-specific deletion of β-arr2 (Cpa3Cre+/β-arr2fl/fl) were passively sensitized with anti-TNP-IgE and challenged with antigen. The generation of SP and MC recruitment in the lung were determined by immunofluorescence and toluidine blue staining, respectively. The transcripts for Tac1, MrgprB2, TNF-α, and Th2 cytokines in lung tissue were assessed by RT-PCR, and the release of selected cytokines in bronchoalveolar lavage (BAL) was determined by ELISA. Eosinophil and neutrophil recruitment in lung tissue and BAL were determined by immunofluorescence staining and flow cytometry, respectively. Goblet cell hyperplasia was determined by periodic acid–Schiff staining. Results: Following IgE sensitization and antigen challenge in WT mice, SP generation, and MC recruitment, transcripts for Tac1, MrgprB2, TNF-α, and Th2 cytokine were upregulated when compared to the control challenge. TNF-α, Th2 cytokine production, eosinophil/neutrophil recruitment, and goblet cell hyperplasia were also increased. These responses were significantly reduced in MrgprB2−/− and Cpa3Cre+/β-arr2fl/fl mice. Discussion: The data presented herein suggest that SP-mediated MrgprB2 activation contributes to AAI and goblet cell hyperplasia in mice. Furthermore, these responses are modulated by β-arr2, which promotes MC recruitment to facilitate their activation through FcεRI. [ABSTRACT FROM AUTHOR]

AIM: This study aimed to observe the analgesic effects of Hegu acupoint catgut embedding in a rat model of labor and investigate its influence on biomarkers such as calcitonin gene-related peptide （CGRP） signals at the Hegu acupoint. METHODS: Thirty-six pregnant rats were randomly divided into three groups: control group, Hegu acupuncture group, and Hegu catgut embedding group. Pain threshold changes were assessed using the tail immersion test and paw withdrawal thermal latency at four time points: pre-induction, before the onset of labor, at the onset of labor, and at the mid-stage of labor. Tissue samples from the Hegu acupoint were collected at the mid-stage of labor to detect the expression of CGRP, substance P （SP）, and mast cells using immunofluorescence. The concentrations of ATP and adenosine were measured using ELISA. RESULTS: Before labor induction, there was no significant difference in tail immersion test and paw withdrawal thermal latency among the three groups （P>0. 05）. Before the onset of labor, both the acupuncture and catgut embedding groups exhibited significantly higher tail-flick times and paw withdrawal latencies compared to the control group （P<0. 05）. At labor initiation and mid-labor, the catgut embedding group had significantly higher tail-flick times and paw withdrawal latencies compared to both the control and acupuncture groups （P<0. 05）. During mid-labor, the expression of CGRP, SP, mast cells, ATP, and adenosine concentrations in the catgut embedding group was significantly higher than that in the control and acupuncture groups （P<0. 05）, with co-expression of CGRP, SP, and mast cells observed. CONCLUSION: Hegu acupoint catgut embedding effectively alleviates labor pain, and its mechanism may involve increased local expression of CGRP and SP, promoting mast cell degranulation, and increasing ATP release and its conversion to adenosine. [ABSTRACT FROM AUTHOR]

Objective: To explore the potent effects of denatonium benzoate (DB) on Mas-related G protein-coupled receptor-B2(MrgprB2)-mediated rat mast cell degranulation. Methods: RBL-2H3 cells were treated with DB overnight, before challenged with MrgprB2 ligands substance P (SP). The release of β-hex from MrgprB2-activated RBL-2H3 was detected by substrate method. Detection of LTC4, IL-6, TNF-α and cPLA2 activity were performed by ELISA. The Ca2+ influx and the expression of RBL-2H3 MrgprB2 receptors were measured by fluorescence assay. Results: The results showed 10 µmol/L, 50 µmol/L, 80 µmol/L, 100 µmol/L DB treatments promoted β-hex and LTC4 releases from activated RBL-2H3, accompanied by increased Ca2+ mobilization and cPLA2 activation. DB treatments did not affect IL-6 and TNF-α LTC4 releases in MrgprB2-activated RBL-2H3, as well as the levels of MrgprB2 expression in mast cells. Conclusion: Taken together, DB enhanced the MrgprB2-mediated RBL-2H3 degranulation in vitro, probably by up-regulating Ca2+ mobilization in activated cells. [ABSTRACT FROM AUTHOR]

Stigma maydis polysaccharide (SMPS) has regulatory effect on the intestinal microflora and promotes gastrointestinal peristalsis. Children with autism spectrum disorder (ASD) often experience gastrointestinal problems and dysbiosis in their gut microbiota. Our previous study revealed that SMPS interventions had an impact on the gut microbiota of valproic acid (VPA)‐induced autism model rats. However, the effects of SMPS on the behavior and gut function of autism model rats remain poorly understood. Therefore, we gave different doses of SMPS intervention in the early stage of autism model rats to observe their developmental conditions and behavior performances. Through histological evaluation and real‐time polymerase chain reaction (PCR), integrity of the intestinal structure and the expression of tight junction‐related gene Zo‐1 and Occludin were detected. The results indicated that SMPS intervention improved the physical development, learning and memory impairment, and social performance of autism model rats. Meanwhile, SMPS promoted intestinal peristalsis and restored the integrity of the intestinal structure, reduced the number of inflammatory cells, and increased the expression of the Zo‐1 and Occludin genes. Furthermore, the expression levels of neurotransmitters (substance P, enkephalin, vasoactive intestinal peptide, and 5‐hydroxytryptamine) in the hippocampal tissues were altered after SMPS treatment. In conclusion, SMPS could ameliorate ASD‐like phenotypes and gut problems in autism model rats. Collectively, these results provide new evidence for the relationship between the gut‐brain axis and ASD and suggest a novel therapeutic target for ASD treatment. [ABSTRACT FROM AUTHOR]

Changes in microcirculation lead to the progression of organ pathology in diabetes. Although neuroimmune interactions contribute to a variety of conditions, it is still unclear whether abnormal neural activities affect microcirculation related to diabetes. Using laser speckle contrast imaging, we examined the skin of patients with type 2 diabetes and found that their microvascular perfusion was significantly compromised. This phenomenon was replicated in a high-fat diet–driven murine model of type 2 diabetes–like disease. In this setting, although both macrophages and mast cells were enriched in the skin, only mast cells and associated degranulation were critically required for the microvascular impairment. Sensory neurons exhibited enhanced TRPV1 activities, which triggered mast cells to degranulate and compromise skin microcirculation. Chemical and genetic ablation of TRPV1+ nociceptors robustly improved skin microcirculation status. Substance P (SP) is a neuropeptide and was elevated in the skin and sensory neurons in the context of type 2 diabetes. Exogenous administration of SP resulted in impaired skin microcirculation, whereas neuronal knockdown of SP dramatically prevented mast cell degranulation and consequently improved skin microcirculation. Overall, our findings indicate a neuron–mast cell axis underlying skin microcirculation disturbance in diabetes and shed light on neuroimmune therapeutics for diabetes-related complications. Article Highlights: Impaired microcirculation is a shared feature of various complications in type 2 diabetes. Mechanisms underlying its pathology remain not fully identified. Compared with internal organs, the skin is superficial and accessible for microcirculation observation. The role neuroimmune elements play in skin microcirculation impairment associated with type 2 diabetes was investigated. Sensory neurons are hypersensitized in diabetes and induce overexpression of substance P, which triggers mast cell degranulation and consequently impairs skin microcirculation. Neuroimmune modulation sheds light on new strategies for treating microcirculation disturbance in type 2 diabetes. [ABSTRACT FROM AUTHOR]

