BACKGROUND Remote ischemic preconditioning (RIPC) can inhibit recurrent ischemic events effectively in patients with acute or chronic cerebral ischemia. However, it is still unclear whether RIPC can impede ischemic injury after carotid artery stenting (CAS) in patients with severe carotid artery stenosis. METHODS Subjects with severe carotid artery stenosis were recruited in this randomized controlled study, and assigned to RIPC, sham, and no intervention (control) groups. All subjects received standard medical therapy. Subjects in the RIPC and sham groups underwent RIPC and sham RIPC twice daily, respectively, for 2 weeks before CAS. Plasma neuron-specific enolase and S-100B were used to evaluate safety, hypersensitive C-reactive protein, and new ischemic diffusion-weighted imaging lesions were used to determine treatment efficacy. The primary outcomes were the presence of ≥1 newly ischemic brain lesions on diffusion-weighted imaging within 48 hours after stenting and clinical events within 6 months after stenting. RESULTS We randomly assigned 189 subjects in this study (63 subjects in each group). Both RIPC and sham RIPC procedures were well tolerated and completed with high compliance (98.41% and 95.24%, respectively). Neither plasma neuron-specific enolase levels nor S-100B levels changed significantly before and after treatment. No severe adverse event was attributed to RIPC and sham RIPC procedures. The incidence of new diffusion-weighted imaging lesions in the RIPC group (15.87%) was significantly lower than in the sham group (36.51%; relative risk, 0.44; 96% confidence interval, 0.20–0.91; P<0.01) and the control group (41.27%; relative risk, 0.39; 96% confidence interval, 0.21–0.82; P<0.01). The volumes of lesions were smaller in the RIPC group than in the control and sham groups (P<0.01 each). Ischemic events that occurred after CAS were 1 transient ischemic attack in the RIPC group, 2 strokes in the control group, and 2 strokes and 1 transient ischemic attack in the sham group, but these results were not significantly different among the 3 groups (P=0.597). CONCLUSIONS RIPC is safe in patients undergoing CAS, which may be able to decrease ischemic brain injury secondary to CAS. However, the mechanisms and effects of RIPC on clinical outcomes in this cohort of patients need further investigation. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01654666

Background and Purpose— Trimethylamine N-oxide (TMAO)—a gut derived metabolite—has been shown to be atherogenic. It remains unknown whether TMAO is associated with the risk of first stroke. We aimed to determine the association between serum TMAO levels and first stroke in hypertensive patients without major cardiovascular diseases and examine any possible effect modifiers. Methods— We used a nested case-control design, using data from the CSPPT (China Stroke Primary Prevention Trial), including 622 patients with first stroke and 622 matched controls. The study was conducted from May 2008 to August 2013. The primary outcome was a first stroke. Results— After adjusting for choline, L-carnitine, and other important covariates, including baseline systolic blood pressure and time-averaged systolic blood pressure, during the treatment period, the risk of first stroke increased with each increment of TMAO level (per natural log [TMAO] increment: odds ratio, 1.22; 95% CI, 1.02–1.46). Consistently, compared with participants in the lowest tertile (<1.79 μmol/L) of serum TMAO levels, a significantly higher risk of first stroke was found in those in higher TMAO tertiles (≥1.79 μmol/L; odds ratio, 1.34; 95% CI, 1.00–1.81) or in TMAO tertile 3 (≥3.19 μmol/L; odds ratio, 1.43; 95% CI, 1.02–2.01). In the exploratory analysis, we observed an interaction between TMAO and folate levels (≥7.7 [median] versus <7.7 ng/mL) on first stroke ( P for interaction, 0.030). Conclusions— Higher TMAO levels were associated with increased risk of first stroke in hypertensive patients. Our finding, if further confirmed, calls for a carefully designed clinical trial to further evaluate the role of higher TMAO levels on outcomes in hypertensive patients. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT00794885.

Background: Berberine is the major alkaloidal component of Rhizoma coptidis, and has multiple pharmacological effects including inhibiting acetylcholinesterase, reducing cholesterol and glucose, lowering mortality in patients with chronic congestive heart failure and anti-inflammation etc. Thus berberine is a promising drug for diabetes, hyperlipemia, coronary artery disease and ischemic stroke etc. The present study was carried out to investigate the effect of berberine chloride on the spatial memory, inflammation factors interleukin-1 beta (IL-1beta) and inducible nitric oxide synthase (iNOS) expression in the rat model of Alzheimer's disease (AD) which was established by injecting Abeta (1-40) (5 microgram) into the rats hippocampuses bilaterally.

BACKGROUND AND PURPOSE:On the basis of the high 1-month stroke and/or death (14.7%) rates associated with stent placement in the Stenting versus Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis trial, modifications in patient selection and procedural aspects for intracranial stent placement have been recommended. We performed a multicenter prospective single-arm trial to determine whether such modifications would result in lower rates of periprocedural stroke and/or death.

