The mechanism and relevant mediators associated with neuronal apoptosis and potential therapeutic targets in subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) is a dominant cause of death and disability worldwide. A sharp increase in intracranial pressure after SAH leads to a reduction in cerebral perfusion and insufficient blood supply for neurons, which subsequently promotes a series of pathophysiological responses leading to neuronal death. Many previous experimental studies have reported that excitotoxicity, mitochondrial death pathways, the release of free radicals, protein misfolding, apoptosis, necrosis, autophagy, and inflammation are involved solely or in combination in this disorder. Among them, irreversible neuronal apoptosis plays a key role in both short- and long-term prognoses after SAH. Neuronal apoptosis occurs through multiple pathways including extrinsic, mitochondrial, endoplasmic reticulum, p53 and oxidative stress. Meanwhile, a large number of blood contents enter the subarachnoid space after SAH, and the secondary metabolites, including oxygenated hemoglobin and heme, further aggravate the destruction of the blood-brain barrier and vasogenic and cytotoxic brain edema, causing early brain injury and delayed cerebral ischemia, and ultimately increasing neuronal apoptosis. Even there is no clear and effective therapeutic strategy for SAH thus far, but by understanding apoptosis, we might excavate new ideas and approaches, as targeting the upstream and downstream molecules of apoptosis-related pathways shows promise in the treatment of SAH. In this review, we summarize the existing evidence on molecules and related drugs or molecules involved in the apoptotic pathway after SAH, which provides a possible target or new strategy for the treatment of SAH.

Taurine-Upregulated Gene 1 Attenuates Cerebral Angiogenesis following Ischemic Stroke in Rats.

Objective: Angiogenesis is one of the therapeutic targets of cerebral infarction. Long noncoding RNAs (lncRNAs) can regulate the pathological process of angiogenesis following ischemic stroke. Taurine-upregulated gene 1 (TUG1), an lncRNA, is correlated to ischemic stroke. We intended to determine the effect of TUG1 on angiogenesis following an ischemic stroke. Materials and Methods: Middle cerebral artery occlusion (MCAO) was adopted to build a focal ischemic model of the rat brain, and pcDNA-TUG1 and miR-26a mimics were injected into rats. Neurological function was estimated through modified neurological severity scores. The volume of focal brain infarction was calculated through 2,3,5-triphenyltetrazolium chloride staining. The level of TUG1 and miR-26a was measured by PCR. The expression of vascular endothelial growth factor (VEGF) and CD31 was checked using immunohistochemistry and western blot. The correlation between miR-26a and TUG1 was verified through a luciferase reporter assay. Results: TUG1 increased noticeably while miR-26a was markedly reduced in MCAO rats. Overexpression of miR-26a improved neurological function recovery and enhanced cerebral angiogenesis in MCAO rats. TUG1 overexpression aggravated neurological deficits and suppressed cerebral angiogenesis in MCAO rats. Bioinformatics analysis revealed that miR-26a was one of the predicted targets of TUG1. Furthermore, TUG1 combined with miR-26a to regulate angiogenesis. TUG1 overexpression antagonized the role of miR-26a in neurological recovery and angiogenesis in MCAO rats. Conclusions: TUG1/miR-26a, which may act as a regulatory axis in angiogenesis following ischemic stroke, can be considered a potential target for cerebral infarction therapy.

Risk of Re-Rupture, Vasospasm, or Re-Stroke after Clipping or Coiling of Ruptured Intracranial Aneurysms: Long-Term Follow-Up with a Propensity Score-Matched, Population-Based Cohort Study.

