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Improving the nutrient content of red soils in southern China is a priority for efficient rice production there. To assess the effectiveness of oilseed rape as green manure for the improvement of soil phosphorus nutrient supply and rice yield in red soil areas, a long-term field plot experiment was conducted comparing two species of rape, Brassica napus (BN) and Brassica juncea (BJ). The effects of returning oilseed rape on soil phosphorus availability, phosphorus absorption, and yield of subsequent rice under rice-green manure rotation mode were analyzed, using data from the seasons of 2020 to 2021. The study found that compared with winter fallow treatment (WT) and no-tillage treatment (NT), the soil available phosphorus content of BN was increased, and that of BJ was significantly increased. The content of water-soluble inorganic phosphorus of BJ increased, and that of BN increased substantially. Compared with the WT, the soil organic matter content and soil total phosphorus content of BN significantly increased, as did the soil available potassium content of BJ, and the soil total phosphorus content of BJ was significantly increased compared with NT. The soil particulate phosphorus content of BJ and BN was significantly increased by 14.00% and 16.00%, respectively. Compared with the WT, the phosphorus activation coefficient of BJ was significantly increased by 11.41%. The rice plant tiller number under the green manure returning treatment was significantly increased by 43.16% compared with the winter fallow treatment. The green manure returning measures increased rice grain yield by promoting rice tiller numbers; BN increased rice grain yield by 9.91% and BJ by 11.68%. Based on these results, returning oilseed rape green manure could augment the phosphorus nutrients of red soil and promote phosphorus availability. Rice-oilseed rape green manure rotation could increase rice grain yield.
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PURPOSE: Preoperative diagnosis of filum terminale ependymomas (FTEs) versus schwannomas is difficult but essential for surgical planning and prognostic assessment. With the advancement of deep-learning approaches based on convolutional neural networks (CNNs), the aim of this study was to determine whether CNN-based interpretation of magnetic resonance (MR) images of these two tumours could be achieved. METHODS: Contrast-enhanced MRI data from 50 patients with primary FTE and 50 schwannomas in the lumbosacral spinal canal were retrospectively collected and used as training and internal validation datasets. The diagnostic accuracy of MRI was determined by consistency with postoperative histopathological examination. T1-weighted (T1-WI), T2-weighted (T2-WI) and contrast-enhanced T1-weighted (CE-T1) MR images of the sagittal plane containing the tumour mass were selected for analysis. For each sequence, patient MRI data were randomly allocated to 5 groups that further underwent fivefold cross-validation to evaluate the diagnostic efficacy of the CNN models. An additional 34 pairs of cases were used as an external test dataset to validate the CNN classifiers. RESULTS: After comparing multiple backbone CNN models, we developed a diagnostic system using Inception-v3. In the external test dataset, the per-examination combined sensitivities were 0.78 (0.71-0.84, 95% CI) based on T1-weighted images, 0.79 (0.72-0.84, 95% CI) for T2-weighted images, 0.88 (0.83-0.92, 95% CI) for CE-T1 images, and 0.88 (0.83-0.92, 95% CI) for all weighted images. The combined specificities were 0.72 based on T1-WI (0.66-0.78, 95% CI), 0.84 (0.78-0.89, 95% CI) based on T2-WI, 0.74 (0.67-0.80, 95% CI) for CE-T1, and 0.81 (0.76-0.86, 95% CI) for all weighted images. After all three MRI modalities were merged, the receiver operating characteristic (ROC) curve was calculated, and the area under the curve (AUC) was 0.93, with an accuracy of 0.87. CONCLUSIONS: CNN based MRI analysis has the potential to accurately differentiate ependymomas from schwannomas in the lumbar segment.
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Cauda Equina , Ependimoma , Neurilemoma , Humanos , Estudos Retrospectivos , Cauda Equina/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Redes Neurais de Computação , Neurilemoma/diagnóstico por imagem , Neurilemoma/cirurgia , Ependimoma/diagnóstico por imagemRESUMO
Effective representation of molecules is a crucial step in AI-driven drug design and drug discovery, especially for drug-drug interaction (DDIs) prediction. Previous work usually models the drug information from the drug-related knowledge graph or the single drug molecules, but the interaction information between molecular substructures of drug pair is seldom considered, thus often ignoring the influence of bond information on atom node representation, leading to insufficient drug representation. Moreover, key molecular substructures have significant contribution to the DDIs prediction results. Therefore, in this work, we propose a novel Graph learning framework of Mutual Interaction Attention mechanism (called GMIA) to predict DDIs by effectively representing the drug molecules. Specifically, we build the node-edge message communication encoder to aggregate atom node and the incoming edge information for atom node representation and design the mutual interaction attention decoder to capture the mutual interaction context between molecular graphs of drug pairs. GMIA can bridge the gap between two encoders for the single drug molecules by attention mechanism. We also design a co-attention matrix to analyze the significance of different-size substructures obtained from the encoder-decoder layer and provide interpretability. In comparison with other recent state-of-the-art methods, our GMIA achieves the best results in terms of area under the precision-recall-curve (AUPR), area under the ROC curve (AUC), and F1 score on two different scale datasets. The case study indicates that our GMIA can detect the key substructure for potential DDIs, demonstrating the enhanced performance and interpretation ability of GMIA.
