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BACKGROUND: Colorectal cancer (CRC) is one of the most frequently encountered malignant tumors in clinical settings. Proteins encoded by the testis-expressed gene 14 (TEX14) are imperative for spermatogenesis, necessitating intercellular bridges between germ cells. Anomalous expression of TEX14 has also been associated with the proliferation and differentiation of certain tumor cells. Recombinant A disintegrin and metalloprotease 17 (ADAM17) is known as a membrane-bound protease that regulates cellular activities and signal transduction by hydrolyzing various substrate proteins on the cell membrane. We hypothesize that TEX14 and ADAM17 may serve as potential biomarkers influencing the staging, invasion, and metastasis of CRC. AIM: To probe the correlation between TEX17 and ADAM17 profiles in the CRC tissues of elderly patients and their association with CRC staging, invasion, and metastasis. METHODS: We gathered data from 86 elderly patients diagnosed pathologically with CRC between April 2020 and December 2023. For each patient, one sample of cancer tissue and one sample of adjacent normal tissue were harvested. Real-time fluorescence quantitative PCR measured the mRNA profiles of TEX14 and ADAM17. Immunohistochemistry ascertained the positivity rates of TEX14 and ADAM17 expressions. Clinical pathological features of neoplasm staging, invasion, and metastasis were collected, and the association between TEX14 and ADAM17 expressions and clinical pathology was evaluated. RESULTS: The mRNA and expression profiles of TEX14 and ADAM17 were significantly elevated in CRC tissues. The positivity rates of TEX14 and ADAM17 proteins in CRC tissues were 70.93% and 77.91%, respectively. There were no significant differences in age, sex, pathological type, and tumor diameter between TEX14 and ADAM17-positive and -negative patients. Patients with higher tumor differentiation degree, deeper infiltration and TNM stages ranging from III to IV exhibited higher positivity rates of TEX14 and ADAM17. Patients with lymph node metastasis and distant metastasis showed higher positivity rates of TEX14 and ADAM17 than those without. Positive expressions of TEX14 and ADAM17 were highly correlated with tumor staging, invasion, and metastasis. CONCLUSION: TEX14 and ADAM17 profiles were significantly elevated in the CRC tissues of elderly patients, and their high expressions were associated with tumor staging, invasion, and metastasis.
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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
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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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
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: 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
BACKGROUND: The association between serum C-peptide concentration and prostate cancer remains unexplored. Therefore, we conducted a meta-analysis to assess whether C-peptide serum concentrations are associated with increased prostate cancer risk. METHODS: Several databases were searched to identify relevant original research articles published before November 2017. Random-effects models were used to summarize the overall estimate of the multivariable-adjusted odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Nine observational studies involving 11,796 participants were identified. The findings of the meta-analysis indicated that the association between serum C-peptide concentration and prostate cancer was not significant (OR: 1.15, 95% CI: 0.85-1.54; for highest versus lowest category C-peptide concentrations, Pâ=â.376). The associations were inconsistent, as indicated by subgroup analyses. CONCLUSION: Although our findings provided no support for the hypothesis that serum C-peptide concentration is associated with excess risk of prostate cancer, people must pay attention to this aspect and increase physical activity or modify dietary habits to constrain insulin secretion, which possibly lead to decreased incidence of prostate cancer. Hence, well-designed observational studies involving different ethnic populations are still needed.
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Peptídeo C/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/epidemiologia , Humanos , Masculino , Estudos Observacionais como Assunto , Fatores de RiscoRESUMO
BACKGROUND: We performed a meta-analysis to determine whether a consistent relationship exists between cadmium exposure and urolithiasis in humans. Accordingly, we summarized and reviewed previously published quantitative studies. METHODS: Eligible studies with reference lists published before June 1, 2017 were obtained from searching several databases. Random effects models were used to summary the overall estimate of the multivariate adjusted odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Six observational studies involving 88,045 participants were identified and stratified into the following categories according to cadmium assessment results: occupational (nâ=â4) and dietary (nâ=â2). The findings of the meta-analysis suggested that the risk of urolithiasis increases significantly by 1.32 times at higher cadmium exposure (ORâ=â1.32; 95% CIâ=â1.08-1.62; for highest vs lowest category urinary cadmium values). The summary OR in occupational exposure (ORâ=â1.56; 95% CIâ=â1.13-2.14) increased at the same condition. Meanwhile, no association was observed between cadmium exposure and urolithiasis risk in dietary exposure (ORâ=â1.13; 95% CIâ=â0.87-1.47). A significant association remained consistent, as indicated by subgroup analyses and sensitivity analyses. CONCLUSIONS: The meta-analysis indicated that increased risk of urolithiasis is associated with high cadmium exposure, and this association is higher in occupational exposure than in dietary exposure. Nevertheless, well-designed observational studies with different ethnic populations are still needed.
