Tuning the Alkyl Chain of Nitrilotriacetamide for Selectively Extracting Trivalent Am over Eu Ions.

The successful management and safe disposal of high-level nuclear waste necessitate the efficient separation of actinides (An) from lanthanides (Ln), which has emerged as a crucial prerequisite. Mixed donor ligands incorporating both soft and hard donor atoms have garnered interest in the field of An/Ln separation and purification. One such example is nitrilotriacetamide (NTAamide) derivatives, which have demonstrated selectivity in extracting minor actinide Am(III) ions over Eu(III) ions. Nevertheless, the Am/Eu complexation behavior and selectivity remain underexplored. In the work, a comprehensive and systematic investigation has been conducted for [M(RL)(NO3)3] complexes (M = Am and Eu) utilizing relativistic density functional theory. The NTAamide ligand (RL) is substituted with various alkyl groups, namely, methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl. Thermodynamic calculations show that the alkyl chain length in NTAamide is capable of tuning the separation selectivity of Am and Eu. Moreover, the differences in calculated free energies between Am and Eu complexes are more negative for R = Bu-Oct than Me-Pr. This indicates that elongation of the alkyl chain can increase the efficiency of selective separation of Am(III) from Eu(III). Based on the quantum theory of atoms in molecules and charge decomposition analyses, it has been observed that the strength of Am-RL bonds is higher than that of Eu-RL bonds. This disparity is attributed to a greater degree of covalency in Am-RL bonds and a higher level of charge transfer from ligands to Am within complexes containing these bonds. Energies of occupied orbitals with the central N character are recognized overall lower for [Am(OctL)(NO3)3] than for [Eu(OctL)(NO3)3], indicative of stronger complexation stability of the former. These results offer valuable insights into the separation mechanism of NTAamide ligands, which can help guide the development of more powerful agents for An/Ln separation in future applications.

A New Concept of Radiation Detection Based on a Fluorochromic and Piezochromic Nanocluster.

Developing materials that possess colorimetric responses to external stimuli is a promising strategy for addressing the current challenges in radiation dosimetry. Currently, colorimetric ionizing-radiation-responsive materials remain underexplored, and those with multistimuli response are rare. Herein, the integration of thorium cation and photoresponsive terpyridine carboxylate ligand gives rise to a thorium nanocluster, Th-101, which displays the second case of fluorochromic response and unprecedented piezochromic behavior among all actinide materials. The emission color of Th-101 exhibits a gradual transition from blue to cyan to green upon irradiation with accumulated dose, which renders colorimetric dosimetry of ionizing radiation based on a red-green-blue (RGB) concept. Further fabricating Th-101 into a custom-built optoelectronic device allows for on-site quantification of radiation dose with merits of ease of operation, rapid readout, and cost-effectiveness.

Uranium-Doped Zinc, Copper, and Nickel Oxides for Enhanced Catalytic Conversion of Furfural to Furfuryl Alcohol: A Relativistic DFT Study.

Transition metal oxides (TMOs) and actinide ones (AnOs) have been widely applied in catalytic reactions due to their excellent physicochemical properties. However, the reaction pathway and mechanism, especially involving TM-An heterometallic centers, remain underexplored. In this respect, relativistic density functional theory (DFT) was used to examine uranium-doped zinc, copper, and nickel oxides for their catalytic activity toward the conversion of furfural to furfuryl alcohol. A comparison was made with their undoped TMOs. It was found that the three TMOs were capable of catalyzing the reaction, where the free energies of adsorption, hydrogenation, and desorption fell between -33.93 and 45.00 kJ/mol. The uranium doping extremely strengthened the adsorption of CuO-U and NiO-U toward furfural, making hydrogenation or desorption much harder. Intriguingly, ZnO-U showed the best catalytic performance among all six catalyst candidates, as its three reaction energies were very small (-10.54-8.12 kJ/mol). The reaction process and mechanism were further addressed in terms of the geometrical, bonding, charge, and electronic properties.

Why do outcomes of CABG care vary between urban and rural areas in Taiwan? A perspective from quality of care.