TGF-b1, via Smad-dependent or Smad-independent signaling, has a central role in the pathogenesis of renal fibrosis. This pathway has been recognized as a potential target for antifibrotic therapy. Here, we identified GQ5, a small molecular phenolic compound isolated from the dried resin of Toxicodendron vernicifluum, as a potent and selective inhibitor of TGF-b1-induced Smad3 phosphorylation. In TGF-b1-stimulated renal tubular epithelial cells and interstitial fibroblast cells, GQ5 inhibited the interaction of Smad3 with TGF-b type I receptor (TbRI) by blocking binding of Smad3 to SARA, suppressed subsequent phosphorylation of Smad3, reduced nuclear translocation of Smad2, Smad3, and Smad4, and downregulated the transcription of major fibrotic genes such as a-smooth muscle actin (a-SMA), collagen I, and fibronectin. Notably, intraperitoneal administration of GQ5 in rats immediately after unilateral ureteral obstruction (UUO) selectively inhibited Smad3 phosphorylation in UUO kidneys, suppressed renal expression of a-SMA, collagen I, and fibronectin, and resulted in impressive renal protection after obstructive injury. Late administration of GQ5 also effectively attenuated fibrotic lesions in obstructive nephropathy. In conclusion, our results suggest that GQ5 hinders renal fibrosis in rats by selective inhibition of TGF-b1-induced Smad3 phosphorylation.

Another study demonstrated anatomic features related to high complication rate of intracranial angioplasty and stenting, Background and Purpose-To investigate the efficacy and safety of percutaneous transluminal angioplasty and stenting (PTAS) for symptomatic middle cerebral artery stenosis compared with standard medical treatment in a low-risk Chinese population. Methods-A prospective, randomized, controlled, single-center clinical trial was conducted comparing PTAS with medical treatment for symptomatic middle cerebral artery stenosis (≥70%). Patients were enrolled according to 1:1 enroll ratio (PTAS: medical). The PTAS group received stenting or balloon angioplasty, whereas the medical treatment group received standard medical treatment (aspirin 100 mg plus clopidogrel 75 mg/d), and all the patients were under strict control of the risk factors. The end point events were any kind of ipsilateral stroke or transient ischemic attack, or death from any origin during 1-year follow-up. Results-The enrollment was stopped after 70 patients were enrolled from August 2007 to December 2010, with a 30-day rate of end point events of 8.3% versus 5.9% (P=0.69) for PTAS and medical group, respectively, and 1-year rate of end point events of 19.4% versus 17.6% (P=0.85), respectively. There was no significant difference in baseline characteristics between the 2 groups. The mean follow-up time, which was ongoing, was 9.9 ± 3.9 and 9.7 ± 4.4 months, respectively. Among the risk factors, hypertension was the independent related to the outcome (P=0.015). Conclusions-This study showed that endovascular treatment is as safe but not better than medical treatment for symptomatic middle cerebral artery stenosis in a low-risk Chinese population. History of hypertension increases the risk of recurrent ischemic events.

The expression of Numb was upregulated in both ischemia-reperfusion- and cisplatin-induced AKI. Depletion of Numb from proximal tubules (PT-Nb-KO) exacerbated AKI shown as more severe renal tubular damage and higher serum creatinine than wild-type mice. Numb depletion alone significantly increased mitochondrial fragmentation without altering mitochondrial mass and function, including adenosine triphosphate production, mitochondrial membrane potential, oxygen consumption, and reactive oxygen species production. However, mitochondrial fragmentation and dysfunction were significantly aggravated after cisplatin exposure in PT-Nb-KO mice. Mechanistically, Numb depletion triggered dynamin-related protein 1 (Drp1) recruitment to mitochondria by increasing the phosphorylation of Drp1 at serine 656 residue (human Drp1 ser). Inhibiting the activity of Rho-associated coiled-coil containing protein kinase (ROCK) by Y-27632 attenuated phosphorylation of Drp1 ser and mitochondrial fragmentation in Numb-deficient cells. Administration of mdivi-1, a pharmacological inhibitor of Drp1, restored mitochondrial morphology, attenuated cisplatin-induced tubular injury, and renal dysfunction in PT-Nb-KO mice. Innovation and Conclusion: Our data suggest that Numb depletion promotes mitochondrial fragmentation by promoting the phosphorylation of Drp1 Ser and thus exacerbates cisplatin-induced mitochondrial dysfunction and tubular cell apoptosis. These findings add a novel insight into modulating mechanism of mitochondrial dynamics during AKI. Antioxid. Redox Signal. 00, 000-000.

Peritoneal fibrosis, a major complication of peritoneal dialysis, limits the effectiveness of peritoneal dialysis as a treatment of end-stage renal disease. Preventing this complication by identifying targets for therapy has recently received much attention. In the present study, we showed that Notch signaling was highly activated in rats in peritoneal dialysis fluid-induced fibrotic peritoneum, as indicated by increased expression of Jagged-1, Notch-1, and HES-1. Blocking Notch signaling activation by intraperitoneal injection of a gamma-secretase inhibitor, DAPT, significantly attenuated peritoneal fibrosis as indicated by the decreased expression of alpha-smooth muscle actin, collagen I, and vascular endothelial growth factor as well as increased expression of E-cadherin. Moreover, compared with control rats, DAPT-treated rats had a thinner peritoneum with less extracellular matrix accumulation, a lower mass transfer of glucose, and a higher ultrafiltration rate. In addition, transforming growth factor (TGF)-beta1 induced Notch signaling activation in primary rat peritoneal mesothelial cells. DAPT blocked this TGF-beta1-induced Notch signaling activation and therefore significantly inhibited TGF-beta1-induced expression of alpha-smooth muscle actin, collagen I, and vascular endothelial growth factor. Thus, a gamma-secretase inhibitor that interferes with Notch signaling prevents biochemical, histological, and functional consequences of peritoneal fibrosis through inhibiting epithelial to mesenchymal transition of rat peritoneal mesothelial cells. These results support the use of gamma-secretase inhibitors as a novel therapeutic approach for peritoneal fibrosis.