Scarce evidence is available in Asia for estimating the long-term risk and prognostic factors of major complications such as re-rupture, vasospasm, or re-stroke for patients with aneurysmal subarachnoid hemorrhage (SAH) undergoing endovascular coil embolization or surgical clipping. This is the first head-to-head propensity score-matched study in an Asian population to demonstrate that endovascular coil embolization for aneurysmal SAH treatment is riskier than surgical clipping in terms of re-rupture, vasospasm, or re-stroke. In addition, the independent poor prognostic factors of vasospasm or re-stroke were endovascular coil embolization, male sex, older age (≥65 years; the risk of vasospasm increases with age), hypertension, congestive heart failure, diabetes, previous transient ischemic attack, or stroke in aneurysmal SAH treatment. BACKGROUND: To estimate the long-term complications and prognostic factors of endovascular coil embolization or surgical clipping for patients with ruptured aneurysmal subarachnoid hemorrhage (SAH). METHODS: We selected patients diagnosed with aneurysmal SAH between 1 January 2011 and 31 December 2017. Propensity score matching was performed, and Cox proportional hazards model curves were used to analyze the risk of re-rupture, vasospasm, and re-stroke in patients undergoing the different treatments. FINDINGS: Multivariate Cox regression analysis revealed that the adjusted hazard ratio (aHR) of re-rupture for endovascular coil embolization compared with surgical clipping was 1.36 (95% confidence interval [CI]: 1.17-1.57; p < 0.0001). The aHRs of the secondary endpoints of vasospasm and re-stroke (delayed cerebral ischemia) for endovascular coil embolization compared with surgical clipping were 1.14 (1.02-1.27; p = 0.0214) and 2.04 (1.83-2.29; p < 0.0001), respectively. The independent poor prognostic factors for vasospasm and re-stroke were endovascular coil embolization, male sex, older age (≥65 years; risk increases with age), hypertension, congestive heart failure, diabetes, and previous transient ischemic attack or stroke. INTERPRETATION: Endovascular coil embolization for aneurysmal SAH carries a higher risk than surgical clipping of both short- and long-term complications including re-rupture, vasospasm, and re-stroke.

Chronic Obstructive Pulmonary Disease and Its Acute Exacerbation before Colon Adenocarcinoma Treatment Are Associated with Higher Mortality: A Propensity Score-Matched, Nationwide, Population-Based Cohort Study.

PURPOSE: To investigate whether chronic obstructive pulmonary disease (COPD) and COPD severity (acute exacerbation of COPD (AECOPD)) affect the survival outcomes of patients with colon adenocarcinoma receiving standard treatments. METHODS: From the Taiwan Cancer Registry Database, we recruited patients with clinical stage I-III colon adenocarcinoma who had received surgery. The Cox proportional hazards model was used to analyze all-cause mortality. We categorized the patients into COPD and non-COPD (Group 1 and 2) groups through propensity score matching. RESULTS: In total, 1512 patients were eligible for further comparative analysis between non-COPD (1008 patients) and COPD (504 patients) cohorts. In the multivariate Cox regression analysis, the adjusted hazard ratio (aHR; 95% confidence interval (CI)) for all-cause mortality for Group 1 compared with Group 2 was 1.17 (1.03, 1.29). In patients with colon adenocarcinoma undergoing curative resection, the aHRs (95% CIs) for all-cause mortality in patients with hospitalization frequencies of ≥1 and ≥2 times for AECOPD within 1 year before adenocarcinoma diagnosis were 1.08 (1.03, 1.51) and 1.55 (1.15, 2.09), respectively, compared with those without AECOPD. CONCLUSION: In patients with colon adenocarcinoma undergoing curative resection, COPD was associated with worse survival outcomes. Being hospitalized at least once for AECOPD within 1 year before colon adenocarcinoma diagnosis was an independent risk factor for poor overall survival in these patients, and a higher number of hospitalizations for AECOPD within 1 year before diagnosis was associated with poorer survival. Our study highlights the importance of COPD management, particularly the identification of frequent exacerbators and the prevention of AECOPD before standard colon adenocarcinoma treatments are applied.

Angelica dahurica and Rheum officinale Facilitated Diabetic Wound Healing by Elevating Vascular Endothelial Growth Factor.

