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Receptor-interacting protein kinase-3 (RIP-3) is a key component for inducing necroptosis following acute brain injury. Purpose of this study is to unveil whether serum RIP-3 levels are related to severity and clinical outcomes after human severe traumatic brain injury (sTBI). In this two-center prospective cohort study, serum RIP-3 levels were detected in 127 healthy controls coupled with 127 sTBI patients. The prognostic indicators encompassed posttraumatic 180-day mortality, overall survival and poor prognosis (defined as extended Glasgow outcome scale scores of 1-4). The prognosis associations were verified via multivariate analysis. There was a significant incremental serum RIP-3 levels in patients with sTBI, relative to the controls. RIP-3 levels of patients were independently correlated with Rotterdam Computed Tomography (CT) scores and Glasgow coma scale (GCS) scores, as well as were independently predictive of mortality, overall survival and poor prognosis. Mortality and poor prognosis were effectively predicted by serum RIP-3 levels under the receiver operating characteristic curve. Linear relationships between RIP-3 levels and their risks were verified. Mortality and poor prognosis models of serum RIP-3 levels combined with GCS and Rotterdam CT scores displayed efficient predictive abilities. The two models were graphically represented, which were of clinical stability and value by employing the calibration and decision curves. Increased serum RIP-3 levels after sTBI are closely linked to heightened trauma severity and poor prognosis, signifying that serum RIP-3 may be an encouraging biomarker for evaluating severity and predicting clinical outcome of sTBI.
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Biomarcadores , Lesiones Traumáticas del Encéfalo , Proteína Serina-Treonina Quinasas de Interacción con Receptores , Humanos , Masculino , Femenino , Persona de Mediana Edad , Pronóstico , Adulto , Lesiones Traumáticas del Encéfalo/sangre , Lesiones Traumáticas del Encéfalo/mortalidad , Lesiones Traumáticas del Encéfalo/diagnóstico , Biomarcadores/sangre , Estudios Prospectivos , Proteína Serina-Treonina Quinasas de Interacción con Receptores/sangre , Anciano , Escala de Coma de Glasgow , Estudios de Cohortes , Adulto JovenRESUMEN
Spontaneous subarachnoid hemorrhage (SAH) is a kind of hemorrhagic stroke which causes neurological deficits in survivors. Huperzine A has a neuroprotective effect, but its role in SAH is unclear. Therefore, we explore the effect of Huperzine A on neurological deficits induced by SAH and the related mechanism. In this study, Evans blue assay, TUNEL staining, immunofluorescence, western blot analysis, and ELISA are conducted. We find that Huperzine A can improve neurological deficits and inhibit the apoptosis of nerve cells in SAH rats. Huperzine A treatment can improve the upregulation of brain water content, damage of blood-brain barrier, fibrinogen and matrix metalloprotein 9 expressions and the downregulation of ZO-1 and occludin expressions induced by SAH. Huperzine A inhibit the expressions of proteins involved in pyroptosis in endothelial cells in SAH rats. The increase in MDA content and decrease in SOD activity in SAH rats can be partly reversed by Huperzine A. The ROS inducer H 2O 2 can induce pyroptosis and inhibit the expressions of ZO-1 and occludin in endothelial cells, which can be blocked by Huperzine A. In addition, the increase in the entry of p65 into the nucleus in endothelial cells can be partly reversed by Huperzine A. Huperzine A may delay the damage of blood-brain barrier in SAH rats by inhibiting oxidative stress-mediated pyroptosis and tight junction protein expression downregulation through the NF-κB pathway. Overall, Huperzine A may have clinical value for treating SAH.
