RESUMEN
OBJECTIVE: To compare the perioperative indexes and long-term effects of craniotomy and neuro-endoscopic hematoma removal in patients with hypertensive intracerebral hemorrhage (HICH) in the basal ganglia region. METHODS: This study involved 128 patients with HICH in the basal ganglia region who were admitted to our hospital from February 2020 to June 2022. They were divided into 2 groups according to the random number table method. The craniotomy group (n = 70) underwent microsurgery with small bone window craniotomy with a side cleft, and the neuro-endoscopy group (n = 58) underwent small bone window neuro-endoscopic surgery. A 3-dimensional Slicer was used to calculate the hematoma volume and clearance rate and the postoperative brain tissue edema volume. The operation time, intraoperative blood loss, postoperative intracranial pressure, complications, mortality, and improvement in the modified Rankin scale score at 6 months postoperatively were compared between the two groups. RESULTS: The clearance rate was significantly higher in the neuro-endoscopy group than in the craniotomy group (94.16% ± 1.86% versus 90.87% ± 1.89%, P < 0.0001). The operation time was significantly lower in the neuro-endoscopy group than in the craniotomy group (89.9 ± 11.7 versus 203.7 ± 57.6 min, P < 0.0001). Intraoperative blood loss was significantly higher in the craniotomy group (248.31 ± 94.65 versus 78.66 ± 28.96 mL, P < 0.0001). The postoperative length of stay in the intensive care unit was 12.6 days in the neuro-endoscopy group and 14.0 days in the craniotomy group with no significant difference ( P = 0.196). Intracranial pressure monitoring showed no significant difference between the two groups on postoperative days 1 and 7. Intracranial pressure was significantly higher in the craniotomy group than in the neuro-endoscopy group on postoperative day 3 (15.1 ± 6.8 versus 12.5 ± 6.8 mm Hg, P = 0.029). There was no significant difference in the mortality or outcome rate at 6 months postoperatively between the two groups. CONCLUSIONS: In patients with HICH in the basal ganglia region, neuro-endoscopy can significantly improve the hematoma clearance rate, reduce intraoperative hemorrhage and postoperative cerebral tissue edema, and improve surgical efficiency. However, the long-term prognosis of patients who undergo craniotomy through the lateral fissure is similar to that of patients who undergo neuro-endoscopic surgery.
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Hemorragia de los Ganglios Basales , Hemorragia Intracraneal Hipertensiva , Neuroendoscopía , Humanos , Hemorragia Intracraneal Hipertensiva/diagnóstico por imagen , Hemorragia Intracraneal Hipertensiva/cirugía , Resultado del Tratamiento , Endoscopía/métodos , Craneotomía/métodos , Ganglios Basales/cirugía , Pérdida de Sangre Quirúrgica , Estudios Retrospectivos , Hematoma/cirugía , Edema/cirugía , Hemorragia de los Ganglios Basales/cirugía , Neuroendoscopía/métodosRESUMEN
BACKGROUND: The microglia-mediated inflammatory response is a vital mechanism of secondary damage following traumatic brain injury (TBI), but the underlying mechanism of microglial activation is unclear. METHODS: Controlled cortical impact (CCI) was induced in adult male C57BL/6J mice, and glutamate was used to construct a classical in vitro injury model in the primary microglia. Microglial activation was determined by western blot and immunostaining. The inflammatory factors were measured by enzyme-linked immunosorbent assay. The oxidative stress marker and mitochondrial reactive oxygen species (ROS) were measured by immunoblotting and MitoSox Red staining. Transmission electron microscopy was used to observe the typical morphology of necroptotic cells. RESULTS: Our quantitative proteomics identified 2499 proteins; 157 were significantly differentially expressed in brain tissue between the 6 h after CCI (CCI6h) group and sham group, and 109 were significantly differentially expressed between the CCI24h and sham groups. Moreover, compared with the sham group, the terms "acute-phase response", "inflammation", and "protein binding" were significantly enriched in CCI groups. Fetuin-A, a liver-secreted acute-phase glycoprotein, was involved in these biological processes. Using an experimental TBI model, we found that the Fetuin-A level peaked at 6 h and then decreased gradually. Importantly, we showed that administration of Fetuin-A reduced the cortical lesion volume and edema area and inhibited the inflammatory response, which was associated with suppressing microglial necroptosis, thus decreasing microglial activation. Furthermore, administration of Fetuin-A attenuated mitochondrial oxidative stress in glutamate-treated microglial cells, which is a critical mechanism of necroptosis suppression. In addition, we demonstrated that Fetuin-A treatment promoted translocation of nuclear factor erythroid 2-related factor 2 (Nrf-2) from the cytoplasm to the nucleus in vivo; however, the Nrf-2 inhibitor ML385 and si-heme oxygenase-1 (si-HO-1) disrupted the regulation of oxidative stress by Fetuin-A and induced increased ROS levels and necroptosis in glutamate-treated microglial cells. Fetuin-A also protected neurons from adverse factors in vivo and in vitro. CONCLUSIONS: Our results demonstrated that Fetuin-A activated Nrf-2/HO-1, suppressed oxidative stress and necroptosis levels, and thereby attenuates the abnormal inflammatory response following TBI. The findings suggest a potential therapeutic strategy for TBI treatment.
