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Long non-coding RNAs (lncRNAs) have emerged as crucial regulators in the central nervous system, yet their role in vestibular compensation remains elusive. To address this knowledge gap, we employed unilateral labyrinthectomy (UL) in rats to establish animal models of peripheral vestibular dysfunction. Utilizing ribonucleic acid sequencing (RNA-seq), we comprehensively analysed the expression profiles of genes dysregulated in the medial vestibular nucleus (MVN) of these rats at distinct time points: 4 h, 4 days, and 14 days post-UL. Through trans-target prediction analysis integrating differentially co-expressed messenger RNAs (mRNAs) and lncRNAs, we constructed lncRNA-mRNA regulatory networks. Validation of selected mRNAs and lncRNAs was performed using RT-qPCR. Our RNA-seq analysis revealed significant aberrant expression of 3054 lncRNAs and 1135 mRNAs compared to control samples. By applying weighted gene co-expression network analysis (WGCNA), we identified 11 co-expressed modules encompassing all genes. Notably, within the MEmagenta module, we observed an initial upregulation of differentially expressed genes (DEGs) at 4 h, followed by downregulation at 4- and 14-days post-UL. Our findings indicated that 3068 lncRNAs positively regulated 1259 DEGs, while 1482 lncRNAs negatively regulated 433 DEGs in the MVN. The RT-qPCR results corroborated the RNA-seq data, validating our findings. This study offers novel insights into the lncRNA-mRNA expression landscape during vestibular compensation, paving the way for further exploration of lncRNA functions in this context.
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Perfilación de la Expresión Génica , Redes Reguladoras de Genes , ARN Largo no Codificante , ARN Mensajero , Núcleos Vestibulares , Vestíbulo del Laberinto , Animales , Núcleos Vestibulares/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Masculino , Vestíbulo del Laberinto/cirugía , Vestíbulo del Laberinto/metabolismo , Regulación de la Expresión Génica , Ratas Sprague-Dawley , Transcriptoma/genéticaRESUMEN
Artificial intelligence transforms drug discovery, with phenotype-based approaches emerging as a promising alternative to target-based methods, overcoming limitations like lack of well-defined targets. While chemical-induced transcriptional profiles offer a comprehensive view of drug mechanisms, inherent noise often obscures the true signal, hindering their potential for meaningful insights. Here, we highlight the development of TranSiGen, a deep generative model employing self-supervised representation learning. TranSiGen analyzes basal cell gene expression and molecular structures to reconstruct chemical-induced transcriptional profiles with high accuracy. By capturing both cellular and compound information, TranSiGen-derived representations demonstrate efficacy in diverse downstream tasks like ligand-based virtual screening, drug response prediction, and phenotype-based drug repurposing. Notably, in vitro validation of TranSiGen's application in pancreatic cancer drug discovery highlights its potential for identifying effective compounds. We envisage that integrating TranSiGen into the drug discovery and mechanism research holds significant promise for advancing biomedicine.
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Aprendizaje Profundo , Descubrimiento de Drogas , Fenotipo , Descubrimiento de Drogas/métodos , Humanos , Reposicionamiento de Medicamentos/métodos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Transcriptoma , Perfilación de la Expresión Génica/métodos , Antineoplásicos/farmacología , Inteligencia ArtificialRESUMEN
Dysregulation of the Hippo pathway has been observed in various cancers. The transcription factor TEAD, together with its coactivators YAP/TAZ, plays a crucial role in regulating the transcriptional output of the Hippo pathway. Recently, extensive research has focused on small molecule inhibitors targeting TEAD, but studies on TEAD degraders are comparatively rare. In this study, we designed and synthesized a series of TEAD PROTACs by connecting a pan-TEAD inhibitor with the CRBN ligand thalidomide. A representative compound, 27, exhibited potent antiproliferative activity against NF2-deficient NCI-H226 cells. It dose-dependently induced TEAD degradation dependent on CRBN and proteasome system and decreased key YAP target genes CYR61 and CTGF expressions in NCI-H226 cells. Further degradation selectivity studies revealed that 27 exhibited more potent activity against TEAD2 compared to those of the other three family members in Flag-TEADs transfected 293T cells. Therefore, 27 may serve as a valuable tool for advancing biological studies related to TEAD2.
