Necrostatin-1 protects against oleic acid-induced acute respiratory distress syndrome in rats.

Necroptosis is a recently discovered necrotic cell death which is regulated by receptor interacting protein kinase 1 (RIPK1) and RIPK3 under the stimulus of death signal and can be inhibited by necrostatin-1 (Nec-1) specifically. Therefore, the aim was to investigate the role of necroptosis in a rat model of acute respiratory distress syndrome (ARDS) induced by oleic acid (OA) and assess the effect of Nec-1 on lung injury in ARDS. Our results found that RIPK1, RIPK3 and mixed lineage kinase domain-like protein (MLKL) were abundantly expressed in rat lung tissues of OA-induced ARDS. Nec-1 pretreatment improved pulmonary function and attenuated lung edema dramatically in OA-induced ARDS rats. Furthermore, Nec-1 reduced RIPK1-RIPK3 interaction and down-regulated RIPK1-RIPK3-MLKL signal pathway, and inhibited inflammatory response by reducing neutrophil infiltration and protein leakage into lung tissue in OA-induced ARDS. Collectively, our study proves the intervention of necroptosis in OA-induced ARDS. Moreover, our findings imply that Nec-1 plays an important role in the treatment of ARDS via inhibiting necroptosis and inflammation.

Activation of necroptosis in a rat model of acute respiratory distress syndrome induced by oleic acid.

The present study was aimed to investigate the role of necroptosis in the pathogenesis of acute respiratory distress syndrome (ARDS). The rat model of ARDS was induced by intravenous injection of oleic acid (OA), and observed for 4 h. The lung injury was evaluated by arterial blood gas, lung wet-dry weight ratio (W/D) and histological analyses. Simultaneously, bronchoalveolar lavage fluid (BALF) was collected for total and differential cell analysis and total protein determination. Tumor necrosis factor alpha (TNF-α) level in BALF was determined with a rat TNF-α ELISA kit. Expressions of receptor interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain-like protein (MLKL) in lung tissue were determined by Western blot and immunohistochemical staining. The interaction between RIPK1 and RIPK3 was explored by immunoprecipitation. The results showed that, compared with those in control group, total white blood cells count (WBC), polymorphonuclear percentage (PMN%), total protein concentration, TNF-α level in BALF, W/D, and the alveolar-arterial oxygen tension difference (P(A-a)O2) in OA group were significantly increased at 4 h after OA injection. Western blot and immunostaining further showed remarkably increased expressions of RIPK1, RIPK3 and MLKL in lung tissue from OA group. Additionally, immunoprecipitation results indicated an enforced interaction between RIPK1 and RIPK3 in OA group. Collectively, the TNF-α level in BALF and the RIPK1-RIPK3-MLKL signaling pathway in lung tissue were found to be upregulated and activated with the process of ARDS. These findings implicate that RIPK1/RIPK3-mediated necroptosis plays a possible role in the pathogenesis of ARDS, which may provide a new idea to develop novel drugs for the therapy of ARDS.

CyPA-CD147-ERK1/2-cyclin D2 signaling pathway is upregulated during rat left ventricular hypertrophy.

The changes of serum cyclophilin A (CyPA), its receptor CD147 and the downstream signaling pathway during the process of cardiac hypertrophy remain unknown. The present study aims to investigate the relationships between CyPA-CD147-ERK1/2-cyclin D2 signaling pathway and the development of cardiac hypertrophy. Left ventricular hypertrophy was prepared by 2-kidney, 2-clip in Sprague-Dawley rats and observed for 1 week, 4 and 8 weeks. Left ventricular hypertrophy was evaluated by ratio of left ventricular heart weight to body weight (LVW/BW) and cardiomyocyte cross sectional area (CSA). CyPA levels in serum were determined with a rat CyPA ELISA kit. Expressions of CyPA, CD147, phospho-ERK1/2 and cyclin D2 in left ventricular myocytes were determined by Western blot and immunostaining. Compared with sham groups, systolic blood pressure reached hypertensive levels at 4 weeks in 2K2C groups. LVW/BW and CSA in 2K2C groups were significantly increased at 4 and 8 weeks after clipping. ELISA results indicated a prominent increase in serum CyPA level associated with the degree of left ventricular hypertrophy. Western blot revealed that the expressions of CyPA, CD147, phospho-ERK1/2 and cyclin D2 in left ventricular tissues were also remarkably increased as the cardiac hypertrophy developed. The results of the present study demonstrates that serum CyPA and CyPA-CD147-ERK1/2-cyclin D2 signaling pathway in ventricular tissues are time-dependently upregulated and activated with the process of left ventricular hypertrophy. These data suggest that CyPA-CD147 signaling cascade might play a role in the pathogenesis of left ventricular hypertrophy, and CyPA might be a prognosticator of the degree of left ventricular hypertrophy.