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Lesiones Traumáticas del Encéfalo , Microglía , Animales , Masculino , Ratones , alfa-2-Glicoproteína-HS/metabolismo , Lesiones Traumáticas del Encéfalo/metabolismo , Glutamatos/metabolismo , Ratones Endogámicos C57BL , Microglía/metabolismo , Necroptosis , Enfermedades Neuroinflamatorias , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND: This study examined whether BI113823, a novel selective kinin B1 receptor antagonist can reverse established pulmonary arterial hypertension (PAH), prevent right heart failure and death, which is critical for clinical translation. METHODS: Left pneumonectomized male Wistar rats were injected with monocrotaline to induce PAH. Three weeks later, when PAH was well established, the rats received daily treatment of BI113823 or vehicle for 3 weeks. RESULTS: Treatment with BI113823 from day 21 to day 42 after monocrotaline injection reversed established PAH as shown by normalized values of mean pulmonary arterial pressure (mPAP). BI113823 therapy reversed pulmonary vascular remodeling, pulmonary arterial neointimal formation, and heart and lung fibrosis, reduced right ventricular pressure, right heart hypertrophy, improved cardiac output, and prevented right heart failure and death. Treatment with BI113823 reduced TNF-α and IL-1ß, and macrophages recruitment in bronchoalveolar lavage, reduced CD-68 positive macrophages and expression of proliferating cell nuclear antigen (PCNA) in the perivascular areas, and reduced expression of iNOS, B1 receptors, matrix metalloproteinase (MMP)-2 and MMP-9 proteins, and the phosphorylation of ERK1/2 and AKT in lung. Treatment with BI113823 reduced mRNA expression of ANP, BNP, ßMHC, CGTF, collange-I and IV in right heart, compared to vehicle treated controls. In human monocytes cultures, BI113823 reduced LPS-induced TNF-α production, MMP-2 and MMP-9 expression, and reduced TNF-α-induced monocyte migration. CONCLUSIONS: We conclude that BI113823 reverses preexisting severe experimental pulmonary hypertension via inhibition of macrophage infiltration, cytokine production, as well as down regulation of matrix metalloproteinase proteins.
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Cininas/antagonistas & inhibidores , Neointima/patología , Hipertensión Arterial Pulmonar/patología , Arteria Pulmonar/patología , Túnica Íntima/patología , Remodelación Vascular/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Humanos , Masculino , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Hipertensión Arterial Pulmonar/metabolismo , Arteria Pulmonar/efectos de los fármacos , Ratas , Ratas Wistar , Túnica Íntima/efectos de los fármacosRESUMEN
Ischemic stroke poses a significant health risk due to its high rate of disability and mortality. To address this problem, several therapeutic approaches have been proposed, including interruption targeting programmed cell death (PCD). Ferroptosis is a newly defined PCD characterized by iron-dependent accumulation of lipid peroxidation, and is becoming a promising target for treating numerous diseases. To explore the underlying mechanisms of the initiation and execution of ferroptosis in ischemic stroke, we established stroke models in vivo and in vitro simulating ischemia/reperfusion (I/R) neuronal injury. Different from previous reports on stroke, we tested ferroptosis by measuring the levels of core proteins, such as ACSL4, 15-LOX2, Ferritin and GPX4. In addition, I/R injury induces excessive degradation of ferritin via the autophagy pathway and subsequent increase of free iron in neurons. This phenomenon has recently been termed ferritinophagy and reported to be regulated by nuclear receptor coactivator 4 (NCOA4) in some cell lines. Increased NCOA4 in cytoplasm was detected in our study and then silenced by shRNA to investigate its function. Both in vivo and in vitro, NCOA4 deletion notably abrogated ferritinophagy caused by I/R injury and thus inhibited ferroptosis. Furthermore, we found that NCOA4 was upregulated by ubiquitin specific peptidase 14 (USP14) via a deubiquitination process in damaged neurons, and we found evidence of pharmacological inhibition of USP14 effectively reducing NCOA4 levels to protect neurons from ferritinophagy-mediated ferroptosis. These findings suggest a novel and effective target for treating ischemic stroke.
