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Abstract Airway hyperreactivity in asthma is mediated by airway nerves, including sensory nerves in airway epithelium and parasympathetic nerves innervating airway smooth muscle. Isolating the function of these two nerve populations in vivo, to distinguish how each is affected by inflammatory processes and contributes to hyperreactivity in asthma, has been challenging. In this study, we used optogenetic activation of airway nerves in vivo to study parasympathetic contributions to airway hyperreactivity in two mouse models of asthma: 1) acute challenge with house dust mite antigen; and 2) chronic airway hypereosinophilia due to genetic IL-5 overexpression in airways. Overall airway hyperreactivity, as measured by bronchoconstriction to an inhaled agonist, was increased in both models. In contrast, optogenetic stimulation of isolated efferent parasympathetic nerves induced bronchoconstriction only in the acute house dust mite antigen challenge group. Using whole-mount tissue immunofluorescence and modeling software, we then measured, in three dimensions, the interactions between eosinophils and parasympathetic nerves in both models and found that eosinophils were more numerous and more proximal to airway parasympathetic nerves in antigen-challenged and IL-5–transgenic mice than in their respective controls but were not significantly different between the two asthma models. Thus, even though eosinophils were increased around nerves in both models, parasympathetic nerves only mediated airway hyperreactivity in the antigen-challenged mice. This study demonstrates divergent effects of acute versus chronic eosinophilia on parasympathetic airway nerve activity and points to eosinophil–nerve interactions as a key regulator of airway hyperreactivity in antigen challenged mice.

PurposeThe autonomic nervous system, consisting of sympathetic and parasympathetic/vagal nerves, is known to control the functions of any organ, maintaining whole-body homeostasis under physiological conditions. Recently, there has been increasing evidence linking sympathetic and parasympathetic/vagal nerves to cancers. The present review aimed to summarize recent developments from studies addressing the relationship between sympathetic and parasympathetic/vagal nerves and cancer behavior.MethodsLiterature review.ResultsHuman and animal studies have revealed that sympathetic and parasympathetic/vagal nerves innervate the cancer microenvironment and alter cancer behavior. The sympathetic nerves have cancer-promoting effects on prostate cancer, breast cancer, and melanoma. On the other hand, while the parasympathetic/vagal nerves have cancer-promoting effects on prostate, gastric, and colorectal cancers, they have cancer-suppressing effects on breast and pancreatic cancers. These neural effects may be mediated by β-adrenergic or muscarinic receptors and can be explained by changes in cancer cell behavior, angiogenesis, tumor-associated macrophages, and adaptive antitumor immunity.ConclusionsSympathetic nerves innervating the tumor microenvironment promote cancer progression and are related to stress-induced cancer behavior. The parasympathetic/vagal nerves have variable (promoting or suppressing) effects on different cancer types. Approaches directed toward the sympathetic and parasympathetic/vagal nerves can be developed as a new cancer therapy. In addition to existing pharmacological, surgical, and electrical approaches, a recently developed virus vector-based genetic local neuroengineering technology is a powerful approach that selectively manipulates specific types of nerve fibers innervating the cancer microenvironment and leads to the suppression of cancer progression. This technology will enable the creation of \"cancer neural therapy\" individually tailored to different cancer types.