Phosphorus (P), an essential macronutrient for various plant processes, is generally a limiting soil component for crop growth and yields. Organic and inorganic types of P are copious in soils, but their phyto-availability is limited as it is present largely in insoluble forms. Although phosphate fertilizers are applied in P-deficit soils, their undue use negatively impacts soil quality and the environment. Moreover, many P fertilizers are lost because of adsorption and fixation mechanisms, further reducing fertilizer efficiencies. The application of phosphate-solubilizing microorganisms (PSMs) is an environmentally friendly, low-budget, and biologically efficient method for sustainable agriculture without causing environmental hazards. These beneficial microorganisms are widely distributed in the rhizosphere and can hydrolyze inorganic and organic insoluble P substances to soluble P forms which are directly assimilated by plants. The present review summarizes and discusses our existing understanding related to various forms and sources of P in soils, the importance and P utilization by plants and microbes,, the diversification of PSMs along with mixed consortia of diverse PSMs including endophytic PSMs, the mechanism of P solubilization, and lastly constraints being faced in terms of production and adoption of PSMs on large scale have also been discussed. [ABSTRACT FROM AUTHOR]

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[Display omitted] • Inflammatory arthritis can cause peripheral nerve sensitization. • GBP can intervene in peripheral nerve sensitization caused by inflammatory arthritis. • NR2B may be the cause of peripheral sensitization in inflammatory arthritis. • GBP may alleviate pain through the downregulation of NR2B. • This study provides a theoretical basis for the inflammatory arthritis. Inflammatory arthritis leads to peripheral nerve sensitization, but the therapeutic effect is often unsatisfactory. Our preliminary studies have found that in mice with inflammatory arthritis, the use of ionotropic glutamate receptor antagonists can produce a good analgesic effect without altering foot swelling, suggesting that pain relief may be related to the improvement of neuropathic pain. However, the underlying mechanisms remain unclear. To further investigate the effects of neuropathic pain medications on inflammatory arthritis and the impact of the ionotropic glutamate receptor NR2B subunit (NR2B) on inflammatory arthritis, this study employed gabapentin (GBP) treatment on the inflammatory arthritis mouse model (the adjuvant induced arthritis, AIA), and we found a significant reduction in pain. Further studies revealed that in AIA, the expression levels of NR2B, TRPV1, pain-related molecules (substance P, PGE 2), inflammatory cytokines (IL-1, IL-6, TNF-α, and GM-CSF) and Ca2+ were elevated in the foot and dorsal root ganglia (DRG). GBP treatment was able to influence the downregulation of the expression levels of NR2B, TRPV1, pain-related molecules, inflammatory cytokines and Ca2+. Mechanistic studies have shown that GBP treatment affects the downregulation of NR2B, and the downregulation of NR2B expression leads to the downregulation of TRPV1, pain-related molecules and inflammatory cytokines, thereby alleviating pain. These results suggest that in peripheral sensitization caused by AIA, GBP can play a role in improving pain, and NR2B may be a key target of peripheral nerve sensitization induced by inflammatory arthritis. GBP provides a theoretical basis for the clinical treatment of inflammatory arthritis. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer is a major health problem that still causes many deaths worldwide. Neuropeptides, such as substance P and calcitonin gene-related peptide, play the neurotransmitter and neurohormone roles that increase tumor invasiveness and metastasis potential. This study aimed to see whether these neuropeptides and their receptors—neurokinin 1 receptor and calcitonin receptor-like receptor—correlate with the diagnosis stage, tumor differentiation grade, and different patient characteristics in colorectal cancer and also to compare them. Methods: We performed serum analyses of substance P and CGRP levels in patients with colorectal cancer and also the immunohistochemical analysis of their receptors in colorectal tumors and then correlated them with the disease stage and with different tumor characteristics. Results: We demonstrated that both substance P and calcitonin gene-related peptide had increased levels in colorectal cancer and that their levels correlated with the stage of the disease and with the tumor differentiation grade. We also demonstrated the correlation of NK-1R and CRLR higher immunohistochemical scores with advanced and poorly differentiated tumors. Conclusions: This study demonstrates that the neuropeptides SP and CGRP and their receptors NK-1R and CRLR could play a role in the pathogenesis of colorectal cancer, and they could be used as diagnostic and prognostic markers and could represent potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Increasing evidences demonstrate the role of sensory innervation in bone metabolism, remodeling and repair, however neurovascular coupling in bone is rarely studied. Using microfluidic devices as an indirect co-culture model to mimic in vitro the physiological scenario of innervation, our group demonstrated that sensory neurons (SNs) were able to regulate the extracellular matrix remodeling by endothelial cells (ECs), in particular through sensory neuropeptides, i.e. calcitonin gene-related peptide (CGRP) and substance P (SP). Nonetheless, still little is known about the cell signaling pathways and mechanism of action in neurovascular coupling. Here, in order to characterize the communication between SNs and ECs at molecular level, we evaluated the effect of SNs and the neuropeptides CGRP and SP on ECs. We focused on different pathways known to play a role on endothelial functions: calcium signaling, p38 and Erk1/2; the control of signal propagation through Cx43; and endothelial functions through the production of nitric oxide (NO). The effect of SNs was evaluated on ECs Ca2+ influx, the expression of Cx43, endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) production, p38, ERK1/2 as well as their phosphorylated forms. In addition, the role of CGRP and SP were either analyzed using respective antagonists in the co-culture model, or by adding directly on the ECs monocultures. We show that capsaicin-stimulated SNs induce increased Ca2+ influx in ECs. SNs stimulate the increase of NO production in ECs, probably involving a decrease in the inhibitory eNOS T495 phosphorylation site. The neuropeptide CGRP, produced by SNs, seems to be one of the mediators of this effect in ECs since NO production is decreased in the presence of CGRP antagonist in the co-culture of ECs and SNs, and increased when ECs are stimulated with synthetic CGRP. Taken together, our results suggest that SNs play an important role in the control of the endothelial cell functions through CGRP production and NO signaling pathway. [ABSTRACT FROM AUTHOR]

Salivary gland branching morphogenesis is regulated by the functional integration of neuronal signaling, but the underlying mechanisms are not fully understood in aging accelerated klotho‐deficient (Kl−/−) mice. Here, we investigated whether the neuropeptides substance P (SP) and neuropeptide Y (NPY) affect the branching morphogenesis of embryonic salivary glands in aging Kl−/− mice. In the salivary glands of embryonic Kl−/− mice, morphological analysis and immunostaining revealed that epithelial bud formation, neuronal cell proliferation/differentiation, and the expression of the salivary gland functional marker ZO‐1 were decreased in embryonic ductal cells. Incubation with SP/NPY at E12‐E13d promoted branching morphogenesis, parasympathetic innervation, and epithelial proliferation in salivary glands of embryonic Kl−/− mice. The ERK inhibitor U0126 specifically inhibited neuronal substance‐induced epithelial bud formation in the embryonic salivary gland. RNA‐seq profiling analysis revealed that the expression of fibroblast growth factors/fibroblast growth factors (FGFs/FGFRs) and their receptors was significantly regulated by SP/NPY treatment in the embryonic salivary gland (E15). The FGFR inhibitor BGJ389 inhibited new branching formation induced by SP and NPY treatment and ERK1/2 expression. These results showed that aging may affect virtually the development of salivary gland by neuronal dysfunction. The neuropeptides SP/NPY induced embryonic salivary gland development through FGF/FGFR/ERK1/2‐mediated signaling. [ABSTRACT FROM AUTHOR]