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Alcaloides , Fármacos Neuroprotectores , Sesquiterpenos , Hemorragia Subaracnoidea , Ratas , Animales , Hemorragia Subaracnoidea/complicaciones , Hemorragia Subaracnoidea/tratamiento farmacológico , Hemorragia Subaracnoidea/metabolismo , Ratas Sprague-Dawley , Piroptosis , Ocludina , Células Endoteliales/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéuticoRESUMEN
Xanthine oxidase (XO) may be involved in the induction of oxidative stress and inflammation. We measured serum XO levels at multiple days to determine whether it is associated with the severity and prognosis of severe traumatic brain injury (sTBI). In this prospective cohort study, we quantified serum XO levels in 112 sTBI patients and 112 controls. Serum XO levels of patients were measured at admission and at days 1, 3, 5, 7, and 10 after sTBI. Extended Glasgow outcome scale scores of 1-4 at post-trauma 180 days were defined as a poor prognosis. Multivariate analysis was employed to determine the relationship between poor prognosis and serum XO levels at multiple days. Serum XO levels were significantly increased at admission among patients, afterwards elevated gradually, peaked at day 3, and then diminished gradually until day 10, and were substantially higher during 10 days in patients than in controls. Serum XO levels at 6 different days were all correlated with admission Rotterdam computed tomography (CT) scores and Glasgow coma scale (GCS) scores. Serum XO levels at 6 different days were all substantially higher in patients with poor prognosis than in those with good prognosis. Serum XO levels at days 7 and 10, but not at days 1, 3, and 5, had significantly lower area under receiver operating characteristic (AUC) than those at admission. Serum XO levels at admission and at days 1 and 3, but not at day 5, were independently associated with 180-day poor prognosis. Prognostic prediction model containing GCS scores, Rotterdam CT scores, and serum XO levels at admission (or at days 1 and 3) showed substantially higher AUC than GCS scores and Rotterdam CT scores alone. The models were visually described using nomograms, which were comparatively stable under calibration curve and were relatively of clinical benefit under decision curve. Elevated serum XO levels during early period of sTBI are more closely associated with trauma severity and clinical adverse outcomes, assuming that serum XO may serve as a potential prognostic biomarker in sTBI.
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Lesiones Traumáticas del Encéfalo , Lesiones Encefálicas , Humanos , Xantina Oxidasa , Estudios Prospectivos , Pronóstico , Escala de Coma de GlasgowRESUMEN
BACKGROUND: Theabrownin (TB) is a bioactive component of tea and has been reported to exert effects against many human cancers, but its efficacy and mechanism on hepatocellular carcinoma (HCC) with different p53 genotypes remains unclarified. METHODS: MTT assay, DAPI staining, flow cytometry and SA-ß-gal staining were applied to evaluate the effects of TB on HCC cells. Quantitative real time PCR (qPCR) and Western blot (WB) were conducted to explore the molecular mechanism of TB. A xenograft model of zebrafish was established to evaluate the anti-tumor effect of TB. RESULTS: MTT assays showed that TB significantly inhibited the proliferation of SK-Hep-1, HepG2, and Huh7 cells in a dose-dependent manner, of which SK-Hep-1 was the most sensitive one with the lowest IC50 values. The animal data showed that TB remarkably suppressed SK-Hep-1 tumor growth in xenograft model of zebrafish. The cellular data showed TB's pro-apoptotic and pro-senescent effect on SK-Hep-1 cells. The molecular results revealed the mechanism of TB that p53 signaling pathway (p-ATM, p-ATR, γ-H2AX, p-Chk2, and p-p53) was activated with up-regulation of downstream senescent genes (P16, P21, IL-6 and IL-8) as well as apoptotic genes (Bim, Bax and PUMA) and proteins (Bax, c-Casp9 and c-PARP). The p53-mediated mechanism was verified by using p53-siRNA. Moreover, by using JNK-siRNA, we found JNK as a bypass regulator in TB's mechanism. CONCLUSIONS: To sum up, TB exerted tumor-inhibitory, pro-senescent and pro-apoptotic effects on SK-Hep-1 cells through ATM-Chk2-p53 signaling axis in accompany with JNK bypass regulation. This is the first report on the pro-senescent effect and multi-target (p53 and JNK) mechanism of TB on HCC cells, providing new insights into the underlying mechanisms of TB's anti-HCC efficacy.
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Alcaloides , Células Endoteliales , Piroptosis , Hemorragia Subaracnoidea , Piroptosis/efectos de los fármacos , Hemorragia Subaracnoidea/tratamiento farmacológico , Hemorragia Subaracnoidea/complicaciones , Hemorragia Subaracnoidea/metabolismo , Animales , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Alcaloides/farmacología , Alcaloides/uso terapéutico , Sesquiterpenos de Guayano/farmacología , Ratones , Humanos , Masculino , SesquiterpenosRESUMEN
Osteosarcoma becomes the second leading cause of cancer death in the younger population. Current outcomes of chemotherapy on osteosarcoma were unsatisfactory to date, demanding development of effective therapies. Tea is a commonly used beverage beneficial to human health. As a major component of tea, theabrownin has been reported to possess anti-cancer activity. To evaluate its anti-osteosarcoma effect, we established a xenograft model of zebrafish and employed U2OS cells for in vivo and in vitro assays. The animal data showed that TB significantly inhibited the tumour growth with stronger effect than that of chemotherapy. The cellular data confirmed that TB-triggered DNA damage and induced apoptosis of U2OS cells by regulation of Mki67, PARP, caspase 3 and H2AX, and Western blot assay showed an activation of p53 signalling pathway. When P53 was knocked down by siRNA, the subsequent downstream signalling was blocked, indicating a p53-dependent mechanism of TB on U2OS cells (p53 wt). Using osteosarcoma cell lines with p53 mutations (HOS, SAOS-2 and MG63), we found that TB exerted stronger inhibitory effect on U2OS cells than that on p53-mut cell lines, but it also exerted obvious effect on SAOS-2 cells (p53 null), suggesting an activation of p53-independent pathway in the p53-null cells. Interestingly, theabrownin was found to have no toxicity on normal tissue in vivo and could even increase the viability of p53-wt normal cells. In sum, theabrownin could trigger DNA damage and induce apoptosis on U2OS cells via a p53-dependent mechanism, being a promising candidate for osteosarcoma therapy.
