RESUMO
Background: Gliomas constitute a category of malignant tumors originating from brain tissue, representing the majority of intracranial malignancies. Previous research has demonstrated the pivotal role of CLEC7A in the progression of various cancers, yet its specific implications within gliomas remain elusive. The primary objective of this study was to investigate the prognostic significance and immune therapeutic potential of CLEC7A in gliomas through the integration of bioinformatics and clinical pathological analyses. Methods: This investigation involved examining and validating the relationship between CLEC7A and glioma using samples from Hospital, along with data from TCGA, GEO, GTEx, and CGGA datasets. Subsequently, we explored its prognostic value, biological functions, expression location, and impact on immune cells within gliomas. Finally, we investigated its potential impact on the chemotaxis and polarization of macrophages. Results: The expression of CLEC7A is upregulated in gliomas, and its levels escalate with the malignancy of tumors, establishing it as an independent prognostic factor. Functional enrichment analysis revealed a significant correlation between CLEC7A and immune function. Subsequent examination of immune cell differential expression demonstrated a robust association between CLEC7A and M2 macrophages. This conclusion was further substantiated through single-cell analysis, immunofluorescence, and correlation studies. Finally, the knockout of CLEC7A in M2 macrophages resulted in a noteworthy reduction in macrophage chemotaxis and polarization factors. Conclusion: CLEC7A expression is intricately linked to the pathology and molecular characteristics of gliomas, establishing its role as an independent prognostic factor for gliomas and influencing macrophage function. It could be a promising target for immunotherapy in gliomas.
Assuntos
Neoplasias Encefálicas , Glioma , Lectinas Tipo C , Macrófagos , Microambiente Tumoral , Humanos , Glioma/imunologia , Glioma/genética , Glioma/patologia , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Prognóstico , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismoRESUMO
Intestinal injury caused by traumatic brain injury (TBI) seriously affects patient prognosis; however, the underlying mechanisms are unknown. Recent studies have demonstrated that ferritinophagy-mediated ferroptosis is involved in several intestinal disorders. However, uncertainty persists regarding the role of ferritinophagy-mediated ferroptosis in the intestinal damage caused by TBI. High-throughput transcriptional sequencing was used to identify the genes that were differentially expressed in the intestine after TBI. The intestinal tissues were harvested for hematoxylin and eosin staining (HE), immunofluorescence, and western blot (WB). Lipid peroxide markers and iron content in the intestines were determined using the corresponding kits. High throughput sequencing revealed that the ferroptosis signaling pathway was enriched, demonstrating that intestinal damage caused by TBI may include ferroptosis. Chiu's score, tight junction proteins, and lipid peroxide indicators demonstrated that TBI caused an intestinal mucosal injury that persisted for several days. The ferroptosis pathway-related proteins, ferritin heavy polypeptide 1 (Fth1) and glutathione peroxidase 4 (GPX4), exhibited dynamic changes. The results indicated that lipid peroxide products were markedly increased, whereas antioxidant enzymes were markedly decreased. WB analysis demonstrated that the expression levels of nuclear receptor coactivator 4 (NCOA4), LC3II/LC3I, and p62 were markedly upregulated, whereas those of GPX4 and Fth1 were markedly downregulated. In addition, ferrostatin-1 attenuates intestinal ferroptosis and injury post-TBI in vivo. Intriguingly, 3-methyladenine (3-MA) reduces intestinal ferritin decomposition, iron accumulation, and ferroptosis after TBI. Moreover, 3-MA markedly reduced intestinal apoptosis. In conclusion, NCOA4 mediated ferritinophagy and ferroptosis play roles in intestinal oxidative stress injury post-TBI. This study provides a deeper understanding of the mechanisms underlying intestinal damage following TBI.
