RESUMO
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.
Assuntos
Desenho de Fármacos , Descoberta de Drogas , Área Sob a Curva , Interações MedicamentosasRESUMO
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.
Assuntos
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
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.
Assuntos
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: 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.
Assuntos
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 NLRP3 inflammasome is a multiprotein complex that regulates the innate immune inflammatory response by activating caspase-1 and subsequent IL-1ß and IL-18. Fluoxetine has been shown to have the anti-inflammatory properties in many disease models. However, the effects and mechanisms of these effects of fluoxetine in early brain injury after subarachnoid hemorrhage (SAH) have not been defined. METHODS: The SAH model was induced by an endovascular perforation in adult male Sprague-Dawley (SD) rats weighing 300-320 g. N-Ac-Tyr-Val-Ala-Asp-chloromethyl ketone (AC-YVAD-CMK) was injected intraperitoneally (5 mg/kg) 1 h after SAH. Fluoxetine was administered via intravenous route 6 h after SAH. 3-Methyladenine (3-MA) was intracerebroventricularly injected 20 min before SAH. SAH grade, neurological function, brain water content, propidium iodide (PI) staining, western blot, double immunostaining, and transmission electron microscopy were performed. RESULTS: Expression of caspase-1 increased and peaked at 24 h after SAH. Caspase activation was along with the increased necrotic cells, which occurred mainly in neurons. Necrotic cell death of microglia and astrocyte were also found. Administration of AC-YVAD-CMK, a caspase-1 inhibitor, reduced the expression of IL-1ß and IL-18 and the number of PI-positive cells, attenuated brain edema, and improved neurological function, which was also observed in fluoxetine-treated rats. Furthermore, fluoxetine treatment significantly decreased the expression of NLRP3 and cleaved caspase-1 and upregulated the expression of beclin-1, a marker for autophagy. Finally, the effects of fluoxetine in NLRP3 inflammasome activation were reversed by additional 3-MA administration. CONCLUSIONS: Together, our present study indicated that NLRP3 inflammasome and caspase-1 activation play a deleterious role in early brain injury and fluoxetine mitigates NLRP3 inflammasome and caspase-1 activation through autophagy activation after SAH, providing a potential therapeutic agent for SAH treatment.
Assuntos
Anti-Inflamatórios/farmacologia , Autofagia/efeitos dos fármacos , Fluoxetina/farmacologia , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Hemorragia Subaracnóidea/patologia , Animais , Lesões Encefálicas/imunologia , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Inflamassomos/efeitos dos fármacos , Inflamassomos/imunologia , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ratos , Ratos Sprague-Dawley , Hemorragia Subaracnóidea/imunologia , Hemorragia Subaracnóidea/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.
Assuntos
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
Traumatic brain injury (TBI) is a serious medical and social problem worldwide. Because of the complex pathophysiological mechanisms of TBI, effective pharmacotherapy is still lacking. The microglial cells are resident tissue macrophages located in the brain and have two major polarization states, M1 phenotype and M2 phenotype, when activated. The M1 phenotype is related to the release of proinflammatory cytokines and secondary brain injury, while the M2 phenotype has been proved to be responsible for the release of anti-inflammation cytokines and for central nervous system (CNS) repair. In animal models, pharmacological strategies inhibiting the M1 phenotype and promoting the M2 phenotype of microglial cells could alleviate cerebral damage and improve neurological function recovery after TBI. In this review, we aimed to summarize the current knowledge about the pathological significance of microglial M1/M2 polarization in the pathophysiology of TBI. In addition, we reviewed several drugs that have provided neuroprotective effects against brain injury following TBI by altering the polarization states of the microglia. We emphasized that future investigation of the regulation mechanisms of microglial M1/M2 polarization in TBI is anticipated, which could contribute to the development of new targets of pharmacological intervention in TBI.