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Desenho de Fármacos , Descoberta de Drogas , Área Sob a Curva , Interações MedicamentosasRESUMO
BACKGROUND: Subarachnoid hemorrhage (SAH) is an uncommon type of potentially fatal stroke. The pathophysiological mechanisms of brain injury remain unclear, which hinders the development of drugs for SAH. We aimed to investigate the pathophysiological mechanisms of SAH and to elucidate the cellular and molecular biological response to SAH-induced injury. METHODS: A cross-species (human and mouse) multiomics approach combining high-throughput data and bioinformatic analysis was used to explore the key pathophysiological processes and cells involved in SAH-induced brain injury. Patient data were collected from the hospital (n = 712). SAH was established in adult male mice via endovascular perforation, and flow cytometry, a bone marrow chimera model, qPCR, and microglial depletion experiments were conducted to explore the origin and chemotaxis mechanism of the immune cells. To investigate cell effects on SAH prognosis, murine neurological function was evaluated based on a modified Garcia score, pole test, and rotarod test. RESULTS: The bioinformatics analysis confirmed that inflammatory and immune responses were the key pathophysiological processes after SAH. Significant increases in the monocyte levels were observed in both the mouse brains and the peripheral blood of patients after SAH. Ly6C-high monocytes originated in the bone marrow, and the skull bone marrow contribute a higher proportion of these monocytes than neutrophils. The mRNA level of Ccl2 was significantly upregulated after SAH and was greater in CD11b-positive than CD11b-negative cells. Microglial depletion, microglial inhibition, and CCL2 blockade reduced the numbers of Ly6C-high monocytes after SAH. With CCR2 antagonization, the neurological function of the mice exhibited a slow recovery. Three days post-SAH, the monocyte-derived dendritic cell (moDC) population had a higher proportion of TNF-α-positive cells and a lower proportion of IL-10-positive cells than the macrophage population. The ratio of moDCs to macrophages was higher on day 3 than on day 5 post-SAH. CONCLUSIONS: Inflammatory and immune responses are significantly involved in SAH-induced brain injury. Ly6C-high monocytes derived from the bone marrow, including the skull bone marrow, infiltrated into mouse brains via CCL2 secreted from microglia. Moreover, Ly6C-high monocytes alleviated neurological dysfunction after SAH.
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Lesões Encefálicas , Acidente Vascular Cerebral , Hemorragia Subaracnóidea , Humanos , Camundongos , Masculino , Animais , Monócitos , Hemorragia Subaracnóidea/complicações , Lesões Encefálicas/etiologia , Macrófagos , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Aggressive variant prostate cancer (AVPC) is a rare disease that progresses rapidly. The first-line treatment for AVPC is currently unknown. We examined a rare case of AVPC with rare brain and bladder metastases. A summary review of the mechanism of development, clinicopathological manifestations, associated treatments and prognosis of this disease is presented. CASE SUMMARY: The patient was diagnosed with prostate cancer (PCA), and was actively treated with endocrine therapy, radiotherapy, chemotherapy, and traditional Chinese medicine. Unfortunately, he was insensitive to treatment, and the disease progressed rapidly. He died five years after being diagnosed with PCA. CONCLUSION: We should reach consensus definitions of the AVPC and other androgen receptor-independent subtypes of PCA and develop new biomarkers to identify groups of high-risk variants. It is crucial to complete a puncture biopsy of the tumor or metastatic lesion as soon as possible in patients with advanced PCA who exhibit clinical features such as low Prostate-specific antigen levels, high carcinoembryonic antigen levels, and insensitivity to hormones to determine the pathological histological type and to create a more aggressive monitoring and treatment regimens.