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Cádmio/toxicidade , Exposição Ocupacional/efeitos adversos , Urolitíase/induzido quimicamente , HumanosRESUMO
Aberrant modulation of mitochondrial dynamic network, which shifts the balance of fusion and fission towards fission, is involved in brain damage of various neurodegenerative diseases including Parkinson's disease, Huntington's disease and Alzheimer's disease. A recent research has shown that the inhibition of mitochondrial fission alleviates early brain injury after experimental subarachnoid hemorrhage, however, the underlying molecular mechanisms have remained to be elucidated. This study was undertaken to characterize the effects of the inhibition of dynamin-related protein-1 (Drp1, a dominator of mitochondrial fission) on blood-brain barrier (BBB) disruption and neuronal apoptosis following SAH and the potential mechanisms. The endovascular perforation model of SAH was performed in adult male Sprague Dawley rats. The results indicated Mdivi-1(a selective Drp1 inhibitor) reversed the morphologic changes of mitochondria and Drp1 translocation, reduced ROS levels, ameliorated the BBB disruption and brain edema remarkably, decreased the expression of MMP-9 and prevented degradation of tight junction proteins-occludin, claudin-5 and ZO-1. Mdivi-1 administration also inhibited the nuclear translocation of nuclear factor-kappa B (NF-κB), leading to decreased expressions of TNF-É, IL-6 and IL-1ß. Moreover, Mdivi-1 treatment attenuated neuronal cell death and improved neurological outcome. To investigate the underlying mechanisms further, we determined that Mdivi-1 reduced p-PERK, p-eIF2α, CHOP, cleaved caspase-3 and Bax expression as well as increased Bcl-2 expression. Rotenone (a selective inhibitor of mitochondrial complexes I) abolished both the anti-BBB disruption and anti-apoptosis effects of Mdivi-1. In conclusion, these data implied that excessive mitochondrial fission might inhibit mitochondrial complex I to become a cause of oxidative stress in SAH, and the inhibition of Drp1 by Mdivi-1 attenuated early brain injury after SAH probably via the suppression of inflammation-related blood-brain barrier disruption and endoplasmic reticulum stress-based apoptosis.
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Barreira Hematoencefálica/efeitos dos fármacos , Dinaminas/genética , Mitocôndrias/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Quinazolinonas/farmacologia , Hemorragia Subaracnóidea/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Claudina-5/genética , Claudina-5/metabolismo , Dinaminas/antagonistas & inibidores , Dinaminas/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/antagonistas & inibidores , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Dinâmica Mitocondrial/genética , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , NF-kappa B/metabolismo , Ocludina/genética , Ocludina/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/agonistas , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Hemorragia Subaracnóidea/genética , Hemorragia Subaracnóidea/mortalidade , Hemorragia Subaracnóidea/patologia , Espaço Subaracnóideo/efeitos dos fármacos , Espaço Subaracnóideo/metabolismo , Espaço Subaracnóideo/patologia , Análise de Sobrevida , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Proteína da Zônula de Oclusão-1/genética , Proteína da Zônula de Oclusão-1/metabolismo , Proteína X Associada a bcl-2/antagonistas & inibidores , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismoRESUMO
Subarachnoid hemorrhage (SAH) is a serious medical problem with few effective pharmacotherapies available, and neuroinflammation has been identified as an important pathological process in early brain injury (EBI) after SAH. Methylene blue (MB) is an older drug that has been recently proven to exert extraordinary neuroprotective effects in several brain insults. However, no study has reported the beneficial effects of MB in SAH. In the current investigation, we studied the neuroprotective effects of MB in EBI after SAH and focused on its anti-inflammatory role. A total of 303 rats were subjected to an endovascular perforation process to produce an SAH model. We found that MB could significantly ameliorate brain edema secondary to BBB disruption and alleviate neurological dysfunction after SAH. MB administration also promoted the phosphorylation of Akt and GSK-3ß, leading to an increased concentration of MEF2D in the nucleus. The cytokine IL-10 was up-regulated, and IL-1ß, IL-6 and TNF-α were down-regulated after MB administration. MB administration could also alleviate neutrophil infiltration and microglia activation after SAH. MK2206, a selective inhibitor of Akt, abolished the neuroprotective effects of MB, inhibited the phosphorylation of Akt and prevented the nuclear localization of MEF2D. MK2206 also reduced the expression of IL-10 and increased the expression of pro-inflammatory cytokines. In conclusion, these data suggested that MB could ameliorate neuroinflammatory responses after SAH, and its anti-inflammatory effects might be exerted via activation of the Akt/GSK-3ß/MEF2D pathway.