Traditional Chinese medicine (TCM) provides alternative treatment choices for diabetic wounds. The aim of this study was to evaluate the effects of Angelica dahurica and Rheum officinale (ARE) on diabetic wounds and its underlying action mechanism. A total of 36 healthy male Sprague-Dawley rats were randomly divided into three groups: diabetes mellitus (DM) rats treated with ARE (DM-ARE), DM rats treated with 0.9% saline (DM-NS), and non-DM rats treated with 0.9% saline (NDM-NS). DM was induced by intraperitoneal administration of 40 mg/kg of streptozotocin after a 2-week high-fat diet feeding. After excisional skin wounds and treatments, the remaining wound area (RWA) in each group was measured. The RWA in the DM-NS group (69.60% ± 2.35%) was greater than that in the DM-ARE (55.70% ± 1.85%) and NDM-NS groups (52.50% ± 2.77%) on day 6. Besides, the DM-ARE group showed higher vascular endothelial growth factor (VEGF), higher inducible nitric oxide synthase (iNOs), higher [Formula: see text]-smooth muscle actin ([Formula: see text]-SMA), and lower nuclear factor kappa-light-chain-enhancer of activated B cell (NF-[Formula: see text]B) expression in the wound skin tissue. These results showed that treatment with ARE shifted the recovery pattern of diabetic rats to the pattern of nondiabetic rats, indicating that ARE may improve wound healing in diabetic conditions.

Long-Term Medical Resource Consumption between Surgical Clipping and Endovascular Coiling for Aneurysmal Subarachnoid Hemorrhage: A Propensity Score-Matched, Nationwide, Population-Based Cohort Study.

PURPOSE: To estimate long-term medical resource consumption in patients with subarachnoid aneurysmal hemorrhage (SAH) receiving surgical clipping or endovascular coiling. PATIENTS AND METHODS: From Taiwan's National Health Insurance Research Database, we enrolled patients with aneurysmal SAH who received clipping or coiling. After propensity score matching and adjustment for confounders, a generalized linear mixed model was used to determine significant differences in the accumulative hospital stay (days), intensive care unit (ICU) stay, and total medical cost for aneurysmal SAH, as well as possible subsequent surgical complications and recurrence. RESULTS: The matching process yielded a final cohort of 8102 patients (4051 and 4051 in endovascular coil embolization and surgical clipping, respectively) who were eligible for further analysis. The mean accumulative hospital stay significantly differed between coiling (31.2 days) and clipping (46.8 days; p < 0.0001). After the generalized linear model adjustment of gamma distribution with a log link, compared with the surgical clipping procedure, the adjusted odds ratios (aOR; 95% confidence interval [CI]) of the medical cost of accumulative hospital stay for the endovascular coil embolization procedure was 0.63 (0.60, 0.66; p < 0·0001). The mean accumulative ICU stay significantly differed between the coiling and clipping groups (9.4 vs. 14.9 days; p < 0.0001). The aORs (95% CI) of the medical cost of accumulative ICU stay in the endovascular coil embolization group was 0.61 (0.58, 0.64; p < 0.0001). The aOR (95% CI) of the total medical cost of index hospitalization in the endovascular coil embolization group was 0·85 (0.82, 0.87; p < 0.0001). CONCLUSIONS: Medical resource consumption in the coiling group was lower than that in the clipping group.

Long-term survival outcomes and prognostic factors related to ruptured intracranial aneurysms: A comparison of surgical and endovascular options in a propensity score-matched, nationwide population-based cohort study.

BACKGROUND AND PURPOSE: To determine the long-term survival outcomes of and prognostic factors for survival in patients with a ruptured intracranial aneurysm (RIA) who underwent endovascular coil embolization or surgical clipping. METHODS: We selected patients who had received a diagnosis of RIA between January 1, 2011 and December 31, 2017. Propensity score matching was performed, and Cox proportional hazards model curves were plotted to analyze all-cause mortality in patients undergoing different treatments. RESULTS: The matching process yielded a final cohort of 8102 patients (4051 and 4051 in endovascular coil embolization and surgical clipping groups, respectively) who were eligible for inclusion. In multivariate Cox regression analyses, the adjusted hazard ratio (aHR) and 95% confidence interval (CI) for endovascular coil embolization compared with surgical clipping were 0.87 (95% CI, 0.79-0.97). The aHRs for the ages of 65 to 74, 75 to 84, and ≥85 years compared with the ages of 20 to 64 years were 1.82 (95% CI, 1.60-2.07), 3.35 (95% CI, 2.93-3.84), and 6.99 (95% CI, 5.51-8.86), respectively. Surgical clipping; old age; male sex; treatment during 2011 to 2013; presence of diabetes, congestive heart failure, hypertension, chronic kidney disease, or end-stage renal disease; history of stroke or transient ischemic attack; Charlson Comorbidity Index ≥2; attendance of nonacademic hospitals; and low income were significant independent prognostic factors for poor survival. CONCLUSIONS: Compared with surgical clipping, endovascular coil embolization led to more favorable survival outcomes in patients with RIAs.