A novel lactate dehydrogenase-based risk score model to predict the prognosis of primary central nervous system germ cell tumor treated with chemoradiotherapy.

BACKGROUND: The prognostic role of lactate dehydrogenase (LDH) has been confirmed in many malignant tumors, but the role of serum LDH in primary central nervous system germ cell tumor (GCT) remains unknown. This study aimed to assess the prognostic value of LDH in GCT patients and develop a nomogram to predict prognosis in patients undergoing chemoradiotherapy. METHODS: A total of 161 patients with GCT were included in this study. Using a restricted cubic spline (RCS) model, the optimal cutoff point for LDH was determined to be 217 U/L. The survival of GCT patients was evaluated using the Kaplan-Meier method and log-rank test to analyze the effects of LDH levels. Univariate Cox regression, multivariate Cox regression, and LASSO Cox regression were conducted to identify prognostic factors, which were incorporated into a nomogram for predicting overall survival (OS). The predictive accuracy of the nomogram was assessed using the C-index, calibration curve, area under the time-dependent receiver operating characteristic curve (time-dependent AUC), and risk group stratification. The net benefits of the nomogram at different threshold probabilities were quantified using decision curve analysis (DCA). RESULTS: The high-LDH group had significantly shorter OS compared to the low-LDH group (P = 0.016). Based on the SYSUCC cohort, three variables were shown to be significant factors for OS and were incorporated in the nomogram: LDH, histopathology, and dissemination. It showed good discrimination ability, with C-index of 0.789 (95% CI, 0.671-0.907). Additionally, the clinical usefulness of the nomogram was confirmed by calibration curves and time-dependent AUC. DCA further highlighted the potential of the nomogram to guide clinical treatment strategies for patients. Moreover, there was a significant difference in OS among patients categorized into different risk groups (P < 0.001). CONCLUSION: LDH levels may serve as a reliable predictor for assessing the therapeutic effect of chemoradiotherapy in GCT. The developed nomogram exhibits high accuracy in predicting survival outcomes, aiding in the classification of prognostic groups, and supporting informed clinical decision-making.

Apatinib for recurrent/progressive glioblastoma multiforme: A salvage option.

Purpose: The recurrent/progressive glioblastoma multiforme (GBM) carries a dismal prognosis and the definitive treatment strategy has not yet been established. This study aimed to assess the efficacy and safety of apatinib in recurrent/progressive GBM patients. Materials and methods: The clinical data of 19 recurrent/progressive GBM patients who received apatinib treatment from November 2015 to December 2019 at Sun Yat-sen University Cancer Center were collected retrospectively in this study. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (AEs) were reviewed and assessed. Results: The overall ORR was 52.6%, and the DCR was 73.7%. Median PFS and OS were 5.1 and 10.4 months, respectively. The 6-month PFS and OS rates were 38.9% and 68.4%, respectively. The 12-month PFS and OS rates were 16.7% and 36.8%, respectively. The treatment-related toxicities were generally well-tolerated. The most common grade 3/4 AEs were hand-foot syndrome (36.8%) and hypertension (21.1%). Conclusion: Our study showed that apatinib therapy provided a better salvaging option for recurrent/progressive GBM patients and the toxicity was manageable.

