Y. Ischemia-induced brain damage is enhanced in human renin and angiotensinogen double-transgenic mice. Am J Physiol Regul Integr Comp Physiol 297: R1526 -R1531, 2009. First published September 16, 2009 doi:10.1152/ajpregu.91040.2008.-To investigate the role of brain angiotensin II (ANG II) in the pathogenesis of injury following ischemic stroke, mice overexpressing renin and angiotensinogen (RϩAϩ) and their wild-type control animals (RϪAϪ) were used for experimental ischemia studies. Focal brain ischemia was induced by middle cerebral artery occlusion (MCAO). The severity of ischemic injury was determined by measuring neurological deficits and histological damage at 24 and 48 h after MCAO, respectively. To exclude the influence of blood pressure and local collateral blood flow, brain slices were used for oxygen and glucose deprivation (OGD) studies. The severity of OGD-induced damage was determined by measuring indicators of tissue swelling and cell death, the intensity of the intrinsic optical signal (IOS), and the number of propidium iodide (PI) staining cells, respectively. Results showed 1) RϩAϩ mice showed higher neurological deficit score (3.8 Ϯ 0.5 and 2.5 Ϯ 0.3 for RϩAϩ and RϪAϪ, respectively, P Ͻ 0.01) and larger infarct volume (22.2 Ϯ 1.6% and 14.1 Ϯ 1.2% for RϩAϩ and RϪAϪ, respectively, P Ͻ 0.01); 2) The RϩAϩ brain slices showed more severe tissue swelling and cell death in the cortex (IOS: 140 Ϯ 6% and 114 Ϯ 10%; PI: 139 Ϯ 20 cells/field and 39 Ϯ 9 cells/field for RϩAϩ and RϪAϪ, respectively, P Ͻ 0.01); 3) treatment with losartan (20 mol/l) abolished OGD-induced exaggeration of cell injury seen in RϩAϩ mice. The data indicate that activation of ANG II/AT 1 signaling is harmful to brain exposed to ischemia. AT1 receptor; mouse; losartan; middle cerebral artery ISCHEMIC STROKE, THE THIRD leading cause of death in the United States, is a severe complication of hypertension and arteriosclerosis. There are limited avenues for prevention and treatment of ischemic stroke. Accumulating evidence suggests that the angiotensin II (ANG II)/AT 1 receptor pathway participates in the pathophysiology of ischemic stroke (8, 32). Blockade of the ANG II/AT 1 pathway has been shown to have beneficial effect on cerebral ischemia in animal studies (11,30) and clinical trials (10, 23). However, the mechanisms of ANG II/AT 1 signaling in conjunction with stroke are still elusive.The protective effect of blocking ANG II/AT 1 receptor pathway on ischemic stroke has been related to blood pressure control and improvement of cerebral blood supply. However, the benefits can go beyond those (10, 38). The ANG II/AT 1 pathway exists in neural/glial cells as well as cerebrovascular cells. AT 1 receptors located in the cerebral vasculature participate in the regulation of the cerebrovascular circulation (31) and platelet-leukocyte-endothelium interactions (19). The ANG II/AT 1 receptors located in the neural/glial cells participate in ischemic damage by inducing inflammation and oxidative stress (16,33,40).Genetically modified mice...

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Cerium oxide (CeO2) nanoparticles (CeNPs) are potent antioxidants that are being explored as potential therapies for diseases in which oxidative stress plays an important pathological role. However, both beneficial and toxic effects of CeNPs have been reported, and the method of synthesis as well as physico-chemical, biological, and environmental factors can impact the ultimate biological effects of CeNPs. In the present study, we explored the effect of different ratios of citric acid (CA) and EDTA (CA/EDTA), which are used as stabilizers during synthesis of CeNPs, on the antioxidant enzyme-mimetic and biological activity of the CeNPs. We separated the CeNPs into supernatant and pellet fractions and used commercially available enzymatic assays to measure the catalase-, superoxide dismutase (SOD)-, and oxidase-mimetic activity of each fraction. We tested the effects of these CeNPs in a mouse hippocampal brain slice model of ischemia to induce oxidative stress where the fluorescence indicator SYTOX green was used to assess cell death. Our results demonstrate that CeNPs stabilized with various ratios of CA/EDTA display different enzyme-mimetic activities. CeNPs with intermediate CA/EDTA stabilization ratios demonstrated greater neuroprotection in ischemic mouse brain slices, and the neuroprotective activity resides in the pellet fraction of the CeNPs. The neuroprotective effects of CeNPs stabilized with equal proportions of CA/EDTA (50/50) were also demonstrated in two other models of ischemia/reperfusion in mice and rats. Thus, CeNPs merit further development as a neuroprotective therapy for use in diseases associated with oxidative stress in the nervous system.

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Objective Fluzoparib (SHR3162) is a novel, potent poly(ADP-ribose) polymerases (PARP)1, 2 inhibitor that showed anti-tumor activity in xenograft models. We conducted a phase I, first-in-human, dose-escalation and expansion (D-Esc and D-Ex) trial in patients with advanced solid cancer. Methods This was a 3+3 phase I D-Esc trial with a 3-level D-Ex at 5 hospitals in China. Eligible patients for D-Esc had advanced solid tumors refractory to standard therapies, and D-Ex enrolled patients with ovarian cancer (OC). Fluzoparib was administered orally once or twice daily (bid) at 11 dose levels from 10 to 400 mg/d. Endpoints included dose-finding, safety, pharmacokinetics, and antitumor activity. Results Seventy-nine patients were enrolled from March, 2015 to January, 2018 [OC (47, 59.5%); breast cancer (BC) (16, 20.3%); colorectal cancer (8, 10.1%), other tumors (8, 10.1%)]; 48 patients were treated in the D-Esc arm and 31 in the D-Ex arm. The maximum tolerated dose (MTD) was 150 mg bid, with a half-life of 9.14 h. Grade 3/4 adverse events included anemia (7.6%) and neutropenia (5.1%). The objective response rate (ORR) was 30% (3/10) in patients with platinum-sensitive OC and 7.7% (1/13) in patients with BC. Among patients treated with fluzoparib ≥120 mg/d, median progression-free survival (mPFS) was 7.2 [95% confidence interval (95% CI), 1.8−9.3] months in OC, 9.3 (95% CI, 7.2−9.3) months in platinum-sensitive OC, and 3.5 (range, 2.0−28.0) months in BC. In patients with germline BC susceptibility gene mutation (g BRCA Mut ) (11/43 OC; 2/16 BC), mPFS was 8.9 months for OC (range, 1.0−23.2; 95% CI, 1.0−16.8) and 14 and 28 months for BC (those two patients both also had somatic BRCA Mut ). Conclusions The MTD of fluzoparib was 150 mg bid in advanced solid malignancies. Fluzoparib demonstrated single-agent antitumor activity in BC and OC, particularly in BRCA Mut and platinum-sensitive OC.