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Antineoplásicos Fitogénicos/farmacología , Neoplasias Óseas/tratamiento farmacológico , Catequina/análogos & derivados , Regulación Neoplásica de la Expresión Génica , Osteosarcoma/tratamiento farmacológico , Proteína p53 Supresora de Tumor/genética , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Neoplasias Óseas/patología , Caspasa 3/genética , Caspasa 3/metabolismo , Catequina/farmacología , Ciclo Celular/efectos de los fármacos , Ciclo Celular/genética , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cisplatino/farmacología , Daño del ADN , Histonas/genética , Histonas/metabolismo , Humanos , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Larva , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Osteoblastos/metabolismo , Osteoblastos/patología , Osteosarcoma/genética , Osteosarcoma/metabolismo , Osteosarcoma/patología , Poli(ADP-Ribosa) Polimerasas/genética , Poli(ADP-Ribosa) Polimerasas/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Transducción de Señal , Proteína p53 Supresora de Tumor/agonistas , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Pez CebraRESUMEN
[This corrects the article DOI: 10.3389/fneur.2024.1341731.].
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Objective: To analyze the relationship between serum complement component 1q (C1q) levels and functional prognosis in patients with aneurysmal subarachnoid hemorrhage (aSAH), and to reveal its clinical value. Methods: In this prospective cohort study, we collected clinical data of aSAH patients admitted to the Department of Neurosurgery, Hangzhou First People's Hospital from January 2020 to October 2022. Parameters such as serum C1q levels, Hunt-Hess grade, modified Fisher grade, and the modified Rankin scale (mRS) at 3 months were included for evaluation. Patients were grouped based on the occurrence of delayed cerebral ischemia (DCI). Spearman rank correlation test and Kruskal-Wallis rank sum test were used to analyze the correlation between serum C1q levels, disease severity, and prognosis. Potential risk factors affecting prognosis and the occurrence of DCI were screened through Independent sample t-test or Mann-Whitney U test. Variables with significant differences (p < 0.05) were incorporated into a logistic regression model to identify independent risk factors affecting prognosis and DCI occurrence. Serum C1q levels were plotted as a ROC curve for predicting prognosis and DCI, and the area under the curve was calculated. Results: A total of 107 aSAH patients were analyzed. Serum C1q levels positively correlated with Hunt-Hess grade, modified Fisher grade and mRS (all p < 0.001). Significant differences were observed in C1q levels among different Hunt-Hess grade, mFisher grade and mRS (all p < 0.001). Notably, higher serum C1q levels were seen in the poor prognosis group and DCI group, and correlated with worse prognosis (OR = 36.927, 95%CI 2.003-680.711, p = 0.015), and an increased risk for DCI (OR = 17.334, 95%CI 1.161-258.859, p = 0.039). ROC analysis revealed the significant discriminative power of serum C1q levels for poor prognosis (AUC 0.781; 95%CI 0.673-0.888; p < 0.001) and DCI occurrence (AUC 0.763; 95%CI 0.637-0.888; p < 0.001). Higher C1q levels independently predicted a poor prognosis and DCI with equivalent predictive abilities to Hunt-Hess grade and modified Fisher grade (both p < 0.05). Conclusion: High levels of C1q in the blood is an independent risk factor for poor prognosis and the development of DCI in patients with aSAH. This can more objectively and accurately predict functional outcomes and the incidence of DCI. C1q may have a significant role in the mechanism behind DCI after aSAH.