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Oncogenic KRAS mutations drive an approximately 25 % of all human cancers. Son of Sevenless 1 (SOS1), a critical guanine nucleotide exchange factor, catalyzes the activation of KRAS. Targeting SOS1 degradation has engaged as a promising therapeutic strategy for KRAS-mutant cancers. Herein, we designed and synthesized a series of novel CRBN-recruiting SOS1 PROTACs using the pyrido[2,3-d]pyrimidin-7-one-based SOS1 inhibitor as the warhead. One representative compound 11o effectively induced the degradation of SOS1 in three different KRAS-mutant cancer cell lines with DC50 values ranging from 1.85 to 7.53 nM. Mechanism studies demonstrated that 11o-induced SOS1 degradation was dependent on CRBN and proteasome. Moreover, 11o inhibited the phosphorylation of ERK and displayed potent anti-proliferative activities against SW620, A549 and DLD-1 cells. Further optimization of 11o may provide us promising SOS1 degraders with favorable drug-like properties for developing new chemotherapies targeting KRAS-driven cancers.
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Antineoplásicos , Proliferación Celular , Diseño de Fármacos , Proteína SOS1 , Humanos , Proteína SOS1/metabolismo , Proteína SOS1/antagonistas & inhibidores , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Línea Celular Tumoral , Estructura Molecular , Ensayos de Selección de Medicamentos Antitumorales , Relación Dosis-Respuesta a Droga , Pirimidinas/farmacología , Pirimidinas/síntesis química , Pirimidinas/química , Pirimidinonas/farmacología , Pirimidinonas/síntesis química , Pirimidinonas/química , Quimera Dirigida a la ProteólisisRESUMEN
BACKGROUND: Breast cancer is a serious threat to women's health with high morbidity and mortality. The development of more effective therapies for the treatment of breast cancer is strongly warranted. Growing evidence suggests that targeting glucose metabolism may be a promising cancer treatment strategy. We previously identified a new glyceraldehyde-3-phosphate dehydrogenase (GAPDH) inhibitor, DC-5163, which shows great potential in inhibiting tumor growth. Here, we evaluated the anticancer potential of DC-5163 in breast cancer cells. METHODS: The effects of DC-5163 on breast cancer cells were investigated in vitro and in vivo. Seahorse, glucose uptake, lactate production, and cellular ATP content assays were performed to examine the impact of DC-5163 on cellular glycolysis. Cell viability, colony-forming ability, cell cycle, and apoptosis were assessed by CCK8 assay, colony formation assay, flow cytometry, and immunoblotting respectively. The anticancer activity of DC-5163 in vivo was evaluated in a mouse breast cancer xenograft model. RESULTS: DC-5163 suppressed aerobic glycolysis and reduced energy supply of breast cancer cells, thereby inhibiting breast cancer cell growth, inducing cell cycle arrest in the G0/G1 phase, and increasing apoptosis. The therapeutic efficacy was assessed using a breast cancer xenograft mouse model. DC-5163 treatment markedly suppressed tumor growth in vivo without inducing evident systemic toxicity. Micro-PET/CT scans revealed a notable reduction in tumor 18F-FDG and 18F-FLT uptake in the DC-5163 treatment group compared to the DMSO control group. CONCLUSIONS: Our results suggest that DC-5163 is a promising GAPDH inhibitor for suppressing breast cancer growth without obvious side effects. 18F-FDG and 18F-FLT PET/CT can noninvasively assess the levels of glycolysis and proliferation in tumors following treatment with DC-5163.
