Ta Liang Chen

Resveratrol Protects against Oxidized LDL-Induced Breakage of the Blood-Brain Barrier by Lessening Disruption of Tight Junctions and Apoptotic Insults to Mouse Cerebrovascular Endothelial Cells

Cerebrovascular endothelial cells (CEC) comprise the blood-brain barrier (BBB). In a previous study, we showed that oxidized LDL (oxLDL) can induce apoptosis of mouse CEC. Resveratrol possesses chemopreventive potential. This study aimed to evaluate the effects of resveratrol on oxLDL-induced insults to mouse CEC and its possible mechanisms. Exposure of mouse CEC to 200 μmol/L oxLDL for 1 h did not cause cell death but significantly altered the permeability and transendothelial electrical resistance of the cell monolayer. However, resveratrol completely normalized such injury. As for the mechanisms, resveratrol completely protected oxLDL-induced disruption of F-actin and microtubule cytoskeletons as well as occludin and zona occludens-1 (ZO-1) tight junctions. The oxLDL-induced decreases in the mitochondrial membrane potential and intracellular ATP levels were normalized by resveratrol. Exposure of mouse CEC to 200 μmol/L oxLDL for 24 h elevated oxidative stress and simultaneously induced cell apoptosis. However, resveratrol partially protected against oxLDL-induced CEC apoptosis. The oxLDL-induced alterations in levels of Bcl-2, Bax, and cytochrome c were completely normalized by resveratrol. Consequently, resveratrol partially decreased oxLDL-induced activation of caspases-9 and -3. Therefore, in this study, we show that resveratrol can protect against oxLDL-induced damage of the BBB through protecting disruption of the tight junction structure and apoptotic insults to CEC.

Risk of epilepsy after traumatic brain injury: a retrospective population-based cohort study

Objective To investigate the associated risk of epilepsy after traumatic brain injury (TBI) in a population-based retrospective cohort study. Methods Using Taiwans National Health Insurance Research Database of reimbursement claims, we conducted a retrospective cohort study of 19u2005336 TBI patients and 540u2005322 non-TBI participants aged ≥15u2005years as reference group. Data on newly developed epilepsy after TBI with 5–8u2005years’ follow-up during 2000 to 2008 were collected. HRs and 95% CIs for the risk of epilepsy associated with TBI were analysed with multivariate Cox proportional hazards regressions. Results Compared with the non-TBI cohort, the adjusted HRs of developing epilepsy among TBI patients with skull fracture, severe or mild brain injury were 10.6 (95% CI 7.14 to 15.8), 5.05 (95% CI 4.40 to 5.79) and 3.02 (95% CI 2.42 to 3.77), respectively. During follow-up, men exhibited higher risks of post-TBI epilepsy. Patients who had mixed types of cerebral haemorrhage were at the highest risk of epilepsy compared with the non-TBI cohort (HR 7.83, 95% CI 4.69 to 13.0). The risk of post-TBI epilepsy was highest within the first year after TBI (HR 38.2, 95% CI 21.7 to 67.0). Conclusions The risk of epilepsy after TBI varied by patient gender, age, latent interval and complexity of TBI. Integrated care for early identification and treatment of post-trauma epilepsy were crucial for TBI patients.

Therapeutic concentrations of propofol protects mouse macrophages from nitric oxide-induced cell death and apoptosis.

