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Frontiers in Cell and Developmental... 2021Asthma is a chronic inflammation of lower airway disease, characterized by bronchial hyperresponsiveness. Type I hypersensitivity underlies all atopic diseases including... (Review)
Review
Asthma is a chronic inflammation of lower airway disease, characterized by bronchial hyperresponsiveness. Type I hypersensitivity underlies all atopic diseases including allergic asthma. However, the role of neurotransmitters (NT) and neuropeptides (NP) in this disease has been less explored in comparison with inflammatory mechanisms. Indeed, the airway epithelium contains pulmonary neuroendocrine cells filled with neurotransmitters (serotonin and GABA) and neuropeptides (substance P[SP], neurokinin A [NKA], vasoactive intestinal peptide [VIP], Calcitonin-gene related peptide [CGRP], and orphanins-[N/OFQ]), which are released after allergen exposure. Likewise, the autonomic airway fibers produce acetylcholine (ACh) and the neuropeptide Y(NPY). These NT/NP differ in their effects; SP, NKA, and serotonin exert pro-inflammatory effects, whereas VIP, N/OFQ, and GABA show anti-inflammatory activity. However, CGPR and ACh have dual effects. For example, the ACh-M3 axis induces goblet cell metaplasia, extracellular matrix deposition, and bronchoconstriction; the CGRP-RAMP1 axis enhances Th2 and Th9 responses; and the SP-NK1R axis promotes the synthesis of chemokines in eosinophils, mast cells, and neutrophils. In contrast, the ACh-α7nAChR axis in ILC2 diminishes the synthesis of TNF-α, IL-1, and IL-6, attenuating lung inflammation whereas, VIP-VPAC1, N/OFQ-NOP axes cause bronchodilation and anti-inflammatory effects. Some NT/NP as 5-HT and NKA could be used as biomarkers to monitor asthma patients. In fact, the asthma treatment based on inhaled corticosteroids and anticholinergics blocks M3 and TRPV1 receptors. Moreover, the administration of experimental agents such as NK1R/NK2R antagonists and exogenous VIP decrease inflammatory mediators, suggesting that regulating the effects of NT/NP represents a potential novel approach for the treatment of asthma.
PubMed: 34055794
DOI: 10.3389/fcell.2021.663535 -
International Journal of Molecular... Oct 2022Disturbances in uterine contractile activity contribute to the development of inflammation, and recent evidence indicates that tachykinins, including substance P (SP)...
Disturbances in uterine contractile activity contribute to the development of inflammation, and recent evidence indicates that tachykinins, including substance P (SP) and neurokinin A (NKA), are involved in controlling uterine function. Here, we determined the effect of (-induced inflammation on expression of protein receptor subtypes for substance P (NK1R) and neurokinin A (NK2R) in the pig myometrium as well as their role in contractility of inflamed uterus. The severe acute endometritis developed in the group and the expression of NK1R and NK2R proteins increased in the myometrium. Compared to the pre-administration period, SP (10 M) reduced the amplitude and frequency in the myometrium of the group and the amplitude was higher and the frequency was lower versus other groups. NKA reduced the amplitude and increased the frequency in endometrium/myometrium of the group. In this group, the amplitude was lower and the frequency was higher than in the CON and SAL groups. Our research showed that NK2R (10 M) antagonist application abolished the NKA inhibitory effect on uterine amplitude. The application of the NK1R (10 M) antagonist together with SP revealed that the inhibitory effect of SP on uterine contractility is achieved independently of the NKR1. Additionally, taking into account the fact that NKA shows an inhibitory effect with the use of NK2R on uterine amplitude suggests the possibility of therapeutic use of the antagonist as a drug increasing uterine contractility in inflammation.