Assuntos
Lesões Encefálicas Traumáticas , Ferroptose , Humanos , Peróxidos Lipídicos , Intestinos , Estresse Oxidativo , Fatores de Transcrição , Ferritinas , Ferro , Autofagia , Coativadores de Receptor Nuclear/genéticaRESUMO
Previous studies have proved that cardiac dysfunction and myocardial damage can be found in TBI patients, but the underlying mechanisms of myocardial damage induced by TBI can't be illustrated. We want to investigate the function of ferroptosis in myocardial damage after TBI and determine if inhibiting iron overload might lessen myocardial injury after TBI due to the involvement of iron overload in the process of ferroptosis and inflammation. We detect the expression of ferroptosis-related proteins in cardiac tissue at different time points after TBI, indicating that TBI can cause ferroptosis in the heart in vivo. The echocardiography and myocardial enzymes results showed that ferroptosis can aggravate TBI-induced cardiac dysfunction. The result of DHE staining and 4-HNE expression showed that inhibition of ferroptosis can reduce ROS production and lipid peroxidation in myocardial tissue. In further experiments, DFO intervention was used to explore the effect of iron overload inhibition on myocardial ferroptosis after TBI, the production of ROS, expression of p38 MAPK and NF-κB was detected to explore the effect of iron overload on myocardial inflammation after TBI. The results above show that TBI can cause heart ferroptosis in vivo. Inhibition of iron overload can alleviate myocardial injury after TBI by reducing ferroptosis and inflammatory response induced by TBI.
Assuntos
Ferroptose , Traumatismos Cardíacos , Sobrecarga de Ferro , Humanos , Espécies Reativas de Oxigênio , Arritmias Cardíacas , Inflamação , Sobrecarga de Ferro/complicaçõesRESUMO
The role of extracellular vesicles (EV) in various diseases is gaining increased attention, particularly due to their potent procoagulant activity. However, there is an urgent need for a bedside test to assess the procoagulant activity of EV in clinical settings. This study proposes the use of thrombin activation time of EV-rich plasma as a measure of EV's procoagulant activity. Standardized procedures were employed to obtain sodium-citrated whole blood, followed by differential centrifugation to obtain EV-rich plasma. The EV-rich plasma and calcium chloride were added to the test cup, and the changes in viscoelasticity were monitored in real-time using an analyzer. The natural coagulation time of EV-rich plasma, referred to as EV-ACT, was determined. The results revealed a significant increase in EV-ACT when EV was removed from plasma obtained from healthy volunteers, while it significantly decreased when EV was enriched. Furthermore, EV-ACT was considerably shortened in human samples from preeclampsia, hip fracture, and lung cancer, indicating elevated levels of plasma EV and promotion of blood hypercoagulation. With its simple and rapid procedure, EV-ACT shows promise as a bedside test for evaluating coagulation function in patients with high plasma EV levels.
Assuntos
Coagulação Sanguínea , Vesículas Extracelulares , Feminino , Gravidez , Humanos , Testes de Coagulação Sanguínea , Plasma , Cloreto de CálcioRESUMO
Traumatic brain injury (TBI) can negatively impact systemic organs, which can lead to more death and disability. However, the mechanism underlying the effect of TBI on systemic organs remains unclear. In previous work, we found that brain-derived extracellular vesicles (BDEVs) released from the injured brain can induce systemic coagulation with a widespread fibrin deposition in the microvasculature of the lungs, kidney, and heart in a mouse model of TBI. In this study, we investigated whether BDEVs can induce heart, lung, liver, and kidney injury in TBI mice. The results of pathological staining and related biomarkers indicated that BDEVs can induce histological damage and systematic dysfunction. In vivo imaging system demonstrated that BDEVs can gather in systemic organs. We also found that BDEVs could induce cell apoptosis in the lung, liver, heart, and kidney. Furthermore, we discovered that BDEVs could cause multi-organ endothelial cell damage. Finally, this secondary multi-organ damage could be relieved by removing circulating BDEVs. Our research provides a novel perspective and potential mechanism of TBI-associated multi-organ damage.