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Absent in melanoma 2 (AIM2) is implicated in neuroinflammation. Here, we explored the prognostic significance of serum AIM2 in human aneurysmal subarachnoid hemorrhage (aSAH). We conducted a consecutive enrollment of 127 patients, 56 of whom agreed with blood-drawings not only at admission but also at days 1, 2, 3, 5, 7 and 10 days after aSAH. Serum AIM2 levels of patients and 56 healthy controls were measured. Disease severity was assessed using the modified Fisher scale (mFisher) and World Federation of Neurological Surgeons Scale (WFNS). Neurological outcome at poststroke 90 days was evaluated via the modified Rankin Scale (mRS). Univariate analysis and multivariate analysis were sequentially done to ascertain relationship between serum AIM2 levels, severity, delayed cerebral ischemia (DCI) and 90-day poor prognosis (mRS scores of 3-6). Patients, in comparison to controls, had a significant elevation of serum AIM2 levels at admission and at days 1, 2, 3, 5, 7 and 10 days after aSAH, with the highest levels at days 1, 2, 3 and 5. AIM2 levels were independently correlated with WFNS scores and mFisher scores. Significantly higher serum AIM2 levels were detected in patients with a poor prognosis than in those with a good prognosis, as well as in patients with DCI than in those without DCI. Moreover, serum AIM2 levels independently predicted a poor prognosis and DCI, and were linearly correlated with their risks. Using subgroup analysis, there were no significant interactions between serum AIM2 levels and age, gender, hypertension and so on. There were substantially high predictive abilities of serum AIM2 for poor prognosis and DCI under the receiver operating characteristic curve. The combination models of DCI and poor prognosis, in which serum AIM2, WFNS scores and mFisher scores were incorporated, showed higher discriminatory efficiencies than anyone of the preceding three variables. Moreover, the models are delineated using the nomogram, and performed well under the calibration curve and decision curve. Serum AIM2 levels, with a substantial enhancement during early phase after aSAH, are closely related to bleeding severity, poor 90-day prognosis and DCI of patients, substantializing serum AIM2 as a potential prognostic biomarker of aSAH.
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Proteínas de Unión al ADN , Hemorragia Subaracnoidea , Humanos , Masculino , Femenino , Persona de Mediana Edad , Hemorragia Subaracnoidea/sangre , Hemorragia Subaracnoidea/diagnóstico , Hemorragia Subaracnoidea/mortalidad , Pronóstico , Estudios Prospectivos , Proteínas de Unión al ADN/sangre , Anciano , Adulto , Biomarcadores/sangre , Estudios de Casos y Controles , Estudios Longitudinales , Índice de Severidad de la Enfermedad , Isquemia Encefálica/sangreRESUMEN
Background: NADPH oxidase 2 (NOX2) is highly expressed in injured brain tissues. We determined serum NOX2 levels of aneurysmal subarachnoid hemorrhage (aSAH) patients and further investigated correlation of serum NOX2 levels with disease severity, delayed cerebral ischemia (DCI) plus prognosis after aSAH. Methods: Serum NOX2 levels were measured in 123 aSAH patients and 123 healthy controls. World Federation of Neurological Surgeons scale (WFNS) score and modified Fisher (mFisher) score were utilized to assess disease severity. Modified Rankin scale (mRS) score was used to evaluate the clinical prognosis at 90 days after aSAH. Relations of serum NOX2 levels to DCI and 90-day poor prognosis (mRS score of 3-6) were analyzed using multivariate analysis. Receiver operating characteristic curve (ROC) was built to evaluate the prognostic predictive capability. Results: Serum NOX2 levels in aSAH patients, compared with healthy controls, were significantly increased, and were independently correlated with WFNS score, mFisher score and post-stroke 90-day mRS score. Patients with poor prognosis or DCI had significantly higher serum NOX2 levels than other remainders, and serum NOX2 levels independently predicted 90-day poor prognosis and DCI. Serum NOX2 had high prognosis and DCI predictive abilities, and their areas under ROC curve were similar to those of WFNS score and mFisher score. Conclusion: Serum NOX2 levels are significantly associated with hemorrhage severity, poor 90-day prognosis and DCI in aSAH patients. Hence, complement NOX2 may serve as a potential prognostic biomarker after aSAH.