RIP3 deficiency protects against traumatic brain injury (TBI) through suppressing oxidative stress, inflammation and apoptosis: Dependent on AMPK pathway.

Traumatic brain injury (TBI) is a leading cause of disability and mortality in young adults worldwide. The pathophysiology is not fully understood. Programmed necrosis (necroptosis) is a newly identified mechanism of cell death combining features of both apoptosis and necrosis. Receptor-interacting protein 3 (RIP3) plays an important role in programmed necrosis. However, the effect of RIP3-related pathway in TBI is little to be known. We attempted to explore the significance of RIP3 in regulating TBI in vivo. Significantly, TBI induced over-expression of RIP3 in the hippocampus of mice, as well as RIP1 and phosphorylated mixed lineage kinase domain-like protein (MLKL). Mice after TBI exhibited cognitive dysfunction and activation of glia cells, which were significantly attenuated by RIP3-knockout (KO). Moreover, inflammation and oxidative stress in hippocampus were markedly induced by TBI in wild type (WT) mice. Of note, the reduction of pro-inflammatory cytokines and oxidants was observed in RIP3-deficient mice, which was linked to the blockage of NLR pyrin domain containing 3 (NLRP3)/apoptosis-associated speck-like protein containing a CARD (ASC)/Caspase-1 and kelch-like ECH-associated protein 1 (Keap 1) pathways. Further, TBI induced hippocampus apoptosis, evidenced by the increase of cleaved Caspase-8/-3 and poly (ADP)-ribose polymerase (PARP) in WT mice, whereas being decreased by RIP3-knockout. In addition, RIP3 knockout led to phosphorylation of AMP-activated protein kinase α (AMPKα) in hippocampus of mice after TBI. And of note, the in vitro findings indicated that RIP3-ablation attenuated oxidative stress, inflammation and apoptosis in astrocytes, which was dependent on AMPKα activation. Together, suppressing RIP3 might be served as a therapeutic target against brain injury through inhibiting inflammation, oxidative stress and apoptosis.

NADPH oxidase inhibitor regulates microRNAs with improved outcome after mechanical reperfusion.

BACKGROUND: Inhibition of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) pathway improves the neurological outcome in the transient middle cerebral artery occlusion (tMCAO) animal model. In this study we analyzed the microRNAs profile targeting NOX2 and NOX4 genes and its response to NOX2/4 inhibitor VAS2870 to understand the mechanisms of this protective effect. METHODS: The intraluminal filament tMCAO model was established in hyperglycemic rats (n=106) with 5 hours ischemia followed by 19 hours reperfusion. NOX inhibitor VAS2870 was delivered intravenously before reperfusion. Infarct volume, hemorrhagic transformation, and mortality were determined at 24 hours after cerebral ischemia. MicroRNAs profile targeting NOX2 and NOX4 genes were predicted by microRNA databases and further evaluated by microRNA microarray and quantitative RT-PCR. RESULTS: Ten microRNAs potentially targeting NOX2 and NOX4 genes (including microRNA-29a, microRNA-29c, microRNA-126a, microRNA-132, microRNA-136, microRNA-138, microRNA-139, microRNA-153, microRNA-337, and microRNA-376a) were significantly downregulated in the ischemic hemisphere in the tMCAO group compared with the sham-operated group, as shown by microRNA microarray and quantitative RT-PCR (all p<0.05). Intravenous treatment with NOX inhibitor VAS2870 before reperfusion increased the expression of microRNA-29a, microRNA-29c, microRNA-126a, and microRNA-132 compared with the tMCAO group (all p<0.05). CONCLUSIONS: Several microRNAs potentially targeting NOX2 and NOX4 genes displayed altered levels in hyperglycemic rats with the tMCAO model, suggesting their regulatory roles and targeting potentials for acute ischemic stroke treatment. Targeting specific microRNAs may represent a novel intervention opportunity to improve outcome and reduce hemorrhagic transformation after mechanical reperfusion for acute ischemic stroke.