Assuntos
Lesões Encefálicas Traumáticas , Lesões Encefálicas , Vesículas Extracelulares , Camundongos , Animais , Encéfalo/patologia , Lesões Encefálicas/patologia , Apoptose , Vesículas Extracelulares/patologiaRESUMO
The procoagulant effect of microparticles (MPs) contributes to hypercoagulability-induced thrombosis. We provide preliminary findings of the MPs-Activated Clotting Time (MPs-ACT) assay to determine the procoagulant activity of MPs. MPs-rich plasma was obtained and recalcified. Changes in plasma viscoelasticity were evaluated and the time to the peak viscoelastic changes was defined as the MPs-ACT. MPs concentration was measured by flow cytometry. Coagulation products produced during plasma clotting were identified by fibrin and fibrinopeptide A. MPs were prepared in vitro and added to standard plasma to simulate pathological samples. In addition, reproducibility and sensitivity were evaluated. We confirmed the linear relationship between MPs-ACT and MP concentrations. Dynamic changes in fibrin production were depicted. We simulated the correlation between MPs-ACT and standard plasma containing MPs prepared in vitro. The reproducibility of high-value and low-value samples was 6.0% and 10.8%, respectively. MPs-ACT sensitively detected hypercoagulable samples from patients with pre-eclampsia, hip fractures, and lung tumors. MPs-ACT largely reflects the procoagulant effect of MPs. MPs-ACT sensitively and rapidly detects hypercoagulability with MPs-rich plasma. It may be promising for the diagnosis of hypercoagulable states induced by MPs.
Assuntos
Micropartículas Derivadas de Células , Trombofilia , Feminino , Humanos , Reprodutibilidade dos Testes , Fosfatidilserinas/farmacologia , Coagulação Sanguínea , FibrinaRESUMO
Traumatic brain injury often causes poor outcomes and has few established treatments. Neuroinflammation and ferroptosis hinder therapeutic progress in this domain. Annexin A5 (A5) has anticoagulant, anti-apoptotic and anti-inflammatory bioactivities. However, its protective effects on traumatic brain injury remain unclear. Thus, we explored whether inhibiting ferroptosis and neuroinflammation using A5 could ameliorate traumatic brain injury. We injected recombinant A5 (50 µg/kg) in the tail vein of mice 30 min after fluid percussion injury. We then assessed modified neurologic severity scores, Morris water maze performance, rotarod test performance, brain water content, and blood-brain barrier permeability to document the neuroprotective effects of A5. Two days after the traumatic brain injury, we collected injured cortex tissues for western blot, Perl's staining, apoptosis staining, Nissl staining, immunofluorescence/immunohistochemistry, and enzyme-linked immunosorbent assay. We also quantified superoxide dismutase and glutathione peroxidase activity and glutathione and malondialdehyde levels. A5 improved neurological deficits, weight loss, cerebral hypoperfusion, brain edema, blood-brain barrier disruption, neuronal apoptosis, and ferroptosis. It also increased the ratio of M2/M1 phenotype microglia, reduced interleukin 1ß and 6 levels, decreased peripheral immune cell infiltration, and increased interleukin 10 levels. A5 reduced neuronal iron accumulation, p53-related cell death, and oxidative stress damage. Finally, A5 downregulated HMGB1 and NF-ĸB pathways and upregulated the nuclear erythroid 2-related factor (Nrf2) and HO-1 pathways. These results suggest that A5 exerts neuroprotection in traumatic brain injury mice and ameliorates neuroinflammation, oxidative stress, and ferroptosis by regulating the NF-kB/HMGB1 pathway and the Nrf2/HO-1 antioxidant system.
Assuntos
Lesões Encefálicas Traumáticas , Ferroptose , Proteína HMGB1 , Camundongos , Animais , NF-kappa B/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Anexina A5/metabolismo , Doenças Neuroinflamatórias , Proteína HMGB1/metabolismo , Fatores de Transcrição NFI , Transdução de Sinais , Lesões Encefálicas Traumáticas/metabolismo , Estresse Oxidativo , Antioxidantes/farmacologiaRESUMO
Brain induced extracellular vesicle (BDEV) elevates after traumatic brain injury (TBI) and contributes to secondary brain injury. However, the role of BDEV in TBI remains unclear. In this study, we determined the mechanisms of BDEV in brain injury and explored whether neuroprotective drug BKca channel opener NS1619 may attenuate BDEV-induced brain injury. We injected BDEV and lactadherin, respectively, to mimic the up and downregulation of BDEV after TBI and illustrated the role of BDEV in vivo. In vitro, the membrane potential and calcium concentration of HT-22, bEnd3, and BV-2 were measured by fluorescent staining. The effects of BDEV and NS1619 on HT-22 were evaluated by CCK-8, LDH release assay, Na+/k+-ATPase activity, JC-1 staining, DHE staining, and 4-HNE staining, respectively. The role of BDEV and NS1619 on the Nrf2/HO-1/p65 pathway was also evaluated in HT-22. Finally, we administrated TBI mice with NS1619 to clarify the role of NS1619 against BDEV in vivo. Our results suggested that BDEV aggravated and lactadherin mitigated TBI-induced EB leakage, brain edema, neuronal degeneration, apoptosis, ROS level, microgliosis, MMP-9 activity, and NF-κB activation. In vitro, BDEV-caused depolarized membrane potential and calcium overload were significantly attenuated by NS1619 in HT-22, bEnd3, and BV-2. BDEV markedly decreased cell viability, Na+/k+-ATPase activity, and caused mitochondrial dysregulation, oxidative stress, and NF-ĸB activation. NS1619 pretreatment alleviated above process and enhanced antioxidant system Nrf2/HO-1 in HT-22. Finally, NS1619 administration significantly inhibited neuroinflammation response and improved TBI outcome after TBI. NS1619 treatment also reduced 4-HNE content and NF-ĸB activation and enhanced Nrf2/HO-1 pathway. Our data showed that BDEV aggravated brain injury by perturbing cell membrane potential, calcium homeostasis, oxidative stress, and neuroinflammation. The BKca channel opener NS1619 attenuated BDEV-induced pathological process in vitro and in vivo by modulating the BKca channel and Nrf2/HO-1/NF-ĸB pathway.