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Kinase-targeted inhibitors hold promise for new therapeutic options, with multi-target inhibitors offering the potential for broader efficacy while minimizing polypharmacology risks. However, comprehensive experimental profiling of kinome-wide activity is expensive, and existing computational approaches often lack scalability or accuracy for understudied kinases. We introduce KinomeMETA, an artificial intelligence (AI)-powered web platform that significantly expands the predictive range with scalability for predicting the polypharmacological effects of small molecules across the kinome. By leveraging a novel meta-learning algorithm, KinomeMETA efficiently utilizes sparse activity data, enabling rapid generalization to new kinase tasks even with limited information. This significantly expands the repertoire of accurately predictable kinases to 661 wild-type and clinically-relevant mutant kinases, far exceeding existing methods. Additionally, KinomeMETA empowers users to customize models with their proprietary data for specific research needs. Case studies demonstrate its ability to discover new active compounds by quickly adapting to small dataset. Overall, KinomeMETA offers enhanced kinome virtual profiling capabilities and is positioned as a powerful tool for developing new kinase inhibitors and advancing kinase research. The KinomeMETA server is freely accessible without registration at https://kinomemeta.alphama.com.cn/.
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Internet , Polifarmacología , Inhibidores de Proteínas Quinasas , Proteínas Quinasas , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Proteínas Quinasas/metabolismo , Proteínas Quinasas/química , Proteínas Quinasas/genética , Humanos , Programas Informáticos , Algoritmos , Inteligencia Artificial , Descubrimiento de Drogas/métodosRESUMEN
Living active collectives have evolved with remarkable self-patterning capabilities to adapt to the physical and biological constraints crucial for their growth and survival. However, the intricate process by which complex multicellular patterns emerge from a single founder cell remains elusive. In this study, we utilize an agent-based model, validated through single-cell microscopy imaging, to track the three-dimensional (3D) morphodynamics of cells within growing bacterial biofilms encased by agarose gels. The confined growth conditions give rise to a spatiotemporally heterogeneous stress landscape within the biofilm. In the core of the biofilm, where high hydrostatic and low shear stresses prevail, cell packing appears disordered. In contrast, near the gel-cell interface, a state of high shear stress and low hydrostatic stress emerges, driving nematic ordering, albeit with a time delay inherent to shear stress relaxation. Strikingly, we observe a robust spatiotemporal correlation between stress anisotropy and nematic ordering within these confined biofilms. This correlation suggests a mechanism whereby stress anisotropy plays a pivotal role in governing the spatial organization of cells. The reciprocity between stress anisotropy and cell ordering in confined biofilms opens new avenues for innovative 3D mechanically guided patterning techniques for living active collectives, which hold significant promise for a wide array of environmental and biomedical applications.
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Biopelículas , Estrés Mecánico , Anisotropía , Modelos BiológicosRESUMEN
Respiratory disease caused by coronavirus infection remains a global health crisis. Although several SARS-CoV-2-specific vaccines and direct-acting antivirals are available, their efficacy on emerging coronaviruses in the future, including SARS-CoV-2 variants, might be compromised. Host-targeting antivirals provide preventive and therapeutic strategies to overcome resistance and manage future outbreak of emerging coronaviruses. Cathepsin L (CTSL) and calpain-1 (CAPN1) are host cysteine proteases which play crucial roles in coronaviral entrance into cells and infection-related immune response. Here, two peptidomimetic α-ketoamide compounds, 14a and 14b, were identified as potent dual target inhibitors against CTSL and CAPN1. The X-ray crystal structures of human CTSL and CAPN1 in complex with 14a and 14b revealed the covalent binding of α-ketoamide groups of 14a and 14b to C25 of CTSL and C115 of CAPN1. Both showed potent and broad-spectrum anticoronaviral activities in vitro, and it is worth noting that they exhibited low nanomolar potency against SARS-CoV-2 and its variants of concern (VOCs) with EC50 values ranging from 0.80 to 161.7 nM in various cells. Preliminary mechanistic exploration indicated that they exhibited anticoronaviral activity through blocking viral entrance. Moreover, 14a and 14b exhibited good oral pharmacokinetic properties in mice, rats and dogs, and favorable safety in mice. In addition, both 14a and 14b treatments demonstrated potent antiviral potency against SARS-CoV-2 XBB 1.16 variant infection in a K18-hACE2 transgenic mouse model. And 14b also showed effective antiviral activity against HCoV-OC43 infection in a mouse model with a final survival rate of 60%. Further evaluation showed that 14a and 14b exhibited excellent anti-inflammatory effects in Raw 264.7 mouse macrophages and in mice with acute pneumonia. Taken together, these results suggested that 14a and 14b are promising drug candidates, providing novel insight into developing pan-coronavirus inhibitors with antiviral and anti-inflammatory properties.