Upfront Cranial Radiotherapy vs. EGFR Tyrosine Kinase Inhibitors Alone for the Treatment of Brain Metastases From Non-small-cell Lung Cancer: A Meta-Analysis of 1465 Patients.

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is revolutionizing the management of brain metastases (BMs). This study was to explore the value of upfront cranial radiotherapy (RT) in EGFR-mutated non-small cell lung cancer (NSCLC) with BMs compared with EGFR-TKIs alone. Methods: We searched all topic-related comparative articles in public databases (MEDLINE, EMBASE, Cochrane Library, and Web of Science) and conference proceedings. Outcomes of interest were intracranial objective response rate (ORR), overall survival (OS), and intracranial progression-free survival (PFS). Statistical analyses were calculated using Review Manager 5.3 software. Results: Thirteen comparative studies that included a total of 1,456 patients were eligible. Upfront brain RT had significantly higher OS (HR = 0.78, 95% CI = 0.65-0.93, P = 0.005) than EGFR-TKI alone. Upfront RT plus TKI had superior OS (HR = 0.71, 95% CI = 0.58-0.86, P = 0.0005) and intracranial PFS (HR = 0.69, 95% CI = 0.49-0.99, P = 0.04). The pooled data favored upfront whole brain RT (WBRT) plus TKI in terms of intracranial PFS (HR = 0.64, 95% CI = 0.48-0.85, P = 0.002) and OS (HR = 0.75, 95% CI = 0.57-1, P = 0.05). Upfront stereotactic radiosurgery (SRS) was associated with better OS (HR = 0.37, 95% CI = 0.26-0.54, P < 0.00001). Similar results were observed when analysis was restricted to the use of erlotinib or geftinib. Conclusions: The upfront use of brain RT seemed critical, especially for SRS. Upfront administration of upfront WBRT plus EGFR-TKI had better survival outcomes and seemed superior to EGFR-TKI alone.

Simvastatin attenuated rat thoracic aorta remodeling by decreasing ROCK2­mediated CyPA secretion and CD147­ERK1/2­cyclin pathway.

Reactive oxygen species­induced cyclophilin A (CyPA) release from vascular smooth muscle cells (VSMCs) may be inhibited by simvastatin in vitro. The present study aimed to further examine the effect of simvastatin on serum CyPA levels and the basigin (CD147)­extracellular signal­regulated kinase (ERK) 1/2­cyclin pathway during thoracic aorta remodeling. The mechanisms through which simvastatin may inhibit CyPA secretion from VSMCs were further investigated. Serum CyPA levels and the expression kinetics of CyPA­associated signaling pathways were examined following simvastatin treatment in rat thoracic aortas during hypertension. Cell lysates were prepared from middle layer of thoracic aortas at 1, 4, 8 and 12 weeks subsequent to surgery. ELISA analysis revealed that serum CyPA levels were gradually increased with the progression of thoracic aorta remodeling. Western blotting demonstrated that the expression of CD147, phosphorylated­ERK1/2, cyclin D1, cyclin A, and cyclin E were increased with the progression of thoracic aorta remodeling. Simvastatin administration for 4, 8 and 12 weeks diminished all these changes, as observed in the hypertensive group. VSMCs from simvastatin­treated rats secreted a decreased amount of CyPA compared with VSMCs from hypertensive rats. In addition, pretreatment with geranylgeraniol partly reversed the inhibitory effect of simvastatin on LY83583­induced CyPA secretion in cultured VSMCs, whereas GGTI­298 and KD025 [a selective Rho­associated protein kinase 2 (ROCK2) inhibitor] mimicked the inhibitory effect of simvastatin. The present study demonstrated that simvastatin alleviated thoracic aorta remodeling by reducing CyPA secretion and expression of the CD147­ERK1/2­cyclin signaling pathway. In addition, the results of the present study demonstrated that the Rho­ROCK2 pathway mediated CyPA secretion from VSMCs.