NADPH oxidase inhibitor improves outcome of mechanical reperfusion by suppressing hemorrhagic transformation.

BACKGROUND: Severe hemorrhagic transformation (HT) after mechanical thrombectomy predicts a poor clinical outcome in acute ischemic stroke. To better understand the mechanism of HT, we investigated the role of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) in HT after reperfusion during acute stroke and whether NOX2/4 inhibitor VAS2870 reduces reperfusion-induced HT after mechanical recanalization. METHODS: A model of reperfusion-induced HT was established in rats (n=182) with hyperglycemic challenge and 5 h middle cerebral artery occlusion followed by 19 h reperfusion. NOX inhibitor VAS2870 was delivered intravenously 30 min before reperfusion. Infarct volume, brain water content, HT, neurological score, mortality rate, blood-brain barrier (BBB) damage, neuronal apoptosis, and reactive oxygen species were determined at 24 h after cerebral ischemia. The expressions of NOX1, NOX2, NOX4, and BBB-associated proteins were measured. RESULTS: NOX2 and NOX4 upregulation and severe HT were observed in hyperglycemic rats after cerebral ischemia/reperfusion. VAS2870 suppressed oxidative stress, neuronal apoptosis, and NOX2/4 upregulation in the ischemic hemisphere. VAS2870 reduced infarct volume (17.2±5.3% vs 37.4±9.2%, p<0.01) and the frequency of reperfusion-induced parenchymal hematoma (29.7% vs 59.5%, p<0.05) at 24 h after ischemia compared with the ischemia/reperfusion group. VAS2870 attenuated brain edema and reduced reperfusion-induced BBB breakdown, resulting in improved neurological outcome (neurological deficit score 1.43±0.50 vs 2.43±0.93, p<0.001) and reduced mortality (11.9% vs 64.1%, p<0.001). CONCLUSIONS: NOX2 and NOX4 may mediate HT in rats with large vessel stroke after mechanical reperfusion. Infusion of NOX inhibitor VAS2870 before mechanical thrombectomy represents a novel adjunctive therapeutic strategy to prevent reperfusion-induced HT and improve outcome of acute stroke treatment.

Targeting brain microvascular endothelial cells: a therapeutic approach to neuroprotection against stroke.

Brain microvascular endothelial cells form the interface between nervous tissue and circulating blood, and regulate central nervous system homeostasis. Brain microvascular endothelial cells differ from peripheral endothelial cells with regards expression of specific ion transporters and receptors, and contain fewer fenestrations and pinocytotic vesicles. Brain microvascular endothelial cells also synthesize several factors that influence blood vessel function. This review describes the morphological characteristics and functions of brain microvascular endothelial cells, and summarizes current knowledge regarding changes in brain microvascular endothelial cells during stroke progression and therapies. Future studies should focus on identifying mechanisms underlying such changes and developing possible neuroprotective therapeutic interventions.

[Imaging and clinical characteristics of patients with coronary artery stenosis located proximally to myocardial bridging].