OBJECTIVE: This study explores the association between coronary artery bypass surgery (CABG) patients' residence and quality of care in terms of 30-day mortality. DESIGN: A retrospective, multilevel study design was conducted using claims data from Taiwan's Universal Health Insurance Scheme. Hospital and surgeon's CABG operation volume, risk-adjusted surgical site infection rate and risk-adjusted 30-day mortality rate in the previous year were adopted as performance indicators, and the level of quality was evaluated via K-means clustering algorithm. Baron and Kenny's procedures for mediation effect were conducted. SETTING: Hospitals in Taiwan. PARTICIPANTS: Patients who underwent CABG surgeries from 1 January 2008 to 30 September 2011 were identified in this study. However, patients who were under the age of 18 years or above the age of 85(n = 164), with missing data for gender (n = 3) or received surgeries from surgeons who never performed any CABG surgeries (n = 27), were excluded. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Thirty-day mortality. RESULTS: There were 9973 CABG surgeries included in this study. Patients who lived in urban areas received better quality of care (28.90 vs. 21.57%) and enjoyed better outcome (4.33 vs. 6.84%). After the procedure of mediation effect testing, the results showed that the relationship between patient residence's urbanization level and 30-day mortality was partially mediated by patterns of quality of care. CONCLUSIONS: The rural-dwelling CABG patients are less likely to approach the better performing healthcare providers, and this tendency indirectly affects their treatment outcomes. Policymakers still need to develop strategies to ensure better equity in access to quality health care.

Do low-income coronary artery bypass surgery patients have equal opportunity to access excellent quality of care and enjoy good outcome in Taiwan?

BACKGROUND: Equity is an important issue in the healthcare research field. Many studies have focused on the relationship between patient characteristics and outcomes of care. These studies, however, have seldom examined whether patients' characteristics affected their access to quality healthcare, which further affected the care outcome. The purposes of this study were to determine whether low-income coronary artery bypass surgery (CABG) patients receive healthcare services with poorer quality, and if such differences in treatment result in different outcomes. METHODS: A retrospective multilevel study design was conducted using claims data from Taiwan's universal health insurance scheme for 2005-2008. Patients who underwent their CABG surgery between 2006 and 2008 were included in this study. CABG patients who were under 18 years of age or had unknown gender or insured classifications were excluded. Hospital and surgeon's performance indicators in the previous one year were used to evaluate the level of quality via k-means clustering algorithm. Baron and Kenny's procedures for mediation effect were conducted to explore the relationship among patient's income, quality of CABG care, and inpatient mortality. RESULTS: A total of 10,320 patients were included in the study. The results showed that 5.65% of the low-income patients received excellent quality of care, which was lower than that of patients not in the low-income group (5.65% vs.11.48%). The mortality rate of low-income patients (12.10%) was also higher than patients not in the low-income group (5.25%). Also, the mortality of patients who received excellent care was half as low as patients receiving non-excellent care (2.63% vs. 5.68%). Finally, after the procedure of mediation effect testing, the results showed that the relationship between patient income level and CABG mortality was partially mediated by patterns of quality of care. CONCLUSIONS: The results of the current study implied that worse outcome in low-income CABG patients might be associated with poorer quality of received services. Health authorities should pay attention to this issue, and propose appropriate solutions.

Is it possible to identify cases of coronary artery bypass graft postoperative surgical site infection accurately from claims data?