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Purpose: To explore the pharmacological effects and mechanisms of Qinghao Biejia decoction (QBD) against non-small-cell lung cancer (NSCLC) based on network pharmacology and to verify the anticancer effect of artemisinin B (ART B), the active ingredient of QBD, on H1299 cells. Methods: Ultra-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UPLC-QTOF-MS/MS) was applied to explore the chemoprofile of QBD. A zebrafish xenograft model was used to determine the anti-cancer efficacy of QBD. Cell counting kit-8 assay, terminal deoxyribonucleotide transferase-mediated-dUTP nick-end labeling assay; immunofluorescence, and flow cytometry were used to evaluate the in vitro anti-proliferative and pro-apoptotic effects of QBD and ART B on H1299 cells. Subsequently, the related targets and action mechanisms of both QBD and ART B predicted by network pharmacological analyses were experimentally validated by real-time PCR and Western blot assays on H1299 cells. Results: UPLC-QTOF-MS/MS identified a total of 69 compounds (such as ART B, mangiferin, and artemisinic acid) in QBD. The in vivo data showed that QBD significantly inhibited the growth of H1299 cells in xenograft larval zebrafish from 125 to 500 µg/mL. The in vitro data showed that QBD induced apoptosis of H1299 cells, accompanied by down-regulating the expression of BCL-2 and up-regulating the expression of BIM, PUMA, BAX, c-PARP, γ-H2A.X, c-CASP3, and c-CASP8. Alike QBD, ART B exerted similar anti-proliferative and pro-apoptotic effects on H1299 cells. Moreover, ART B inhibited expressions of BCL2L1, AKT1, AKT2, MMP-2, and EGFR, and up-regulated ALB expression. Mechanistically, ART B promoted apoptosis of H1299 cells by inhibiting PI3K/Akt signaling pathway. Conclusion: This study revealed the anti-NSCLC efficacy of QBD. ART B, the effective component of QBD, plays an anti-NSCLC role by down-regulating the PI3K-Akt signaling pathway. It suggests that QBD and ART B are promising drug candidates for NSCLC treatment.
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Artemisia annua , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Animales , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Pez Cebra , Farmacología en Red , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Espectrometría de Masas en Tándem , Neoplasias Pulmonares/tratamiento farmacológicoRESUMEN
BACKGROUND: α-melanocyte-stimulating hormone (α-MSH) exerts anti-inflammatory and brain protective effects. We determined plasma α-MSH concentrations and discovered the relationship between plasma α-MSH concentrations and severity plus clinical outcome after intracerebral hemorrhage (ICH). METHODS: A total of 117 ICH patients and 117 healthy controls were included in this study. Glasgow coma scale (GCS) score and hematoma volume were recorded to assess disease severity. We used Glasgow outcome scale (GOS) score to evaluate the 3-month clinical prognosis. And multivariate analysis was done to discern the relation of plasma α-MSH concentrations to disease severity plus poor prognosis. Receiver operating characteristic curve (ROC) was built to evaluate the prognostic predictive capability. RESULTS: Plasma α-MSH concentrations in ICH patients, compared with healthy controls, were significantly decreased (median, 25.37 vs 46.80 pg/ml; P < 0.001), and were independently correlated with GCS score (t = 4.091, P < 0.001). Plasma α-MSH concentrations were highly correlated with GOS scores (ρ = 0.548, P < 0.001), were substantially lower with poor prognosis (GOS scores 1-3) than good prognosis, and efficiently discriminated patients at risk of poor prognosis (AUC ROC, 0.793; 95 % CI: 0.709-0.863). Using Youden method, plasma α-MSH concentrations < 23.63 pg/ml predicted poor prognosis with sensitivity of 72.7 % and specificity of 82.2 %. Alternatively, plasma α-MSH concentrations emerged as an independent predictor of poor prognosis with odds ratio of 0.888 (95 % CI: 0.793-0.995; P = 0.040). CONCLUSION: Plasma α-MSH concentrations are significantly associated with disease severity and poor 3-month prognosis in patients with ICH, indicating that plasma α-MSH may serve as a useful potential prognostic biomarker for ICH.
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Hemorragia Cerebral , alfa-MSH , Humanos , Estudios Prospectivos , Pronóstico , Hemorragia Cerebral/diagnóstico , Biomarcadores , Curva ROCRESUMEN
The bioactive extract of green tea, theabrownin (TB), is known to exhibit pro-apoptotic and antitumor effects on non-small cell lung cancer (NSCLC). Gallic acid (GA) is a crucial component of TB; however, its mechanism of action in NSCLC has been rarely studied. To date, little attention has been paid to the anti-NSCLC activity of GA. Therefore, the present study investigated the effects of GA in vivo and in vitro. Cell Counting Kit (CCK)-8 assay, DAPI staining and flow cytometry, wound-healing assay and western blotting were used to assess cell viability, apoptosis, migration and protein expression, respectively. In addition, a xenograft model was generated, and TUNEL assay and immunohistochemistry analysis were performed. The CCK-8 data showed that the viability of H1299 cells was significantly inhibited by GA in a dose- and time-dependent manner. DAPI staining, Annexin-V/PI staining and wound-healing data showed that GA exerted pro-apoptotic and anti-migratory effects on H1299 cells in a dose-dependent manner. Furthermore, the results of western blotting showed that GA significantly upregulated the levels of pro-apoptotic proteins [cleaved (c-)PARP, c-caspase8, c-caspase-9 and the ratio of γ-H2A.X/H2A.X]. In vivo data confirmed the antitumor effect of GA through apoptosis induction in an autophagy-dependent manner. In conclusion, the present study confirmed the anti-proliferative, pro-apoptotic and anti-migratory effects of GA against NSCLC in vitro and in vivo, providing considerable evidence for its potential as a novel candidate for the treatment of NSCLC.
