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BACKGROUND: Neurotrophic factors have been implicated in hyperalgesia and peripheral levels of these molecules are altered in migraine pathophysiology. Artemin, a vasculature-derived neurotrophic factor, contributes to pain modulation and trigeminal primary afferent sensitization through binding its selective receptor GFRα3. The distribution of artemin and GFRα3 in the dura mater raises an anatomy supports that they may be involved in migraine. In this study we evaluated the expression of artemin and GFRα3 in an animal migraine model that may be relevant for migraine. METHODS: In this study, using a rat migraine model by administration of nitroglycerin (NTG), we investigated the expression of artemin in the dura mater and GFRα3 in the trigeminal ganglia (TG) by means of quantitative reverse transcription-polymerase chain reaction, western blot and immunofluorescence labeling. RESULTS: Artemin immunoreactivity was found in the smooth muscle cells of dural vasculature and GFRα3 was present in cytoplasm of TG neurons. The mRNA levels of artemin and GFRα3 were significantly elevated after NTG treatment at 2 and 4 h respectively (P < 0.05). The expression of artemin protein was increased at 4 h and continually up to 8 h in the dura mater following NTG administration (P < 0.05). The expression of GFRα3 protein was elevated at 4 h and continually up to 10 h in the TG following NTG administration (P < 0.05). CONCLUSION: The findings suggest that artemin and GFRα3 play an important role in the pathogenesis of migraine and may represent potential therapeutic targets for the treatment of migraine.
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Duramadre/metabolismo , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Trastornos Migrañosos/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Ganglio del Trigémino/metabolismo , Animales , Modelos Animales de Enfermedad , Masculino , Trastornos Migrañosos/inducido químicamente , Ratas , Ratas WistarRESUMEN
Background: There have been studies on the role of sperm-associated antigen 6 (SPAG6) in cytoskeleton formation and growth cone stability, but it is also unknown how spag6 affect tumor growth and development. The aim of this study was to clarify the role of SPAG6 in pan-cancer, with some findings about thyroid carcinoma (THCA) validated through experiments. Methods: We examined the role of SPAG6 in pan-cancer, with the data being collected from databases. Further analysis was conducted to assess its correlations with prognosis, gene heterogeneity, stemness, and tumor immunity. The interacting proteins of SPAG6 were also identified, and gene ontology enrichment analysis was performed to determine its biological function. We preliminarily confirmed the role of SPAG6 via in vitro experiments and immunofluorescence staining. Results: This study found that SPAG6 expression was differentially expressed in cancers and at various tumor stages and grades. In stomach and esophageal carcinoma (STES), stomach adenocarcinoma (STAD), kidney renal clear cell carcinoma (KIRC), lung squamous cell carcinoma (LUSC), and adrenocortical carcinoma (ACC), SPAG6 expression was correlated with gender. SPAG6 expression was also found to be correlated with prognostic value, with low expression being associated with poor prognosis. Furthermore, SPAG6 expression was positively linked with immune-related cells in HNSC, chemokine receptors in LUSC, and immune checkpoint genes in THCA. Furthermore, SPAG6 overexpression suppressed the malignant phenotypes of THCA cells, manifested by slower proliferation and decreased migration. The different SPAG6 expression in THCA led to different malignant phenotypes, which are involved in the upregulation of DNA repair, MYC targets, peroxisome, and G2M checkpoint. Conclusions: SPAG6 plays a significant role as an oncogene and can be used as a marker to predict the prognosis of cancer. SPAG6 influences both the tumor immune infiltration and microenvironment, making it a promising immunotherapeutic target for tumor therapy.
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Background: Meniere disease, characterized by intermittent episodes of vertigo, fluctuating sensorineural hearing loss, tinnitus, and aural pressure, is a common cause of vertigo in humans. The pathogenesis of Meniere disease remains unknown. The current study aimed to describe a novel pathological change discovered in the inner ears of patients with Meniere disease who underwent labyrinthectomy. Methods: This retrospective case-control study was conducted with 21 patients with MD who underwent labyrinthectomy. A total of 15 patients diagnosed with acoustic neuroma or glomus jugular tumor were review over the same period of time as control. The clinical information of the patients and the pathological features of the membrane are described. Results: The new pathological tissue was a morbid membrane structure sealing the round window, characterized by the formation of lymphatic capillaries. Histochemical and immunofluorescent staining was positive for D2-40, LYVE-1, podoplanin, and PROX1, which are the classical markers of the lymphatic vessels. Transmission electron microscopy revealed that the lymph capillaries lacked a typical basement membrane and that their ends were blind, composed of a single layer of endothelial cells with valval connection structures between adjacent capillary epithelial cells. Conclusion: This is the first report of lymphatic vessels in the human inner ear, and this pathological structure is a completely new discovery. The lymphatic vessels may develop due to inflammation or decompensation of pressure in the inner ear, suggesting that the inner ear can reactively form lymphatic vessels in some inflammation and fluid flow-dependent pathological conditions. The current findings help in improving our understanding of the pathogenesis of Meniere disease.