BACKGROUND: Claims data has usually been used in recent studies to identify cases of healthcare-associated infection. However, several studies have indicated that the ICD-9-CM codes might be inappropriate for identifying such cases from claims data; therefore, several researchers developed alternative identification models to correctly identify more cases from claims data. The purpose of this study was to investigate three common approaches to develop alternative models for the identification of cases of coronary artery bypass graft (CABG) surgical site infection, and to compare the performance between these models and the ICD-9-CM model. METHODS: The 2005-2008 National Health Insurance claims data and healthcare-associated infection surveillance data from two medical centers were used in this study for model development and model verification. In addition to the use of ICD-9-CM codes, this study also used classification algorithms, a multivariable regression model, and a decision tree model in the development of alternative identification models. In the classification algorithms, we defined three levels (strict, moderate, and loose) of the criteria in terms of their strictness. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were used to evaluate the performance of each model. RESULTS: The ICD-9-CM-based model showed good specificity and negative predictive value, but sensitivity and positive predictive value were poor. Performances of the other models were varied, except for negative predictive value. Among the models, the performance of the decision tree model was excellent, especially in terms of positive predictive value. CONCLUSION: The accuracy of identification of cases of CABG surgical site infection is an important issue in claims data. Use of the decision tree model to identify such cases can improve the accuracy of patient-level outcome research. This model should be considered when performing future research using claims data.

The coupling of graphene, graphitic carbon nitride and cellulose to fabricate zinc oxide-based sensors and their enhanced activity towards air pollutant nitrogen dioxide.

It is desirable but challenging to sense toxic nitrogen dioxide (NO2) for it has become one of the most prominent air pollutants. Zinc oxide-based gas sensors are known to detect NO2 gas efficiently, however, the sensing mechanism and involved intermediates structures remain underexplored. In the work, a series of sensitive materials, including zinc oxide (ZnO) and its composites ZnO/X [X = Cel (cellulose), CN (g-C3N4) and Gr (graphene)] have been comprehensively examined by density functional theory. It is found that ZnO favors adsorbing NO2 over ambient O2, and produces nitrate intermediates; and H2O is chemically held by zinc oxide, in line with the non-negligible impact of humidity on the sensitivity. Of the formed composites, ZnO/Gr exhibits the best NO2 gas-sensing performance, which is proved by the calculated thermodynamics and geometrical/electronic structures of reactants, intermediates and products. The interfacial interaction has been elaborated on for composites (ZnO/X) as well as their complexes (ZnO- and ZnO/X-adsorbates). The current study well explains experimental findings and opens up a way to design and unearth novel NO2 sensing materials.

Integrated therapeutic plasma exchange and traditional Chinese medicine treatment in a patient with severe COVID-19: A case report.

This report presents the case of a 59-year-old man with severe COVID-19 that gradually progressed to cytokine release syndrome and then acute respiratory distress syndrome; he was successfully treated via integration of therapeutic plasma exchange and traditional Chinese medicine. The patient initially presented with a sore throat, severe muscle aches, productive cough and fever. On the worsening of symptoms, remdesivir was administered. However, as the symptoms continued to worsen and a cytokine release syndrome was suspected, oxygen was provided through a high-flow nasal cannula (50 L/min) and therapeutic plasma exchange was performed to prevent worsening of the acute respiratory distress syndrome. On the same day, a course of traditional Chinese medicine was introduced in consultation with the infectious house staff. The patient's symptoms gradually improved; the levels of C-reactive protein and D-dimers reduced, and the patient was weaned to a simple oxygen mask and eventually to room air. This is the first reported case of the integration of these treatments. Together, they prevented the patient from requiring intubation, played a role in cytokine management, and also improved the clinical symptoms, including productive purulent sputum, cough, frequent stool passage and intermittent fever, with no adverse effects. As a result, the patient was discharged within two weeks of the integration of these treatments. Therefore, the integration of therapeutic plasma exchange and traditional Chinese medicine is an effective therapy for patients with severe COVID-19.

Prodigiosin inhibits gp91(phox) and iNOS expression to protect mice against the oxidative/nitrosative brain injury induced by hypoxia-ischemia.