Assuntos
Lesões Encefálicas Traumáticas , Lesões Encefálicas , Vesículas Extracelulares , Animais , Camundongos , Adenosina Trifosfatases , Encéfalo , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas Traumáticas/tratamento farmacológico , Cálcio , Fator 2 Relacionado a NF-E2 , NF-kappa BRESUMO
BACKGROUND AND PURPOSE: Neuroinflammation has been shown to play a critical role in secondary craniocerebral injury, leading to poor outcomes for TBI patients. Abrocitinib, a Janus kinase1 (JAK1) selective inhibitor approved to treat atopic dermatitis (AD) by the Food and Drug Administration (FDA), possesses a novel anti-inflammatory effect. In this study, we investigated whether abrocitinib could ameliorate neuroinflammation and exert a neuroprotective effect in traumatic brain injury (TBI) models. METHODS: First, next-generation sequencing (NGS) was used to select genes closely related to neuroinflammation after TBI. Then, magnetic resonance imaging (MRI) was used to dynamically observe the changes in traumatic focus on the 1st, 3rd, and 7th days after the induction of fluid percussion injury (FPI). Moreover, abrocitinib's effects on neurobehaviors were evaluated. A routine peripheral blood test was carried out and Evans blue dye extravasation, cerebral cortical blood flow, the levels of inflammatory cytokines, and changes in the numbers of inflammatory cells were evaluated to investigate the function of abrocitinib on the 1st day post-injury. Furthermore, the JAK1/signal transducer and activator of transcription1 (STAT1)/nuclear factor kappa (NF-κB) pathway was assessed. RESULTS: In vivo, abrocitinib treatment was found to shrink the trauma lesions. Compared to the TBI group, the abrocitinib treatment group showed better neurological function, less blood-brain barrier (BBB) leakage, improved intracranial blood flow, relieved inflammatory cell infiltration, and reduced levels of inflammatory cytokines. In vitro, abrocitinib treatment was shown to reduce the pro-inflammatory M1 microglia phenotype and shift microglial polarization toward the anti-inflammatory M2 phenotype. The WB and IHC results showed that abrocitinib played a neuroprotective role by restraining JAK1/STAT1/NF-κB levels after TBI. CONCLUSIONS: Collectively, abrocitinib treatment after TBI is accompanied by improvements in neurological function consistent with radiological, histopathological, and biochemical changes. Therefore, abrocitinib can indeed reduce excessive neuroinflammation by restraining the JAK1/STAT1/NF-κB pathway.