Acinar cells play an essential role in the secretory function of exocrine organs. Despite this requirement, how acinar cells are generated during organogenesis is unclear. Using the acini-ductal network of the developing human and murine salivary gland, we demonstrate an unexpected role for SOX2 and parasympathetic nerves in generating the acinar lineage that has broad implications for epithelial morphogenesis. Despite SOX2 being expressed by progenitors that give rise to both acinar and duct cells, genetic ablation of SOX2 results in a failure to establish acini but not ducts. Furthermore, we show that SOX2 targets acinar-specific genes and is essential for the survival of acinar but not ductal cells. Finally, we illustrate an unexpected and novel role for peripheral nerves in the creation of acini throughout development via regulation of SOX2. Thus, SOX2 is a master regulator of the acinar cell lineage essential to the establishment of a functional organ. The salivary glands produce fluid that contains enzymes to help us to digest our food. These glands contain a tree-like network of cells – known as acinar cells – that produce the fluid, and cells that form ducts to transport the fluid out of the glands. Both types of cells form from stem cells as animal embryos develop. Like all developing organs, the salivary glands receive many different signals that guide how they grow. However, the identity of the cues that instruct a stem cell to produce a new acinar cell or duct cell are not known. Emmerson et al. studied how the salivary glands develop in mouse embryos. The experiments show that a protein called SOX2 – which is an essential regulator of stem cells in embryos – is required for acinar cells to form. Loss of SOX2 inhibited the production of acinar but not duct cells. Furthermore, nerves that surround the gland provide support to cells that produce SOX2 and promote the formation of acinar cells. Further experiments suggest that the nerves also play the same role in humans. Adult organs often use developmental signals to repair or regenerate tissue. As such, understanding how an organ develops may lead to new therapies that can stimulate salivary glands and other organs to regenerate after they have been damaged in adults.

Many researchers have focused on the role of the autonomic nervous system in the tumor microenvironment. Autonomic nerves include the sympathetic and parasympathetic nerves, which are known to induce cancer growth and metastasis. However, in salivary duct carcinoma (SDC), a rare and highly malignant tumor, the issue should be investigated from both biological and therapeutic perspectives. We explored the clinicopathological and prognostic implications of the autonomic nerves in 129 SDCs. Immunohistochemistry was performed to determine the nature of each nerve using antibodies against S100, tyrosine hydroxylase (TH) as a sympathetic marker, and vesicular acetylcholine transporter (VAChT) as a parasympathetic marker. The area of each marker-positive nerve was digitized and evaluated quantitatively. Double immunofluorescence for TH and VAChT was performed in selected cases. The expression of the secreted neurotrophins was also examined. S100-positive nerves were present in the cancer tissue in 94 of 129 cases (72.9%). Among them, TH-positive sympathetic nerves and/or VAChT-positive parasympathetic nerves were identified in 92 cases (97.9%), and 59 cases (62.8%) had TH/VAChT-co-expressing nerves. Double immunofluorescence revealed a mosaic pattern of sympathetic and parasympathetic fibers in co-expressing nerve bundles. The presence of autonomic nerves, regardless of their area, was significantly associated with aggressive histological features, advanced T/N classification, and a poor prognosis, with shorter disease-free and overall survival. There was an association between some tumor immune microenvironment-related markers and the autonomic nerve status, but not the latter and the secreted neurotrophin expression. This study suggests that autonomic nerves might play a role in the progression of SDC.

Xerostomia, the subjective feeling of a dry mouth associated with dysfunction of the salivary glands, is mainly caused by radiation and chemotherapy, various systemic and autoimmune diseases, and drugs. As saliva plays numerous essential roles in oral and systemic health, xerostomia significantly reduces quality of life, but its prevalence is increasing. Salivation mainly depends on parasympathetic and sympathetic nerves, and the salivary glands responsible for this secretion move fluid unidirectionally through structural features such as the polarity of acinar cells. Saliva secretion is initiated by the binding of released neurotransmitters from nerves to specific G-protein-coupled receptors (GPCRs) on acinar cells. This signal induces two intracellular calcium (Ca2+) pathways (Ca2+ release from the endoplasmic reticulum and Ca2+ influx across the plasma membrane), and this increased intracellular Ca2+ concentration ([Ca2+]i) causes the translocation of the water channel aquaporin 5 (AQP5) to the apical membrane. Consequently, the GPCR-mediated increased [Ca2+]i in acinar cells promotes saliva secretion, and this saliva moves into the oral cavity through the ducts. In this review, we seek to elucidate the potential of GPCRs, the inositol 1,4,5-trisphosphate receptor (IP3R), store-operated Ca2+ entry (SOCE), and AQP5, which are essential for salivation, as cellular targets in the etiology of xerostomia.