This study aimed to explore the mechanisms by which prodigiosin protects against hypoxia-induced oxidative/nitrosative brain injury induced by middle cerebral artery occlusion/reperfusion (MCAo/r) injury in mice. Hypoxia in vitro was modeled using oxygen-glucose deprivation (OGD) followed by reoxygenation of BV-2 microglial cells. Our results showed that treatment of mice that have undergone MCAo/r injury with prodigiosin (10 and 100µg/kg, i.v.) at 1h after hypoxia ameliorated MCAo/r-induced oxidative/nitrosative stress, brain infarction, and neurological deficits in the mice, and enhanced their survival rate. MCAo/r induced a remarkable production in the mouse brains of reactive oxygen species (ROS) and a significant increase in protein nitrosylation; this primarily resulted from enhanced expression of NADPH oxidase 2 (gp91(phox)), inducible nitric oxide synthase (iNOS), and the infiltration of CD11b leukocytes due to breakdown of blood-brain barrier (BBB) by activation of nuclear factor-kappa B (NF-κB). All these changes were significantly diminished by prodigiosin. In BV-2 cells, OGD induced ROS and nitric oxide production by up-regulating gp91(phox) and iNOS via activation of the NF-κB pathway, and these changes were suppressed by prodigiosin. In conclusion, our results indicate that prodigiosin reduces gp91(phox) and iNOS expression possibly by impairing NF-κB activation. This compromises the activation of microglial and/or inflammatory cells, which then, in turn, mediates prodigiosin's protective effect in the MCAo/r mice.

Experimental and first-principle computational exploration on biomass cellulose/magnesium hydroxide composite: Local structure, interfacial interaction and antibacterial property.

The specification of the local structure and clarification of interfacial interactions of biomass composites is of tremendous significance in synthesizing novel materials and advancing their performance in various demanding applications. However, it remains challenging due to the limitations of experimental techniques, particularly for the manner that biomass composites commonly have hydrogen bonds involved in the vicinity of active sites and interfaces. Herein, the cellulose/Mg(OH)2 nanocomposite has been synthesized via a simple hydrothermal approach and examined by density functional theory (DFT) calculations. The composite exhibits a layered morphology; Mg(OH)2 flakes are around 50 nm in size and well-dispersed. They either anchor onto the cellulose surface or intercalate between layers. The specific composite structure was confirmed theoretically, in line with XRD, SEM and TEM observations. The interfacial interactions were found to be hydrogen bonding. The average adsorption energy per hydroxyl group was computed to be within -0.47 and -0.26 eV for a composite model comprising three cellulose chains and a two-layered Mg(OH)2 cluster. The combined computational/experimental results allow to postulate the antibacterial mechanism of the nanocomposite.

Early intervention combining Chinese and Western medicine in traumatic brain injury with diffuse axonal injury: A report of three cases.

BACKGROUND: Traumatic brain injury (TBI) is characterized by high prevalence, morbidity, and mortality. Diffuse axonal injury (DAI) is a specific type of TBI leading to prolonged consciousness impairment and disability. There is still no standard treatment for DAI, so we introduced traditional Chinese medicine into the treatment of these patients. CASE SUMMARIES: Three patients had TBI after traffic accidents. Their Glasgow Coma Scale (GCS) scores in the intensive care unit (ICU) were E1VEM2-3, E1VEM2-3, and E1VEM2 respectively. All of them were diagnosed with DAI based on magnetic resonance imaging (MRI). Because of continuing consciousness disturbances, their families agreed to combine traditional Chinese medicine and modern medicine treatments through inpatient consultation in Taoyuan General hospital. Two patients took Buyang Huanwu Decoction, and one Tianma Gouteng Decoction twice a day. All of them received 20 min of acupuncture treatments 5 times per week. Acupuncture points included Baihui (GV20), Sishencong (EX-HN1), Shuigou (GV26), Hegu (LI4), and Taichong (LR3). All of them started Traditional Chinese medicine treatment within 2 weeks after TBI. The GCS of all three patients recovered to E4M5V6. CONCLUSIONS: The early addition of traditional Chinese medicine treatments to Western medical care can improve the prognosis of patients with diffuse axonal injury.

Prescription of Chinese herbal products is associated with a decreased risk of uterine fibroids: A population-based cohort study.