Assuntos
Lesões Encefálicas Traumáticas , NF-kappa B , Estados Unidos , Humanos , NF-kappa B/metabolismo , Microglia/metabolismo , Doenças Neuroinflamatórias , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/patologia , Anti-Inflamatórios/farmacologia , Citocinas/metabolismo , Fator de Transcrição STAT1/metabolismo , Janus Quinase 1/metabolismoRESUMO
Cerebral vasospasm is a frequently encountered clinical problem, especially in patients with traumatic brain injury and subarachnoid hemorrhage. Continued cerebral vasospasm can cause cerebral ischemia, even infarction and delayed ischemic neurologic deficits. It significantly affects the course of the disease and the outcome of the patient. However, the underlying mechanism of cerebral vasospasm is still unclear. Recently, increasing studies focus on the pathogenic mechanism of microparticles. It has been found that microparticles have a non-negligible role in promoting vasospasm. This research aims to summarize the dynamics of microparticles in vivo and identify a causal role of microparticles in the occurrence and development of cerebral vasospasm. We found that these various microparticles showed dynamic characteristics in body fluids and directly or indirectly affect the cerebral vasospasm or prompt it. Due to the different materials carried by microparticles from different cells, there are also differences in the mechanisms that lead to abnormal vasomotor. We suggest that microparticle scavengers might be a promising therapeutic target against microparticles associated complications.
RESUMO
Aims: Annexin A5 (ANXA5) exhibited potent antithrombotic, antiapoptotic, and anti-inflammatory properties in a previous study. The role of ANXA5 in traumatic brain injury (TBI)-induced intestinal injury is not fully known. Main methods: Recombinant human ANXA5 (50 µg/kg) or vehicle (PBS) was administered to mice via the tail vein 30 min after TBI. Mouse intestine tissue was gathered for hematoxylin and eosin staining 0.5 d, 1 d, 2 d, and 7 d after modeling. Intestinal Western blotting, immunofluorescence, TdT-mediated dUTP nick-end labeling staining, and enzyme-linked immunosorbent assays were performed 2 days after TBI. A series of kits were used to assess lipid peroxide indicators such as malonaldehyde, superoxide dismutase activity, and catalase activity. Key findings: ANXA5 treatment improved the TBI-induced intestinal mucosa injury at different timepoints and significantly increased the body weight. It significantly reduced apoptosis and matrix metalloproteinase-9 and inhibited the degradation of tight-junction-associated protein in the small intestine. ANXA5 treatment improved intestinal inflammation by regulating inflammation-associated factors. It also mitigated the lipid peroxidation products 4-HNE, 8-OHDG, and malonaldehyde, and enhanced the activity of the antioxidant enzymes, superoxide dismutase and catalase. Lastly, ANXA5 significantly enhanced nuclear factor E2-related factor 2 (Nrf2) and hemeoxygenase-1, and decreased high mobility group box 1 (HMGB1). Significance: Collectively, the results suggest that ANXA5 inhibits TBI-induced intestinal injury by restraining oxidative stress and inflammatory responses. The mechanisms involved sparking the Nrf2/hemeoxygenase-1-induced antioxidant system and suppressing the HMGB1 pathway. ANXA5 may be an attractive therapeutic candidate for protecting against TBI-induced intestinal injury.
Assuntos
Lesões Encefálicas Traumáticas , Proteína HMGB1 , Enteropatias , Animais , Anexina A5/metabolismo , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Encéfalo/metabolismo , Lesões Encefálicas Traumáticas/tratamento farmacológico , Catalase/metabolismo , Amarelo de Eosina-(YS) , Fibrinolíticos/farmacologia , Proteína HMGB1/metabolismo , Hematoxilina/metabolismo , Hematoxilina/farmacologia , Hematoxilina/uso terapêutico , Heme Oxigenase-1/metabolismo , Humanos , Inflamação/tratamento farmacológico , Enteropatias/metabolismo , Peróxidos Lipídicos , Malondialdeído/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Transdução de Sinais , Superóxido Dismutase/metabolismoRESUMO
Artificial enzymes have attracted wide interest in disease diagnosis and biotechnology due to high stability, easy synthesis, and cost effectiveness. Unfortunately, their catalytic rate is limited to surface electron transfer, affecting the catalytic and biological activity. Here, we report an oligomeric nanozyme (O-NZ) with ultrafast electron transfer, achieving ultrahigh catalytic activity. O-NZ shows electron transfer of 1.8 nanoseconds in internal cores and 1.2 picoseconds between core and ligand molecule, leading to ultrahigh superoxidase dismutaselike and glutathione peroxidaselike activity (comparable with natural enzyme, Michaelis constant = 0.87 millimolars). Excitingly, O-NZ can improve the 1-month survival rate of mice with acute brain trauma from 50 to 90% and promote the recovery of long-term neurocognition. Biochemical experiments show that O-NZ can decrease harmful peroxide and superoxide via in vivo catalytic chain reaction and reduce acute neuroinflammation via nuclear factor erythroid-2 related factor 2mediated up-regulation of heme oxygenase-1 expression.