Inappropriate sympathetic activation is closely associated with the development and progression of hypertension. Renal denervation (RDN) is a neuromodulation therapy performed using an intraarterial catheter in patients with hypertension. Recent randomized sham-operated controlled trials have shown that RDN has significant antihypertensive effects that last for at least 3 years. Based on this evidence, RDN is nearly ready for general clinical application. On the other hand, there are remaining issues to be addressed, including elucidation of the precise antihypertensive mechanisms of RDN, the appropriate endpoint of RDN during the procedure, and the association between reinnervation after RDN and the long-term effects of RDN. This mini review focuses on studies implicating anatomy of the renal nerves, which consist of afferent or efferent and sympathetic or parasympathetic nerves, the response of blood pressure to renal nerve stimulation, and reinnervation of renal nerves after RDN. A comprehensive understanding of the anatomical and functional aspects of the renal nerves and the antihypertensive mechanisms of RDN, including its long-term effects, will enhance our ability to incorporate RDN into strategies to treat hypertension in clinical practice. This mini review focuses on studies implicating anatomy of the renal nerves, which consist of afferent or efferent and sympathetic or parasympathetic nerves, the response of blood pressure to renal nerve stimulation, and reinnervation of renal nerves after renal denervation. Whether the ablation site is sympathetic dominant or parasympathetic dominant, and afferent dominant or efferent dominant, would in turn determine the final output of renal denervation. BP: blood pressure.

Respiratory viral infections are associated with the majority of asthma attacks. Inhibitory M2 receptors on parasympathetic nerves, which normally limit acetylcholine (ACh) release, are dysfunctional after respiratory viral infection. Because IL-1β is up-regulated during respiratory viral infections, we investigated whether IL-1β mediates M2 receptor dysfunction during parainfluenza virus infection. Virus-infected guinea pigs were pretreated with the IL-1β antagonist anakinra. In the absence of anakinra, viral infection increased bronchoconstriction in response to vagal stimulation but not to intravenous ACh, and neuronal M2 muscarinic receptors were dysfunctional. Pretreatment with anakinra prevented virus-induced increased bronchoconstriction and M2 receptor dysfunction. Anakinra did not change smooth muscle M3 muscarinic receptor response to ACh, lung viral loads, or blood and bronchoalveolar lavage leukocyte populations. Respiratory virus infection decreased M2 receptor mRNA expression in parasympathetic ganglia extracted from infected animals, and this was prevented by blocking IL-1β or TNF-α. Treatment of SK-N-SH neuroblastoma cells or primary cultures of guinea pig parasympathetic neurons with IL-1β directly decreased M2 receptor mRNA, and this was not synergistic with TNF-α treatment. Treating guinea pig trachea segment with TNF-α or IL-1β in vitro increased tracheal contractions in response to activation of airway nerves by electrical field stimulation. Blocking IL-1β during TNF-α treatment prevented this hyperresponsiveness. These data show that virus-induced hyperreactivity and M2 dysfunction involves IL-1β and TNF-α, likely in sequence with TNF-α causing production of IL-1β.

BACKGROUND: Although feeding with a liquid diet does not affect the growth of rat submandibular glands, it inhibits the growth of rat parotid glands during growth periods. In these growth-inhibited parotid glands, the growth of parasympathetic nerves is also suppressed. Meanwhile, the mature parotid glands of animals maintained on a liquid diet become morphologically and functionally atrophic, however, there is no effect of a liquid diet on mature submandibular glands. The objective of the present study was to clarify whether the nerve distribution in the mature salivary glands of rats was affected by a liquid diet. MATERIALS AND METHODS: Seven-week-old male Wistar rats were used in this study. Half of the rats were kept on a pellet diet, and half were kept on a liquid diet, for 3, 7, 14, or 21 days. All rats were euthanised by isoflurane at each endpoint.Then, the parotid and submandibular glands were removed, frozen in liquid nitrogen, cryosectioned, and stained with antibodies against protein gene product 9.5 (PGP 9.5; general nerve marker), tyrosine hydroxylase (TH; sympathetic nerve marker), or neuronal nitric oxide synthase (nNOS; parasympathetic nerve marker). RESULTS: In parotid and submandibular glands of the pellet diet group, PGP 9.5- and TH-like immunoreactivity were seen around acini and ducts, and nNOS-like immunoreactivity was lower than PGP 9.5- and TH-like immunoreactivity. In theparotid glands of the liquid diet group, similar immunoreactivities were seen throughout the experimental period. The distribution of antibody labelling in the submandibular glands of the liquid diet group was similar to that of the pellet dietgroup and remained unchanged during the experimental period. CONCLUSIONS: The present study demonstrated no regressive effects of a liquid diet on the distribution of sympathetic or parasympathetic nerves in mature parotid glands and submandibular glands. This differed from inhibitory effects on the growth of parotid glands seen during growth periods.