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Spinal cord injury (SCI) could lead to severe disabilities in motor and sensory functions, and cause a heavy burden on patient physiology and psychology due to lack of specific repair measures so far. ANXA7 is an annexin with Ca2+ -dependent GTPase activity, which were mainly expressed in neuron in spinal cord and downregulated significantly after SCI in mice. In our study, GTPase activity activation of ANXA7 plays the protective role in neuron after OGD/R through inhibiting neuron apoptosis, which mediated by enhancing autophagy via mTOR/TFEB pathway. We also discovered that ANXA7 has significant interaction with neural-specific lysosomal-associated membrane protein LAMP5, which together with ANXA7 regulates autophagy and apoptosis. Asp411 mutation of ANXA7 obviously impaired the interaction of ANXA7 and LAMP5 compared with the wild type. Furthermore, it was found that activation of ANXA7 could help to stabilize the protein expression of LAMP5. Overexpression of LAMP5 could attenuate the destruction of lysosomal acidic environment, inhibition of autophagy and activation of apoptosis caused by ANXA7 downregulation after OGD/R. We verified that injecting ANXA7 overexpression lentivirus and activation of ANXA7 both have significant repair effects on SCI mice by using CatWalk assay and immunohistochemistry staining. In summary, our findings clarify the new role of ANXA7 and LAMP5 in SCI, provided a new specific target of neuronal repair and discovered new molecular mechanisms of ANXA7 to regulate autophagy and apoptosis. Targeting ANXA7 may be a prospective therapeutic strategy for SCI in future.
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BACKGROUND: Prostate lymphoma has no characteristic clinical symptomatology, is often misdiagnosed, and currently, clinical case reports of this disease are relatively rare. The disease develops rapidly and is not sensitive to conventional treatment. A delay in the treatment of hydronephrosis may lead to renal function injury, often causing physical discomfort and rapid deterioration with the disease. This paper presents two patients with lymphoma of prostate origin, followed by a summary of the literature concerning the identification and treatment of such patients. CASE SUMMARY: This paper reports on the cases of two patients with prostate lymphoma admitted to the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, one of whom died of the disease 2 mo after diagnosis, while the other was treated promptly, and his tumor was significantly reduced at the 6-mo follow-up. CONCLUSION: The literature shows that prostate lymphoma is often seen as a benign prostate disease during its pathogenesis, even though primary prostate lymphoma enlarges rapidly and diffusely with the invasion of surrounding tissues and organs. In addition, prostate-specific antigen levels are not elevated and are not specific. There are no significant features in single imaging either, but during dynamic observation of imaging, it can be found that the lymphoma is diffusely enlarged locally and that systemic symptoms metastasize rapidly. The two cases of rare prostate lymphoma reported herein provide a reference for clinical decision making, and the authors conclude that early nephrostomy to relieve the obstruction plus chemotherapy is the most convenient and effective treatment option for the patient.
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Hydrocephalus has been observed in rats with spontaneous hypertension (SHRs). It has been demonstrated that activation of the oxidative stress related protein retinoic acid receptor alpha (RARα) has neuroprotective impacts. Our investigation aims to determine the potential role and mechanism of RARα in hydrocephalus. The RARα-specific agonist (Am80) and RARα inhibitor (AGN196996) were used to investigate the role of RARα in cerebrospinal fluid (CSF) secretion in the choroid plexus of SHRs. Evaluations of CSF secretion, ventricular volume, Western blotting, and immunofluorescent staining were performed. Hydrocephalus and CSF hypersecretion were identified in SHRs but not in Wistar-Kyoto rats, occurring at the age of 7 weeks. The RARα/MAFB/MSR1 pathway was also activated in SHRs. Therapy with Am80 beginning in week 5 decreased CSF hypersecretion, hydrocephalus development, and pathological changes in choroid plexus alterations by week 7. AGN196996 abolished the effect of Am80. In conclusion, activation of the RARα attenuated CSF hypersecretion to inhibit hydrocephalus development via regulating the MAFB/MSR1 pathway. RARα may act as a possible therapeutic target for hydrocephalus.