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Ferroptosis , Infarto de la Arteria Cerebral Media , Accidente Cerebrovascular Isquémico , Coactivadores de Receptor Nuclear , Daño por Reperfusión , Animales , Encéfalo/metabolismo , Células Cultivadas , Glutatión/metabolismo , Glutatión Peroxidasa/metabolismo , Infarto de la Arteria Cerebral Media/genética , Infarto de la Arteria Cerebral Media/metabolismo , Accidente Cerebrovascular Isquémico/genética , Accidente Cerebrovascular Isquémico/metabolismo , Peroxidación de Lípido , Masculino , Malondialdehído/metabolismo , Ratones Endogámicos C57BL , Neuronas/metabolismo , Coactivadores de Receptor Nuclear/genética , Coactivadores de Receptor Nuclear/metabolismo , Pirroles/farmacología , Pirrolidinas/farmacología , Daño por Reperfusión/genética , Daño por Reperfusión/metabolismo , Ubiquitina Tiolesterasa/antagonistas & inhibidores , Ubiquitina Tiolesterasa/metabolismoRESUMEN
Mitochondrial energy production is essential for normal brain function. Traumatic brain injury (TBI) increases brain energy demands, results in the activation of mitochondrial respiration, associated with enhanced generation of reactive oxygen species. This chain of events triggers neuronal apoptosis via oxidation of a mitochondria-specific phospholipid, cardiolipin (CL). One pathway through which cells can avoid apoptosis is via elimination of damaged mitochondria by mitophagy. Previously, we showed that externalization of CL to the mitochondrial surface acts as an elimination signal in cells. Whether CL-mediated mitophagy occurs in vivo or its significance in the disease processes are not known. In this study, we showed that TBI leads to increased mitophagy in the human brain, which was also detected using TBI models in male rats. Knockdown of CL synthase, responsible for de novo synthesis of CL, or phospholipid scramblase-3, responsible for CL translocation to the outer mitochondrial membrane, significantly decreased TBI-induced mitophagy. Inhibition of mitochondrial clearance by 3-methyladenine, mdivi-1, or phospholipid scramblase-3 knockdown after TBI led to a worse outcome, suggesting that mitophagy is beneficial. Together, our findings indicate that TBI-induced mitophagy is an endogenous neuroprotective process that is directed by CL, which marks damaged mitochondria for elimination, thereby limiting neuronal death and behavioral deficits.SIGNIFICANCE STATEMENT Traumatic brain injury (TBI) increases energy demands leading to activation of mitochondrial respiration associated with enhanced generation of reactive oxygen species and resultant damage to mitochondria. We demonstrate that the complete elimination of irreparably damaged organelles via mitophagy is activated as an early response to TBI. This response includes translocation of mitochondria phospholipid cardiolipin from the inner membrane to the outer membrane where externalized cardiolipin mediates targeted protein light chain 3-mediated autophagy of damaged mitochondria. Our data on targeting phospholipid scramblase and cardiolipin synthase in genetically manipulated cells and animals strongly support the essential role of cardiolipin externalization mechanisms in the endogenous reparative plasticity of injured brain cells. Furthermore, successful execution and completion of mitophagy is beneficial in the context of preservation of cognitive functions after TBI.
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Lesiones Traumáticas del Encéfalo/metabolismo , Encéfalo/metabolismo , Cardiolipinas/metabolismo , Mitofagia/fisiología , Neuronas/metabolismo , Animales , Apoptosis/fisiología , Encéfalo/ultraestructura , Lesiones Traumáticas del Encéfalo/patología , Humanos , Masculino , Membranas Mitocondriales/metabolismo , Neuronas/ultraestructura , Ratas Sprague-Dawley , Transducción de SeñalRESUMEN
Microglial cells are key component of central nervous system (CNS) and mediate the immune response of the brain under physiological or pathological conditions. It tends to activate into a pro-inflammatory M1 phenotype after traumatic brain injury (TBI) and promote secondary brain damage. Recently, necroptosis was found to promote microglial activation and neuroinflammation after TBI. However, the mechanism and specific interventions of microglial necroptosis after TBI remain poorly investigated. Here, we reported that overexpress the charged multivesicular body protein 4b (CHMP4B) which is a core member of the endosomal sorting required for transport complex III (ESCRT-III) significantly decreased the level of necroptosis in microglia, improved neurological function recovery and protected against cell death after TBI. Further investigation showed that forkhead transcription factor O1 (FOXO1) was a crucial transcription factor that increased CHMP4B transcription by binding to the promoter region, thereby inhibiting necroptosis in microglia. Collectively, our findings demonstrated that CHMP4B relieved microglial necroptosis and neuroinflammation after TBI, and promote the recovery of nerve function. FOXO1 is an important factor in promoting CHMP4B expression. This study provides the novel viewpoint for TBI prevention and treatment.