RESUMO
Natural enzymes are efficient and versatile biocatalysts but suffer in their environmental tolerance and catalytic stability. As artificial enzymes, nanozymes can improve the catalytic stability, but it is still a challenge to achieve high catalytic activity. Here, we employed atomic engineering to build the artificial enzyme named Au24Ag1 clusterzyme that hosts an ultrahigh catalytic activity as well as strong physiological stability via atom manipulation. The designed Au24Ag1 clusterzyme activates the Ag-S active site via lattice expansion in the oligomer atom layer, showing an antioxidant property 72 times higher than that of natural antioxidant Trolox. Enzyme-mimicked studies find that Au24Ag1 clusterzyme exhibits high catalase-like (CAT-like) and glutathione peroxidase-like (GPx-like) activity with a maximum reaction rate of 68.9 and 17.8 µM/min, respectively. Meanwhile, the unique catalytic landscape exhibits distinctive reactions against inflammation by inhibiting the cytokines at an early stage in the brain. Atomic engineering of clusterzymes provides a powerful and attractive platform with satisfactory atomic dispersion for tailoring biocatalysts freely at the atomic level.
Assuntos
Catálise , Catalase/genéticaRESUMO
Traumatic brain injury (TBI) is a sudden injury to the brain, accompanied by the production of large amounts of reactive oxygen and nitrogen species (RONS) and acute neuroinflammation responses. Although traditional pharmacotherapy can effectively decrease the immune response of neuron cells via scavenging free radicals, it always involves in short reaction time as well as rigorous clinical trial. Therefore, a noninvasive topical treatment method that effectively eliminates free radicals still needs further investigation. Methods: In this study, a type of catalytic patch based on nanozymes with the excellent multienzyme-like activity is designed for noninvasive treatment of TBI. The enzyme-like activity, free radical scavenging ability and therapeutic efficacy of the designed catalytic patch were assessed in vitro and in vivo. The structural composition was characterized by the X-ray diffraction, X-ray photoelectron spectroscopy and high-resolution transmission electron microscopy technology. Results: Herein, the prepared Cr-doped CeO2 (Cr/CeO2) nanozyme increases the reduced Ce3+ states, resulting in its enzyme-like activity 3-5 times higher than undoped CeO2. Furthermore, Cr/CeO2 nanozyme can improve the survival rate of LPS induced neuron cells via decreasing excessive RONS. The in vivo experiments show the Cr/CeO2 nanozyme can promote wound healing and reduce neuroinflammation of mice following brain trauma. The catalytic patch based on nanozyme provides a noninvasive topical treatment route for TBI as well as other traumas diseases. Conclusions: The catalytic patch based on nanozyme provides a noninvasive topical treatment route for TBI as well as other traumas diseases.
Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Catálise/efeitos dos fármacos , Cério/administração & dosagem , Compostos de Cromo/administração & dosagem , Oxirredução/efeitos dos fármacos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Lesões Encefálicas Traumáticas/metabolismo , Linhagem Celular , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Taxa de Sobrevida , Cicatrização/efeitos dos fármacosRESUMO
Traumatic brain injury frequently leads to serious mortality and physical disability, yet effective treatments remains insufficient. TBI always leads to a series of secondary brain injuries including neuronal apoptosis, continuous inflammation, endoplasmic reticulum stress, and disruption of the blood-brain barrier. Sartans that block angiotensin II type 1 receptors are strongly neuroprotective, neurorestorative and anti-inflammatory. However, whether losartan, a FDA-approved and widely used drug for regulating blood pressure, is beneficial for improving the prognosis of TBI need more evidence. Through a controlled cortical impact injury mice model, we confirmed that losartan treatment could ameliorate CCI-induced secondary brain injury. We found that losartan treatment decreased brain lesion volume, neuronal apoptosis and ER stress protein ATF4 and eIF2α. Moreover, our results showed that losartan also improved neurological and motor function. It is worth pointing out that losartan increased the expression of tight junction proteins ZO-1 and alleviated brain edema and blood brain barrier leakage. Additionally, losartan inhibited pro-inflammatory factor TNF-α and improve anti-inflammatory factor IL-10. Taken together, our data demonstrated that losartan could improve the prognosis of TBI and may be a promising therapeutic method for mitigating TBI.