The finding of a decrease in subsequent fibroid-related operation following the use of Chinese herbal products (CHPs) has led to speculation that CHPs might play a role in uterine fibroids prevention.This study provides an overview of uterine fibroids incidence, comparing CHP users with those who do not use CHPs, referred to as non-CHP users. The results can provide information to clinicians for counseling women about the preventive use of CHPs.A total of 52,151 women (20-45 years of age) were recruited from a nationwide 1-million-person representative sample of those covered by National Health Insurance in Taiwan and were followed from 2000 to 2013. Exact matching was performed for comparative analysis. The age-specific hazard ratios (HRs) of uterine fibroids in relation to either CHP or the phytoestrogen use were calculated with multivariate Cox proportional hazard regression.More than 71% of patients had used a CHP at some point previously. The overall incidence density rate of uterine fibroids for non-CHP users was estimated at 27.5 per 1000 patient-years. The corresponding values for CHP and the phytoestrogen users were lower than those of the non-CHP group (CHP group = 15.5; the phytoestrogen group = 12.5 per 1000 patient-years). The covariate adjusted HRs for uterine fibroid were 0.73 (95% confidence interval [CI] 0.63-0.85) and 0.65 (95% CI 0.52-0.82) in women using CHPs and the phytoestrogen, respectively.CHPs seem to contribute to a decreased risk in developing uterine fibroids. Although the mechanism of action of these products is unclear, their use as a preventive agent for uterine fibroids might be taken into consideration.

Anti-inflammatory effects and mechanisms of the ethanol extract of Evodia rutaecarpa and its bioactive components on neutrophils and microglial cells.

Evodia rutaecarpa is commonly used as an anti-inflammatory drug in traditional Chinese medicine. We previously identified four bioactive compounds (dehydroevodiamine (I), evodiamine (II), rutaecarpine (III), and synephrine (IV)) from the ethanol extract of E. rutaecarpa, but their effects and mechanism(s) of action remain unclear. To study the anti-inflammatory potential and the possible underlying mechanism(s), their effects on phorbol-12-myristate-13-acetate (PMA)- and N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced reactive oxygen species production in neutrophils was studied, as well as lipopolysaccharide (LPS)-induced nitric oxide (NO) production and inducible NO synthetase (iNOS) expression in microglial cells. The ethanol extract of E. rutaecarpa displayed potent antioxidative effects against both PMA- and fMLP-induced reactive oxygen species production in neutrophils (with IC50 values of around 2.7-3.3 microg/ml). Although less potent than the ethanol extract of E. rutaecarpa, compounds I-IV all concentration-dependently inhibited PMA- and fMLP-induced reactive oxygen species production, with compound IV consistently being the most potent agent among these active components. The antioxidative effects of the ethanol extract of E. rutaecarpa and these compounds were partially due to inhibition (10%-33%) of NADPH oxidase activity, a predominant reactive oxygen species-producing enzyme in neutrophils, and to a minor extent to their direct radical-scavenging properties. The ethanol extract of E. rutaecarpa also inhibited LPS-induced NO production (with an IC50 of around 0.8 microg/ml) and iNOS upregulation in microglial cells that was partially mimicked by compounds I, II, and III, but not compound IV. Our results suggest that the ethanol extract of E. rutaecarpa and its four bioactive components all exhibited anti-inflammatory activities which could be partially explained by their different potentials for inhibiting NADPH oxidase-dependent reactive oxygen species and/or iNOS-dependent NO production in activated inflammatory cells.

The inhibitory effect of phenylpropanoid glycosides and iridoid glucosides on free radical production and beta2 integrin expression in human leucocytes.