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Hidrocefalia , Hipertensão , Animais , Ratos , Plexo Corióideo/metabolismo , Hidrocefalia/metabolismo , Hipertensão/metabolismo , Fator de Transcrição MafB/metabolismo , Proteínas Oncogênicas/metabolismo , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Receptores Depuradores Classe A/metabolismoRESUMO
BACKGROUND: Schwannoma, a benign peripheral nerve sheath tumor, is perhaps only secondary to degenerative pathology as the most common lesion at neural foramen. The surgical dilemma here is either risking nerve injury because of inadequate exposure or the need for internal fixation because of facet joint sacrifice. OBJECTIVE: To evaluate the feasibility and safety of management of foraminal schwannomas by percutaneous full-endoscopic technique. METHODS: A single-center retrospective review was conducted on patients who underwent full-endoscopic resection of neural foraminal schwannomas. Tumors were grouped into either medial type or lateral type based on relevant location to the neural foramen, and respective surgical approaches were adopted. Data including preoperative neurological status, tumor size, surgery time, the extension of resection, and clinical outcomes were collected. The learning curve was plotted as surgical time/tumor size against case number. RESULTS: A total of 25 patients were treated between May 2015 and March 2022. Gross total resection was achieved in 24 patients, and near-total resection in 1 case, with 1 patient experienced transient voiding difficulty. No tumor recurrence or spinal instability was detected in the short-term follow-up (median follow-up 22 months, range 3 months-6 years). Surgical efficiency improved with the number of cases operated on and remained stable after the initial 10 cases. CONCLUSION: Percutaneous full-endoscopic technique is a safe and minimally invasive technique for the resection of foraminal schwannomas.
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Neoplasias de Bainha Neural , Neurilemoma , Neoplasias do Sistema Nervoso Periférico , Humanos , Resultado do Tratamento , Recidiva Local de Neoplasia/cirurgia , Neurilemoma/diagnóstico por imagem , Neurilemoma/cirurgia , Neoplasias de Bainha Neural/patologia , EndoscopiaRESUMO
The combination of optogenetics and electrophysiological recording enables high-precision bidirectional interactions between neural interfaces and neural circuits, which provides a promising approach for the study of progressive neurophysiological phenomena. Opto-electrophysiological neural probes with sufficient flexibility and biocompatibility are desirable to match the low mechanical stiffness of brain tissue for chronic reliable performance. However, lack of rigidity poses challenges for the accurate implantation of flexible neural probes with less invasiveness. Herein, we report a hybrid probe (Silk-Optrode) consisting of a silk protein optical fiber and multiple flexible microelectrode arrays. The Silk-Optrode can be accurately inserted into the brain and perform synchronized optogenetic stimulation and multichannel recording in freely behaving animals. Silk plays an important role due to its high transparency, excellent biocompatibility, and mechanical controllability. Through the hydration of the silk optical fiber, the Silk-Optrode probe enables itself to actively adapt to the environment after implantation and reduce its own mechanical stiffness to implant into the brain with high fidelity while maintaining mechanical compliance with the surrounding tissue. The probes with 128 recording channels can detect high-yield well-isolated single units while performing intracranial light stimulation with low optical losses, surpassing previous work of a similar type. Two months of post-surgery results suggested that as-reported Silk-Optrode probes exhibit better implant-neural interfaces with less immunoreactive glial responses and tissue lesions. A silk optical fiber-based Silk-Optrode probe consisting of a natural silk optical fiber and a flexible micro/nano electrode array is reported. The multifunctional soft probe can modify its own Young's modulus through hydration to achieve accurate implantation into the brain. The low optical loss and single-unit recording abilities allow simultaneous optogenetic stimulation and multichannel readout, which expands the applications in the operation and parsing of neural circuits in behavioral animals.
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OBJECTIVE: To present a retrospective review of a single-institute experience with bypass surgery of complex anterior cerebral artery aneurysm. METHODS: Eight patients (5 females and 3 males; mean age, 34.2 years) with complex anterior cerebral artery aneurysms were treated with bypass. There were 3 precommunicating aneurysms, 1 communicating artery aneurysm, and 4 postcommunicating aneurysms (2 in A2 and 2 in A3). A3-A3 side-to-side in situ bypass was performed in 6 cases. A3-radial artery-A3 interpositional bypass was performed in 1 case with A3 segments located far apart, and A3-A3 transplantation was performed in 1 case with nonparallel aligned A3 segments. Of the 8 aneurysms, 3 were secured with proximal clipping, 1 was secured with distal clipping, 1 was secured with direct clipping, 1 was secured with isolation, and 2 were secured with embolization. RESULTS: Aneurysm obliteration was achieved in all cases. Only 1 in situ bypass from a smaller donor artery to a larger recipient artery failed with minor postoperative infarction. Intraoperative bleeding from the site of anastomosis occurred in 1 case during embolization. All patients had complete recovery with normal neurological function during follow-up at outpatient clinics. CONCLUSIONS: We established a simplified surgical algorithm for complex anterior cerebral artery aneurysms based on the geometrical and spatial relationship between efferent arteries. The reasons for bypass failure and hemorrhagic complication were also discussed.