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OBJECTIVES: The study goals were to compare the long-term efficacy of semicircular canal plugging (SCP) with labyrinthectomy in the treatment of advanced Meniere's disease (MD). STUDY DESIGN: A retrospective study. SETTING: Single tertiary medical center. METHODS: A total of 116 MD patients (TSCP group of 90; labyrinthectomy group of 26) with complete medical documents in Shandong Provincial ENT Hospital, from March 2017 to March 2019 were retrospectively analyzed, including a battery of auditory and vestibular function tests, recovery time from imbalance and function level scores (FLS). RESULTS: The total control rate of vertigo in the TSCP group was 96.7% (87/90). The rate of hearing loss was 23.3% (21/90). The control rate of vertigo in the labyrinthectomy group was 100% (26/26). All patients lost their auditory function after labyrinthectomy with a 100% hearing loss rate. There was no significant difference in the vertigo control rate between the two groups (P > 0.05). The hearing loss rate in the TSCP group was significantly lower than that in the labyrinthectomy group (P < 0.00). The median time recovered from imbalance was 15 days in TSCP group and 21 days in labyrinthectomy group, which is significantly different (P < 0.05). There was no significant difference in the FLS between the two groups (P > 0.05). CONCLUSIONS: Compared to labyrinthectomy, TSCP can preserve hearing at a high probability; meanwhile, otolith organ function preservation benefits patients from faster vestibular compensation. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:3178-3184, 2023.
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Sordera , Pérdida Auditiva , Enfermedad de Meniere , Humanos , Enfermedad de Meniere/cirugía , Estudios Retrospectivos , Canales Semicirculares/cirugía , Vértigo/etiología , Vértigo/cirugíaRESUMEN
The etiology of Ménière's disease (MD) remains controversial. Allergies are potential extrinsic factors that, in conjunction with underlying intrinsic factors, may cause MD. The link between allergies and MD was first described in 1923. For nearly a century, studies have demonstrated a possible link between allergies and MD, even though a causal relationship has not been definitively determined. Previous reviews have mainly focused on clinical epidemiology studies of patients. In this review, we shed light on the association between allergies and MD not only in terms of its epidemiology, but also from an immunology, pathophysiology, and immunotherapy perspective in both patients and animal models. Patients with MD tend to have a high risk of comorbid allergies or an allergy history, showing positive allergy immunology characteristics. Other MD-related diseases, such as migraine, may also interact with allergies. Allergy mediators such as IgE may worsen the symptoms of MD. Deposits of IgE in the vestibular end organs indicate the ability of the inner ear to participate in immune reactions. Allergic challenges can induce vertigo in animals and humans. Anti-allergy therapy plays a positive role in patients with MD and animal models of endolymphatic hydrops.
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Hidropesía Endolinfática , Hipersensibilidad , Enfermedad de Meniere , Animales , Humanos , Enfermedad de Meniere/epidemiología , Enfermedad de Meniere/etiología , Enfermedad de Meniere/terapia , Hidropesía Endolinfática/diagnóstico , Hidropesía Endolinfática/etiología , Hipersensibilidad/epidemiología , Hipersensibilidad/terapia , Hipersensibilidad/complicaciones , Inmunoterapia , Inmunoglobulina ERESUMEN
Ménière's disease, a multifactorial disorder of the inner ear, is characterized by severe vertigo episodes and hearing loss. Although the role of immune responses in Ménière's disease has been proposed, the precise mechanisms remain undefined. Here, we show that downregulation of serum/glucocorticoid-inducible kinase 1 is associated with activation of NLRP3 inflammasome in vestibular-resident macrophage-like cells from Ménière's disease patients. Serum/glucocorticoid-inducible kinase 1 depletion markedly enhances IL-1ß production which leads to the damage of inner ear hair cells and vestibular nerve. Mechanistically, serum/glucocorticoid-inducible kinase 1 binds to the PYD domain of NLRP3 and phosphorylates it at Serine 5, thereby interfering inflammasome assembly. Sgk-/- mice show aggravated audiovestibular symptoms and enhanced inflammasome activation in lipopolysaccharide-induced endolymphatic hydrops model, which is ameliorated by blocking NLRP3. Pharmacological inhibition of serum/glucocorticoid-inducible kinase 1 increases the disease severity in vivo. Our studies demonstrate that serum/glucocorticoid-inducible kinase 1 functions as a physiologic inhibitor of NLRP3 inflammasome activation and maintains inner ear immune homeostasis, reciprocally participating in models of Ménière's disease pathogenesis.