Assuntos
Lesões Encefálicas Traumáticas/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encefalite/metabolismo , Microglia/efeitos dos fármacos , Microglia/metabolismo , Fármacos Neuroprotetores/farmacologia , Animais , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/tratamento farmacológico , Terapia Baseada em Transplante de Células e Tecidos/métodos , Citocinas/metabolismo , Encefalite/complicações , Humanos , Mediadores da Inflamação , Fármacos Neuroprotetores/uso terapêuticoRESUMO
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.
Assuntos
Medicina Tradicional Chinesa , Estadiamento de Neoplasias , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Progressão da Doença , Humanos , Masculino , Qualidade de VidaRESUMO
BACKGROUND: Hypertension is a complex trait that often co-occurs with other conditions such as obesity and is affected by genetic and environmental factors. Aggregate indices such as principal components among these variables and their responses to environmental interventions may represent novel information that is potentially useful for genetic studies. RESULTS: In this study of families participating in the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) Study, blood pressure (BP) responses to dietary sodium interventions are explored. Independent component analysis (ICA) was applied to 20 variables indexing obesity and BP measured at baseline and during low sodium, high sodium and high sodium plus potassium dietary intervention periods. A "heat map" protocol that classifies subjects based on risk for hypertension is used to interpret the extracted components. ICA and heat map suggest four components best describe the data: (1) systolic hypertension, (2) general hypertension, (3) response to sodium intervention and (4) obesity. The largest heritabilities are for the systolic (64%) and general hypertension (56%) components. There is a pattern of higher heritability for the component response to intervention (40-42%) as compared to those for the traditional intervention responses computed as delta scores (24%-40%). CONCLUSIONS: In summary, the present study provides intermediate phenotypes that are heritable. Using these derived components may prove useful in gene discovery applications.
Assuntos
Pressão Sanguínea , Suplementos Nutricionais , Potássio/administração & dosagem , Sódio/administração & dosagem , Adiposidade , Adulto , Feminino , Predisposição Genética para Doença , Humanos , Hipertensão/epidemiologia , Hipertensão/etiologia , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Fatores de RiscoRESUMO
Neurogenic pulmonary edema (NPE) is a serious non-neurological complication that can occur after a subarachnoid hemorrhage (SAH) and is associated with decreased survival and a poor neurological outcome. Melatonin is a strong antioxidant that has beneficial effects against SAH in rats, including reduced mortality and reduced neurological deficits. The molecular mechanisms underlying these clinical effects in the SAH model, however, have not been clearly identified. This study was undertaken to determine the influence of melatonin on SAH-induced NPE and the potential mechanism of these effects using the filament perforation model of SAH in male Sprague Dawley rats. Either melatonin (150 mg/kg) or a vehicle was given via an intraperitoneal injection 2 hr after an SAH induction. Lung samples were extracted 24 hr after SAH. The results show that the melatonin treatment attenuated SAH-induced NPE by preventing alveolar-capillary barrier dysfunctions via inhibiting the disruption of tight junction proteins (ZO-1 and occludin). Moreover, the treatment downregulated the levels of mature interleukin (IL) -1ß, myeloperoxidase (MPO), and matrix metallopeptidase (MMP) 9 expression/activation, which were increased in the lung; also, melatonin treatment improved neurological deficits. Furthermore, the melatonin treatment markedly reduced caspase-3 activity and the number of TUNEL-positive cells in the lung. Taken together, these findings show that administration of melatonin attenuates NPE by preventing alveolar-capillary barrier dysfunctions via repressing the inflammatory response and by anti-apoptosis effects after SAH.