Rapid production of reactive oxygen species (ROS) and upregulation of beta2 integrin by leucocytes are two important inflammatory responses in human leucocytes. To evaluate whether three phenylpropanoid glycosides (acteoside, crenatoside, and rossicaside B) and two iridoid glucosides (boschnaloside and 8-epideoxyloganic acid) identified from two medicinal plants with similar indications (Orobanche caerulescens and Boschniakia rossica) exhibited anti-inflammatory activity, their effects on N-formyl-methionyl-leucyl-phenylalanine (fMLP) and phorbol-12-myristate-13-acetate (PMA)-activated peripheral human neutrophils (PMNs) and mononuclear cells were examined. Pretreatment with 1-50 microM phenylpropanoid glycoside concentration-dependently diminished PMA- and fMLP-induced ROS production with IC50 values of approximately 6.8-23.9 and 3.0-8.8 muM, respectively. Iridoid glucoside was less effective than phenylpropanoid glycoside with an IC50 value of approximately 8.9-28.4 microM in PMA-activated PMNs and 19.1-21.1 microM in fMLP-activated mononuclear cells. Phenylpropanoid glycosides also effectively inhibited NADPH oxidase (NOX) and displayed potent free radical-scavenging activity, but did not interfere with pan-protein kinase C (PKC) activity. Furthermore, all compounds, except rossicaside B, significantly inhibited PMA- and fMLP-induced Mac-1 (a beta2 integrin) upregulation at 50 microM but not that of fMLP-induced intracellular calcium mobilization. These drugs had no significant cytotoxicity as compared with the vehicle control. Our data suggested that inhibition of ROS production, possibly through modulation of NOX activity and/or the radical scavenging effect, and beta2 integrin expression in leucocytes indicated that these compounds had the potential to serve as anti-inflammatory agents during oxidative stress.

Do the Preferences of Healthcare Provider Selection Vary among Rural and Urban Patients with Different Income and Cause Different Outcome?

BACKGROUND: Equal access to healthcare facilities and high-level quality of care are important strategies to eliminate the disparity in outcome of care. However, the existing literature regarding how urban or rural dwelling patients with different income level select healthcare providers is insufficient. The purposes of this study were to examine whether differences of healthcare provider selection exist among urban and rural coronary artery bypass surgery (CABG) patients with different income level. If so, we further investigated the associated impact on mortality. METHODS: A retrospective, multilevel study design was conducted using claims data from 2007-2011 Taiwan's Universal Health Insurance Scheme. Healthcare providers' performance and patients' travelling distance to hospitals were used to define the patterns of healthcare provider selection. Baron and Kenny's procedures for mediation effect were conducted. RESULTS: There were 10,108 CABG surgeries included in this study. The results showed that urban dwelling and higher income patients were prone to receive care from better-performance providers. The travelling distances of urban dwelling patients was 15 KM shorter, especially when they received better-performance provider's care. The results also showed that the difference of healthcare provider selection and mortality rate existed between rural and urban dwelling patients with different income levels. After the procedure of mediation effect testing, the results showed that the healthcare provider selection partially mediated the relationships between patients' residential areas with different income levels and 30-day mortality. CONCLUSION: Preferences of healthcare provider selection vary among rural and urban patients with different income, and such differences partially mediated the outcome of care. Health authorities should pay attention to this issue, and propose appropriate solutions to eliminate the disparity in outcome of CABG care.

Salvianolic acid A alleviates ischemic brain injury through the inhibition of inflammation and apoptosis and the promotion of neurogenesis in mice.

Salvianolic acid A (SalA), a chemical type of caffeic acid trimer, has drawn great attention for its potent bioactivities against ischemia-induced injury both in vitro and in vivo. In this study, we evaluated SalA's protective effects against acute ischemic stroke by inducing middle cerebral artery occlusion/reperfusion (MCAO) injuries in mice. Treatment of the mice with SalA (50 and 100µg/kg, i.v.) at 2h after MCAO enhanced their survival rate, improved their moving activity, and ameliorated the severity of brain infarction and apoptosis seen in the mice by diminishing pathological changes such as the extensive breakdown of the blood-brain barrier (BBB), nitrosative stress, and the activation of an inflammatory transcriptional factor p65 nuclear factor-kappa B (NF-κB) and a pro-apoptotic kinase p25/Cdk5. SalA also intensively limited cortical infarction and promoted the expression of neurogenesis protein near the peri-infarct cortex and subgranular zone of the hippocampal dentate gyrus by compromising the activation of GSK3ß and p25/Cdk5, which in turn upregulated ß-catenin, doublecortin (DCX), and Bcl-2, most possibly through the activation of PI3K/Akt signaling via the upregulation of brain-derived neurotrophic factor. We conclude that SalA blocks inflammatory responses by impairing NF-κB signaling, thereby limiting inflammation/nitrosative stress and preserving the integrity of the BBB; SalA also concomitantly promotes neurogenesis-related protein expression by compromising GSK3ß/Cdk5 activity to enhance the expression levels of ß-catenin/DCX and Bcl-2 for neuroprotection.