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BACKGROUND: A20 may be a neuroprotective factor. Herein, we aimed to investigate whether serum A20 levels were associated with disease severity, delayed cerebral ischemia (DCI), and outcome after aneurysmal subarachnoid hemorrhage (aSAH). METHODS: In this prospective cohort study containing 112 aSAH patients and 112 controls, serum A20 levels were quantified. At 90 d poststroke, Modified Rankin Scale (MRS) scores ≥3 were defined as a poor outcome. All correlations and associations were assessed using multivariate analysis. RESULTS: Compared with controls, there was a significant elevation of serum A20 levels in patients (median 123.7 pg/mL vs. 25.8 pg/mL; P<0.001). Serum A20 levels were independently correlated with Hunt-Hess scores (ß 9.854; 95% confidence interval [95% CI] 2.481-17.227, P=0.009) and modified Fisher scores (ß 10.349, 95% CI 1.273-19.424, P=0.026). Independent associations were found between serum A20 levels and poor outcome (odds ratio [OR] 1.015, 95% CI 1.000-1.031, P=0.047) and DCI (OR 1.018, 95% CI 1.001-1.035, P=0.042). Areas under the curve for predicting poor outcome and DCI were 0.771 (95% CI 0.682-0.845) and 0.777 (95% CI 0.688-0.850), respectively. Serum A20 levels ≥128.15 pg/mL predicted poor outcome, with a sensitivity of 73.9% and specificity of 74.2%, and A20 levels ≥160.55 pg/mL distinguished the risk of DCI with 65.5% sensitivity and 89.2% specificity. Its ability to predict poor outcome and DCI was similar to those of Hunt-Hess scores and modified Fisher scores (both P>0.05). CONCLUSION: Enhanced serum A20 levels are significantly associated with stroke severity and poor clinical outcome after aSAH, implying that serum A20 may be a potential prognostic biomarker for aSAH.
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Ginkgolide B (GB) has been demonstrated to have a variety of pharmacological actions. Accumulating evidence indicates that GB may exert a protective effect on brain injury. The study was designed to investigate the influence of GB on toll-like receptor 4 (TLR-4) and nuclear factor κB (NF-κB)-dependent inflammatory responses and neuronal cell apoptosis after traumatic brain injury (TBI). Wistar rats were subjected to 5, 10 and 20 mg/kg GB daily for 5 days, intraperitoneally, following TBI. Rats were sacrificed at hour 2, 6 and 12, as well as day 1, 2, 3 and 5 after TBI. The administration of 10 and 20 mg/kg GB could significantly (least-significant difference test: p < 0.05) suppress gene expressions of TLR-4 and NF-κB, lessen concentrations of tumour necrosis factor α, interleukin-1ß and interleukin-6, as well as reduce the number of apoptotic neuronal cells in traumatic rat brain tissues, but the administration of 5 mg/kg GB did not (p > 0.05). However, a clear concentration-response relationship was not found. Thus, GB may inhibit TLR-4 and NF-κB-dependent inflammatory responses, and furthermore lessen neuronal cell apoptosis after TBI, which may support the use of GB for the treatment of TBI.