Assuntos
Antioxidantes/uso terapêutico , Inflamação/tratamento farmacológico , Melatonina/uso terapêutico , Edema Pulmonar/tratamento farmacológico , Hemorragia Subaracnóidea/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Peroxidase/metabolismo , Edema Pulmonar/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Melatonin is a strong anti-oxidant that has beneficial effects against early brain injury (EBI) following a subarachnoid hemorrhage (SAH) in rats; protection includes the reduction of both mortality and neurological deficits. The molecular mechanisms underlying these clinical effects in the SAH model have not been clearly identified. This study examined the influence of melatonin on brain edema secondary to disruption of the blood-brain barrier (BBB) and the relationship between these effects and pro-inflammatory cytokines in EBI following SAH using the filament perforation model of SAH in male Sprague-Dawley rats. Melatonin (150 mg/kg) or vehicle was given via an intraperitoneal injection 2 hr after SAH induction. Brain samples were extracted 24 hr after SAH. Melatonin treatment markedly attenuated brain edema secondary to BBB dysfunctions by preventing the disruption of tight junction protein expression (ZO-1, occludin, and claudin-5). Melatonin treatment also repressed cortical levels of pro-inflammatory cytokines (IL-1ß, IL-6, and TNF-α), which were increased in EBI 24 hr after SAH. To further identify the mechanism of this protection, we demonstrated that administration of melatonin attenuated matrix metallopeptidase 9 expression/activity and vascular endothelial growth factor expression, which are related to the inflammatory response and BBB disruption in EBI after SAH. Taken together, this report shows that melatonin prevents disruption of tight junction proteins which might play a role in attenuating brain edema secondary to BBB dysfunctions by repressing the inflammatory response in EBI after SAH, possibly associated with regulation of pro-inflammatory cytokines.
Assuntos
Edema Encefálico/prevenção & controle , Lesões Encefálicas/complicações , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Melatonina/administração & dosagem , Hemorragia Subaracnóidea/complicações , Animais , Edema Encefálico/etiologia , Masculino , Melatonina/uso terapêutico , Ratos , Ratos Sprague-DawleyRESUMO
Melatonin is a strong antioxidant that has beneficial effects against early brain injury (EBI) following a subarachnoid hemorrhage (SAH) in rats; protection includes reduced mortality and brain water content. The molecular mechanisms underlying these clinical effects in the SAH model, however, have not been clearly identified. This study was undertaken to determine the influence of melatonin on neural apoptosis and the potential mechanism of these effects in EBI following SAH using the filament perforation model of SAH in male Sprague Dawley rats. Melatonin (150 mg/kg) or vehicle was given via an intraperitoneal injection 2 hr after SAH induction. Brain samples were extracted 24 hr after SAH. The results show that melatonin treatment markedly reduced caspase-3 activity and the number of TUNEL-positive cells, while the treatment increased the LC3-II/LC3-I, an autophagy marker, which indicated that melatonin-enhanced autophagy ameliorated apoptotic cell death in rats subjected to SAH. To further identify the mechanism of autophagy protection, we demonstrated that melatonin administration reduced Bax translocation to the mitochondria and the release of cytochrome c into the cytosol. Taken together, this report demonstrates that melatonin improved the neurological outcome in rats by protecting against neural apoptosis after the induction of filament perforation SAH; moreover, the mechanism of these antiapoptosis effects was related to the enhancement of autophagy, which ameliorated cell apoptosis via a mitochondrial pathway.
Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Melatonina/farmacologia , Melatonina/uso terapêutico , Mitocôndrias/efeitos dos fármacos , Hemorragia Subaracnóidea/tratamento farmacológico , Análise de Variância , Animais , Lesões Encefálicas/tratamento farmacológico , Citocromos c/metabolismo , Marcação In Situ das Extremidades Cortadas , Masculino , Ratos , Ratos Sprague-Dawley , Hemorragia Subaracnóidea/patologia , Proteína X Associada a bcl-2/metabolismoRESUMO
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.
RESUMO
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.