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COVID-19 , Hepatitis C Crónica , Humanos , Animales , Ratones , Ratas , Perros , Calpaína , Catepsina L , Antivirales/farmacología , Vacunas contra la COVID-19 , Modelos Animales de Enfermedad , Ratones Transgénicos , AntiinflamatoriosRESUMEN
Noise-induced hearing loss (NIHL) is a prevalent form of adult hearing impairment, characterized by oxidative damage to auditory sensory hair cells. Although certain dihydropyridines, the L-type calcium channel blockers, exhibit protective properties against such damage, the ability of third-generation dihydropryidines like lercanidipine to mitigate NIHL remains unclear.We utilized glucose oxidase (GO)-treated OC1 cell lines and cochlear explants to evaluate the protective influence of lercanidipine on hair cells. To further investigate its effectiveness, we exposed noise-stimulated mice in vivo and analyzed their hearing thresholds. Additionally, we assessed the antioxidative capabilities of lercanidipine by examining oxidation-related enzyme expression and levels of oxidative stress markers, including 3-nitrotyrosine (3NT) and 4-hydroxynonenal (4HNE). Our findings demonstrate that lercanidipine significantly reduces the adverse impacts of GO on both OC-1 cell viability (0.3 to 2.5 µM) and outer hair cell (OHC) survival in basal turn cochlear explants (7 µM). These results are associated with increased mRNA expression of antioxidant enzyme genes (HO-1, SOD1/2, and Txnrd1), along with decreased expression of oxidase genes (COX-2, iNOS). Crucially, lercanidipine administration prior to, and following, noise exposure effectively ameliorates NIHL, as evidenced by lowered hearing thresholds and preserved OHC populations in the basal turn, 14 days post-noise stimulation at 110 dB SPL. Moreover, our observations indicate that lercanidipine's antioxidative action persists even three days after simultaneous drug and noise treatments, based on 3-nitrotyrosine and 4-hydroxynonenal immunostaining in the basal turn. Based on these findings, we propose that lercanidipine has the capacity to alleviate NIHL and safeguard OHC survival in the basal turn, potentially via its antioxidative mechanism. These results suggest that lercanidipine holds promise as a clinically viable option for preventing NIHL in affected individuals.
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Regulatory T (Treg) cells are critical for immune tolerance but also form a barrier to antitumor immunity. As therapeutic strategies involving Treg cell depletion are limited by concurrent autoimmune disorders, identification of intratumoral Treg cell-specific regulatory mechanisms is needed for selective targeting. Epigenetic modulators can be targeted with small compounds, but intratumoral Treg cell-specific epigenetic regulators have been unexplored. Here, we show that JMJD1C, a histone demethylase upregulated by cytokines in the tumor microenvironment, is essential for tumor Treg cell fitness but dispensable for systemic immune homeostasis. JMJD1C deletion enhanced AKT signals in a manner dependent on histone H3 lysine 9 dimethylation (H3K9me2) demethylase and STAT3 signals independently of H3K9me2 demethylase, leading to robust interferon-γ production and tumor Treg cell fragility. We have also developed an oral JMJD1C inhibitor that suppresses tumor growth by targeting intratumoral Treg cells. Overall, this study identifies JMJD1C as an epigenetic hub that can integrate signals to establish tumor Treg cell fitness, and we present a specific JMJD1C inhibitor that can target tumor Treg cells without affecting systemic immune homeostasis.
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Enfermedades Autoinmunes , Humanos , Citocinas , Epigenómica , Histona Demetilasas , Homeostasis , Oxidorreductasas N-Desmetilantes , Histona Demetilasas con Dominio de Jumonji/genéticaRESUMEN
Speckle-type POZ protein (SPOP) acts as a cullin3-RING ubiquitin ligase adaptor, which facilitates the recognition and ubiquitination of substrate proteins. Previous research suggests that targeting SPOP holds promise in the treatment of clear cell renal cell carcinoma (ccRCC). On the basis of the reported SPOP inhibitor 230D7, a series of ß-lactam derivatives were synthesized in this study. The biological activity assessment of these compounds revealed E1 as the most potent inhibitor, which can disrupt the SPOP-substrate interactions in vitro and suppress the colony formation of ccRCC cells. Taken together, this study provided compound E1 as a potent inhibitor against ccRCC and offered insight into the development of the ß-lactam SPOP inhibitor.