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Artérias Cerebrais/diagnóstico por imagem , Artérias Cerebrais/cirurgia , Revascularização Cerebral/métodos , Aneurisma Intracraniano/diagnóstico por imagem , Aneurisma Intracraniano/cirurgia , Adolescente , Adulto , Idoso , Atenção , Angiografia Cerebral/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Neuroinflammation is closely associated with poor prognosis in patients with subarachnoid hemorrhage (SAH). The purpose of this study was to investigate the role of neutrophil extracellular traps (NETs), which are important regulators of sterile inflammation, in SAH. In this study, markers of NET formation, quantified by the level of citrullinated histone H3 (CitH3), were significantly increased after SAH and correlated with SAH severity. CitH3 peaked at 12 h in peripheral blood and at 24 h in the brain. Administration of the peptidyl arginine deiminase 4 (PAD4) selective antagonist GSK484 substantially attenuated SAH-induced brain edema and neuronal injury. Moreover, the benefit of NET inhibition was also confirmed by DNAse I treatment and neutrophil depletion. Mechanistically, NETs markedly exacerbated microglial inflammation in vitro. NET formation aggravated neuroinflammation by promoting microglial activation and increased the levels of TNF-α, IL-1ß, and IL-6, while inhibiting NETs demonstrated anti-inflammatory effects by decreasing the levels of these proinflammatory factors. Moreover, neurogenic pulmonary edema (NPE), a severe nonneurological complication after SAH, is associated with a high level of NET formation. However, GSK484 effectively inhibited the formation of NETs in the lungs of NPE mice, thereby preventing the diffusion of neutrophilic infiltration and attenuating the swelling of the alveolar interstitium. In conclusion, NETs promoted neuroinflammation after SAH, while pharmacological inhibition of PAD4-NETs could reduce the inflammatory damage caused by SAH. These results supported the idea that NETs might be potential therapeutic targets for SAH.
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Lesões Encefálicas , Armadilhas Extracelulares , Hemorragia Subaracnóidea , Animais , Lesões Encefálicas/complicações , Lesões Encefálicas/tratamento farmacológico , Humanos , Inflamação/complicações , Camundongos , Microglia , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/tratamento farmacológicoRESUMO
Subarachnoid hemorrhage (SAH) is a devastating cerebrovascular disease with high mortality and disability. Aberrant neuroinflammation has been identified as a critical factor accounting for the poor prognosis of SAH patients. Mast cells (MCs), the sentinel cells of the immune system, play a critical in the early immune reactions and participate in multiple pathophysiological process. However, the exact role of MCs on the pathophysiological process after SAH has not been fully understood. The current study was conducted to determine the role of MCs and MC stabilization in the context of SAH. Mouse SAH model was established by endovascular perforation process. Mice received saline or cromolyn (MC stabilizer) or compound 48/80 (MCs degranulator). Post-SAH evaluation included neurobehavioral test, western blot, immunofluorescence, and toluidine blue staining. We demonstrated that SAH induced MCs activation/degranulation. Administration of MC stabilizer cromolyn conferred a better neurologic outcome and decreased brain edema when compared with SAH+vehicle group. Furthermore, cromolyn significantly inhibited neuroinflammatory response and alleviated neuronal damage after SAH. However, pharmacological activation of MCs with compound 48/80 dramatically aggravated SAH-induced brain injury and exacerbated neurologic outcomes. Notably, pharmacological inhibition of microglial PAR-2 significantly reversed MCs-induced inflammatory response and neurological impairment. Additionally, the effect of MCs-derived tryptase in mediating neuroinflammation was also abolished by the microglial PAR-2 blockage in vitro. Taken together, MCs yielded inflammatory injury through activating microglia-related neuroinflammation after SAH. These data shed light on the notion that MCs might be a novel and promising therapeutic target for SAH.