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Lesiones Traumáticas del Encéfalo/genética , Complejos de Clasificación Endosomal Requeridos para el Transporte/genética , Microglía/patología , Necroptosis/genética , Regulación hacia Arriba/genética , Adulto , Anciano , Animales , Encéfalo/patología , Lesiones Traumáticas del Encéfalo/patología , Línea Celular , Femenino , Proteína Forkhead Box O1/genética , Regulación de la Expresión Génica/genética , Humanos , Inflamación/genética , Inflamación/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Regiones Promotoras Genéticas/genética , Adulto JovenRESUMEN
Glioblastoma (GBM) is the most universal type of primary brain malignant tumour, and the prognosis of patients with GBM is poor. S100A11 plays an essential role in tumour. However, the role and molecular mechanism of S100A11 in GBM are not clear. Here, we found that S100A11 was up-regulated in GBM tissues and higher S100A11 expression indicated poor prognosis of GBM patients. Overexpression of S100A11 promoted GBM cell growth, epithelial-mesenchymal transition (EMT), migration, invasion and generation of glioma stem cells (GSCs), whereas its knockdown inhibited these activities. More importantly, S100A11 interacted with ANXA2 and regulated NF-κB signalling pathway through decreasing ubiquitination and degradation of ANXA2. Additionally, NF-κB regulated S100A11 at transcriptional level as a positive feedback. We also demonstrated the S100A11 on tumour growth in GBM using an orthotopic tumour xenografting. These data demonstrate that S100A11/ANXA2/NF-κB positive feedback loop in GBM cells that promote the progression of GBM.
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Anexina A2/metabolismo , Neoplasias Encefálicas/genética , Retroalimentación Fisiológica , Glioblastoma/genética , FN-kappa B/metabolismo , Oncogenes , Proteínas S100/metabolismo , Animales , Neoplasias Encefálicas/patología , Carcinogénesis/genética , Carcinogénesis/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica , Glioblastoma/patología , Humanos , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Pronóstico , Complejo de la Endopetidasa Proteasomal/metabolismo , Estabilidad Proteica , Proteolisis , Transducción de Señal , Esferoides Celulares/patología , Transcripción Genética , Ubiquitinación , Regulación hacia Arriba/genéticaRESUMEN
Phospholipase A2 is a known aggravator of inflammation and deteriorates neurological outcomes after traumatic brain injury (TBI), however the exact inflammatory mechanisms remain unknown. This study investigated the role of bradykinin and its receptor, which are known initial mediators within inflammation activation, as well as the mechanisms of the cytosolic phospholipase A2 (cPLA2)-related inflammatory responses after TBI. We found that cPLA2 and bradykinin B2 receptor were upregulated after a TBI. Rats treated with the bradykinin B2 receptor inhibitor LF 16-0687 exhibited significantly less cPLA2 expression and related inflammatory responses in the brain cortex after sustaining a controlled cortical impact (CCI) injury. Both the cPLA2 inhibitor and the LF16-0687 improved CCI rat outcomes by decreasing neuron death and reducing brain edema. The following TBI model utilized both primary astrocytes and primary neurons in order to gain further understanding of the inflammation mechanisms of the B2 bradykinin receptor and the cPLA2 in the central nervous system. There was a stronger reaction from the astrocytes as well as a protective effect of LF16-0687 after the stretch injury and bradykinin treatment. The protein kinase C pathway was thought to be involved in the B2 bradykinin receptor as well as the cPLA2-related inflammatory responses. Rottlerin, a Protein Kinase C (PKC) δ inhibitor, decreased the activity of the cPLA2 activity post-injury, and LF16-0687 suppressed both the PKC pathway and the cPLA2 activity within the astrocytes. These results indicated that the bradykinin B2 receptor-mediated pathway is involved in the cPLA2-related inflammatory response from the PKC pathway.
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Bradiquinina/metabolismo , Lesiones Traumáticas del Encéfalo/patología , Inflamación/patología , Fosfolipasas A2 Citosólicas/metabolismo , Receptor de Bradiquinina B2/metabolismo , Acetofenonas/farmacología , Adulto , Anciano , Animales , Animales Recién Nacidos , Astrocitos/efectos de los fármacos , Astrocitos/patología , Benzopiranos/farmacología , Bradiquinina/administración & dosificación , Bradiquinina/sangre , Bradiquinina/líquido cefalorraquídeo , Antagonistas del Receptor de Bradiquinina B2/farmacología , Encéfalo/citología , Encéfalo/efectos de los fármacos , Encéfalo/patología , Lesiones Traumáticas del Encéfalo/sangre , Lesiones Traumáticas del Encéfalo/líquido cefalorraquídeo , Lesiones Traumáticas del Encéfalo/etiología , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Epilepsia/líquido cefalorraquídeo , Epilepsia/patología , Femenino , Humanos , Inflamación/sangre , Inflamación/líquido cefalorraquídeo , Inflamación/etiología , Masculino , Persona de Mediana Edad , Quinolinas/farmacología , Ratas , Ratas Sprague-Dawley , Regulación hacia Arriba , Adulto JovenRESUMEN
Acute lung injury (ALI) is one of several complications in patients with traumatic brain injury (TBI). Autophagy is a primary homeostatic process that promotes cell survival under stress. Accumulating evidence implicates autophagy in the pathogenesis of ALI under various conditions. However, the role of autophagy in TBI-induced ALI remains unknown. The aim of this study was to adjust autophagy with pharmacological agents to determine its functional significance in TBI-induced ALI. Rats were preconditioned with autophagy promoter rapamycin or inhibitor 3-methyladenine before they were challenged with TBI. Extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor U0126, mechanistic target of rapamycin (mTOR) inhibitor rapamycin, and signal transducer and activator of transcription 3 (Stat3) inhibitor S31-201 were used to test the role of ERK1/2/mTOR/Stat3 signaling pathway in regulating autophagy. Autophagy is activated in lung tissues after TBI. Enhancement of autophagy suppressed apoptosis, inflammation and oxidative stress in lung tissues, which were activated after TBI, whereas inhibition of autophagy aggravated these critical pathological changes. Autophagy also improved TBI-induced impairment in pulmonary barrier function, oxygenation function and static compliance. Furthermore, TBI-induced autophagy was mediated by ERK1/2/mTOR/Stat3 pathway, which may serve to reduce ALI and improve pulmonary barrier function, oxygenation function and static compliance. These findings are important for the prevention and treatment of TBI-induced ALI.