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The vestibular system may have a critical role in the integration of sensory information and the maintenance of cognitive function. A dysfunction in the vestibular system has a significant impact on quality of life. Recent research has provided evidence of a connection between vestibular information and cognitive functions, such as spatial memory, navigation and attention. Although the exact mechanisms linking the vestibular system to cognition remain elusive, researchers have identified various pathways. Vestibular dysfunction may lead to the degeneration of cortical vestibular network regions and adversely affect synaptic plasticity and neurogenesis in the hippocampus, ultimately contributing to neuronal atrophy and cell death, resulting in memory and visuospatial deficits. Furthermore, the extent of cognitive impairment varies depending on the specific type of vestibular disease. In the present study, the current literature was reviewed, potential causal relationships between vestibular dysfunction and cognitive performance were discussed and directions for future research were proposed.
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Disfunción Cognitiva , Enfermedades Vestibulares , Humanos , Cognición/fisiología , Disfunción Cognitiva/etiología , Calidad de Vida , Memoria Espacial/fisiología , Enfermedades Vestibulares/psicologíaRESUMEN
KRASG12D, the most frequent KRAS oncogenic mutation, is a promising target for cancer therapy. Herein, we report the design, synthesis, and biological evaluation of a series of KRASG12D PROTACs by connecting the analogues of MRTX1133 and the VHL ligand. Structural modifications of the linker moiety and KRAS inhibitor part suggested a critical role of membrane permeability in the degradation activity of the KRASG12D PROTACs. Mechanism studies with the representative compound 8o demonstrated that the potent, rapid, and selective degradation of KRASG12D induced by 8o was via a VHL- and proteasome-dependent manner. This compound selectively and potently suppressed the growth of multiple KRASG12D mutant cancer cells, displayed favorable pharmacokinetic and pharmacodynamic properties in mice, and showed significant antitumor efficacy in the AsPC-1 xenograft mouse model. Further optimization of 8o appears to be promising for the development of a new chemotherapy for KRASG12D-driven cancers as the complementary therapeutic strategy to KRAS inhibition.
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Proteínas Proto-Oncogénicas p21(ras) , Animales , Humanos , Ratones , Modelos Animales de Enfermedad , Mutación , Proteínas Proto-Oncogénicas p21(ras)/genéticaRESUMEN
AIMS: To investigate the role of mGluR1α in cerebellar unipolar brush cells (UBC) in mediating vestibular compensation (VC), using mGluR1α agonist and antagonist to modulate ON UBC neurons, and explore the mGluR1/IP3/extracellular signal-regulated kinase (ERK) signaling pathway. METHODS: First, AAV virus that knockdown ON UBC (mGluR1α) were injected into cerebellar UBC by stereotactic, and verified by immunofluorescence and western blot. The effect on VC was evaluated after unilateral labyrinthectomy (UL). Second, saline, (RS)-3,5-dihydroxyphenylglycine (DHPG), and LY367385 were injected into tubes implanted in rats at different time points after UL separately. The effect on ON UBC neuron activity was evaluated by immunofluorescence. Then, Phosphoinositide (PI) and p-ERK1/2 levels of mGluR1α were analyzed by ELISA after UL. The protein levels of p-ERK and total ERK were verified by western blot. In addition, the effect of mGluR1α activation or inhibition on VC-related behavior was observed. RESULTS: mGluR1α knockdown induced VC phenotypes. DHPG increased ON UBC activity, while LY367385 reduced ON UBC activity. DHPG group showed an increase in PI and p-ERK1/2 levels, while LY367385 group showed a decrease in PI and p-ERK1/2 levels in cerebellar UBC of rats. The western blot results of p-ERK and total ERK confirm and support the observations. DHPG alleviated VC-related behavior phenotypes, while LY367385 exacerbated vestibular decompensation-like behavior induced by UL. CONCLUSION: mGluR1α activity in cerebellar ON UBC is crucial for mediating VC through the mGluR1/IP3/ERK signaling pathway, which affects ON UBC neuron activity and contributes to the pathogenesis of VC.