PurposeTo evaluate the potential effect of a clinically relevant concentration of propofol (PPF) on cell viability and nitric oxide-induced macrophage apoptosis.MethodsMouse macrophages (cell line Raw 264.7) were cultured and incubated with a nitric oxide donor sodium nitroprusside (SNP), PPF, and a combination of PPF and SNP for one, six and 24 hr. Cell viability was determined by the colorimetric 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay. Apoptotic cells were determined by analyzing the percentages of sub-G1 phase in macrophages. The amounts of nitric oxide were assayed.ResultsThe amounts of nitric oxide in macrophages were increased with time when incubated with SNP (P < 0.05). Simultaneously SNP caused cell death of macrophages in a concentration-and time-dependent manner (P < 0.05). PPFper se did not alter the amount of basal and SNP-provided nitric oxide in macrophages. A therapeutic concentration of PPF (30 μM) exhibited no cytotoxicity. After incubation with SNP for one and six hours, PPF could completely or partially block nitric oxide-induced cell death, respectively (P < 0.05).Administration of SNP to macrophages resulted in a time-dependent pattern of increase of apoptotic cells (P < 0.05). Similar to the results of the cell viability analyses, PPF was able to protect macrophages from nitric oxide-induced apoptosis in one and six hour-treated groups (P < 0.05) but not in the 24 hr treated group.ConclusionPPF at a therapeutic concentration, can protect mouse macrophagesin vitro from nitric oxide-induced cell apoptosis as well as cell death.RésuméObjectifÉvaluer l’effet potentiel d’une concentration thérapeutique de propofol (PPF) sur la viabilité cellulaire et l’apoptose des macrophages induite par l’oxyde nitrique.MéthodeDes macrophages de souris (souche cellulaire 264,7) ont été mis en culture et incubés avec un donneur d’oxyde nitrique, le nitroprussiate de sodium (NPS), du PPF et une combinaison de PPF et de NPS pendant une, six et 24 h. La viabilité cellulaire a été déterminée par une analyse colorimétrique du bromure 3-(4,5-diméthylthiazol-2-yl)-2, 5-diphényltétrazolium. Les cellules apoptotiques ont été déterminées en analysant les pourcentages de phase sous-G1 dans les macrophages. Les quantités d’oxyde nitrique ont été analysées.RésultatsLa quantité d’oxyde nitrique dans les macrophages a augmenté avec le temps dans le cas de l’incubation avec le NPS (P < 0,05). Simultanément, le NPS a causé la mort cellulaire des macrophages en fonction du temps et de la concentration (P < 0,05). Le PPF par luimême n’a pas modifié la quantité d’oxyde nitrique de base ou fournie par le NPS dans les macrophages. Une concentration thérapeutique de PPF (30 μM) n’a révélé aucune toxicité. Après l’incubation avec le NPS pendant une et six heures, le PPF a pu arrêter complètement ou partiellement la mort cellulaire induite par l’oxyde nitrique, respectivement (P < 0,05).L’administration de NPS aux macrophages a entraîné l’augmentation du nombre de cellules apoptotiques selon un modèle dépendant du temps (P < 0,05). Le PPF a pu protéger les macrophages de l’apoptose induite par l’oxyde nitrique dans les groupes traités pendant une et six heures (P < 0,05) mais non dans le groupe de 24 h.ConclusionLe PPF en concentration thérapeutique peut protéger les macrophages de souris in vitro de l’apoptose cellulaire aussi bien que de la mort cellulaire induites par l’oxyde nitrique.

Resveratrol attenuates oxidized LDL-evoked Lox-1 signaling and consequently protects against apoptotic insults to cerebrovascular endothelial cells

Cerebrovascular endothelial cells (CECs) are crucial components of the blood—brain barrier. Our previous study showed that oxidized low-density lipoprotein (oxLDL) induces apoptosis of CECs. This study was designed to further evaluate the effects of resveratrol on oxLDL-induced CEC insults and its possible molecular mechanisms. Resveratrol decreased the oxidation of LDL into oxLDL. Additionally, the oxLDL-caused oxidative stress and cell damage were attenuated by resveratrol. Exposure of CECs to oxLDL induced cell shrinkage, DNA fragmentation, and cell apoptosis, but resveratrol defended against such injuries. Application of Lox-1 small interference (si)RNA into CECs reduced the translation of this membrane receptor, and simultaneously increased resveratrol protection from oxLDL-induced cell apoptosis. By comparison, overexpression of Lox-1 attenuated resveratrol protection. Resveratrol inhibited oxLDL-induced Lox-1 mRNA and protein expressions. Both resveratrol and Lox-1 siRNA decreased oxLDL-enhanced translocation of proapoptotic Bcl-2-associated X protein (Bax) from the cytoplasm to mitochondria. Sequentially, oxLDL-induced alterations in the mitochondrial membrane potential, cytochrome c release, and activities of caspases-9, -3, and -6 were decreased by resveratrol. Pretreatment with Z-VEID-FMK (benzyloxycarbonyl-Leu-Glu-His-Asp-fluoromethyl ketone) synergistically promoted resveratrols protection against DNA fragmentation and cell apoptosis. Therefore, this study shows that resveratrol can protect CECs from oxLDL-induced apoptotic insults via downregulating Lox-1-mediated activation of the Bax-mitochondria—cytochrome c—caspase protease pathway.