RESUMO
Free radical-induced oxidative damage and nitrosative stress have been identified as key factors in neuroinflammation responses after traumatic brain injury (TBI), with which reactive oxygen and nitrogen species (RONS), especially nitrogen signaling molecules, are strongly associated. Here, we prepared ultrasmall carbon dot (CD) by using a simple and facile method. In vitro assessment experiments show that the antioxidative CD exhibits an ultrahigh target-scavenging effect for nitrogen signaling molecules, especially the highly reactive ËNO and ONOO-. However, CD can only partially eliminate conventional oxygen radials such as O2Ë- and ËOH, indicating CD has a preference for RNS modulation. Moreover, in vitro cell experiments and in vivo mice experiments reveal that CD can reduce the reactive oxygen species (ROS) level and lipid peroxidation, enhance superoxide dismutase (SOD) activity and GSSG level, and further improve the survival rate of neuron cells and TBI mice. These results declare that antioxidative CD could serve as an effective therapeutic for TBI.
Assuntos
Antioxidantes/química , Lesões Encefálicas Traumáticas/tratamento farmacológico , Carbono/química , Pontos Quânticos/química , Espécies Reativas de Nitrogênio/química , Animais , Antioxidantes/farmacologia , Transporte Biológico , Barreira Hematoencefálica/metabolismo , Morte Celular/efeitos dos fármacos , Cisteína/química , Modelos Animais de Doenças , Radicais Livres/química , Radicais Livres/metabolismo , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Lisina/química , Camundongos , Camundongos Endogâmicos C57BL , Teste do Labirinto Aquático de Morris/efeitos dos fármacos , Neurônios/citologia , Estresse Oxidativo/efeitos dos fármacos , Pontos Quânticos/metabolismo , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/química , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Distribuição TecidualRESUMO
OBJECTIVE: Mitochondrial dysfunction plays an essential role in secondary brain injury following traumatic brain injury (TBI). Interestingly, accumulating evidence has shown that therapeutic benefits of mitochondrial transplantation exist. Therefore, we hypothesized that the injection of exogenous mitochondria would contribute to the mitigation of cellular energy metabolism disorders and neurologic functions after TBI. METHODS: We first extracted isolated mitochondria from fresh brain tissue using a kit and then identified their activity and purity. The role of exogenous mitochondria was assessed using the glucose oxygen deprivation-induced cellular damage model and controlled cortical impact-induced mice with TBI. RESULTS: The results showed that treatment with exogenous mitochondria improved the cellular respiratory control rate, the expression of tight junction-associated proteins, and synaptic plasticity-related proteins in vitro. Moreover, the application of exogenous mitochondria significantly reduced cellular apoptosis, promoted angiogenesis and alleviated brain edema and blood-brain barrier leakage in mice subjected to TBI. Additionally, exogenous mitochondria significantly reduced excessive inhibition of long-term depression in the hippocampus 7 days after TBI. CONCLUSIONS: Taken together, the data suggested that exogenous mitochondrial intervention ameliorated glucose oxygen deprivation-induced cell damage and controlled cortical impact-induced TBI in a mouse model. The new discovery in the current study inspires us to suggest that mitochondrial transplantation might serve as a new therapeutic strategy for TBI.