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Azul de Metileno/farmacologia , Hemorragia Subaracnóidea/tratamento farmacológico , Animais , Anti-Inflamatórios/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/metabolismo , Edema Encefálico/tratamento farmacológico , Lesões Encefálicas/metabolismo , Citocinas/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Fatores de Transcrição MEF2/metabolismo , Masculino , Neuroimunomodulação/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Hemorragia Subaracnóidea/fisiopatologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Neuronal apoptosis is a central pathological process in subarachnoid hemorrhage (SAH)-induced early brain injury. Endoplasmic reticulum (ER) stress was reported to have a vital role in the pathophysiology of neuronal apoptosis in the brain. The present study was designed to investigate the potential effects of ER stress and its downstream signals in early brain injury after SAH. One hundred thirty-four rats were subjected to an endovascular perforation model of SAH. The RNA-activated protein kinase-like ER kinase (PERK) inhibitor GSK2606414 and the Akt inhibitor MK2206 were injected intracerebroventricularly. SAH grade, neurologic scores, and brain water content were measured 72 h after subarachnoid hemorrhage. Expression of PERK and its downstream signals, Akt, Bcl-2, Bax, and cleaved caspase-3, were examined using Western blot analysis. Specific cell types that expressed PERK were detected with double immunofluorescence staining. Neuronal cell death was demonstrated with terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL). Our results showed that the expression of p-PERK and its downstream targets, p-eIF2α and ATF4, increased after SAH and peaked at 72 h after SAH. PERK was expressed mostly in neurons. The inhibition of PERK with GSK2606414 reduced p-PERK, p-eIF2α, and ATF4 expression. Furthermore, GSK2606414 treatment increased p-Akt levels and the Bcl-2/Bax ratio as well as decreased cleaved caspase-3 expression and neuronal death, thereby improving neurological deficits at 72 h after SAH. The selective Akt inhibitor MK2206 abolished the beneficial effects of GSK2606414. PERK, the major transducer of ER stress, is involved in neuronal apoptosis after SAH. The inhibition of PERK reduces early brain injury via Akt-related anti-apoptosis pathways. PERK may serve as a promising target for future therapeutic intervention.