Lipopolysaccharide induces apoptotic insults to human alveolar epithelial A549 cells through reactive oxygen species-mediated activation of an intrinsic mitochondrion-dependent pathway

Alveolar type II epithelial cells can regulate immune responses to sepsis-induced acute lung injury. Lipopolysaccharide (LPS), an outer membrane component of Gram-negative bacteria, can cause septic shock. This study was designed to evaluate the cytotoxic effects of LPS on human alveolar epithelial A549 cells and its possible molecular mechanisms. Exposure of A549 cells to LPS decreased cell viability in concentration- and time-dependent manners. In parallel, LPS concentration- and time-dependently induced apoptosis of A549 cells. Meanwhile, LPS only at a high concentration of 10xa0μg/ml caused mildly necrotic insults to A549 cells. In terms of the mechanism, exposure of A549 cells to LPS increased the levels of cellular nitric oxide and reactive oxygen species (ROS). Pretreatment with N-acetylcysteine (NAC), an antioxidant, significantly lowered LPS-caused enhancement of intracellular ROS in A549 cells and simultaneously attenuated the apoptotic insults. Sequentially, treatment of A549 cells with LPS caused significant decreases in the mitochondrial membrane potential and biosynthesis of adenosine triphosphate. In succession, LPS triggered the release of cytochrome c from the mitochondria to the cytoplasm. Activities of caspase-9 and caspase-6 were subsequently augmented following LPS administration. Consequently, exposure of A549 cells induced DNA fragmentation in a time-dependent manner. Pretreatment of A549 cells with NAC significantly ameliorated LPS-caused alterations in caspase-9 activation and DNA damage. Therefore, this study shows that LPS specifically induces apoptotic insults to human alveolar epithelial cells through ROS-mediated activation of the intrinsic mitochondrion–cytochrome c-caspase protease mechanism.

Adverse outcomes after noncardiac surgery in patients with diabetes: a nationwide population-based retrospective cohort study.

OBJECTIVE To investigate whether diabetes affects perioperative complications or mortality and to gauge its impact on medical expenditures for noncardiac surgeries. RESEARCH DESIGN AND METHODS With the use of reimbursement claims from the Taiwan National Health Insurance system, we performed a population-based cohort study of patients with and without diabetes undergoing noncardiac surgeries. Outcomes of postoperative complications, mortality, hospital stay, and medical expenditures were compared between patients with and without diabetes. RESULTS Diabetes increased 30-day postoperative mortality (odds ratio 1.84 [95% CI 1.46–2.32]), particularly among patients with type 1 diabetes or uncontrolled diabetes and patients with preoperative diabetes-related comorbidities, such as eye involvement, peripheral circulatory disorders, ketoacidosis, renal manifestations, and coma. Compared with nondiabetic control patients, coexisting medical conditions, such as renal dialysis (5.17 [3.68–7.28]), liver cirrhosis (3.59 [2.19–5.88]), stroke (2.87 [1.95–4.22]), mental disorders (2.35 [1.71–3.24]), ischemic heart disease (2.08 [1.45–2.99]), chronic obstructive pulmonary disease (1.96 [1.29–2.97]), and hyperlipidemia (1.94 [1.01–3.76]) were associated with mortality for patients with diabetes undergoing noncardiac surgery. Patients with diabetes faced a higher risk of postoperative acute renal failure (3.59 [2.88–4.48]) and acute myocardial infarction (3.65 [2.43–5.49]). Furthermore, diabetes was associated with prolonged hospital stay (2.30 [2.16–2.44]) and increased medical expenditures (1.32 [1.25–1.40]). CONCLUSIONS Diabetes increases postoperative 30-day mortality, complications, and medical expenditures in patients undergoing in-hospital noncardiac surgeries.

High risk of gastrointestinal hemorrhage in patients with epilepsy: a nationwide cohort study.

OBJECTIVEnTo examine the association between epilepsy and gastrointestinal hemorrhage.nnnPATIENTS AND METHODSnWe conducted a nationwide retrospective cohort study by using data from Taiwans National Health Insurance Research Database. Patients 20 years and older newly diagnosed as having epilepsy and nonepileptic adults were identified between January 1, 2000, and December 31, 2003, and were observed through December 31, 2008. Cox proportional hazards models were performed to calculate adjusted hazard ratios (HRs) and 95% CIs of gastrointestinal hemorrhage associated with epilepsy.nnnRESULTSnCompared with the nonepileptic group (n=449,541), epileptic patients (n=1412) had a higher incidence of gastrointestinal hemorrhage (13.4 vs 2.9 per 1000 person-years), with an HR of 2.97 (95% CI, 2.49-3.53). The HRs of gastrointestinal hemorrhage for patients with generalized epilepsy, inpatient care, emergency care, and frequent outpatient visits for epilepsy were 3.50 (95% CI, 2.59-4.72), 3.96 (95% CI, 2.85-5.50), 4.35 (95% CI, 3.15-6.01), and 4.96 (95% CI, 3.97-6.21), respectively. Risks were significantly higher in epileptic patients with mental disorders (HR, 3.20; 95% CI, 2.55-4.01), aged 70 years and older (HR, 4.08; 95% CI, 2.89-5.77), and in the first year after epilepsy (HR, 4.81; 95%, CI, 3.14-7.34).nnnCONCLUSIONnEpilepsy is an independent determinant for gastrointestinal hemorrhage in a chronological and severity-dependent pattern. We urge the development of an adequate surveillance policy and strategy for the early prevention of gastrointestinal hemorrhage in epileptic patients.