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Lesión Pulmonar Aguda/metabolismo , Autofagia , Lesiones Traumáticas del Encéfalo/metabolismo , Sistema de Señalización de MAP Quinasas , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Factor de Transcripción STAT3/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Lesión Pulmonar Aguda/etiología , Lesión Pulmonar Aguda/patología , Animales , Apoptosis , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/patología , Pulmón/metabolismo , Pulmón/patología , Masculino , Proteína Quinasa 3 Activada por Mitógenos/antagonistas & inhibidores , Ratas , Ratas Sprague-Dawley , Serina-Treonina Quinasas TOR/antagonistas & inhibidoresRESUMEN
IL-27 plays an important role in anti-cancer activity. The -964A/G polymorphism in IL-27 gene has been implicated in susceptibility to cancer, but the results were conflicting. The aim of this study was to assess the association between this polymorphism and cancer risk. Pubmed and Wanfang database were searched for all publications concerning IL-27 -964A/G polymorphism and cancer risk. Odds ratio (OR) and 95% confidence interval (CI) were used to assess the strength of association. Statistical analysis was performed using Stata 11.0 software. A total of eight case-control studies including 2044 cancer cases and 2197 controls were identified. Overall, significant association between IL-27 -964A/G polymorphism and cancer risk was observed (GG versus AA: OR = 1.26, 95% CI = 1.03-1.52; GG versus AG + AA: OR = 1.20, 95% CI = 1.00-1.44). In subgroup analysis based on cancer type, significant association was found in colorectal cancer (GG versus AA: OR = 1.55, 95% CI = 1.07-2.27; AG versus AA: OR = 1.31, 95% CI = 1.02-1.67). The current meta-analysis suggests that IL-27 -964A/G polymorphism might enhance cancer risk. However, large-scale and well-designed studies are still needed to confirm the result of our meta-analysis. The association of IL-27 polymorphism with colorectal cancer may provide insight for future therapies.
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Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Interleucinas/genética , Neoplasias/genética , China , Femenino , Humanos , Masculino , Neoplasias/patología , Polimorfismo de Nucleótido Simple/genética , Factores de RiesgoRESUMEN
Melatonin functions as a crucial mediator of sterile neuroinflammation; however, the underlying mechanisms remain poorly understood. Dysfunctional mitochondria, a main source of reactive oxygen species, are impacted in inflammation activation. This study aimed to examine the effect of melatonin on inflammation via elimination of damaged mitochondria after controlled cortical impact, an in vivo model of traumatic brain injury (TBI). Here, we demonstrated that inhibition of mitophagy, the selective degradation of damaged mitochondria by autophagy, markedly enhanced inflammation induced by TBI. Melatonin treatment activated mitophagy through the mTOR pathway, then to attenuate TBI-induced inflammation. Furthermore, treatment with melatonin significantly ameliorated neuronal death and behavioral deficits after TBI, while 3-methyladenine reversed this effect by inhibiting mitophagy. Taken together, these results highlight a role for melatonin in protecting against TBI-triggered immunopathology, which is accomplished by negatively regulating inflammation activation and IL-1ß secretion via the autophagy of damaged mitochondria.
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Lesiones Traumáticas del Encéfalo/dietoterapia , Melatonina/farmacología , Mitofagia/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Animales , Lesiones Traumáticas del Encéfalo/metabolismo , Lesiones Traumáticas del Encéfalo/patología , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Interleucina-1beta/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Frontotemporal lobe abnormalities are linked to neuropsychiatric disorders and cognition, but the role of cellular heterogeneity between temporal lobe (TL) and frontal lobe (FL) in the vulnerability to genetic risk factors remains to be elucidated. We integrated single-nucleus transcriptome analysis in 'fresh' human FL and TL with genetic susceptibility, gene dysregulation in neuropsychiatric disease and psychoactive drug response data. We show how intrinsic differences between TL and FL contribute to the vulnerability of specific cell types to both genetic risk factors and psychoactive drugs. Neuronal populations, specifically PVALB neurons, were most highly vulnerable to genetic risk factors for psychiatric disease. These psychiatric disease-associated genes were mostly upregulated in the TL, and dysregulated in the brain of patients with obsessive-compulsive disorder, bipolar disorder and schizophrenia. Among these genes, GRIN2A and SLC12A5, implicated in schizophrenia and bipolar disorder, were significantly upregulated in TL PVALB neurons and in psychiatric disease patients' brain. PVALB neurons from the TL were twofold more vulnerable to psychoactive drugs than to genetic risk factors, showing the influence and specificity of frontotemporal lobe differences on cell vulnerabilities. These studies provide a cell type resolved map of the impact of brain regional differences on cell type vulnerabilities in neuropsychiatric disorders.