Objective To explore the clinical efficacy and mechanism of mirror neuron therapy in the treatment of phase I complex regional pain syndrome (CRPS) following stroke. Methods A total of 40 patients with CRPS phase I were selected from the Rehabilitation Department for this study. The patients were randomly divided into a control group and a mirror therapy group, with 20 patients in each group. Both groups received basic and conventional rehabilitation treatments, while the mirror therapy group additionally received mirror therapy. Treatment was administered twice daily, five times per week, for three weeks. Pain in the shoulder joint was evaluated using the Resting State Visual Analogue Scale (R-VAS) and the Passive Movement State Visual Analogue Scale (P-VAS). Hand swelling was assessed using the water displacement method, and upper limb motor function was evaluated with the Fugl-Meyer scale. Serum levels of calcitonin gene related peptide (CGRP) and substance P (SP) were measured using ELISA. Results After three weeks of treatment, patients in the mirror therapy group showed lower R-VAS and P-VAS scores, reduced hand swelling, and higher Fugl - Meyer scores compared to the control group (P<0.05). Additionally, the mirror therapy group had lower serum SP levels and higher CGRP levels than the control group (P<0.05). Conclusion Mirror therapy is more effective in alleviating shoulder joint pain, hand swelling, and upper limb dysfunction in CRPS phase I patients, and it regulates serum CGRP and SP levels. [ABSTRACT FROM AUTHOR]

Long-lasting COVID-19 (long COVID) diseases constitute a real life-changing burden for many patients around the globe and, overall, can be considered societal and economic issues. They include a variety of symptoms, such as fatigue, loss of smell (anosmia), and neurological–cognitive sequelae, such as memory loss, anxiety, brain fog, acute encephalitis, and stroke, collectively called long neuro-COVID-19 (long neuro-COVID). They also include cardiopulmonary sequelae, such as myocardial infarction, pulmonary damage, fibrosis, gastrointestinal dysregulation, renal failure, and vascular endothelial dysregulation, and the onset of new diabetes, with each symptom usually being treated individually. The main unmet challenge is to understand the mechanisms of the pathophysiologic sequelae, in particular the neurological symptoms. This mini-review presents the main mechanistic hypotheses considered to explain the multiple long neuro-COVID symptoms, namely immune dysregulation and prolonged inflammation, persistent viral reservoirs, vascular and endothelial dysfunction, and the disruption of the neurotransmitter signaling along various paths. We suggest that the nucleoprotein N of SARS-CoV-2 constitutes a "hub" between the virus and the host inflammation, immunity, and neurotransmission. [ABSTRACT FROM AUTHOR]

Objective: To compare the application effects of thoracoscopic assisted anterior mediastinal tumor resection by lateral thoracic approach or subxiphoid approach. Methods: According to the random number table method, 115 patients undergoing thoracoscopic assisted anterior mediastinal tumor resection were divided into group A (n=57, lateral thoracic approach) and group B (n=58, subxiphoid approach). The perioperative related indexes, stress response indexes and inflammatory factors were compared between two groups, and the occurrence of postoperative complications was observed. Results: Compared with group A, group B had longer operation time, less intraoperative blood loss and postoperative drainage volume, shorter postoperative hospital stay and drainage tube indwelling time (P<0.05). 1 day after operation, neuropeptide Y (NPY), 5-hydroxytryptamine (5-HT), substance P (SP) and prostaglandin E2 (PGE2) in two groups increased, but group B were lower than those of group A (P<0.05). 1 day after operation, C-reactive protein (CRP), white blood cell count (WBC) and neutrophils increased in two groups, but group B were lower than those of group A (P<0.05). The total incidence of complications in group A was 12.28%, and that in group B was 6.90%, there was no difference between two groups (P>0.05). Conclusion: During thoracoscopic assisted anterior mediastinal tumor resection, although the subxiphoid approach takes longer than the lateral thoracic approach, which can reduce intraoperative injury, reduce stress response and inflammatory response, and promote postoperative recovery. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the therapeutic efficacy of topical application of a neurokinin-1 receptor (NK1R) antagonist in a rabbit model of nonallergic ocular redness. Methods: Nonallergic ocular redness was induced in rabbits by a single, topical application of dapiparzole hydrochloride eye drops (0.5%, 1%, 2%, or 5%). The NK1R antagonist L-703,606 was topically applied to the eye at the same time of induction or 20 min after induction, and phosphate buffered saline (PBS) treatment served as the control. Superior bulbar conjunctival images were taken every 30 s for the first 2 min, followed by every 4 min for 8 min, and then every 10 min until 1 h. The severity of ocular redness was evaluated on the images using ImageJ-based ocular redness index (ORI) calculations. Results: The ORI scores were significantly increased after the application of 0.5%, 1%, 2%, or 5% dapiparzole at each time point evaluated, with the most severe redness induced by the 5% dapiprazole that led to a maximal mean increase in ORI score of 14 at 20 min post-induction and thus used for subsequent evaluation of therapeutic efficacy of NK1R antagonism. Topical L-703,606, when applied at the same time as dapiprazole induction, significantly suppressed the increase of ORI scores at all time points (∼40% decrease). Furthermore, when applied at 20 min after dapiprazole induction, L-703,606 rapidly and effectively suppressed the increase of ORI scores at 30, 40, 50, and 60 min (∼30% decrease). Conclusions: Topical blockade of NK1R effectively prevents and alleviates nonallergic ocular redness in a novel animal model. [ABSTRACT FROM AUTHOR]

Simple Summary: In male rats, the major pelvic ganglion is the principal component of the pelvic plexus and plays a crucial role in regulating various physiological functions such as urination, defecation, erection, ejaculation, and glandular secretion. This ganglion is considered mixed, as it receives both sympathetic and parasympathetic innervation through the hypogastric and pelvic nerves, respectively. Homologous structures with similar functions are present in other species, including cats, dogs, and pigs; however, differences exist in nomenclature, anatomical complexity, and functionality. Although anatomical, histological, and immunohistochemical studies have been conducted on these structures across various species, the major pelvic ganglion of the rat has been the most extensively studied due to its ease of identification and manipulation. This review provides a comprehensive analysis of the pelvic plexus and its regulation across various mammalian species, including rats, cats, dogs, and pigs. The pelvic and hypogastric nerves play crucial roles in regulating pelvic functions such as micturition, defecation, and erection. The anatomical organization of these nerves varies, forming either well-defined ganglia or complex plexuses. Despite these variations, the neurons within these structures are consistently regulated by key neurotransmitters, norepinephrine and acetylcholine. These neurons also possess receptors for testosterone and prolactin, particularly in rats, indicating the significant role of these hormones in neuronal function and development. Moreover, neuropeptides such as vasoactive intestinal peptide (VIP), substance P, neuropeptide Y (NPY), somatostatin (SOM), galanin (GAL), and calcitonin gene-related peptide (CGRP) are co-released with neurotransmitters to modulate pelvic functions. This review highlights the complex interplay between neurotransmitters, neuropeptides, and hormones in regulating pelvic physiology and emphasizes the importance of hormonal regulation in maintaining the functionality and health of the pelvic plexus across different species. [ABSTRACT FROM AUTHOR]