Topics: Animals; Female; Escherichia coli; Escherichia coli Infections; Inflammation; Neurokinin A; Substance P; Swine; Uterus
PubMed: 36361972
DOI: 10.3390/ijms232113184 -
Health Psychology Research 2022Migraine headache is a widespread and complex neurobiological disorder that is characterized by unilateral headaches that are often accompanied by photophobia and... (Review)
Review
Migraine headache is a widespread and complex neurobiological disorder that is characterized by unilateral headaches that are often accompanied by photophobia and phonophobia. Migraine is one of the leading chief complaints in the emergency department with negative impacts on quality of life and activities of daily living. The high number of emergency presentations also results in a significant economic burden. Its risk factors include family history, genetics, sex, race, socioeconomics, the existence of comorbid conditions, and level of education. Triggers include stress, light, noise, menstruation, weather, changes in sleep pattern, hunger, dehydration, dietary factors, odors, and alcohol. The International Headache Society has defined criteria for the diagnosis of migraine with and without aura. The pathophysiology of migraine headaches is multifactorial so there are a variety of treatment approaches. The current treatment approach includes abortive medications and prophylactic medications. Abortive medications include the first-line treatment of triptans, followed by ergot alkaloids, and calcitonin gene-related peptide (CGRP) receptor antagonists along with supplemental caffeine and antiemetics. Trigeminal afferents from the trigeminal ganglion innervate most cranial tissues and many areas of the head and face. These trigeminal afferents express certain biomarkers such as calcitonin gene-related peptide (CGRP), substance P, neurokinin A, and pituitary adenylate cyclase-activating polypeptide that are important to the pain and sensory aspect of migraines. In this comprehensive review, we discuss Zavegepant, a calcitonin gene-related peptide receptor antagonist, as a new abortive medication for migraine headaches.
PubMed: 35774914
DOI: 10.52965/001c.35506 -
Cancers Mar 2023The roles played by the peptides belonging to the tachykinin (neurokinin A and B) and calcitonin/calcitonin gene-related peptide (adrenomedullin, adrenomedullin 2,... (Review)
Review
The roles played by the peptides belonging to the tachykinin (neurokinin A and B) and calcitonin/calcitonin gene-related peptide (adrenomedullin, adrenomedullin 2, amylin, and calcitonin gene-related peptide (CGRP)) peptide families in cancer development are reviewed. The structure and dynamics of the neurokinin (NK)-2, NK-3, and CGRP receptors are studied together with the intracellular signaling pathways in which they are involved. These peptides play an important role in many cancers, such as breast cancer, colorectal cancer, glioma, lung cancer, neuroblastoma, oral squamous cell carcinoma, phaeochromocytoma, leukemia, bladder cancer, endometrial cancer, Ewing sarcoma, gastric cancer, liver cancer, melanoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, renal carcinoma, and thyroid cancer. These peptides are involved in tumor cell proliferation, migration, metastasis, angiogenesis, and lymphangiogenesis. Several antitumor therapeutic strategies, including peptide receptor antagonists, are discussed. The main research lines to be developed in the future are mentioned.
PubMed: 36980580
DOI: 10.3390/cancers15061694 -
Frontiers in Immunology 2023Periodontitis is one of the most common oral diseases in humans, affecting over 40% of adult Americans. Pain-sensing nerves, or nociceptors, sense local environmental...
Periodontitis is one of the most common oral diseases in humans, affecting over 40% of adult Americans. Pain-sensing nerves, or nociceptors, sense local environmental changes and often contain neuropeptides. Recent studies have suggested that nociceptors magnify host response and regulate bone loss in the periodontium. A subset of nociceptors projected to periodontium contains neuropeptides, such as calcitonin gene-related peptide (CGRP) or substance P (SP). However, the specific roles of neuropeptides from nociceptive neural terminals in periodontitis remain to be determined. In this study, we investigated the roles of neuropeptides on host responses and bone loss in ligature-induced periodontitis. Deletion of tachykinin precursor 1 (), a gene that encodes SP, or treatment of gingiva with SP antagonist significantly reduced bone loss in ligature-induced periodontitis, whereas deletion of calcitonin related polypeptide alpha (), a gene that encodes CGRP, showed a marginal role on bone loss. Ligature-induced recruitment of leukocytes, including neutrophils, and increase in cytokines leading to bone loss in periodontium was significantly less in knockout mice. Furthermore, intra-gingival injection of SP, but not neurokinin A, induced a vigorous inflammatory response and osteoclast activation in alveolar bone and facilitated bone loss in ligature-induced periodontitis. Altogether, our data suggest that SP plays significant roles in regulating host responses and bone resorption in ligature-induced periodontitis.