Assuntos
Lesões Encefálicas Traumáticas/terapia , Encéfalo/metabolismo , Células Endoteliais/metabolismo , Hipocampo/fisiopatologia , Mitocôndrias/transplante , Neovascularização Fisiológica/fisiologia , Neurônios/metabolismo , Proteínas de Junções Íntimas/metabolismo , Animais , Apoptose/fisiologia , Barreira Hematoencefálica/metabolismo , Encéfalo/fisiopatologia , Edema Encefálico/metabolismo , Edema Encefálico/fisiopatologia , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/fisiopatologia , Hipóxia Celular , Respiração Celular/fisiologia , Modelos Animais de Doenças , Células Endoteliais/fisiologia , Hipoglicemia , Depressão Sináptica de Longo Prazo/fisiologia , Camundongos , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Células PC12 , RatosRESUMO
BACKGROUND AND PURPOSE: Previous studies have identified many risk factors related to the recurrence of chronic subdural hematomas (CSDHs). Among these factors, there may be deviations in measuring the midline shift, preoperative hematoma volume (PreHV), postoperative hematoma residual volume, and postoperative pneumocephalus in bilateral CSDHs. The aims of this study were to eliminate the impact of complicated situations on parameter measurement and to identify actual predictors for CSDH recurrence, and finally, to develop a grading system to predict unilateral CSDH (uCSDH) recurrence. PATIENTS AND METHODS: A total of 342 patients with uCSDH were identified. Predictors of uCSDH recurrence were obtained from univariable and multivariable logistic regression models. A prognostic grading system was developed based on the results of multivariable logistic regression and receiver operating characteristic (ROC) analyses. All patients were scored according to the grading system, and differences in the recurrence rate were reanalyzed according to the scores. RESULTS: Age, antiplatelet or anticoagulant use, midline shift, severe brain atrophy, drainage volume, and the ratio of the postoperative pneumocephalus volume (PostPV) to the postoperative hematoma cavity volume (PostHCV) were identified as independent risk factors for predicting the recurrence of uCSDH. The cut-off values of age, drainage volume, midline shift, and the ratio of the PostPV to the PostHCV were 67 years, 101 mL, 11.2 mm, and 31.61%, respectively. The recurrence rates were 1.7%, 12.4%, 19.4%, 53.3%, and 58.3% for scores of 0-1, 2, 3, 4, and 5-6, respectively, which significantly increased as the score increased (P<0. 001). CONCLUSION: The prognostic grading system for uCSDH on the basis of multivariable logistic regression and ROC analyses is applicable and reliable.
RESUMO
Objective: To investigate whether methylene blue (MB) treatment can reverse neuronal mitochondrial dysfunction caused by oxygen glucose deprivation/reoxygenation (OGD) injury and then investigate whether MB treatment can reduce neuronal apoptosis and improve blood-brain barrier (BBB) integrity in traumatic brain injury (TBI) animals. Methods: Reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and adenosine triphosphate (ATP) were used to evaluate mitochondrial function. The terminal deoxynucleotidyl transferase-dUTP nick end labeling (TUNEL) assay was used to assess neuronal apoptosis in vitro. TUNEL and immunofluorescence staining for neuronal nuclei (NeuN) were combined to assess neuronal apoptosis in vivo. An Evans blue (EB) permeability assay and brain water content (BWC) were used to measure BBB permeability in vivo. The Morris water maze (MWM), rotarod test, and modified Neurological Severity Score (mNSS) test were employed to assess the prognosis of TBI mice. Results: MB treatment significantly reversed neuronal mitochondrial dysfunction caused by OGD injury. Both in vitro and in vivo, MB treatment reduced neuronal apoptosis and improved BBB integrity. In TBI animals, treatment with MB not only improved cognitive and motor function caused by TBI but also significantly improved overall neurological function. Conclusions: Our findings suggest that MB is a potential candidate for the treatment of TBI. Future research should focus on other therapeutic effects and mechanisms of MB in secondary brain injury.
RESUMO
Neurotrauma is one of the most serious traumatic injuries, which can induce an excess amount of reactive oxygen and nitrogen species (RONS) around the wound, triggering a series of biochemical responses and neuroinflammation. Traditional antioxidant-based bandages can effectively decrease infection via preventing oxidative stress, but its effectiveness is limited to a short period of time due to the rapid loss of electron-donating ability. Herein, we developed a nanozyme-based bandage using single-atom Pt/CeO2 with a persistent catalytic activity for noninvasive treatment of neurotrauma. Single-atom Pt induced the lattice expansion and preferred distribution on (111) facets of CeO2, enormously increasing the endogenous catalytic activity. Pt/CeO2 showed a 2-10 times higher scavenging activity against RONS as well as 3-10 times higher multienzyme activities compared to CeO2 clusters. The single-atom Pt/CeO2 retained the long-lasting catalytic activity for up to a month without obvious decay due to enhanced electron donation through the Mars-van Krevelen reaction. In vivo studies disclosed that the nanozyme-based bandage at the single-atom level can significantly improve the wound healing of neurotrauma and reduce neuroinflammation.