Abstract Increasing evidences demonstrate the role of sensory innervation in bone metabolism, remodeling and repair, however neurovascular coupling in bone is rarely studied. Using microfluidic devices as an indirect co-culture model to mimic in vitro the physiological scenario of innervation, our group demonstrated that sensory neurons (SNs) were able to regulate the extracellular matrix remodeling by endothelial cells (ECs), in particular through sensory neuropeptides, i.e. calcitonin gene-related peptide (CGRP) and substance P (SP). Nonetheless, still little is known about the cell signaling pathways and mechanism of action in neurovascular coupling. Here, in order to characterize the communication between SNs and ECs at molecular level, we evaluated the effect of SNs and the neuropeptides CGRP and SP on ECs. We focused on different pathways known to play a role on endothelial functions: calcium signaling, p38 and Erk1/2; the control of signal propagation through Cx43; and endothelial functions through the production of nitric oxide (NO). The effect of SNs was evaluated on ECs Ca2+ influx, the expression of Cx43, endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) production, p38, ERK1/2 as well as their phosphorylated forms. In addition, the role of CGRP and SP were either analyzed using respective antagonists in the co-culture model, or by adding directly on the ECs monocultures. We show that capsaicin-stimulated SNs induce increased Ca2+ influx in ECs. SNs stimulate the increase of NO production in ECs, probably involving a decrease in the inhibitory eNOS T495 phosphorylation site. The neuropeptide CGRP, produced by SNs, seems to be one of the mediators of this effect in ECs since NO production is decreased in the presence of CGRP antagonist in the co-culture of ECs and SNs, and increased when ECs are stimulated with synthetic CGRP. Taken together, our results suggest that SNs play an important role in the control of the endothelial cell functions through CGRP production and NO signaling pathway.

Clostridioides difficile infection (CDI) is a major cause of healthcare-associated gastrointestinal infections1,2. The exaggerated colonic inflammation caused by C. difficile toxins such as toxin B (TcdB) damages tissues and promotes C. difficile colonization3-6, but how TcdB causes inflammation is unclear. Here we report that TcdB induces neurogenic inflammation by targeting gut-innervating afferent neurons and pericytes through receptors, including the Frizzled receptors (FZD1, FZD2 and FZD7) in neurons and chondroitin sulfate proteoglycan 4 (CSPG4) in pericytes. TcdB stimulates the secretion of the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) from neurons and pro-inflammatory cytokines from pericytes. Targeted delivery of the TcdB enzymatic domain, through fusion with a detoxified diphtheria toxin, into peptidergic sensory neurons that express exogeneous diphtheria toxin receptor (an approach we term toxogenetics) is sufficient to induce neurogenic inflammation and recapitulates major colonic histopathology associated with CDI. Conversely, mice lacking SP, CGRP or the SP receptor (neurokinin 1 receptor) show reduced pathology in both models of caecal TcdB injection and CDI. Blocking SP or CGRP signalling reduces tissue damage and C. difficile burden in mice infected with a standard C. difficile strain or with hypervirulent strains expressing the TcdB2 variant. Thus, targeting neurogenic inflammation provides a host-oriented therapeutic approach for treating CDI.

BACKGROUND: Acupuncture is an effective method for lumbar pain in lumbar disc herniation, but its mechanism has not yet been clarified. Factors related to the JAK2/STAT3 signaling pathway regulate the body’s inflammatory response and are involved in the process of neuropathic pain. OBJECTIVE: To study the mechanism of acupuncture on lumbar disc herniation in a rat model based on the JAK2/STAT3 signaling pathway. METHODS: Forty Sprague-Dawley rats were randomly divided into four groups: sham operation group, model group, acupuncture group, and acupuncture+agonist group, with 10 rats in each group. Animal models of L5 lumbar disc herniation was constructed through autologous disc cell transplantation in the model group, acupuncture group, and acupuncture+agonist group. Rats in the acupuncture group and the acupuncture+agonist group received acupuncture treatment (Yanglingquan, Shenshu, Huantiao, and Dachangshu acupoints) at 3 days after modeling, and acupuncture treatment was given once a day, 20 minutes each, for 15 consecutive days. Rats in the acupuncture+agonist group were injected intrathecally with coumermycin A1, a JAK2 agonist, into the L4/L5 intervertebral space, once a day, 20 minutes each, prior to the acupuncture at 6, 12, and 18 days after modeling. Paw withdrawal mechanical threshold was detected before and 3, 6, 9, 12, 15, and 18 days after modeling. At 18 days after modeling, serum inflammatory factor levels were detected, hematoxylin-eosin staining was performed to observe the morphology of L5-L6 tissues, RT-PCR was performed to detect the expression of JAK2 and STAT3 mRNAs in L5-L6 tissues, and western blot was performed to detect the expression of JAK2, p-JAK2 and p-STAT3 proteins in L5-L6 tissues. RESULTS AND CONCLUSION: The paw withdrawal mechanical thresholds of rats in the model group at different time points after modeling were lower than those in the sham operation group (P < 0.05), the paw withdrawal mechanical thresholds of rats in the acupuncture group were higher than those in the model group at 9, 12, 15, and 18 days after modeling (P < 0.05), and the paw withdrawal mechanical thresholds of rats in the acupuncture+agonist group were lower than those in the acupuncture group at 9, 12, 15, and 18 days after modeling (P < 0.05). The levels of interleukin 6, tumor necrosis factor α, neurotransmitter substance P, and brain neuropeptide Y were elevated in the model group compared with the sham operation group (P < 0.05); the levels of all four inflammatory factors were reduced in the acupuncture group compared with the model group (P < 0.05); and the levels of all four inflammatory factors were elevated in the acupuncture+agonist group compared with the acupuncture group (P < 0.05). Hematoxylin-eosin staining showed that lumbar degeneration was obvious in the model group but reduced in the acupuncture group and the acupuncture+agonist group. Moreover, the reduction was more obvious in the acupuncture group compared with the acupuncture+agonist group. The JAK2 and STAT3 mRNA expression as well as the p-JAK2 and p-STAT3 protein expression were elevated in the model group compared with the sham operation group (P < 0.05), were decreased in the acupuncture group compared with the model group (P < 0.05), and were increased in the acupuncture+agonist group compared with the acupuncture group (P < 0.05). To conclude, acupuncture can alleviate inflammation to exert analgesic effects in the rat model of lumbar disc herniation, and its mechanism of action may be related to the inhibition of the JAK2/STAT3 signaling pathway. [ABSTRACT FROM AUTHOR]

Substance P (SP) and a calcitonin‐related gene alpha (αCGRP−/−) are implicated in musculoskeletal pain perception and were shown to have different effects on the pathogenesis of osteoarthritis (OA). However, it has not been investigated, whether deficiency for SP or αCGRP impacts pain‐related behavior and well‐being as well as gait during development of experimental OA. We induced OA in the right knee of wild‐type (WT) mice and mice either deficient for SP (tachykinin 1, Tac‐1) or αCGRP (male, n = 8 per genotype) by destabilizing the medial meniscus (DMM). We monitored body weight and food and water intake as indicators of wellbeing, determined nest building and composite pain score, and performed CatWalk gait analysis over 12 weeks. Cartilage degeneration was determined by OARSI scoring. The 12‐week post‐DMM, cartilage degradation in the medial compartment was significantly reduced in Tac1−/− mice compared to the WT and to αCGRP−/− mice, coinciding with highest unloading of the operated limb in Tac1−/−. Behavioral and gait analysis revealed only minor differences between the genotypes. Paw print area was most prominently reduced in Tac1−/− over the observation period; at 12 weeks, we found a significant reduction in normalized print area in Tac1−/− compared to presurgery and to the WT at the same time‐point. Calculated weight bearing was significantly reduced only in Tac1−/−. Overall, we observed minor impact of DMM on gait and behavior in the present study. The reduced cartilage damage in the absence of SP might be in part due to reduced loading, however, the mechanism is not clear yet. [ABSTRACT FROM AUTHOR]