Topics: Animals; Humans; Mice; Alveolar Bone Loss; Calcitonin Gene-Related Peptide; Osteoclasts; Periodontitis; Substance P
PubMed: 37122730
DOI: 10.3389/fimmu.2023.1099017 -
Temperature (Austin, Tex.) 2023The transient receptor potential ankyrin 1 (TRPA1), a member of the TRP superfamily of channels, has a major role in different types of pain. TRPA1 is primarily... (Review)
Review
The transient receptor potential ankyrin 1 (TRPA1), a member of the TRP superfamily of channels, has a major role in different types of pain. TRPA1 is primarily localized to a subpopulation of primary sensory neurons of the trigeminal, vagal, and dorsal root ganglia. This subset of nociceptors produces and releases the neuropeptide substance P (SP) and calcitonin gene-related peptide (CGRP), which mediate neurogenic inflammation. TRPA1 is characterized by unique sensitivity for an unprecedented number of reactive byproducts of oxidative, nitrative, and carbonylic stress and to be activated by several chemically heterogenous, exogenous, and endogenous compounds. Recent preclinical evidence has revealed that expression of TRPA1 is not limited to neurons, but its functional role has been reported in central and peripheral glial cells. In particular, Schwann cell TRPA1 was recently implicated in sustaining mechanical and thermal (cold) hypersensitivity in mouse models of macrophage-dependent and macrophage-independent inflammatory, neuropathic, cancer, and migraine pain. Some analgesics and herbal medicines/natural products widely used for the acute treatment of pain and headache have shown some inhibitory action at TRPA1. A series of high affinity and selective TRPA1 antagonists have been developed and are currently being tested in phase I and phase II clinical trials for different diseases with a prominent pain component. 4-HNE, 4-hydroxynonenal; ADH-2, alcohol dehydrogenase-2; AITC, allyl isothiocyanate; ANKTD, ankyrin-like protein with transmembrane domains protein 1; B2 receptor, bradykinin 2 receptor; CIPN, chemotherapeutic-induced peripheral neuropathy; CGRP, calcitonin gene related peptide; CRISPR, clustered regularly interspaced short palindromic repeats; CNS, central nervous system; COOH, carboxylic terminal; CpG, C-phosphate-G; DRG, dorsal root ganglia; EP, prostaglandins; GPCR, G-protein-coupled receptors; GTN, glyceryl trinitrate; MAPK, mitogen-activated protein kinase; M-CSF, macrophage-colony stimulating factor; NAPQI, N-Acetyl parabenzoquinone-imine; NGF, nerve growth factor; NH2, amino terminal; NKA, neurokinin A; NO, nitric oxide; NRS, numerical rating scale; PAR2, protease-activated receptor 2; PMA, periorbital mechanical allodynia; PLC, phospholipase C; PKC, protein kinase C; pSNL, partial sciatic nerve ligation; RCS, reactive carbonyl species; ROS, reactive oxygen species; RNS, nitrogen oxygen species; SP, substance P; TG, trigeminal ganglion; THC, Δ9-tetrahydrocannabinol; TrkA, neurotrophic receptor tyrosine kinase A; TRP, transient receptor potential; TRPC, TRP canonical; TRPM, TRP melastatin; TRPP, TRP polycystin; TRPM, TRP mucolipin; TRPA, TRP ankyrin; TRPV, TRP vanilloid; VG, vagal ganglion.
PubMed: 37187829
DOI: 10.1080/23328940.2022.2075218 -
Cureus Jul 2022The role of neurogenic inflammation in various systemic diseases has been well established, but there is a dearth of studies and evidence regarding its role in... (Review)
Review
The role of neurogenic inflammation in various systemic diseases has been well established, but there is a dearth of studies and evidence regarding its role in periodontitis. This study aimed to systematically review the evidence in establishing the role of neurogenic inflammation in chronic periodontitis. Databases such as PubMed, Scopus, and Google Scholar were reviewed. We analyzed studies of any design that compared and evaluated the presence of neuropeptides such as substance P, calcitonin gene-related peptide, neurokinin A, neuropeptide Y, and vasoactive intestinal polypeptide in systemically healthy patients with and without periodontitis. We screened 2,495 articles and abstracts electronically and manually, which yielded 191 articles relevant to our study. Full-text examination of these 191 articles led to the final inclusion of 14 publications. Most studies here confirmed an association between various neuropeptides and periodontitis, but there is a high heterogeneity between the studies, making it necessary to clarify the mechanism between these two. Although most studies included in this review found a positive association between neurogenic inflammation and periodontitis, the evidence is of moderate to low quality.