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Lóbulo Frontal , Trastornos Mentales , Psicotrópicos , Lóbulo Temporal , Humanos , Psicotrópicos/farmacología , Lóbulo Frontal/metabolismo , Lóbulo Frontal/patología , Lóbulo Temporal/metabolismo , Lóbulo Temporal/patología , Trastornos Mentales/genética , Trastornos Mentales/metabolismo , Neuronas/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Predisposición Genética a la Enfermedad , Perfilación de la Expresión Génica , Transcriptoma , Regulación de la Expresión Génica , Esquizofrenia/genética , Esquizofrenia/metabolismo , Trastorno Bipolar/genética , Trastorno Bipolar/metabolismoRESUMEN
Regulation of the oxidative stress response is crucial for the management and prognosis of traumatic brain injury (TBI). The copper chaperone Antioxidant 1 (Atox1) plays a crucial role in regulating intracellular copper ion balance and impacting the antioxidant capacity of mitochondria, as well as the oxidative stress state of cells. However, it remains unknown whether Atox1 is involved in modulating oxidative stress following TBI. Here, we investigated the regulatory role of Atox1 in oxidative stress on neurons both in vivo and in vitro, and elucidated the underlying mechanism through culturing hippocampal HT-22 cells with Atox1 mutation. The expression of Atox1 was significantly diminished following TBI, while mice with overexpressed Atox1 exhibited a more preserved hippocampal structure and reduced levels of oxidative stress post-TBI. Furthermore, the mice displayed notable impairments in learning and memory functions after TBI, which were ameliorated by the overexpression of Atox1. In the stretch injury model of HT-22 cells, overexpression of Atox1 mitigated oxidative stress by preserving the normal morphology and network connectivity of mitochondria, as well as facilitating the elimination of damaged mitochondria. Mechanistically, co-immunoprecipitation and mass spectrometry revealed the binding of Atox1 to DJ-1. Knockdown of DJ-1 in HT-22 cells significantly impaired the antioxidant capacity of Atox1. Mutations in the copper-binding motif or sequestration of free copper led to a substantial decrease in the interaction between Atox1 and DJ-1, with overexpression of DJ-1 failing to restore the antioxidant capacity of Atox1 mutants. The findings suggest that DJ-1 mediates the ability of Atox1 to withstand oxidative stress. And targeting Atox1 could be a potential therapeutic approach for addressing post-traumatic neurological dysfunction.
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Lesiones Traumáticas del Encéfalo , Proteínas Transportadoras de Cobre , Hipocampo , Mitofagia , Neuronas , Estrés Oxidativo , Proteína Desglicasa DJ-1 , Animales , Lesiones Traumáticas del Encéfalo/metabolismo , Lesiones Traumáticas del Encéfalo/patología , Lesiones Traumáticas del Encéfalo/genética , Ratones , Hipocampo/metabolismo , Hipocampo/patología , Neuronas/metabolismo , Proteína Desglicasa DJ-1/metabolismo , Proteína Desglicasa DJ-1/genética , Proteínas Transportadoras de Cobre/metabolismo , Proteínas Transportadoras de Cobre/genética , Mitocondrias/metabolismo , Modelos Animales de Enfermedad , Chaperonas Moleculares/metabolismo , Chaperonas Moleculares/genética , Masculino , Antioxidantes/metabolismo , Línea Celular , HumanosRESUMEN
The oncogene Aurora kinase A (AURKA) has been implicated in various tumor, yet its role in meningioma remains unexplored. Recent studies have suggested a potential link between AURKA and ferroptosis, although the underlying mechanisms are unclear. This study presented evidence of AURKA upregulation in high grade meningioma and its ability to enhance malignant characteristics. We identified AURKA as a suppressor of erastin-induced ferroptosis in meningioma. Mechanistically, AURKA directly interacted with and phosphorylated kelch-like ECH-associated protein 1 (KEAP1), thereby activating nuclear factor erythroid 2 related factor 2 (NFE2L2/NRF2) and target genes transcription. Additionally, forkhead box protein M1 (FOXM1) facilitated the transcription of AURKA. Suppression of AURKA, in conjunction with erastin, yields significant enhancements in the prognosis of a murine model of meningioma. Our study elucidates an unidentified mechanism by which AURKA governs ferroptosis, and strongly suggests that the combination of AURKA inhibition and ferroptosis-inducing agents could potentially provide therapeutic benefits for meningioma treatment.