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BACKGROUND: Complex changes in the brain microenvironment following traumatic brain injury (TBI) can cause neurological impairments for which there are few efficacious therapeutic interventions. The reactivity of astrocytes is one of the keys to microenvironmental changes, such as neuroinflammation, but its role and the molecular mechanisms that underpin it remain unclear. METHODS: Male C57BL/6J mice were subjected to the controlled cortical impact (CCI) to develop a TBI model. The specific ligand of AXL receptor tyrosine kinase (AXL), recombinant mouse growth arrest-specific 6 (rmGas6) was intracerebroventricularly administered, and selective AXL antagonist R428 was intraperitoneally applied at 30 min post-modeling separately. Post-TBI assessments included neurobehavioral assessments, transmission electron microscopy, immunohistochemistry, and western blotting. Real-time polymerase chain reaction (RT-PCR), siRNA transfection, and flow cytometry were performed for mechanism assessments in primary cultured astrocytes. RESULTS: AXL is upregulated mainly in astrocytes after TBI and promotes astrocytes switching to a phenotype that exhibits the capability of ingesting degenerated neurons or debris. As a result, this astrocytic transformation promotes the limitation of neuroinflammation and recovery of neurological dysfunction. Pharmacological inhibition of AXL in astrocytes significantly decreased astrocytic phagocytosis both in vivo and in primary astrocyte cultures, in contrast to the effect of treatment with the rmGas6. AXL activates the signal transducer and activator of the transcription 1 (STAT1) pathway thereby further upregulating ATP-binding cassette transporter 1 (ABCA1). Moreover, the supernatant from GAS6-depleted BV2 cells induced limited enhancement of astrocytic phagocytosis in vitro. CONCLUSION: Our work establishes the role of AXL in the transformation of astrocytes to a phagocytic phenotype via the AXL/STAT1/ABCA1 pathway which contributes to the separation of healthy brain tissue from injury-induced cell debris, further ameliorating neuroinflammation and neurological impairments after TBI. Collectively, our findings provide a potential therapeutic target for TBI.
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Astrócitos/enzimologia , Lesões Encefálicas Traumáticas/metabolismo , Córtex Cerebral/enzimologia , Fagocitose/fisiologia , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Animais , Astrócitos/patologia , Lesões Encefálicas Traumáticas/patologia , Células Cultivadas , Córtex Cerebral/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptor Tirosina Quinase AxlRESUMO
BACKGROUND: Subarachnoid hemorrhage (SAH) is a life-threatening disease worldwide, and effective pharmaceutical treatment is still lacking. Celastrol is a plant-derived triterpene which showed neuroprotective potential in several types of brain insults. This study aimed to investigate the effects of celastrol on early brain injury (EBI) after SAH. METHODS: A total of sixty-one male Sprague-Dawley rats were used in this study. Rat SAH endovascular perforation model was established to mimic the pathological changes of EBI after SAH. Multiple methods such as 3.0T MRI scanning, immunohistochemistry, western blotting and propidium iodide (PI) labeling were used to explore the therapeutic effects of celastrol on SAH. RESULTS: Celastrol treatment attenuated SAH-caused brain swelling, reduced T2 lesion volume and ventricular volume in MRI scanning, and improved overall neurological score. Albumin leakage and the degradation of tight junction proteins were also ameliorated after celastrol administration. Celastrol protected blood-brain bairrer integrity through inhibiting MMP-9 expression and anti-neuroinflammatory effects. Additionally, necroptosis-related proteins RIP3 and MLKL were down-regulated and PI-positive cells in the basal cortex were less in the celastrol-treated SAH group than that in untreated SAH group. CONCLUSIONS: Celastrol exhibits neuroprotective effects on EBI after SAH and deserves to be further investigated as an add-on pharmaceutical therapy.
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Barreira Hematoencefálica/patologia , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/etiologia , Necroptose/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Triterpenos Pentacíclicos/uso terapêutico , Hemorragia Subaracnóidea/complicações , Albuminas/metabolismo , Animais , Barreira Hematoencefálica/diagnóstico por imagem , Barreira Hematoencefálica/efeitos dos fármacos , Edema Encefálico/complicações , Edema Encefálico/diagnóstico por imagem , Edema Encefálico/tratamento farmacológico , Lesões Encefálicas/diagnóstico por imagem , Ventrículos Cerebrais/efeitos dos fármacos , Ventrículos Cerebrais/patologia , Regulação para Baixo/efeitos dos fármacos , Inflamação/patologia , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Fármacos Neuroprotetores/farmacologia , Tamanho do Órgão/efeitos dos fármacos , Triterpenos Pentacíclicos/farmacologia , Proteínas Quinases/metabolismo , Ratos Sprague-Dawley , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Transdução de Sinais/efeitos dos fármacos , Hemorragia Subaracnóidea/diagnóstico por imagem , Análise de Sobrevida , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
Intracerebral hemorrhage (ICH) is a cerebrovascular disease with high mortality and morbidity for which effective treatments are currently lacking. Wogonin is a major flavonoid compound isolated from Scutellaria radix. Accumulating evidence suggests that wogonin plays a crucial role in anti-inflammatory and anti-oxidative stress. Treatment of microglia with nuclear receptor agonists augments the expression of phagocytosis-related genes. However, the neuroprotective effects of wogonin in ICH remain obscure. In this study, we elucidated an innovative mechanism by which wogonin acts to enhance phagocytosis in a murine model of ICH. Wogonin promoted hematoma clearance and improved neurological recovery after ICH by upregulating the expression of Axl, MerTK, CD36, and LAMP2 in perihematomal microglia and BV2 cells. Treatment of a murine model of ICH with wogonin stimulated microglial phagocytosis in vitro. Further, we demonstrated that wogonin dramatically attenuated inflammatory and oxidative stress responses in a murine model of ICH by reducing the expression of pro-inflammatory cytokines and pro-oxidant enzymes such as TNF-α, IL-1ß, and inducible nitric oxide synthase (iNOS) after ICH. The effects of wogonin were abolished by administration of the PPAR-γ inhibitor GW9662. In conclusion, our data suggest that wogonin facilitates hematoma clearance and neurobehavioral recovery by targeting PPAR-γ.