PubMed: 35978739
DOI: 10.7759/cureus.26889 -
Frontiers in Neurology 2022Migraine headaches are highly prevalent, affecting 15% of the population. However, despite many studies to determine this disease's mechanism and efficient management,... (Review)
Review
Migraine headaches are highly prevalent, affecting 15% of the population. However, despite many studies to determine this disease's mechanism and efficient management, its pathophysiology has not been fully elucidated. There are suggested hypotheses about the possible mediating role of mast cells, immunoglobulin E, histamine, and cytokines in this disease. A higher incidence of this disease in allergic and asthma patients, reported by several studies, indicates the possible role of brain mast cells located around the brain vessels in this disease. The mast cells are more specifically within the dura and can affect the trigeminal nerve and cervical or sphenopalatine ganglion, triggering the secretion of substances that cause migraine. Neuropeptides such as calcitonin gene-related peptide (CGRP), neurokinin-A, neurotensin (NT), pituitary adenylate-cyclase-activating peptide (PACAP), and substance P (SP) trigger mast cells, and in response, they secrete pro-inflammatory and vasodilatory molecules such as interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) as a selective result of corticotropin-releasing hormone (CRH) secretion. This stress hormone contributes to migraine or intensifies it. Blocking these pathways using immunologic agents such as CGRP antibody, anti-CGRP receptor antibody, and interleukin-1 beta (IL-1β)/interleukin 1 receptor type 1 (IL-1R1) axis-related agents may be promising as potential prophylactic migraine treatments. This review is going to summarize the immunological aspects of migraine.
PubMed: 36247795
DOI: 10.3389/fneur.2022.944791 -
Journal of International Society of... 2023The levels of neuropeptides neurokinin A (NKA) and substance P (SP) in the gingival crevicular fluid of patients with symptomatic irreversible pulpitis (SIP) were... (Review)
Review
AIMS AND OBJECTIVES
The levels of neuropeptides neurokinin A (NKA) and substance P (SP) in the gingival crevicular fluid of patients with symptomatic irreversible pulpitis (SIP) were evaluated using a comprehensive review and meta-analysis.
MATERIALS AND METHODS
The data bases of Pubmed, Scopus, EBSCOhost, Science Direct, Proquest and Cochrane library databases were thoroughly searched. The quality of the study was evaluated using the Joanna Briggs Criteria. Twenty four studies were listed following a thorough search of full texts, abstracts, and removal of duplicates. Only two of these papers were eligible for inclusion in the meta-analysis. Since the results obtained were in mean and standard deviation, the levels of neuropeptides in the test and control groups were examined using the meta-analysis.
RESULTS
When compared with healthy teeth, NKA was not significantly elevated in GCF of individuals with SIP ( = 0.06; odd ratio = 1.34 [-0.05 to 2.74] at 95% confidence interval [CI]). Additionally, there was no evidence of an association between SP and SIP ( = 0.08; odds ratio = 0.84 [-0.10 to 1.77] at 95% CI).
CONCLUSION
This systematic research demonstrated that in individuals with SIP, NKA, and SP are not substantially linked. However, the lack of study in this area makes it evident that additional research is needed, particularly in relation to pulpal disorders and NKA.
PubMed: 37876583
DOI: 10.4103/jispcd.JISPCD_55_23 -
Cancer Science Aug 2022Neurokinin 2 receptor (NK2R), a G protein-coupled receptor for neurokinin A (NKA), a tachykinin family member, regulates various physiological functions including pain...
Neurokinin 2 receptor (NK2R), a G protein-coupled receptor for neurokinin A (NKA), a tachykinin family member, regulates various physiological functions including pain response, relaxation of smooth muscle, dilation of blood vessels, and vascular permeability. However, the precise role and regulation of NK2R expression in cancer cells have not been fully elucidated. In this study, we found that high NK2R gene expression was correlated with the poor survival of colorectal cancer patients, and Interferon (IFN-α/β) stimulation significantly enhanced NK2R gene expression level of colon cancer cells in a Janus kinas 1/2 (JAK 1/2)-dependent manner. NKA stimulation augmented viability/proliferation and phosphorylation of Extracellular-signal-regulated kinase 1/2 (ERK1/2) levels of IFN-α/β-treated colon cancer cells and NK2R blockade by using a selective antagonist reduced the proliferation in vitro. Administration of an NK2R antagonist alone or combined with polyinosinic-polycytidylic acid, a synthetic analog of double-stranded RNA, to CT26-bearing mice significantly suppressed tumorigenesis. NK2R-overexpressing CT26 cells showed enhanced tumorigenesis and metastatic colonization in both lung and liver after the inoculation into mice. These findings indicate that IFN-α/β-mediated NK2R expression is related to the malignancy of colon cancer cells, suggesting that NK2R blockade may be a promising strategy for colon cancers.
Topics: Animals; Carcinogenesis; Colonic Neoplasms; Gene Expression; Humans; Interferon-alpha; Interferon-beta; Mice; Neurokinin A; Receptors, Neurokinin-2
PubMed: 35561088
DOI: 10.1111/cas.15397