Common and unique mechanisms of Chinese herbal remedies on ischemic stroke mice revealed by transcriptome analyses.

ETHNOPHARMACOLOGICAL RELEVANCE: Four traditional Chinese herbal remedies (CHR) including Buyang Huanwu decoction (BHD), Xuefu Zhuyu decoction (XZD), Tianma Gouteng decoction (TGD) and Shengyu decoction (SYD) are popular used in treating brain-related dysfunction clinically with different syndrome/pattern based on traditional Chinese medicine (TCM) principles, yet their neuroprotective mechanisms are still unclear. MATERIALS AND METHODS: Mice were subjected to an acute ischemic stroke to examine the efficacy and molecular mechanisms of action underlying these CHR. RESULTS: CHR treatment significantly enhanced the survival rate of stroke mice, with BHD being the most effective CHR. All CHR were superior to recombinant tissue-type plasminogen activator (rt-PA) treatment in successfully ameliorating brain function, infarction, and neurological deficits in stroke mice that also paralleled to improvements in blood-brain barrier damage, inflammation, apoptosis, and neurogenesis. Transcriptome analyses reveals that a total of 774 ischemia-induced probe sets were significantly modulated by four CHR, including 52 commonly upregulated genes and 54 commonly downregulated ones. Among them, activation of neurogenesis-associated signaling pathways and down-regulating inflammation and apoptosis pathways are key common mechanisms in ischemic stroke protection by all CHR. Besides, levels of plasma CX3CL1 and S100a9 in patients could be used as biomarkers for therapeutic evaluation before functional recovery could be observed. CONCLUSION: Our results suggest that using CHR, a combinatory cocktail therapy, is a better way than rt-PA for treating cerebral ischemic-associated diseases through modulating a common as well as a specific group of genes/pathways that may partially explain the syndrome differentiation and treatment principle in TCM.

Prevention of macrophage adhesion molecule-1 (Mac-1)-dependent neutrophil firm adhesion by taxifolin through impairment of protein kinase-dependent NADPH oxidase activation and antagonism of G protein-mediated calcium influx.

Taxifolin has been reported to down-regulate the expression of intercellular adhesion molecule-1 (ICAM-1), a receptor-mediating firm adhesion with beta2 integrin (e.g., Mac-1) expressed on leukocytes. To evaluate whether taxifolin could modulate Mac-1-dependent firm adhesion by neutrophils, and the possible mechanism(s) underlying its anti-inflammatory action, its effects on N-formyl-methionyl-leucyl-phenylalanine (fMLP) or phorbol-12-myristate-13-acetate (PMA)-activated peripheral human neutrophils were studied. Pretreatment with taxifolin (1-100 microM) concentration-dependently diminished fMLP- or (PMA)-induced Mac-1-dependent firm adhesion and upexpression of surface Mac-1. Mobilisation of intracellular calcium and production of reactive oxygen species (ROS) signal the upexpression of Mac-1 and firm adhesion by neutrophils. Taxifolin impeded the calcium influx induced by fMLP (a receptor-mediated activator) or AlF(4)(-) (a G protein-mediated activator). Taxifolin also effectively inhibited the fMLP- or PMA-induced ROS production with 50% inhibitory concentration (IC(50)) less than 10microM, possibly through impairing the activation of NADPH oxidase, a major ROS-generating enzyme in neutrophils, by restricting the activation of p38 mitogen-activated protein kinase (p38 MAPK) and protein kinase C (PKC). In conclusion, we propose that impairment of ROS production by NADPH oxidase through interfering with p38 MAPK- and/or PKC-dependent signals, and antagonism of G protein-mediated calcium influx may account for the inhibition of Mac-1-dependent neutrophil firm adhesion that confers taxifolin the anti-inflammatory activity.