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Flavanonas , Hematoma , Animais , Hemorragia Cerebral/tratamento farmacológico , Flavanonas/farmacologia , Camundongos , Microglia , PPAR gamaRESUMO
BACKGROUND: Neuroinflammation is closely associated with the poor prognosis in subarachnoid hemorrhage (SAH) patients. This study was aimed to determine the role of stimulator of IFN genes (STING), an essential regulator to innate immunity, in the context of SAH. METHODS: A total of 344 male C57BL/6 J mice were subjected to endovascular perforation to develop a model of SAH. Selective STING antagonist C-176 and STING agonist CMA were administered at 30 min or 1 h post-modeling separately. To investigate the underlying mechanism, the AMPK inhibitor compound C was administered intracerebroventricularly at 30 min before surgery. Post-SAH assessments included SAH grade, neurological test, brain water content, western blotting, RT-PCR, and immunofluorescence. Oxygenated hemoglobin was introduced into BV2 cells to establish a SAH model in vitro. RESULTS: STING was mainly distributed in microglia, and microglial STING expression was significantly increased after SAH. Administration of C-176 substantially attenuated SAH-induced brain edema and neuronal injury. More importantly, C-176 significantly alleviated both short-term and persistent neurological dysfunction after SAH. Meanwhile, STING agonist CMA remarkably exacerbated neuronal injury and deteriorated neurological impairments. Mechanically, STING activation aggravated neuroinflammation via promoting microglial activation and polarizing into M1 phenotype, evidenced by microglial morphological changes, as well as the increased level of microglial M1 markers including IL-1ß, iNOS, IL-6, TNF-α, MCP-1, and NLRP3 inflammasome, while C-176 conferred a robust anti-inflammatory effect. However, all the mentioned beneficial effects of C-176 including alleviated neuroinflammation, attenuated neuronal injury and the improved neurological function were reversed by AMPK inhibitor compound C. Meanwhile, the critical role of AMPK signal in C-176 mediated anti-inflammatory effect was also confirmed in vitro. CONCLUSION: Microglial STING yielded neuroinflammation after SAH, while pharmacologic inhibition of STING could attenuate SAH-induced inflammatory injury at least partly by activating AMPK signal. These data supported the notion that STING might be a potential therapeutic target for SAH.
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Inflamação/patologia , Proteínas de Membrana/metabolismo , Hemorragia Subaracnóidea/patologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Modelos Animais de Doenças , Inflamação/imunologia , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/fisiologia , Hemorragia Subaracnóidea/imunologia , Hemorragia Subaracnóidea/metabolismoRESUMO
Despite the substantial efforts to elucidate the role of early brain injury in subarachnoid hemorrhage (SAH), an effective pharmaceutical therapy for patients with SAH continues to be unavailable. This study aims to reveal the role of necroptosis after SAH, and explore whether the disruption of the blood-brain barrier (BBB) and RIP3-mediated necroptosis following SAH in a rat SAH model are altered by necrostatin-1 via its selective inhibition of receptor-interacting protein kinase 1 (RIP1). Sixty-five rats were used in the experiments. The SAH model was established using endovascular perforation. Necrostatin-1 was intracerebroventricularly injected 1 h before SAH induction. The neuroprotective effects of necrostatin-1 were evaluated with multiple methods such as magnetic resonance imaging (MRI) scanning, immunohistochemistry, propidium iodide (PI) labeling, and western blotting. Pretreatment with necrostatin-1 attenuated brain swelling and reduced the lesion volume on T2 sequence and ventricular volume on MRI 72 h after SAH induction. Albumin leakage and the degradation of tight junction proteins were also ameliorated by necrostatin-1 administration. In addition, necrostatin-1 decreased the number of PI-positive cells in the basal cortex, reduced the levels of the RIP3 and MLKL proteins, and inhibited the production of the pro-inflammatory cytokines IL-1ß, IL-6, and TNF-α. Based on the findings from the present study, the selective RIP1 inhibitor necrostatin-1 functioned as a neuroprotective agent after SAH by attenuating brain swelling and BBB disruption. Moreover, the necrostatin-1 pretreatment prevented SAH-induced necroptosis by suppressing the activity of the RIP3/MLKL signaling pathway. These results will provide insights into new drugs and pharmacological targets to manage SAH, which are worth further study.