RESUMO
Although hypoxia-inducible factor-1α (HIF-1α) has been extensively studied in brain injury following hypoxia-ischemia, the role of HIF-1α in early brain injury (EBI) after subarachnoid hemorrhage (SAH) remains unclear. The present study was under taken to investigate a potential role of HIF-1α in EBI after SAH. Rats (n=60) were randomly divided into sham+vehicle, SAH+2-methoxyestradiol (2ME2), and SAH+vehicle groups. The SAH model was induced by endovascular perforation and all the rats were subsequently sacrificed at 24h after SAH. We found that treatment with 2ME2 suppressed the expression of HIF-1α, BNIP3 and VEGF and reduced cell apoptosis, blood-brain barrier (BBB) permeability, brain edema, and neurologic scores. Double fluorescence labeling revealed that HIF-1α was expressed predominantly in the nuclei of neurons and TUNEL-positive cells. Our work demonstrated that HIF-1α may play a role in EBI after SAH, causing cell apoptosis, BBB disruption, and brain edema by up-regulating its downstream targets, BNIP3 and VEGF. These effects were blocked by the HIF-1α inhibitor, 2ME2.
Assuntos
Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/etiologia , Estradiol/análogos & derivados , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Hemorragia Subaracnóidea/complicações , 2-Metoxiestradiol , Animais , Lesões Encefálicas/metabolismo , Modelos Animais de Doenças , Procedimentos Endovasculares/métodos , Estradiol/administração & dosagem , Estradiol/uso terapêutico , Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Masculino , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/biossíntese , Proteínas Mitocondriais , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/uso terapêutico , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/biossíntese , Ratos , Ratos Sprague-Dawley , Hemorragia Subaracnóidea/tratamento farmacológico , Hemorragia Subaracnóidea/metabolismo , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/biossínteseRESUMO
BACKGROUND: Coronary artery disease (CAD) is a major cause of death and disability worldwide. Depression has complex bidirectional adverse associations with CAD, although the mechanisms mediating these relationships remain unclear. Compared to European Americans, African Americans (AAs) have higher rates of morbidity and mortality from CAD. Although depression is common in AAs, its role in the development and features of CAD in this group has not been well examined. This project hypothesizes that the relationships between depression and CAD can be explained by common physiological pathways and gene-environment interactions. Thus, the primary aims of this ongoing project are to: a) determine the prevalence of CAD and depression phenotypes in a population-based sample of community-dwelling older AAs; b) examine the relationships between CAD and depression phenotypes in this population; and c) evaluate genetic variants from serotoninP and inflammatory pathways to discover potential gene-depression interactions that contribute significantly to the presence of CAD in AAs. METHODS/DESIGN: The St. Louis African American Health (AAH) cohort is a population-based panel study of community-dwelling AAs born in 1936-1950 (inclusive) who have been followed from 2000/2001 through 2010. The AAH-Heart study group is a subset of AAH participants recruited in 2009-11 to examine the inter-relationships between depression and CAD in this population. State-of-the-art CAD phenotyping is based on cardiovascular characterizations (coronary artery calcium, carotid intima-media thickness, cardiac structure and function, and autonomic function). Depression phenotyping is based on standardized questionnaires and detailed interviews. Single nucleotide polymorphisms of selected genes in inflammatory and serotonin-signaling pathways are being examined to provide information for investigating potential gene-depression interactions as modifiers of CAD traits. Information from the parent AAH study is being used to provide population-based prevalence estimates. Inflammatory and other biomarkers provide information about potential pathways. DISCUSSION: This population-based investigation will provide valuable information on the prevalence of both depression and CAD phenotypes in this population. The study will examine interactions between depression and genetic variants as modulators of CAD, with the intent of detecting mechanistic pathways linking these diseases to identify potential therapeutic targets. Analytic results will be reported as they become available.
Assuntos
Negro ou Afro-Americano/etnologia , Doenças Cardiovasculares/etnologia , Depressão/etnologia , Nível de Saúde , Vigilância da População/métodos , Negro ou Afro-Americano/genética , Idoso , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/genética , Estudos de Coortes , Estudos Transversais , Depressão/diagnóstico , Depressão/genética , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Missouri/etnologia , Estados Unidos/etnologiaRESUMO
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.
RESUMO
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.