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Benzoatos , Quinasas MAP Reguladas por Señal Extracelular , Glicina/análogos & derivados , Metoxihidroxifenilglicol/análogos & derivados , Receptores de Glutamato Metabotrópico , Transducción de Señal , Ratas , AnimalesRESUMEN
BACKGROUND: With rapid urban sprawl, growing people are living in the vicinity of major roadways. However, little is known about the relationship between residential proximity to major roadways and hearing impairment (HI). METHODS: We derived data from the 2018 wave of the Chinese Longitudinal Healthy Longevity Survey, and included 13,775 participants aged 65 years or older. Multivariate logistic regressions were employed to examine the association between residential proximity to major roadways and HI. The effects of corresponding potentially modifiable factors were studied by three-way interaction analyses. Sensitivity analyses were performed to verify the robustness of the results. RESULTS: The prevalence of HI was 38.3%. Participants living near major roadways were more likely to have a higher socioeconomic status. An exposure-response relation between residential proximity to major roadways and HI was observed (Ptrend < 0.05). Compared with individuals living > 300 m away from major roadways, the adjusted odds ratios (OR) were 1.07 (95% CI: 0.96-1.24), 1.15 (95% CI: 1.07-1.34), and 1.12 (95% CI: 1.01-1.31) for those living 101-200 m, 50-100 m, and < 50 m away from the roadways, respectively. Particularly, the association was more pronounced among individuals exposed to carbon monoxide (CO) pollution or opening windows frequently (Pinteraction < 0.05). Three-way interaction analyses confirmed that participants exposed to CO pollution and frequently leaving windows open had the highest OR of 1.73 (95% CI: 1.58-1.89). CONCLUSIONS: This nation-wide cohort study suggested that residential proximity to major roadways was significantly associated with an increased exposure-response risk of HI in Chinese older adults. Exposure to CO pollution and opening windows frequently might strengthen the relations.
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Contaminantes Atmosféricos , Contaminación del Aire , Pérdida Auditiva , Humanos , Anciano , Estudios de Cohortes , Emisiones de Vehículos/análisis , Características de la Residencia , Pérdida Auditiva/epidemiología , China/epidemiología , Exposición a Riesgos Ambientales/efectos adversos , Contaminantes Atmosféricos/análisisRESUMEN
Kinase inhibitors are crucial in cancer treatment, but drug resistance and side effects hinder the development of effective drugs. To address these challenges, it is essential to analyze the polypharmacology of kinase inhibitor and identify compound with high selectivity profile. This study presents KinomeMETA, a framework for profiling the activity of small molecule kinase inhibitors across a panel of 661 kinases. By training a meta-learner based on a graph neural network and fine-tuning it to create kinase-specific learners, KinomeMETA outperforms benchmark multi-task models and other kinase profiling models. It provides higher accuracy for understudied kinases with limited known data and broader coverage of kinase types, including important mutant kinases. Case studies on the discovery of new scaffold inhibitors for membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase and selective inhibitors for fibroblast growth factor receptors demonstrate the role of KinomeMETA in virtual screening and kinome-wide activity profiling. Overall, KinomeMETA has the potential to accelerate kinase drug discovery by more effectively exploring the kinase polypharmacology landscape.