Asunto(s)
Aurora Quinasa A , Ferroptosis , Proteína Forkhead Box M1 , Meningioma , Factor 2 Relacionado con NF-E2 , Piperazinas , Ferroptosis/efectos de los fármacos , Ferroptosis/genética , Proteína Forkhead Box M1/metabolismo , Proteína Forkhead Box M1/genética , Aurora Quinasa A/metabolismo , Aurora Quinasa A/genética , Humanos , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Animales , Ratones , Meningioma/metabolismo , Meningioma/genética , Meningioma/patología , Piperazinas/farmacología , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/genética , Neoplasias Meníngeas/metabolismo , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/patología , Neoplasias Meníngeas/tratamiento farmacológico , Resistencia a Antineoplásicos/genéticaRESUMEN
Ferroptosis is a newly identified form of regulated cell death (RCD) characterized by the iron-dependent lipid reactive oxygen species (ROS) accumulation, but its mechanism in gliomas remains elusive. Acyl-coenzyme A (CoA) synthetase long-chain family member 4 (Acsl4), a pivotal enzyme in the regulation of lipid biosynthesis, benefits the initiation of ferroptosis, but its role in gliomas needs further clarification. Erastin, a classic inducer of ferroptosis, has recently been found to regulate lipid peroxidation by regulating Acsl4 other than glutathione peroxidase 4 (GPX4) in ferroptosis. In this study, we demonstrated that heat shock protein 90 (Hsp90) and dynamin-related protein 1 (Drp1) actively regulated and stabilized Acsl4 expression in erastin-induced ferroptosis in gliomas. Hsp90 overexpression and calcineurin (CN)-mediated Drp1 dephosphorylation at serine 637 (Ser637) promoted ferroptosis by altering mitochondrial morphology and increasing Acsl4-mediated lipid peroxidation. Importantly, promotion of the Hsp90-Acsl4 pathway augmented anticancer activity of erastin in vitro and in vivo. Our discovery reveals a novel and efficient approach to ferroptosis-mediated glioma therapy.
Asunto(s)
Ferroptosis , Glioma , Coenzima A Ligasas/genética , Coenzima A Ligasas/metabolismo , Dinaminas , Glioma/genética , Humanos , Lípidos , SerinaRESUMEN
Glioblastoma (GBM) is the most aggressive primary brain tumor as one of the deadliest cancers. The TGF-ß signaling acts as an oncogenic factor in GBM, and plays vital roles in development of GBM. SMAD7 is a major inhibitor of TGF-ß signaling, while the deubiquitination of SMAD7 has been poorly studied in GBM. Here, we found USP2 as a new prominent candidate that could regulate SMAD7 stability. USP2 was lost in GBM, leading to the poor prognosis in patients. Moreover, aberrant DNA methylation mediated by DNMT3A induced the low expression of USP2 in GBM. USP2 depletion induced TGF-ß signaling and progression of GBM. In contrast, overexpressed USP2 suppressed TGF-ß signaling and GBM development. Specifically, USP2 interacted with SMAD7 and prevented SMAD7 ubiquitination. USP2 directly cleaved Lys27- and Lys48-linked poly-ubiquitin chains of SMAD7, and Lys27-linked poly-ubiquitin chains of SMAD7 K185 mediated the recruitment of SMAD7 to HERC3, which regulated Lys63-linked poly-ubiquitination of SMAD7. Moreover, we demonstrated that the DNMT3A inhibitor SGI-1027 induced USP2, suppressed TGF-ß signaling and GBM development. Thus, USP2 repressed development of GBM by inhibition TGF-ß signaling pathway via the deubiquitination of SMAD7.
Asunto(s)
Glioblastoma , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Poliubiquitina/metabolismo , Transducción de Señal , Proteína smad7/genética , Proteína smad7/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Ubiquitina Tiolesterasa/genética , Ubiquitina Tiolesterasa/metabolismo , UbiquitinaciónRESUMEN
Prokineticin-2 (Prok2) is an important secreted protein likely involved in the pathogenesis of several acute and chronic neurological diseases through currently unidentified regulatory mechanisms. The initial mechanical injury of neurons by traumatic brain injury triggers multiple secondary responses including various cell death programs. One of these is ferroptosis, which is associated with dysregulation of iron and thiols and culminates in fatal lipid peroxidation. Here, we explore the regulatory role of Prok2 in neuronal ferroptosis in vitro and in vivo. We show that Prok2 prevents neuronal cell death by suppressing the biosynthesis of lipid peroxidation substrates, arachidonic acid-phospholipids, via accelerated F-box only protein 10 (Fbxo10)-driven ubiquitination, degradation of long-chain-fatty-acid-CoA ligase 4 (Acsl4), and inhibition of lipid peroxidation. Mice injected with adeno-associated virus-Prok2 before controlled cortical impact injury show reduced neuronal degeneration and improved motor and cognitive functions, which could be inhibited by Fbxo10 knockdown. Our study shows that Prok2 mediates neuronal cell deaths in traumatic brain injury via ferroptosis.