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Apoptosis/efectos de los fármacos , Lesiones Encefálicas/tratamiento farmacológico , Ginkgólidos/farmacología , Lactonas/farmacología , FN-kappa B/metabolismo , Neuronas/efectos de los fármacos , Receptor Toll-Like 4/metabolismo , Animales , Encéfalo/citología , Encéfalo/efectos de los fármacos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Masculino , Neuronas/citología , RatasRESUMEN
Objective: Numerous studies have shown that neuroinflammation and brain edema play an important role in early brain injury (EBI) after subarachnoid hemorrhage (SAH). 2-Methoxyestradiol (2-ME) has been shown to have anti-inflammatory and anti-angiogenic effects. This study aimed to investigate the effects of 2-ME on neuroinflammation and brain edema after SAH and its underlying mechanism of action. Methods: Rats were used to produce an endovascular puncture model of SAH. 2-ME or the control agent was injected intraperitoneally 1 h after SAH induction. At 24 h after surgery, the neurological score, SAH grading, brain water content, and blood-brain barrier (BBB) permeability were examined. The microglial activation level in the rat brain tissue was determined using immunofluorescence staining, whereas the cell apoptosis in the rat brain tissue was assessed using terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, the levels of Interleukin (IL)-1ß, IL-6 and tumor necrosis factor (TNF)-α were measured by enzyme linked immunosorbent assay, and the expression levels of ZO-1, occludin, hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and matrix metallopeptidase (MMP)-9 in the rat brain tissue were determined using western blotting. Results: Twenty-four hours after SAH, brain water content, BBB permeability, microglial activation, and cell apoptosis were significantly increased, whereas neurological function deteriorated significantly in rats. Treatment with 2-ME significantly decreased brain water content, BBB permeability, microglial cell activation, and cell apoptosis and improved neurological dysfunction in rats. Treatment with 2-ME reduced the expression levels of inflammatory factors (IL-1ß, IL-6, and TNF-α), which were significantly elevated 24 h after SAH. Treatment with 2-ME alleviated the disruption of tight junction proteins (ZO-1 and occludin), which significantly decreased 24 h after SAH. To further determine the mechanism of this protective effect, we found that 2-ME inhibited the expression of HIF-1α, MMP-9, and VEGF, which was associated with the inflammatory response to EBI and BBB disruption after SAH. Conclusion: 2-ME alleviated neuroinflammation and brain edema as well as improved neurological deficits after SAH in rats. The neuroprotective effect of 2-ME on EBI after SAH in rats may be related to the inhibition of neuroinflammation and brain edema.
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Background: Gem nuclear organelle-associated protein 6 (GEMIN6) is a component of the GEMINS protein family involved in the survival of motor neuron (SMN) complex. SMN interfered with snRNP assembly and mRNA processing resulting in tumorigenesis. We performed this study to explore the association between GEMIN6 and lung adenocarcinoma (LUAD). Methods: We used The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to collect transcriptomic expression data of LUAD patients and analyze the difference in GEMIN6 expression between normal and tumor tissues of LUAD. qRT-PCR analysis was also performed to detect the expression of GEMIN6 in normal and LUAD cells. The expression of GEMIN6 on the LUAD patient survival outcome was estimated by the Kaplan-Meier curves and Cox analyses. In addition, the Metascape online tool and single-sample GSEA were employed to find out the underlying biological mechanisms of GEMIN6. Furthermore, the correlations of GEMIN6 expression with immune cell infiltration in LUAD were analyzed by ssGSEA and Spearman correlation analysis. Results: Compared with the normal tissues and cells, the expression of GEMIN6 was significantly higher in LUAD tissues and cells; the high expression GEMIN6 was also found in the advanced pathologic stage and advanced N and T stages of LUAD. GEMIN6 high expression was significantly associated with inferior overall survival. The heat map revealed the top 20 coexpressed genes with GEMIN6, including SF3B6, CPSF3, and PSMB3. Functional enrichment analysis demonstrated that enrichment genes are associated with the cell cycle, mRNA processing, and energy metabolism. Additionally, GEMIN6 was negatively related to the immune cell infiltration in LUAD. Conclusions: This study demonstrated that GEMIN6 was involved in the tumorigenesis and progression of LUAD. GEMIN6 could be an important molecular marker of poor prognosis and a therapeutic target of LUAD.
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OBJECTIVES: Periostin is found associated with trauma severity and mortality following head injury. In this study, the role and mechanism of periostin in the traumatic brain injury were investigated. METHODS: Male Sprague-Dawley adult rats underwent sham or TBI modeling. Vehicle or recombinant periostin was administered intracerebroventricularly at 30 minutes post-TBI, and U0126, a specific MEK1/2 inhibitor, was administered intravenously at 30 minutes pre-TBI. Garcia neuroscore, limb function and brain water content assessments, as well as TUNEL and Western blotting assays were performed to evaluate the status of the above rats at 24 hours post-TBI. Finally, the motor test and Morris water maze test were performed to measure the effects of periostin and U0126 in the late phase of TBI. RESULTS: Periostin expression significantly increased 24 hours post-TBI. Treatment with R-periostin aggravated post-TBI neurobehavioral impairment, brain edema, induced apoptosis and raised the quantity of phospho-p38, phospho-JNK, phospho-ERK and MMP-9, and lowered the expression of ZO-1. However, U0126, a kind of inhibitor of MEK, lowered the quantities of phospho-ERK and MMP-9, raised the expression of ZO-1, and suppressed apoptosis. U0126 also ameliorated the neurobehavioral impairments and brain edema induced by R-periostin. Additionally, U0126 didn't inhibit the expression of periostin in the early phase of TBI model. IU0126 was also able to ameliorate the pathological conditions in the late phase of TBI. DISCUSSION: Periostin could aggravate neurobehavioral impairments and brain edema following TBI, and was involved in the early phase of TBI via the MAPK/ERK pathway.