Introduction: In percutaneous endoscopic lumbar discectomy (PELD), pain occurs when the posterior longitudinal ligament (PLL) is exposed, removed, and decompressed. However, pain characteristics of the PLL stimulated in PELD have not been reported. Methods: A total of 932 patients underwent PELD under local anesthesia. Pain distribution and intensity were recorded on a posterior body diagram during the operation. Pain intensity was assessed by the visual analog scale scores for the back (VAS-B). The PLL specimens were collected and observed using hematoxylin–eosin (HE) staining and immunohistochemistry. Results: Patients with lumbar disc herniation (LDH) at L4/5 and L5/S1 had pain foci in different regions. The mean VAS-B scores between the ventral and dorsal sides of the PLL were 6.14 ± 0.97 and 4.80 ± 1.15, respectively (P < 0.05). The distribution of nociceptive nerve fibers in the dorsal side was uniform and scattered, while those in the ventral side were mainly distributed near the outer surface of the annulus fibrosus. The positive expression of substance P (SP) and calcitonin gene-related peptide (CGRP) was higher in the ventral side of the PLL than in the dorsal side (P < 0.0001). Conclusions: Differences in pain distribution and intensity were observed when the PLL was incited at different spinal levels during PELD surgery. [ABSTRACT FROM AUTHOR]

Background and Aims: Postoperative nausea and vomiting (PONV) is a common complication after surgery. Preventing PONV in high-risk patients often requires a multimodal approach combining antiemetic drugs with diverse mechanisms. While aprepitant, a neurokinin-1 receptor antagonist, is recognised as highly effective for PONV prevention, uncertainties remain regarding its effectiveness. Methods: This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The analysis assessed the effectiveness of aprepitant (A), aprepitant plus ondansetron (AO) and aprepitant plus dexamethasone and ondansetron (ADO) in preventing PONV compared to ondansetron alone (O) or in combination with dexamethasone (DO). Results: In the analysis of 12 studies involving 2729 patients, aprepitant demonstrated significant efficacy in preventing PONV compared to ondansetron alone (A versus [vs.] O: PONV incidence 12.5% vs. 28.5%, relative risk [RR] = 0.45, P < 0.001; complete response rate 55.97% vs. 50.35%, RR = 1.13, P = 0.010). The combination of aprepitant with ondansetron (AO) also showed a significantly lower incidence of PONV compared to ondansetron alone (11.3% vs. 26.8%, RR = 0.43, P < 0.001) and a higher complete response rate (38.1% vs. 26.84%, RR = 1.41, P = 0.020). In addition, ADO significantly reduced PONV incidence compared to DO (ADO vs. DO: 13.63% vs. 35.38%, RR = 0.38, P = 0.006). Conclusion: Aprepitant, whether used alone or in combination with ondansetron or both ondansetron and dexamethasone, consistently outperforms ondansetron in achieving a complete response as it lowers vomiting rates and reduces the need for rescue therapy during the crucial 24–48-h postoperative period.

Abstract The objectives of this prospective, randomized, blinded, crossover, experimental study were to detect the potential anaesthetic- and analgesic-sparing effects of classical music provided to dogs undergoing skin surgery, and to investigate the role of substance P as an intraoperative pain indicator. Twenty dogs were included, each subjected to three different treatments: Chopin music, Mozart music and no music. They were premedicated with acepromazine, butorphanol and meloxicam and anaesthetized with propofol and isoflurane. Fentanyl was used as rescue analgesia. The anaesthetic depth was monitored by using the bispectral index along with standard anaesthetic monitoring, and autonomic nervous system responses were used to monitor the adequacy of analgesia. Furthermore, measurements of substance P serum concentration were carried out. Dogs exposed to music required less isoflurane and fentanyl. Furthermore, a statistically significant effect of time on substance P concentration was observed regardless of exposure to music, and there was a significant interaction effect between different timepoints and the type of acoustic stimulus. Classical music seems to have an isoflurane and fentanyl sparing effect on dogs undergoing minor surgery. Following surgical stimulation, the serum substance P concentration increases rapidly, and thus appears to be a potentially useful pain indicator.

Objective: To observe the effects of dexmedetomidine combined with ultrasound-guided nerve block on postoperative analgesia, immune stress and pain mediators in patients with hip fracture complicated with diabetes. Methods: 120 patients with hip fracture complicated with diabetes who were admitted to our hospital from June 2020 to June 2023 were divided into control group 60 cases (ultrasound-guided nerve block) and study group 60 cases (dexmedetomidine combined with ultrasound-guided nerve block) according to the random number table method. Postoperative patient-controlled intravenous analgesia (PCIA) was performed in both groups. The sedation, analgesia, PCIA pressing times, immune function, stress response and pain mediators were compared between two groups, and the occurrence of adverse reactions during the treatment was observed. Results: 12 h, 24 h and 48 h after operation, the visual analogue scale (VAS) score in study group was lower than that in control group, and the Ramsay sedation score was higher than that in control group (P＜0.05). The number of PCIA compressions in study group was less than that in control group (P＜0.05). 1 d after operation,CD3+, CD4+, CD4+/CD8+ in study group were higher than those in control group, and cortisol (Cor), norepinephrine (NE), prostaglandin E2 (PGE2), epinephrine (E), calcitonin gene-related peptide (CGRP), substance P (SP) and CD8+were lower than those in control group (P＜0.05). In terms of incidence of adverse reactions, there was no difference observed between the two groups in comparison (P＞0.05). Conclusion: Ultrasound-guided nerve block combined with dexmedetomidine in patients with hip fracture and diabetes, which can exert good sedative and analgesic effects, reduce immunosuppression and postoperative pain. [ABSTRACT FROM AUTHOR]

Objective: To compare the clinical effect of Zusanli electroacupuncture with different frequency in the treatment of patients with spleen deficiency qi depression syndrome mixed hemorrhoid external stripping and internal ligation surgery, and to provide clinical guidance for the rehabilitation of patients with spleen deficiency qi depression syndrome mixed hemorrhoid external stripping and internal ligation surgery. Methods: A total of 106 cases of patients with spleen deficiency qi depression syndrome mixed hemorrhoid external stripping and internal ligation surgery were selected and divided into study group (n=53) and control group (n=53) by random number table method. Both groups were given basic treatment with hemostatic, anti-inflammatory and analgesic drugs, while the control group was given Zusanli electroacupuncture 30 min before surgery, once a day. The study group was given Zusanli electroacupuncture30min before surgery and 2 h after surgery, twice a day. The scores of anal pain score, anal edema score, symptom relief time and pain stress mediators were compared between the two groups. Results: The anal pain score of both groups decreased 24 h after operation (P＜0. 05) and the study group was lower than the control group (P＜0. 05). The anal edema score decreased 24 h after operation in both groups (P＜0. 05), and the score in the study group was lower than that in the control group (P＜0. 05). The symptom relief (edema, pain) time in the study group was shorter than that in the control group (P＜0. 05). Prostaglandin E2 (PGE²), Substance P (SP), cortisol (COR) and adrenocorticotropin (ACTH) decreased 24 h after operation in both groups (P＜0. 05), and the study group was lower than the control group (P＜0. 05). Conclusion: The effect of Zusanli electroacupuncture is better in patients with spleen deficiency qi depression syndrome mixed hemorrhoid external stripping and internal ligation surgery. Compared with Zusanli electroacupuncture once a day, Zusanli electroacupuncture twice a day is more beneficial to improve the scores of anal pain and anal edema, clinical symptoms and pain stress mediators. [ABSTRACT FROM AUTHOR]

