Recombinant human brain natriuretic peptide attenuates ischemic brain injury in mice by inhibiting oxidative stress and cell apoptosis via activation of PI3K/AKT/Nrf2/HO-1 pathway.

Ischemic stroke followed by cerebral artery occlusion is a main cause of chronic disability worldwide. Recombinant human brain natriuretic peptide (rhBNP) has been reported to alleviate sepsis-induced cognitive dysfunction and brain I/R injury. However, the function and molecular mechanisms of rhBNP in ischemic brain injury have not been clarified. For establishment of an animal model of ischemic brain injury, C57BL/6 mice were treated with middle cerebral artery occlusion (MCAO) surgery for 1 h and reperfusion for 24 h. After subcutaneous injection of rhBNP into model mice, neurologic deficits were assessed by evaluating behavior of mice according to Longa scoring system, and TTC staining was utilized to determine the brain infarct size of mice. The levels of oxidative stress markers, superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and malondialdehyde (MDA), were detected in hippocampal tissues of mice by corresponding kits. Cell apoptosis in hippocampus tissues was examined by TUNEL staining. Protein levels of antioxidant enzymes (HO-1 and NQO1) in cerebral cortex, apoptotic markers (Bax, Bcl-2, and cleaved caspase), and PI3K/AKT pathway-associated factors in hippocampus were tested by western blot analysis. The results revealed that injection of rhBNP decreased neurologic deficit scores, the percent of brain water content, and infarct volume. Additionally, rhBNP downregulated MDA level, upregulated the levels of SOD, CAT, and GSH in hippocampus of mice, and increased protein levels of HO-1 and NQO1 in the cortex. Cell apoptosis in hippocampus tissues of model mice was inhibited by rhBNP which was shown as the reduced TUNEL-positive cells, the decreased Bax, cleaved caspase-3, and cleaved caspase-9 protein levels, and the enhanced Bcl-2 protein level. In addition, rhBNP treatment activated the PI3K/AKT signaling pathway and upregulated the protein levels of HO-1 and NRF2. Overall, rhBNP activates the PI3K/AKT/HO-1/NRF2 pathway to attenuate ischemic brain injury in mice after MCAO by suppression of cell apoptosis and oxidative stress.

The biomarkers and potential pathogenesis of lung cancer related cerebral hemorrhage.

Cerebral hemorrhage is one of the common complications in patients with lung cancer (LC). Although cancer related cerebral hemorrhage was aware, the pathogenesis and biomarkers of lung cancer related cerebral hemorrhage (LCRCH) remained not well known. The aim of this study was to investigate the pathogenesis and plasma biomarkers of LCRCH.A retrospective review was conducted on acute cerebral hemorrhage patients with active LC who was admitted to the hospital between January 2007 and December 2017. A total of 56 patients with LCRCH (active LC patients with acute cerebral hemorrhage but without conventional vascular risks) was recruited. Meanwhile, 112 patients with active LC alone and gender, age, and subtype of cancer cell matched were recruited as control group.In LCRCH patients, most of the hemorrhagic lesions were located in lobes. And most of them with adenocarcinoma were in medium to terminal stage with poor prognosis short-term. Moreover, LCRCH patients had a lengthened prothrombin time (PT), elevated plasma carcinoembryonic antigen (CEA), cancer antigen 125 (CA125) and cancer antigen 199 (CA199) levels and decreased platelet (PLT) level than did the patients with LC. Multivariate logistic regression analysis showed that lengthened PT, elevated plasm CEA, and CA199 levels were independent risk factors for LCRCH.It was suggested that lengthened PT, elevated plasm CEA and CA199 levels associated with the pathogenesis of LCRCH, and that the Index derived from independent risks should be serve as a specific biomarker of LCRCH.

Biomarkers of gastric cancer-related ischemic stroke and its underlying pathogenesis.

This study aimed to investigate the biomarkers and underlying pathogenesis of ischemic stroke in patients with gastric cancer (GC).Patients with active gastric cancer who had experienced acute ischemic stroke without conventional vascular risk factors (gastric cancer-related stroke [GCS] group) and visited The First Affiliated Hospital of Guangxi Medical University and First Affiliated Hospital of Sun Yat-sen University from January 2003 to December 2016 were retrospectively enrolled. The patients' clinical features and laboratory findings were compared with those of age-, sex-, and disease progression-matched patients with GC without ischemic stroke (GC group) who had been admitted to the same hospital during the same period (GCS:GC ratio = 1:2).Among the 9166 patients diagnosed with GC, 70 had experienced a cerebral infarction and were enrolled in this study. Among them, 53 (75.71%) harbored multiple lesions in multiple vascular territories. Notably, patients in the GCS group exhibited significant increases in the D-dimer and cancer antigen 125 (CA125) levels and platelet-to-neutrophil ratio (PNR), compared to their counterparts in the GC group. A multiple logistic regression analysis identified all 3 factors as independent risk factors for cerebral infarction in patients with GC (D-dimer, odds ratio [OR] = 1.006 per 1 ng/mL increase, 95% confidence interval [CI], 1.004-1.009, P = .000; CA125, OR = 1.016 per 1 U/mL increase, 95% CI, 1.005-1.027, P = .005; PNR, OR = 1.025 per 1 point increase, 95% CI: 1.003-1.048, P = .023).Elevated plasma D-dimer and CA125 levels and an increased PNR might affect the occurrence of GC-related ischemic stroke and could therefore serve as potential biomarkers.