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Lesões Encefálicas/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Hemorragia Subaracnóidea/metabolismo , eIF-2 Quinase/antagonistas & inibidores , eIF-2 Quinase/metabolismo , Adenina/análogos & derivados , Adenina/farmacologia , Adenina/uso terapêutico , Animais , Lesões Encefálicas/prevenção & controle , Compostos Heterocíclicos com 3 Anéis/farmacologia , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Indóis/farmacologia , Indóis/uso terapêutico , Masculino , Ratos , Ratos Sprague-Dawley , Hemorragia Subaracnóidea/tratamento farmacológicoRESUMO
OBJECTIVE: Moyamoya disease is a progressive stenosis or occlusion of the internal carotid artery. Revascularization surgery is considered the standard treatment. We conducted a retrospective study in hopes of finding indications for electing different surgical methods. METHODS: A total of 55 hemispheres in 49 patients who received revascularization surgery between January 2013 and December 2015 were included. Medical data such as age and sex were extracted and risk factor analysis for vascular anastomosis patency was conducted with multivariable logistic regression. RESULTS: In this study, direct or combined bypass surgery had a higher incidence of perioperative neurologic defects than did indirect surgery (30.3% vs. 4.5%; P = 0.046). The rates of postsurgery stroke (6.2% vs. 18.2%) and modified Rankin Scale improvement (39.4% vs. 18.2%) were better in the direct or combined bypass surgery group, but no significant difference was found. Moreover, longer operative time (209 ± 29.4 minutes vs. 101 ± 16.5 minutes; P < 0.01) and longer hospital stay (9.0 ± 3.11 days vs. 5.3 ± 2.03 days; P < 0.01) made direct or combined bypass surgery less advantageous. Multivariable binary logistic regression showed that the late Suzuki stage is a more favorable factor than the early Suzuki stage (odd ratio, 7.78; confidence interval, 1.059-57.155; P = 0.044). CONCLUSIONS: Because vascular anastomosis patency in symptomatic patients with moyamoya disease at early Suzuki stage is relatively lower, indirect bypass surgery may be more beneficial for these patients in view of shorter operative time and hospital stay.
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Revascularização Cerebral/métodos , Doença de Moyamoya/diagnóstico por imagem , Doença de Moyamoya/cirurgia , Adolescente , Adulto , Idoso , Artéria Carótida Interna/diagnóstico por imagem , Artéria Carótida Interna/cirurgia , Criança , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento , Adulto JovemRESUMO
Authors raised that staging based strategies and practice of integrative medicine (IM) by combining syndrome typing and disease identification, and choosing suitable measures in accordance with different persons and seasonal conditions after more than ten years' clinical practice and researches. Radical operation as prior (as evil eliminating) and strengthening vital qi in perioerative period are best strategy for promoting rapid rehabilitation of early stage prostate cancer patients. Strengthening body resistance to eliminate evil was used in treating advanced prostate cancer patients. For example, a comprehensive treatment program for hormone-dependent patients was combined with endocrinotherapy and Chinese herbs for synergisic efficacy-enhancing actions. In this way, these patients' quality of life (QOL) were improved and time to castration resistant prostate cancer (CRPC) was delayed, even some patients were clinically cured. There are lack of effective medicines and methods for CRPC patients. Greatly tonifying original qi is mainly used for improving their clinical symptoms and prolonging survivals. Practice has proved staging based strategies and practice of IM has favorable advantages in treating prostate cancer, especially showing prospect in prolonging survival and postponing progression of advanced prostate cancer patients. Besides, it also could provide beneficial considerations and inspiration for combination of syndrome typing and disease identification.
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Medicina Tradicional Chinesa , Estadiamento de Neoplasias , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Progressão da Doença , Humanos , Masculino , Qualidade de VidaRESUMO
Poly (ADP-ribose) polymerases (PARPs) play an important role in a range of neurological disorders, however, the role of PARP in early brain injury after subarachnoid hemorrhage (SAH) remains unclear. This study was designed to explore the role and the potential mechanisms of PARP in early brain injury after SAH. Eighty-nine male SD rats were randomly divided into the Sham group, SAH+Vehicle group and SAH+PARP inhibitor (PJ34) group. An endovascular perforation model was used to induce SAH in rats. PJ34 (10mg/kg) or vehicle (0.9% NaCl) was intraperitoneally administered at 5min and 8h after SAH induction. Mortality, SAH grades, neurological function, evans blue extravasation, brain edema, immunofluorescence staining and western blotting were performed. PJ34 reduced BBB permeability and brain edema, improved neurological function and attenuated neuronal cell death in the rat model of SAH. Moreover, PJ34 inhibited the nuclear translocation of NF-κB, decreased the expression of the proinflammatory cytokines IL-1ß, IL-6 and TNF-α, reduced the expression of MMP-9, prevented the degradation of tight junction proteins, and decreased microglia activation. These data indicated that PARP inhibition through PJ34 might be an important therapeutic drug for SAH.