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Antineoplásicos , Polifarmacología , Proteínas Serina-Treonina Quinasas , Descubrimiento de DrogasRESUMEN
BACKGROUND: This study aimed to investigate the effects of unilateral labyrinthectomy (UL) on monoamine neurotransmitters in the medial vestibular nucleus (MVN) of rats. METHODS: Adult Sprague-Dawley rats were utilized for the vestibular impaired animal model through UL. The success of the model establishment and the recovery process were evaluated using vestibular behavioral tests, including spontaneous nystagmus, postural asymmetry, and balance beam test. Additionally, the expression levels of c-Fos protein in the MVN were assessed by immunofluorescence. Furthermore, changes in the expression levels of monoamine neurotransmitters, including 5-hydroxytryptamine (5-HT), norepinephrine (NE), dopamine (DA), and histamine in the MVN, were analyzed using high-performance liquid chromatography (HPLC) at different time points after UL (4 h, 8 h, 1 day, 2 days, 4 days, and 7 days). RESULTS: Compared to the sham control group, the UL group exhibited the most pronounced vestibular impairment symptoms at 4 h post-UL, which significantly decreased at 4 days and almost fully recovered by 7 days. Immunofluorescence results showed a notable upregulation of c-Fos expression in the MVN subsequent to the UL-4 h, serving as a reliable indicator of heightened neuronal activity. In comparison with the sham group, HPLC analysis showed that the levels of 5-HT and NE in the ipsilesional MVN of the UL group were significantly elevated within 4 days after UL, and peaked on 1 day and 2 days, respectively. DA showed an increasing trend at different time points up to 7 days post-UL, while histamine levels significantly increased only at 1 day post-UL. CONCLUSIONS: UL-induced dynamic changes in monoamine neurotransmitters during the early compensation period in the rat MVN may be associated with the regulation of the central vestibular compensation mechanism by the MVN.
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Histamina , Vestíbulo del Laberinto , Ratas , Animales , Ratas Sprague-Dawley , Histamina/metabolismo , Serotonina/metabolismo , Neurotransmisores/metabolismo , Núcleos Vestibulares/metabolismoRESUMEN
Objective: This study proposes a "modular management" approach for vestibular neuritis (VN) to reduce chronicization and improve patient prognosis. The approach involves multi-factor grading and hierarchical intervention and was found to be more effective than traditional treatment strategies. Methods: This retrospective analysis compared two groups of VN patients from two medical institutions. The intervention group of 52 patients received "modular management," while the control group of 51 patients did not receive this kind of management. Analyzed the early treatment strategies, 6-month prognosis, and other indicators of the two groups of patients, compared and analyzed their overall prognosis, and identified the risk factors affecting the chronicization. Results: The modular management group had lower dizziness severity, better balance, lower anxiety, and higher video head impulse testing (v-HIT) gain after 6 months of onset. Analysis of factors related to persistent postural-perceptual dizziness (PPPD) in patients with VN showed positive correlations between the time from onset to diagnosis and PPPD, and Vertigo Symptom Scale (VSS), Dizziness Handicap Inventory (DHI), anxiety, and depression. Normalized vestibular rehabilitation was negatively correlated with PPPD, while gender, age, and early steroid use had no significant correlation. The multi-factor logistic regression model correctly classified 93.20% of the study subjects with a sensitivity of 87.50% and specificity of 94.90%. Conclusion: The proposed "modular management" scheme for VN is a comprehensive and dynamic approach that includes health education, assessment, rehabilitation, therapy, evaluation, and prevention. It can significantly improve patient prognosis and reduce chronicization by shifting from simple acute treatment to continuous management.
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(1) Background: Patients with vestibular migraine (VM) often present with positional vertigo. A portion of these patients have features of benign paroxysmal positional vertigo (BPPV). It is a challenge to rapidly identify the BPPV component of VM associated with positional vertigo. (2) Methods: Retrospective data collected from 60 VM and 47 VM + BPPV patients were used to build a diagnostic model, and then prospective data from 47 patients were used for the external validation. All patients had VM manifesting as positional vertigo, with or without accompanying BPPV. The clinical manifestations and the results of vestibular function tests were comprehensively analyzed using logistic regression. (3) Results: The univariate and multivariate analyses showed that the age, symptom duration, tinnitus, ear fullness, nausea, head shaking nystagmus, the direction of the Dix-Hallpike and roll tests, and horizontal gain could help differentiate between the two groups. A nomogram and an online calculator were generated. The C-index was 0.870. The diagnostic model showed good discriminative power and calibration performance during internal and external validation. (4) Conclusions: This study provided a new perspective for diagnosing VM with positional vertigo by identifying the BPPV component and, for the first time, offers a prediction model integrating multiple predictors.