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Hidropesía Endolinfática , Enfermedad de Meniere , Animales , Ratones , Glucocorticoides , Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , MacrófagosRESUMEN
Background: To explore the long-term efficacy and safety of resection of the lateral wall of the endolymphatic sac for the treatment of intractable Meniere's disease (MD) as an alternative surgical procedure for treating this disorder. Methods: Data from 73 patients who were referred to our hospital and diagnosed with unilateral MD between January 2015 and June 2019 were retrospectively analyzed in this study. Seventy-three patients who had frequent vertigo even after receiving standardized conservative treatment for at least half a year underwent resection of the lateral wall of the endolymphatic sac. Vertigo control and auditory function were assessed. Pure tone audiometry, caloric test, and vestibular evoked myogenic potential were performed to evaluate audiological and vestibular functions. The post-operative follow-up duration was more than 2 years. Results: Among the 73 patients (male 34 cases, female 39 cases; age 20-69 years, average 51.4), vertigo was controlled effectively for 66 cases (90.4%) after 2 years of follow-up; 45 cases (61.6%) were completely controlled, and 21 cases (28.8%) were substantially controlled in this study. The patients of 16.4% had hearing loss with more than 10 dB change based on the four-tone average (0.5, 1, 2 and 3 kHz). No patient had a facial nerve weakness, cerebrospinal fluid leakage, or other complications. Conclusion: Resection of the lateral wall of the endolymphatic sac, which can effectively control vertiginous symptoms in intractable MD patients, represents an effective and safe therapy for this disease. Resection of the lateral wall of the endolymphatic sac is expected to be used as an alternative treatment for MD.
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Introduction: Ménière's disease (MD), a common disease in the inner ear, is characterized by an increase in endolymph in the cochlear duct and vestibular labyrinth. The pathophysiology of the condition appears to be the immune response. Studies have shown that basal levels of the IL-1ß increased in some MD patients. Methods: Here, we used a murine model of endolymphatic hydrops (EH) to study the effect of anakinra on auditory and vestibular function. Mice were intraperitoneal injected with anakinra or saline before LPS by postauricular injection. Weight and disease severity were measured, histologic changes in auditory were assessed, and inflammation state was evaluated. Results: We found that anakinra therapy reduced LPS-induced EH, alleviated LPS-induced hearing loss and vestibular dysfunction, and inhibited the expression of the inflammatory cytokines and macrophage infiltration in the cochlea of mice. We further demonstrated that anakinra ameliorated the disorganization and degeneration of myelin sheath, and reduced the neuron damage in cochlea of EH mice. Discussion: Consequently, anakinra contributes to a promising therapeutic approach to MD, by restricting EH, alleviating auditory and vestibular function, inhibiting inflammation of the inner ear and protecting the cochlear nerve. Further investigations are needed to assess the potential therapeutic benefits of anakinra in patients with MD.
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Mitochondria are believed to have originated ~2.5 billion years ago. As well as energy generation in cells, mitochondria have a role in defence against bacterial pathogens. Despite profound changes in mitochondrial morphology and functions following bacterial challenge, whether intracellular bacteria can hijack mitochondria to promote their survival remains elusive. We report that Listeria monocytogenes-an intracellular bacterial pathogen-suppresses LC3-associated phagocytosis (LAP) by modulation of mitochondrial Ca2+ (mtCa2+) signalling in order to survive inside cells. Invasion of macrophages by L. monocytogenes induced mtCa2+ uptake through the mtCa2+ uniporter (MCU), which in turn increased acetyl-coenzyme A (acetyl-CoA) production by pyruvate dehydrogenase. Acetylation of the LAP effector Rubicon with acetyl-CoA decreased LAP formation. Genetic ablation of MCU attenuated intracellular bacterial growth due to increased LAP formation. Our data show that modulation of mtCa2+ signalling can increase bacterial survival inside cells, and highlight the importance of mitochondrial metabolism in host-microbial interactions.