Instant Cascara (IC) is a sustainable beverage made from dried coffee cherry pulp, a by-product of coffee processing. It is rich in nutrients and bioactive compounds and has a high concentration of antioxidants. This study explored the impact of regular IC consumption on colonic motor function and innervation. Over a period of 4 weeks, male and female healthy rats were given drinking water containing 10 mg/mL of IC. Thereafter, colon samples were obtained to evaluate the longitudinal (LM) and circular (CM) smooth muscle contractile response to acetylcholine (ACh) and electrical field stimulation (EFS) in an organ bath, before and after atropine administration (10−6 M). Histological and immunohistochemical analyses assessed colon damage, muscle thickness, and immunoreactivity to substance P (SP) and neuronal nitric oxide synthase (nNOS). ACh and EFS induced similar responses across groups, but the CM response to EFS was greater in females compared with males, despite their lower body weight. Atropine completely blocked the response to ACh but only partially antagonized the neural response to EFS, particularly that of CM in females treated with IC, which had a greater liquid intake than those exposed to water. However, in the myenteric ganglia, no statistically significant differences were observed in SP or nNOS. Our results suggest that regular IC exposure may enhance specific neural pathway functions, particularly in females, possibly due to their increased IC consumption. [ABSTRACT FROM AUTHOR]

• Several inflammatory pathways have been described in IBM. • Our results show there was a greater number of mast cells present in IBM and neurogenic myositis than in normal muscle and steroid-responsive inflammatory myopathy. • Neurogenic inflammation may play a role in the pathogenesis of IBM and neurogenic myositis, and this could explain in part the lack of response to immunosuppressive treatment of IBM. Inclusion body myositis is the commonest acquired myopathy in those over 50 years of age. Although it is classified as an idiopathic inflammatory myopathy and the most frequent finding on muscle biopsy in inclusion body myositis is an endomysial inflammatory infiltrate, it is clinically distinct from other myositis, including a lack of response to immunosuppressive medication. Neurogenic changes are commonly reported in inclusion body myositis and inflammatory changes are observed in muscle following neurogenic injury. The objective of our study was to explore whether neurogenic inflammation plays a role in the pathogenesis of inclusion body myositis, possibly explaining its resistance to immunosuppression. The number of mast cells and presence of neuropeptides, substance P and calcitonin gene-related peptide, were assessed in 48 cases of inclusion body myositis, 11 cases of steroid responsive myositis, two cases of focal myositis associated with neurogenic injury, and ten normal controls. The number of mast cells in inclusion body myositis focal and myositis associated to neurogenic injury were significantly greater than that observed in steroid responsive myositis. Our findings suggest that neurogenic inflammation mediated through mast cells may play a role in the pathogenesis of inclusion body myositis, and focal myositis associated to neurogenic injury, and thus, explain in some part its lack of response to immunosuppressive treatments. [ABSTRACT FROM AUTHOR]

We investigated the use of boron-doped diamond (BDD) with different surface morphologies for the enhanced detection of nine different peptides by matrix-assisted laser desorption/ionisation mass spectrometry (MALDI-MS). For the first time, we compared three different nanostructured BDD film morphologies (Continuous, Nanograss, and Nanotips) with differently terminated surfaces (-H, -O, and -F) to commercially available Ground Steel plates. All these surfaces were evaluated for their effectiveness in detecting the nine different peptides by MALDI-MS. Our results demonstrated that certain nanostructured BDD surfaces exhibited superior performance for the detection of especially hydrophobic peptides (e.g., bradykinin 1–7, substance P, and the renin substrate), with a limit of detection of down to 2.3 pM. Further investigation showed that hydrophobic peptides (e.g., bradykinin 1–7, substance P, and the renin substrate) were effectively detected on hydrogen-terminated BDD surfaces. On the other hand, the highly acidic negatively charged peptide adrenocorticotropic hormone fragment 18–39 was effectively identified on oxygen-/fluorine-terminated BDD surfaces. Furthermore, BDD surfaces reduced sodium adduct contamination significantly. [ABSTRACT FROM AUTHOR]

Introduction: Epithelial barrier disruption is the initial cause of various diseases. We previously reported that acupoint catgut embedding (AE) improves tight junction proteins (TJs) in rats with allergic rhinitis. However, whether AE improves the epithelial barrier in local allergic rhinitis (LAR) remains unknown. Methods: A total of 36 Sprague Dawley (SD) male rats aged 5–7 weeks were divided into 6 groups with 6 rats each: control group, LAR model group, false acupoint embedding + LAR group, acupoint embedding + LAR group, capsaicin + LAR group, and tunicamycin + acupoint embedding + LAR group. Behavioral observation, ELISA to detect inflammatory factors in nasal lavage fluid and serum IgE, nasal mucosal permeability test, hematoxylin-eosin staining, PCR to detect Substance P (SP), Western blot, and immunofluorescence to detect endoplasmic reticulum stress (ERS) index and TJs were used to investigate the mechanism of AE in LAR. Results: AE improved the symptoms and pathological features of nasal mucosa of LAR rats, reduced the inflammatory factors (IL4, IL5, IL13) of nasal lavage fluid, and showed no significant change in serum IgE levels in all groups. In addition, AE decreased the expression of SP in nasal mucosa of LAR rats, inhibited ERS, increased the expression of tight junction protein, reduced the permeability of nasal mucosa, and improved the function of nasal mucosal barrier. Conclusion: This study confirms that AE can improve the nasal mucosal barrier function of LAR by reducing the expression of SP, inhibiting ERS and increasing the expression of TJs, thus enhancing the nasal mucosal barrier function. [ABSTRACT FROM AUTHOR]

Substance P (SP), an important neuropeptide, has a crucial role in the progression of several cancers, including prostate cancer, through interacting with the neurokinin-1 receptor (NK1R). Oxidative stress is also involved in the onset and progression of prostate cancer. However, no studies have been performed on the cross-talk between the SP/NK1R system and cellular redox balance in prostate cancer, and how it is involved in tumorogenesis. We aimed to investigate the effect of the SP/NK1R system and the blockage of NK1R with its specific antagonist (aprepitant) on the cellular redox status of the prostate cancer cell line (PC3 and LNCaP). We performed the resazurin assay to evaluate the toxicity of the aprepitant on the PC3 and LNCaP cell lines. The intracellular reactive oxygen species (ROS) level was measured after SP and aprepitant treatment. The alterations of expression and activity of two crucial cellular oxidoreductases, glutaredoxin, and thioredoxin were evaluated by qRT-PCR and commercial kits (ZellBio GmbH), respectively. Our results revealed that SP increased ROS production and decreased the expression and activity of glutaredoxin and thioredoxin. On the other hand, treatment of cells with aprepitant showed reverse results. In conclusion, we found that the SP/NK1R system could promote prostate cancer progression by inducing oxidative stress. In addition, the inhibition of NK1R by aprepitant modulated the effect of the SP/NK1R system on the cellular redox system. Aprepitant might therefore be introduced as a candidate for the treatment of prostate cancer; however, more studies are required to confirm the validation of this hypothesis. [ABSTRACT FROM AUTHOR]