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Edema Encefálico , Lesiones Traumáticas del Encéfalo , Moléculas de Adhesión Celular , Animales , Edema Encefálico/complicaciones , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Moléculas de Adhesión Celular/metabolismo , Sistema de Señalización de MAP Quinasas , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Apolipoprotein J (Apo-J) may act as a neuroprotective factor after acute brain injury. We gauged plasma Apo-J concentrations in patients with acute intracerebral hemorrhage (ICH) and investigated its predictive value for 90-day outcome and disease severity. METHODS: This prospective cohort study included 123 ICH patients and 123 healthy controls. The severity of ICH was assessed using the Glasgow Coma Scale (GCS) score and hematoma volume. Poor outcome was referred to as a Glasgow Outcome Scale (GOS) score of 1-3 at 90 days after stroke. Multivariate analysis was performed to identify associations of plasma Apo-J concentrations with disease severity and poor outcome. RESULTS: The plasma Apo-J concentrations of patients were significantly higher than those of healthy controls (median, 95.50 mg/l versus 55.71 mg/l; P < 0.001), and were independently correlated with hematoma volume (t = 2.716; P = 0.008) and GCS score (t = -5.978; P < 0.001). Plasma Apo-J significantly differentiated patients at risk of poor outcome (area under receiver operating characteristic curve (AUC), 0.772; 95% confidence interval (CI), 0.688-0.843; P < 0.001), and its predictive ability was similar to those of GCS score (AUC, 0.851; 95% CI, 0.776-0.909; P = 0.056) and hematoma volume (AUC, 0.849; 95% CI, 0.774-0.907, P = 0.089). Using maximum Youden index, plasma Apo-J concentrations >113.21 mg/l distinguished the development of poor outcome, with a sensitivity of 67.3% and a specificity of 87.3%. Plasma Apo-J concentrations >113.21 mg/l (odds ratio, 4.042; 95% CI, 1.093-14.951; P = 0.036) and hematoma volume (odds ratio, 1.124; 95% CI, 1.014-1.247; P = 0.027) were independently associated with poor outcome. CONCLUSIONS: Plasma Apo-J concentrations are markedly associated with disease severity and 90-day poor outcome in ICH patients. Hence, plasma Apo-J is presumed to be used as a potential prognostic biomarker of ICH.
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Hemorragia Cerebral , Clusterina , Biomarcadores , Hemorragia Cerebral/diagnóstico , Estudios de Cohortes , Hematoma , Humanos , Pronóstico , Estudios ProspectivosRESUMEN
Background: Cellular prion protein (PRPC) exerts brain-protective effects. We determined the relationship between plasma PRPC levels and disease severity plus clinical outcome after acute intracerebral hemorrhage (ICH). Methods: A total of 138 ICH patients and 138 healthy controls were included in this prospective, observational study. Hematoma volume and Glasgow coma scale (GCS) score were used to assess disease severity. Glasgow outcome scale (GOS) scores of 1-3 and 4-5 at 90 days after stroke were defined as a poor outcome and good outcome, respectively. Using multivariate analysis, we discerned the relation of plasma PRPC levels to disease severity and poor outcome. The receiver operating characteristic (ROC) curve was built to evaluate the prognostic predictive capability. Results: Plasma PRPC levels in ICH patients were significantly higher than those in healthy controls (median, 4.20 vs. 2.02 ng/ml; P < 0.001), and were independently correlated with GCS score (r = -0.645, P < 0.001) and hematoma volume (r = 0.627, P < 0.001). Plasma PRPC levels were highly correlated with GOS score (r = -0.762, P < 0.001), and were substantially higher in patients with poor outcomes than in those with the good outcomes. Using maximum Youden index, plasma PRPC levels >3.893 ng/ml distinguished the risk of poor outcome at 90 days, with a sensitivity of 86.4% and a specificity of 65.8% (area under the curve, 0.809; 95% confidence interval (CI), 0.737-0.881, P < 0.001). Plasma PRPC levels >3.893 ng/ml were independently associated with a poor 90-day outcome with an odds ratio of 12.278 (95% CI, 5.101-29.554). Conclusion: Elevated plasma PRPC levels are significantly associated with disease severity and poor 90-day outcome in ICH patients, indicating that plasma PRPC may be used as a potential prognostic biomarker after ICH.