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Señalización del Calcio , Listeria monocytogenes/fisiología , Proteínas Asociadas a Microtúbulos/antagonistas & inhibidores , Mitocondrias/metabolismo , Fagocitosis , Acetilcoenzima A/metabolismo , Acetilación , Animales , Proteínas Relacionadas con la Autofagia/metabolismo , Calcio/metabolismo , Canales de Calcio/genética , Canales de Calcio/metabolismo , Interacciones Huésped-Patógeno , Humanos , Listeria monocytogenes/crecimiento & desarrollo , Listeria monocytogenes/metabolismo , Macrófagos/metabolismo , Macrófagos/microbiología , Ratones , Proteínas Asociadas a Microtúbulos/metabolismo , Mutación , NADPH Oxidasas/metabolismoRESUMEN
Background: TSCP has shown its efficacy in vertigo control for intractable Meniere's disease. However, hearing impairment remains a problem and hampered the application of the surgery.Aims/objectives: To investigate the effect of dexamethasone on the hearing of Meniere's disease patients after TSCP to determine whether inflammation is involved in this processMaterial and methods: Meniere's disease patients who received TSCP surgeries were treated with or without dexamethasone postoperatively. All patients' hearing function were evaluated during a follow up of 2 years after surgery and compared between the two groups.Results: Hearing worsening and word recognition score loss were milder in the dexamethasone group than in the non-dexamethasone group. The rates of profound hearing worsening and word recognition score loss remained significantly lower in the dexamethasone group than in the non-dexamethasone group even 2 years after surgery.Conclusions: Dexamethasone protects the hearing of Meniere's patients after TSCP. Inflammation may be involved in the mechanism by which TSCP causes hearing impairment in these patients.Significance: This finding suggests that steroids should be used routinely after TSCP for hearing preservation, and operative precedures need to be modified to minimize inflammation in the inner ear.
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Antiinflamatorios/uso terapéutico , Dexametasona/uso terapéutico , Trastornos de la Audición/prevención & control , Enfermedad de Meniere/tratamiento farmacológico , Complicaciones Posoperatorias/prevención & control , Canales Semicirculares/cirugía , Adulto , Anciano , Femenino , Humanos , Masculino , Enfermedad de Meniere/cirugía , Persona de Mediana Edad , Pruebas de Discriminación del HablaRESUMEN
INTRODUCTION: Meniere's disease is a common chronic inner ear disease. Because the definitive pathogenesis is still unknown, there is currently no cure for this disorder. Semicircular canal plugging (SCP), first used to treat patients with intractable benign paroxysmal positional vertigo, has since been applied to patients with intractable peripheral vertigo. This study was aimed to explore the long-term efficacy of triple semicircular canal plugging (TSCP) in the treatment of intractable Meniere's disease (MD) so as to provide a new method in the framework of treatment with MD. METHODS: Three hundred and sixty-one unilateral MD patients, who were treated with TSCP in our hospital between Dec. 2010 and Sep. 2016, were recruited in this study for retrospective analysis. Vertigo control and auditory function were monitored during a period of two-year follow-up. Seventy three patients who were subjected to intratympanic gentamicin were selected as a control group. Pure tone audiometry, caloric test, vestibular evoked myogenic potential (VEMP) were performed in two-year follow-up. RESULTS: The total control rate of vertigo in TSCP group was 97.8% (353/361) in the two-year follow-up, with complete control rate of 80.3% (290/361) and substantial control rate of 17.5% (63/361). The rate of hearing loss was 26.3% (95/361). The total control rate of vertigo in intratympanic gentamicin group was 83.6% (61/73), with complete control rate of 63.0% (46/73) and substantial control rate of 20.5% (15/73). The rate of hearing loss was 24.7% (18/73). The vertigo control rate of TSCP was significantly higher than that of chemical labyrinthectomy(χ2â=â24.798, pâ< â0.05). There was no significant difference of hearing loss rate between two groups. (χ2â=â0.087, pâ> â0.05). CONCLUSION: Triple semicircular canal plugging (TSCP), which can reduce vertiginous symptoms in patients with intractable Meniere's disease (MD), represents an effective therapy for this disorder. It might become a new important method in the framework of treatment with MD.