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Barreira Hematoencefálica/metabolismo , Encéfalo/efeitos dos fármacos , Imidazóis/uso terapêutico , Indóis/uso terapêutico , Necroptose/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Hemorragia Subaracnóidea/tratamento farmacológico , Animais , Encéfalo/citologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Edema Encefálico/tratamento farmacológico , Citocinas/metabolismo , Imageamento por Ressonância Magnética , Metaloproteinase 9 da Matriz/metabolismo , Necroptose/genética , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Ratos Sprague-Dawley , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Hemorragia Subaracnóidea/metabolismo , Hemorragia Subaracnóidea/mortalidade , Hemorragia Subaracnóidea/patologia , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/patologiaRESUMO
The abnormal aggregation of αsynuclein (αsyn), which is an important pathological feature of Parkinson's disease (PD), is cytotoxic to dopaminergic neurons and causes cellular damage and apoptosis. Salidroside (SAL) is the main active component of the traditional Chinese medicine Rhodiola rosea. Previous research has demonstrated that SAL exerts cellular protection against cell senescence and neurodegeneration. However, the role and mechanism of action of SAL in PD remain unclear. The present study used overexpression of the wildtype and the A53T mutation of αsyn to induce a neuronal model of PD in SHSY5Y cells, which led to neuronal toxicity and a reduced cell proliferation index. SAL increased the cell proliferation index of both PD model groups in a dosedependent manner. Additionally, SAL alleviated pathogenic phosphorylated (Ser129) αsyn expression as well as the ratio of microtubuleassociated proteins 1A/1B light chain 3 (LC3)I to LC3II expression, which is related to autophagic function. Furthermore, the results suggested that the underlying mechanism for the SALinduced protection of PD model neurons may involve the preservation of autophagy, which attenuates the phosphorylation of αsyn in neurons predominantly via mTOR/p70S6K, and is independent of the PI3K/Akt signaling pathway.
Assuntos
Autofagia/efeitos dos fármacos , Glucosídeos/farmacologia , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Fenóis/farmacologia , alfa-Sinucleína/genética , Linhagem Celular , Glucosídeos/química , Humanos , Fármacos Neuroprotetores/química , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Fenóis/química , Mutação Puntual , Rhodiola/química , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , alfa-Sinucleína/metabolismoRESUMO
Hydrocephalus has been reported to occur in spontaneous hypertensive rats (SHRs). The purposes of this study were (1) to use T2 magnetic resonance imaging to examine time of onset, (2) to elucidate potential underlying mechanisms and (3) to determine whether minocycline could prevent hydrocephalus development. Ventriculomegaly was evaluated by T2 imaging in SHRs and Wistar-Kyoto rats from weeks 4 to 7 after birth. Brain histology and transmission electron microscopy were used to assess the periventricular and choroid plexus damage. SHRs were also treated with either vehicle or minocycline. We found that hydrocephalus was observed in SHRs but not in Wistar-Kyoto rats. It occurred at seven weeks of age but was not present at four and five weeks. The hydrocephalus was associated with epiplexus cell (macrophage) activation, choroid plexus cell death and damage to the ventricle wall. Treatment with minocycline from week 5 attenuated hydrocephalus development and pathological changes in choroid plexus and ventricular wall at week 7. The current study found that spontaneous hydrocephalus arises at â¼7 weeks in male SHRs. The early development of hydrocephalus (persistent ventricular dilatation) may result from epiplexus cell activation, choroid plexus cell death and periventricular damage, which can be ameliorated by treatment with minocycline.