2-Methoxystypandrone ameliorates brain function through preserving BBB integrity and promoting neurogenesis in mice with acute ischemic stroke.

2-Methoxystypandrone (2-MS), a naphthoquinone, has been shown to display an immunomodulatory effect in a cellular model. To explore whether 2-MS could protect mice against cerebral ischemic/reperfusion (I/R)-induced brain injury, we evaluated 2-MS's protective effects on an acute ischemic stroke by inducing a middle cerebral artery occlusion/reperfusion (MCAO) injury in murine model. Treatment of mice that have undergone I/R injury with 2-MS (10-100 µg/kg, i.v.) at 2 h after MCAO enhanced survival rate and ameliorated neurological deficits, brain infarction, neural dysfunction and massive oxidative stress, due to an enormous production of free radicals and breakdown of blood-brain barrier (BBB) by I/R injury; this primarily occurred with extensive infiltration of CD11b-positive inflammatory cells and upexpression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 and p65 nuclear factor-kappa B (NF-κB). All of these pathological changes were diminished by 2-MS; 2-MS also intensively limited cortical infarction and promoted upexpression of neurodevelopmental genes near peri-infarct cortex and endogenous neurogenesis near subgranular zone of hippocampal dentate gyrus and the subventricular zone, most possibly by inactivation of GSK3ß which in turn upregulating ß-catenin, Bcl-2 adam11 and adamts20. We conclude that 2-MS blocks inflammatory responses by impairing NF-κB signaling to limit the inflammation and oxidative stress for preservation of BBB integrity; 2-MS also concomitantly promotes neurodevelopmental protein expression and endogenous neurogenesis through inactivation of GSK3ß to enhance ß-catenin signaling for upexpression of neuroprotective genes and proteins.

Unique mechanisms of sheng yu decoction ( shèng yù tang) on ischemic stroke mice revealed by an integrated neurofunctional and transcriptome analysis.

Sheng Yu Decoction ( Shèng Yù Tang; SYD) is a popular traditional Chinese medicine (TCM) remedy used in treating cardiovascular and brain-related dysfunction clinically; yet, its neuroprotective mechanisms are still unclear. Here, mice were subjected to an acute ischemic stroke to examine the efficacy and mechanisms of action of SYD by an integrated neurofunctional and transcriptome analysis. More than 80% of the mice died within 2 days after ischemic stroke with vehicle treatment. Treatments with SYD (1.0 g/kg, twice daily, orally or p.o.) and recombinant thrombolytic tissue plasminogen activator (rt-PA; 10 mg/kg, once daily, intravenously or i.v.) both significantly extended the lifespan as compared to that of the vehicle-treated stroke group. SYD successfully restored brain function, ameliorated cerebral infarction and oxidative stress, and significantly improved neurological deficits in mice with stroke. Molecular impact of SYD by a genome-wide transcriptome analysis using brains from stroke mice showed a total of 162 out of 2081 ischemia-induced probe sets were significantly influenced by SYD. Mining the functional modules and genetic networks of these 162 genes revealed a significant upregulation of neuroprotective genes in Wnt receptor signaling pathway (3 genes) and regulation of cell communication (7 genes) and downregulation of destructive genes in response to stress (13 genes) and in the induction of inflammation (5 genes), cytokine production (4 genes), angiogenesis (3 genes), vasculature (6 genes) and blood vessel (5 genes) development, wound healing (7 genes), defense response (7 genes), chemotaxis (4 genes), immune response (7 genes), antigen processing and presenting (3 genes), and leukocyte-mediated cytotoxicity (2 genes) by SYD. Our results suggest that SYD could protect mice against ischemic stroke primarily through significantly downregulating the damaging genes involved in stress, inflammation, angiogenesis, blood vessel formation, immune responses, and wound healing, as well as upregulating the genes mediating neurogenesis and cell communication, which make SYD beneficial for treating ischemic stroke.