OBJECTIVE: To explore the imaging and clinical characteristics and related risk factors of patients with coronary artery stenosis located proximally to myocardial bridging. METHODS: This study enrolled 603 patients with angiography evidenced myocardial bridging-mural coronary artery between May 2004 to May 2009. Angiographic and clinic data were collected according to uniform protocol and standard questionnaires were used to obtain patients' demographic and clinical information. Univariate and multivariate analysis were performed to explore related risk factors. RESULTS: Chest pain was present in 247 cases (41.0%). Dynamic ST-T changes were found in 229 cases (38%). A total of 644 myocardial bridging-mural coronary arteries were detected including 382 (62.4%) segments located proximally to myocardial bridging. Diastolic vessel diameters in the myocardial bridging segment were significantly smaller than reference segments (all P < 0.01). Stepwise multiple regression analysis suggested that vascular bifurcation lesions, the degree of narrowing and the number of diseased coronary vessels of non- myocardial bridging-mural coronary arteries, age, LDL-C/HDL-C, male gender, diabetes, and systolic narrow rate of myocardial bridging-mural coronary arteries were positively related with the narrowing degree of the first coronary artery stenosis located proximally to myocardial bridging (P < 0.05 or P < 0.01). Vascular bifurcation lesions, the degree of narrowing and the number of diseased coronary vessels of non- myocardial bridging-mural coronary arteries, age, LDL-C/HDL-C, male, diabetes and dyslipidemia were positively related with the narrowing degree of the most severe coronary artery stenosis located proximally to myocardial bridging (P < 0.05 or P < 0.01). CONCLUSIONS: Myocardial ischemia is common in patients with myocardial bridging and the artery segments located proximally to myocardial bridging are prone to stenosis. Systolic narrow rate of myocardial bridging-mural coronary arteries is one of major determinants of coronary artery stenosis located proximally to myocardial bridging. Whereas the other coronary heart disease risk factors are likely to play more important roles.

[Clinical predictive factors of coronary artery stenosis located distally to myocardial bridging].

OBJECTIVE: To explore the clinical predictive factors of coronary artery stenosis located distally to myocardial bridging (MB). METHODS: A total of 603 patients with MB-mural coronary artery (MB-MCA) diagnosed by angiography initially were enrolled during May 2004 to May 2009. Their angiographic and clinical data were collected according to an uniform protocol. And standard questionnaires were used to acquire demographic information and clinical examinations. Univariate and multivariate analysis were performed to explore the related clinical predictive factors. RESULTS: A total of 644 MB-MCAs were detected. Diastolic vessel diameters in MCAs were significantly smaller than those in reference segments ( (2.29 ± 0.39) vs (2.48 ± 0.40) mm, P < 0.001) . Lesions located distally to MB detected in 36 patients were significantly fewer than those proximally to MB in 382 patients (5.9% vs 62.4%, P < 0.001) . Univariate analysis suggested that the narrowing degree of vessel located proximally to MB, the narrowing degree and the number of diseased coronary vessels of non-MB-MCAs and course of hypertension were positively correlated with the narrowing degree of vessel located distally to MB (all P < 0.05) . Multivariate Logistic regression analysis suggested that the number of cigarettes per day, the narrowing degree of diseased coronary vessels of non-MB-MCAs, the narrowing degree of vessel located proximally to MB and diastolic narrow rate of MCA were positively correlated with the occurrence of coronary artery stenosis located distally to MB (all P < 0.05) . Their standardized coefficients (ß) were 0.763, 0.727, 0.420 and 0.403 respectively. And the corresponding Exp (ß) were 2.146 (1.089-4.229) , 2.070 (1.371-3.125) , 1.521 (1.050-2.204) and 1.496 (1.094-2.045) . CONCLUSION: The number of cigarettes per day, the narrowing degree of diseased coronary vessels of non-MB-MCAs, the narrowing degree of vessel located proximally to MB and diastolic narrowing rate of MCA are likely to be important clinical predictive factors of coronary artery stenosis located distally to MB.

Effective synthetic peptide vaccine for foot-and-mouth disease in swine.

We have designed a peptide-based vaccine for foot-and-mouth disease (FMD) effective in swine. The peptide immunogen has a G-H loop domain from the VP1 capsid protein of foot-and-mouth disease virus (FMDV) and a novel promiscuous T helper (Th) site for broad immunogenicity in multiple species. The G-H loop VP1 site was optimised for cross-reactivity to FMDV by the inclusion into the peptide of cyclic constraint and adjoining sequences. The incorporation of consensus residues into the hypervariable positions of the VP1 site provided for broad immunogenicity. The vaccine protected 20 out of 21 immunised pigs from infectious challenge by FMDV O1 Taiwan using peptide doses as low as 12.5 microg, and a mild adjuvant that caused no lesions. A safe chemically-defined product would have considerable advantages for vaccination against FMD.