Heart rate variability (HRV) is believed to possess the potential for disease detection. However, early identification of heart disease remains challenging, as HRV analysis in dogs primarily reflects the advanced stages of the disease. The aim of this study is to compare 24-h HRV with sleep HRV to assess the potential utility of sleep HRV analysis. Thirty healthy dogs with no echocardiographic abnormalities were included in the study, comprising 23 females and 7 males ranging in age from 2 months to 8 years (mean [standard deviation], 1.4 [1.6]). This study employed a cross-sectional study. 24-h HRV and sleep HRV were measured from 48-h Holter recordings. Both linear analysis, a traditional method of heart rate variability analysis, and nonlinear analysis, a novel approach, were conducted. Additionally, circadian rhythm parameters were assessed. In frequency analysis of linear analysis, the parasympathetic index nHF was significantly higher during sleep compared to the mean 24-h period (mean sleep HRV [standard deviation] vs. mean 24 h [standard deviation], 95% confidence interval, value, r-family: 0.24 [0.057] vs. 0.23 [0.045], 0.006-0.031,  = 0.005,  = 0.49). Regarding time domain analysis, the parasympathetic indices SDNN and RMSSD were also significantly higher during sleep (SDNN: 179.7 [66.9] vs. 156.6 [53.2], 14.5-31.7,  < 0.001,  = 0.71 RMSSD: 187.0 [74.0] vs. 165.4 [62.2], 13.2-30.0,  < 0.001,  = 0.70). In a geometric method of nonlinear analysis, the parasympathetic indices SD1 and SD2 showed significantly higher values during sleep (SD1: 132.4 [52.4] vs. 117.1 [44.0], 9.3-21.1,  < 0.001,  = 0.70 SD2: 215.0 [80.5] vs. 185.9 [62.0], 17.6-40.6,  < 0.001,  = 0.69). Furthermore, the circadian rhythm items of the parasympathetic indices SDNN, RMSSD, SD1, and SD2 exhibited positive peaks during sleep. The findings suggest that focusing on HRV during sleep can provide a more accurate representation of parasympathetic activity, as it captures the peak circadian rhythm items.

Breast cancer (BC) exhibits marked biological heterogeneity and remains a major cause of cancer-related death in women. With advances in molecular subtyping and tumor microenvironment research, the nervous system has emerged as an important regulator of BC initiation, progression, and metastasis. Tumor-associated nerves influence cancer not only locally through sympathetic, parasympathetic, and sensory innervation, but also systemically by modulating immunity via psychological stress, circadian rhythms, and neuroendocrine pathways. Increasing evidence shows that nerve fiber density is elevated in BC tissues and correlates with greater invasiveness and poorer prognosis. The sympathetic nervous system promotes tumor growth, angiogenesis, and metastasis mainly through β-adrenergic signaling and suppression of anti-tumor immunity. Chronic psychological stress further enhances tumor-promoting immune changes through sustained neuroendocrine activation. In contrast, parasympathetic signaling may exert inhibitory effects on tumor progression, while sensory nerves and neuropeptides display context-dependent roles in inflammation, pain, and immune regulation. Moreover, circadian rhythm disruption and reduced melatonin impair tumor immune surveillance. Clinical and retrospective studies suggest that neural-targeted interventions, such as β-blockers and psychological therapies, may improve the immune microenvironment and clinical outcomes in BC. The nervous system plays a crucial role in shaping the BC microenvironment and promoting immune escape through complex, multi-level mechanisms. Different types of nerves exert distinct effects on tumor progression. Targeting neuro-immune interactions may therefore offer a promising strategy for adjuvant BC therapy.