Postoperative pain affects most patients after major surgery and can transition to chronic pain. The considerable side effects and limited efficacy of current treatments underline the need for new therapeutic options. We observed increased amounts of the metabolites BH4 and serotonin after skin injury. Mast cells were primary postoperative sources of Gch1, the rate-limiting enzyme in BH4 synthesis, itself an obligate cofactor in serotonin production by tryptophan hydroxylase (Tph1). Mice deficient in mast cells or in mast cell–specific Gch1 or Tph1 showed drastically decreased postoperative pain. We found that injury induced the nociceptive neuropeptide substance P, mast cell degranulation, and granule nerve colocalization. Substance P triggered serotonin release in mouse and human mast cells, and substance P receptor blockade substantially ameliorated pain hypersensitivity. Our findings highlight the importance of mast cells at the neuroimmune interface and substance P–driven mast cell BH4 and serotonin production as a therapeutic target for postoperative pain treatment. Editor's summary: Inflammation caused by surgical tissue injury can evolve into chronic pain. Starkl et al. used a mouse model of surgical tissue injury to decipher a role for mast cell–derived metabolites in postoperative pain. Tetrahydrobiopterin (BH4) has been previously detected in injured nerves and correlates with pain intensity and is required for serotonin production by tryptophan hydroxylase (Tph1). Nerve-proximal mast cells were identified as a source of GTP cyclohydrolase 1 (Gch1), a rate-limiting enzyme for BH4 synthesis. Deletion of Gch1 or Tph1 from mast cells or mast cell depletion reduced tissue injury pain. The nociceptive neuropeptide substance P was detected at tissue injury sites and triggered BH4-dependent serotonin release from mast cells, thus defining how neuropeptides can act on mast cells and propagate pain responses. —Christiana Fogg [ABSTRACT FROM AUTHOR]

Patients with primary cutaneous T-cell lymphoma (CTCL) often experience severe and difficult-to-treat pruritus that negatively affects their quality of life (QoL). However, the mechanisms of pruritus in CTCL, including mycosis fungoides (MF), remain largely unknown, and detailed characteristics of CTCL-associated pruritus is not fully elucidated. To characterize pruritus in CTCL, cutaneous B-cell lymphoma (CBCL), and large plaque parapsoriasis (LPP), and to identify potential itch mediators involved in the pathogenesis of pruritus in CTCL patients. Clinical data and blood samples were collected from 129 healthy subjects and 142 patients. Itch intensity, QoL impairment, psychological distress, and sleep quality were assessed using validated questionnaires and instruments. Blood levels of BDNF, CCL24, GRP, IL-31, IL-33, sST2, substance P, TSLP, tryptase and total IgE were measured using ELISA or ImmunoCAP. Pruritus was prevalent in CTCL, LPP and CBCL patients, with higher prevalence and severity observed in CTCL. In CTCL, pruritus correlated with significant impairment in QoL, sleep, psychological distress. Compared to healthy controls, elevated levels of IL-31, IL-33, substance P, total IgE, tryptase, and TSLP were found in MF patients. A comparison of MF patients with and without pruritus revealed higher levels of IL-31, substance P, GRP, and CCL24 in the former. Itch intensity positively correlated with IL-31, GRP, CCL24, and tryptase levels. Pruritus significantly burdens CTCL patients, necessitating appropriate therapeutic management. Our findings suggest that various non-histaminergic mediators such as tryptase and IL-31 could be explored as novel therapeutic targets for managing pruritus in MF patients. [ABSTRACT FROM AUTHOR]

Diabetes, which is associated with cardiovascular disease and related microvascular complications, affects life expectancy and decrease quality of life. A trial reports that the risk of patients with diabetes having cardiovascular disease is 2–4 times compared with that in patients without diabetes. This study aims to investigate the relationship between depth of general anesthesia in patients with diabetes mellitus This clinical study totally includes 40 patients with diabetes mellitus, and these patients are divided into following two groups: diabetes mellitus deep anesthesia group and diabetes mellitus light anesthesia group, and then these patients receive general anesthesia combined with laparoscopic surgery. Preoperative patient general data and intraoperative patient general data are collected and analyzed. Calcitonin gene-related peptide (CGRP) and substance P (SP) level are determined by Enzyme-linked immunosorbent assay (ELISA) This study included a total of 40 patients. There were no significant differences in demographic and preoperative patient general data between the two groups. Measurements were taken for operative time, anesthesia time, recovery time after drug withdrawal, dwell time in the recovery room, intraoperative fluid volume, intraoperative blood loss, and intraoperative urine output between the two groups. Significant differences were observed in the recovery time after drug withdrawal between the two groups. CGRP and SP level in diabetes mellitus deep anesthesia group are evidently more than those in diabetes mellitus light anesthesia group. CGRP and SP level are involved in the diabetes mellitus and up-regulated CGRP and SP can prevent the development of diabetes mellitus. Our study extends the existing literature by addressing a gap in knowledge regarding the impact of anesthesia depth on neuropeptide levels in diabetes mellitus patients. By delineating this relationship, we aim to contribute to the advancement of perioperative care practices and ultimately improve outcomes for individuals with diabetes undergoing surgical procedures. Our study’s findings provide valuable insights into the complex interactions between anesthesia, neuropeptides, and diabetes mellitus, offering the potential for personalized perioperative care, enhanced pain management, and improved surgical outcomes. These implications highlight the clinical relevance of our research and its potential to inform future advancements in perioperative care for diabetic patients undergoing surgery. [ABSTRACT FROM AUTHOR]

Chronic spontaneous urticaria (CSU), atopic dermatitis (AD), psoriasis and rosacea are highly prevalent inflammatory skin conditions which impose a significant burden on patients' quality of life. Their pathophysiology is likely multifactorial, involving genetic, immune and environmental factors. Recent advancements in the field have demonstrated the key role of mast cells (MC) in the pathophysiology of these conditions. The Mas‐related G protein‐coupled receptor X2 (MRGPRX2) has emerged as a promising non‐IgE‐mediated MC activation receptor. MRGPRX2 is predominately expressed on MC and activated by endogenous and exogenous ligands, leading to MC degranulation and release of various pro‐inflammatory mediators. Mounting evidence on the presence of endogenous MRGPRX2 agonists (substance P, cortistatin‐14, LL37, PAMP‐12 and VIP) and its high expression among patients with CSU, AD, rosacea, psoriasis and chronic pruritus emphasizes the pathogenic role of MRGPRX2 in these conditions. Despite the currently available treatments, there remains a pressing need for novel drug targets and treatment options for these chronic inflammatory skin conditions. Here, we reviewed the pathogenic role of MRGPRX2 and its potential as a novel therapeutic target and provided an update on future research directions. [ABSTRACT FROM AUTHOR]