Risk and outcomes for traumatic brain injury in patients with mental disorders

Objective To investigate the risk of traumatic brain injury (TBI) and post-injury mortality in patients with mental disorders. Background Patients with mental disorders are at higher risk of injuries. However, the association between mental disorders and TBI is still not understood. We conducted case-control studies to investigate whether people with pre-existing mental disorders are at higher risk of TBI and post-injury mortality. Methods Using reimbursement claims, we analysed 16u2008635 patients with TBI and 66u2008540 controls with adjustment of covariates to study the association of mental disorders and TBI. A nested case-control study was also conducted to analyse contributory factors for post-injury mortality. Results People with mental disorders were at increased risk of TBI (odds ratio (OR) 1.94, 95% confidence interval (CI) 1.86 to 2.02). Men, older age, living in highly urbanised areas and patients on low income had a higher risk of TBI and post-injury mortality. Psychiatric medication intensity and frequency of psychiatric visits was significantly correlated with TBI in a severity dependent relationship (p for trend <0.0001). Patients receiving advanced psychiatric healthcare had an increased risk of TBI (OR 2.98, 95% CI 2.67 to 3.33) and post-injury mortality (OR 1.92, 95% CI 1.34 to 2.77). A history of receiving psychiatric related outpatient care (OR 1.77, 95% CI 1.70 to 1.85), hospitalisation (OR 3.21, 95% CI 2.79 to 3.70) or emergency visits (OR 3.53, 95% CI 3.15 to 3.94) were highly associated with subsequent TBI. Conclusions Patients with mental disorders have an increased risk of TBI. Intensity of psychiatric medication is associated with increased post-injury mortality. Special attention to prevent TBI among this disabled population is mandatory.

Stroke Risk and Outcomes in Patients With Traumatic Brain Injury: 2 Nationwide Studies

OBJECTIVEnTo investigate whether patients with traumatic brain injury (TBI) have an increased risk of stroke or poststroke mortality.nnnPARTICIPANTS AND METHODSnUsing Taiwans National Health Insurance Research Database, we conducted a retrospective cohort study of 30,165 patients with new TBI and 120,660 persons without TBI between January 1, 2000, and December 31, 2004. The risk of stroke was compared between 2 cohorts through December 31, 2008. To investigate the association between in-hospital mortality after stroke and history of TBI, we conducted a case-control study of 7751 patients with newly diagnosed stroke between January 1, 2005, and December 31, 2008.nnnRESULTSnThe TBI cohort had an increased stroke risk (hazard ratio [HR], 1.98; 95% CI, 1.86-2.11). Among patients with stroke, those with a history of TBI had a higher risk of poststroke mortality compared with those without TBI (odds ratio, 1.57; 95% CI, 1.13-2.19). In the TBI cohort, factors associated with stroke were history of TBI hospitalization (HR, 3.14; 95% CI, 2.77-3.56), emergency care for TBI (HR, 3.37; 95% CI, 2.88-3.95), brain hemorrhage (HR, 2.69; 95% CI, 2.43-2.99), skull fracture (HR, 3.00; 95% CI, 2.42-3.71), low income (HR, 2.65; 95% CI, 2.16-3.25), and high medical expenditure for TBI care (HR, 2.26; 95% CI, 2.09-2.43). The severity of TBI was also correlated with poststroke mortality.nnnCONCLUSIONSnTraumatic brain injury was associated with risk of stroke and poststroke mortality. The relationship between TBI and poststroke mortality does not seem to transcend all age groups. This research shows the importance of prevention, early recognition, and treatment of stroke in this vulnerable population.

Postoperative adverse outcomes in surgical patients with epilepsy: A population-based study

Purpose:u2002 People with epilepsy are more likely than healthy people to experience comorbidities and complications in various medical situations. However, the prevalence of postoperative complications, mortality, and use of medical resources in surgical patients with epilepsy has not been studied. The purpose of this study is to examine whether epilepsy is an independent risk factor for postoperative adverse outcomes of patients receiving major surgery.