Asunto(s)
Lesiones Traumáticas del Encéfalo/patología , Corteza Cerebral/patología , Ferroptosis , Hormonas Gastrointestinales/metabolismo , Neuropéptidos/metabolismo , Adulto , Anciano , Animales , Lesiones Traumáticas del Encéfalo/cirugía , Células Cultivadas , Corteza Cerebral/citología , Coenzima A Ligasas/metabolismo , Modelos Animales de Enfermedad , Proteínas F-Box/genética , Proteínas F-Box/metabolismo , Femenino , Hormonas Gastrointestinales/genética , Técnicas de Silenciamiento del Gen , Humanos , Peroxidación de Lípido , Masculino , Ratones , Persona de Mediana Edad , Mitocondrias/patología , Neuronas/citología , Neuronas/patología , Neuropéptidos/genética , Fosfolípidos/biosíntesis , Cultivo Primario de Células , Proteolisis , UbiquitinaciónRESUMEN
PURPOSE: Glioblastoma (GBM) is one of the most aggressive and lethal cancer types in humans. The standard treatment approach is surgery followed by chemoradiation. However, the molecular mechanisms of innate tumor radioresistance remain poorly understood. EXPERIMENTAL DESIGN: We tested the expression of Smoothened (Smo) in primary and recurrent GBM tissues and cells. Then, we determined radiation effectiveness against primary and recurrent GBM cells. Lastly, the functional role of Smo in GBM radioresistance was further confirmed by in vitro and in vivo experiments. RESULTS: We reported that Smo was significantly upregulated in recurrent GBM cell lines and tumor tissues following radiation treatment. Higher Smo expression indicated poor prognosis of GBM patients after radiation treatment. Smo had radioresistance effects in both GBM cells and human tumor xenografts. The mechanisms underlying these effects involved the attenuation of DNA damage repair caused by IR. Importantly, we found that the effect of Smo on radioresistance was mediated by Claspin polyubiquitination and proteasomal degradation, leading to the regulation of ATR-Chk1 signaling. Moreover, we found that Smo reduced Claspin polyubiquitination and proteasomal degradation by promoting USP3 transcription. Furthermore, we demonstrated that the Smo inhibitor GDC-0449 induced radiosensitivity to GBM. CONCLUSIONS: These data suggest that Smo confers radiation resistance in GBM by promoting USP3 transcription, leading to the activation of Claspin-dependent ATR-Chk1 signaling. These findings identify a potential mechanism of GBM resistance to radiation and suggest a potential therapeutic target for radiation resistance in GBM.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Neoplasias Encefálicas/radioterapia , Reparación del ADN , Glioblastoma/radioterapia , Recurrencia Local de Neoplasia/radioterapia , Receptor Smoothened/genética , Proteasas Ubiquitina-Específicas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Adulto , Anciano , Animales , Biomarcadores de Tumor/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Transducción de Señal , Receptor Smoothened/metabolismo , Proteasas Ubiquitina-Específicas/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Cognitive decline is one of the most obvious symptoms of traumatic brain injury (TBI). Previous studies have demonstrated that cognitive decline is related to substantially increased neuroinflammation and decreased neurogenesis in the hippocampus in a rat model of TBI. Using this model, we explored the role of curcumin (Cur) in ameliorating TBI-impaired spatial memory because Cur has been shown to exhibit anti-chronic-neuroinflammatory, neurogenesis-promoting, and memory-improving properties. Animals received daily Cur or vehicle treatment for 28 days after TBI and also received 50-bromodeoxyuridine(BrdU) for the first 7 days of the treatment for assaying neurogenesis. An optimal Cur dose of 30 mg/kg, selected from a range of 10-50 mg/kg, was used for the present study. Neuroinflammation was evaluated by astrocyte hypertrophy, activated microglia, and inflammatory factors in the hippocampus. Behavioral water-maze studies were conducted for 5 days, starting at 35-day post-TBI. The tropomyosin receptor kinase B (Trkb) inhibitor, ANA-12, was used to test the role of the brain-derived neurotrophic factor (BDNF)/ TrkB/Phosphoinositide 3-kinase (PI3K)/Akt signaling pathway in regulating inflammation and neurogenesis in the hippocampus. Treatment with Cur ameliorated the spatial memory of TBI rats, reduced TBI-induced chronic inflammation, typified by diminished astrocyte hypertrophy, reduction in activated microglia, declined inflammatory factors, and increased neurogenesis in the hippocampus. We also found that BDNF/Trkb/PI3K/Akt signaling was involved in the effects of Cur in TBI rats. Thus, Cur treatment can ameliorate the spatial memory in a murine model of TBI, which may be attributable to decreased chronic neuroinflammation, increased hippocampal neurogenesis, and/or BDNF/Trkb/PI3K/Akt signaling.