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Polysulfides are endogenously produced in mammals and generally associated with protective functions. Our aim was to investigate the effect of dimethyl trisulfide (DMTS) in a mouse model of acute stress. DMTS activates transient receptor potential ankyrin 1 (TRPA1) channels and leads to neuropeptide release, potentially that of substance P (SP). We hypothesize that DMTS might inhibit the degrading enzymes of endocannabinoids, so this system was also investigated as another possible pathway for mediating the effects of DMTS. Trpa1 gene wild-type (WT) and knockout (KO) mice were used to confirm the role of the TRPA1 ion channel in mediating the effects of DMTS. C57BL/6J, NK1 gene KO, and Tac1 gene KO mice were used to evaluate the effect of DMTS on the release and expression of SP. Some C57BL/6J animals were treated with AM251, an inhibitor of the cannabinoid CB1 receptor, to elucidate the role of the endocannabinoid system in these processes. Open field test (OFT) and forced swim test (FST) were performed in each mouse strain. A tail suspension test (TST) was performed in Trpa1 WT and KO animals. C-FOS immunohistochemistry was carried out on Trpa1 WT and KO animals. The DMTS treatment increased the number of highly active periods and decreased immobility time in the FST in WT animals, but had no effect on the Trpa1 KO mice. The DMTS administration induced neuronal activation in the Trpa1 WT mice in the stress-related brain areas, such as the locus coeruleus, dorsal raphe nucleus, lateral septum, paraventricular nucleus of the thalamus, and paraventricular nucleus of the hypothalamus. DMTS may have a potential role in the regulation of stress-related processes, and the TRPA1 ion channel may also be involved in mediating the effects of DMTS. DMTS can be an ideal candidate for further study as a potential remedy for stress-related disorders. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the effect of homemade green ripe period chewing tablets on gastrointestinal function in mice. The free combination of Kunming mice was divided into a blank control group, a positive control group, a model control group, a green ripe period Tuokexun apricot fruit group, a low-dose group of green ripe period Tuokexun apricot chewable tablets, a medium dose group of green ripe period Tuokexun apricot chewable tablets, and a high-dose group of green ripe period Tuokexun apricot chewable tablets. After 7 days of adaptive feeding, loperamide hydrochloride was used in the mouse model of constipation, through studies of gastrointestinal function in mice, the effects of first blue stool time, the number of defecation grains, fecal moisture content, small bowel propulsion rate, colon water content, and gastric emptying rate were obtained. Results showed that there were significant differences in various indicators between the low, medium, and high dose groups of the green ripening stage Tuokexun apricot chewing tablets and the constipation model control group, positive control group, and green ripening stage Tuokexun apricot fruit group. This indicated that the green ripe period Tuokexun apricot chewing tablets could significantly improve the small intestine propulsion rate, shorten the defecation time, increase the number of defecated particles in 6 hours, increase gastric emptying rate, fecal water content, and colon water content in constipation model mice, through deeply studying the laxative mechanism, showing that it could regulate the content of P substance and vasoactive intestinal peptide, promote intestinal peristalsis, and improve constipation. [ABSTRACT FROM AUTHOR]

One of the prevalent chronic inflammatory disorders of the nasal mucosa, allergic rhinitis (AR) has become more widespread in recent years. Acupuncture pterygopalatine ganglion (aPPG) is an emerging alternative therapy that is used to treat AR, but the molecular mechanisms underlying its anti-inflammatory effects are unclear. This work methodically demonstrated the multi-target mechanisms of aPPG in treating AR based on bioinformatics/topology using techniques including text mining, bioinformatics, and network topology, among others. A total of 16 active biomarkers and 108 protein targets related to aPPG treatment of AR were obtained. A total of 345 Gene Ontology terms related to aPPG of AR were identified, and 135 pathways were screened based on Kyoto Encyclopedia of Genes and Genomes analysis. Our study revealed for the first time the multi-targeted mechanism of action of aPPG in the treatment of AR. In animal experiments, aPPG ameliorated rhinitis symptoms in OVA-induced AR rats; decreased serum immunoglobulin E, OVA-sIgE, and substance P levels; elevated serum neuropeptide Y levels; and modulated serum Th1/Th2/Treg/Th17 cytokine expression by a mechanism that may be related to the inhibition of activation of the TLR4/NF-κB/NLRP3 signaling pathway. In vivo animal experiments once again validated the results of the bioinformatics analysis. This study revealed a possible multi-target mechanism of action between aPPG and AR, provided new insights into the potential pathogenesis of AR, and proved that aPPG was a promising complementary alternative therapy for the treatment of AR. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to establish features of inflammation in histologically normal gallbladders with gallstones and compare the expression of inflammatory markers in acutely and chronically inflamed gallbladders. Methods: Immunohistochemistry was performed on formalin‐fixed paraffin‐embedded gallbladders for tumor necrosis factor (TNF)‐α, interleukin (IL)‐6, IL‐2R, and substance p in three groups: Group I (n = 60) chronic cholecystitis, Group II (n = 57) acute cholecystitis and Group III (n = 45) histologically normal gallbladders with gallstones. Expression was quantified using the H‐scoring system. Results: Median, interquartile range expression of mucosal IL‐2R in Groups I (2.65, 0.87–7.97) and II (12.30, 6.15–25.55) was significantly increased compared with group III (0.40, 0.10–1.35, p < 0.05). Submucosal IL‐2R expression in Groups I (2.0, 1.12–4.95) and II (10.0, 5.95–14.30) was also significantly increased compared with Group III (0.50, 0.15–1.05, p < 0.05). There was no difference in the lymphoid cell IL‐6 expression between Groups I (5.95, 1.60–18.15), II (6.10, 1.1–36.15) and III (8.30, 2.60–26.35, p > 0.05). Epithelial IL‐6 expression of Group III (8.3, 2.6–26.3) was significantly increased compared with group I (0.5, 0–10.2, p < 0.05) as was epithelial TNF‐α expression in Group III (85.0, 70.50–92.0) compared with Groups I (72.50, 45.25.0–85.50, p < 0.05) and II (61.0, 30.0–92.0, p < 0.05). Lymphoid cell Substance P expression in Groups I (1.90, 1.32–2.65) and II (5.62, 2.50–20.8) was significantly increased compared with Group III (1.0,1.0–1.30, p < 0.05). Epithelial cell expression of Substance P in Group III (121.7, 94.6–167.8) was significantly increased compared with Groups I (75.7, 50.6–105.3, p < 0.05) and II (78.9, 43.5–118.5, p < 0.05). Conclusion: Histologically normal gallbladders with gallstones exhibited features of inflammation on immunohistochemistry. [ABSTRACT FROM AUTHOR]

OnabotulinumtoxinA (BT-A) is used in different medical fields for its beneficial effects. BT-A, a toxin originally produced by the bacterium Clostridium botulinum, is widely known for its ability to temporarily paralyze muscles by blocking the release of acetylcholine, a neurotransmitter involved in muscle contraction. The literature continually reports new hypotheses regarding potential applications that do not consider blockade of acetylcholine release at the neuromuscular junction as a common pathway. In this opinion article, it is our aim to investigate the different pathway targets of BT-A in different medical applications. First of all, the acetylcholine effect of BT-A is used to reduce wrinkles for cosmetic purposes, in the treatment of urological problems, excessive sweating, temporomandibular joint disorders, obesity, migraine, spasticity in neurological diseases, and in various cases of muscle overactivity such as cervical dystonia, blepharospasm, and essential head tremor. In another potential pathway, glutamate A, CGRP, and substance P are targeted for pain inhibition with BT-A application in conditions such as migraine, trigeminal neuralgia, neuropathic pain, and myofascial pain syndrome. On the other hand, as a mechanism different from acetylcholine and pain mediators, BT-A is used in the treatment of hair loss by increasing oxygenation and targeting transforming growth factor-beta 1 cells. In addition, the effect of BT-A on the apoptosis of cancer cells is also known and is being developed. The benefits of BT-A applied in different doses to different regions for different medical purposes are shown in literature studies, and it is also emphasized in those studies that repeating the applications increases the benefits in the long term. The use of BT-A continues to expand as researchers discover new potential therapeutic uses for this versatile toxin. [ABSTRACT FROM AUTHOR]