Oral glutamate intake reduces acute and chronic effects of ethanol in rodents

Purpose: To assess the effects of oral glutamate intake on acute motor effects and chronic intake of ethanol in rodents. Methods: The acute effects of ethanol on motor function were studied in ICR mice by giving 2 or 6 g/kg of ethanol 2 h after distilled water or 2.5 g/kg glutamate per os. Thirty minutes after ethanol treatment, behavioral assays, including rotarod tests and foot print analysis were monitored. In chronic ethanol treatment, male Wistar rats were trained to consume ethanol-sucrose solution during a 2-h period daily, starting with 2 % ethanol/10 % sucrose and gradually increasing to 10 % ethanol/5 % sucrose solution over 56 days. After training session, the drug treatment phase was done for 10 days. The animals were force-fed 50 mg/kg/day topiramate or 2.5 g/kg/day glutamate 2 h before ethanol treatment sessions. Each day, ethanol intake, water intake, food intake and body weight were recorded. Results: Mice that received 2 or 6 g/kg of ethanol orally, showed a significant reduction in time on the rod in the rotarod test and a significant increase in both forelimb and hindlimb stride lengths when compared to control. Oral treatment with 2.5 g/kg of glutamate reversed the acute motor effects of ethanol. In chronic ethanol treatment, the intake of 10 % ethanol/5 % sucrose, accessible for 2 h, was significantly decreased in rats treated with either topiramate or glutamate. Conclusion: These results provide evidence that oral glutamate administration help to reduce the acute motor effects of ethanol in mice and ethanol intake in the chronic ethanol drinking rats.

Protective effect of rhamnopyranosyl vanilloyl isolated from Scrophularia ningpoensis Hemsl (Scrophulariaceae) root against acute liver injury in mice

Purpose: To investigate the protective effect of rhamnopyranosyl vanilloyl (RV) from Scrophularia ningpoensis root against tetrachloromethane (CCl4)-induced acute liver injury (ALI) in mice. Methods: RV was isolated from S. ningpoensis by column chromatography. ALI model of mice was established by intraperitoneal injection of CCl4. Liver index, liver function indices, as well as serum alanine transaminase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBIL) were evaluated. Lipid peroxidation (LPO)-related indices, including malonaldehyde (MDA), glutathione (GSH), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). Apoptotic proteins (Bcl-2, Bax and caspase-3) in liver tissue were determined by enzyme-linked immunosorbent assay (ELISA) and Western blot. Results: After treatment with RV (10, 20 or 40 mg/kg), liver index (5.65 - 5.21 vs. 6.68 %), ALT (90.18 - 79.68 vs. 112.47 U/L), AST (64.44 - 57.63 vs. 75.41 U/L) and TBIL (2.68 - 1.95 vs. 3.21 U/L) activities, as well as MDA (3.58 - 2.88 vs. 4.13 μmol/g), Bax and caspase-3 levels significantly (p < 0.05 or 0.01) decreased, compared with those in control group. After treatment with RV (10, 20 or 40 mg/kg), GSH (16.58 - 22.14 vs. 12.34 μmol/g), Bcl-2, SOD (86.45 - 107.61 vs. 68.43 U/mg) and GSH-Px (295.64 - 329.47 vs. 268.49 U/mg) levels or activities significantly (p < 0.05 or 0.01) increased, compared with those in control group. Conclusion: RV has protective effect against CCl4-induced ALI in mice, and the mechanisms involve the inhibition of LPO and apoptosis in liver cells. Thus, RV is a potential drug for the treatment of liver injury

Clinical efficacy and safety of edaravone therapy in acute cerebral haemorrhage

Purpose: To evaluate the clinical efficacy and safety of edaravone in the treatment of acute cerebral haemorrhage (ACH). Methods: This study recruited 120 patients who developed ACH. The patients were divided into control and treatment groups with 60 patients per group. The control group underwent conventional treatment and the treatment group also received intravenous edaravone. The volumes of cerebral edema and cerebral hematoma, high-sensitivity C-reactive protein (hs-CRP) and interleukin-6 (IL-6) levels, and Chinese Stroke Scale (CSS) score before and after treatment were compared between the two groups. Results: The respective cerebral edema volumes of the control and treatment groups decreased from 20.99 ± 12.09 and 21.80 ± 12.01 mL on day 0 to 11.23 ± 6.34 and 12.11 ± 5.98 mL at day 7 and 4.69 ± 4.03 and 4.64 ± 3.9 mL on day 14 (P < 0.05). The respective cerebral hematoma volumes of the control and treatment groups decreased from 18.98 ± 12.04 and 18.97 ± 12.07 mL on day 0 to 12.34 ± 6.57 and 11.89 ± 4.01 mL at day 7 and 9.49 ± 3.95 and 9.52 ± 3.96 mL on day 14. Compared with pretreatment, hs-CRP and IL-6 levels and CSS score of the two groups decreased significantly following treatment (p < 0.05); the differences in the cerebral edema and hematoma volumes of the two groups on days 7 and 14 were not significant (p > 0.05). The hs-CRP and IL-6 levels and CSS scores of the treatment group decreased appreciably (p < 0.05), while the incidence of adverse reactions in the treatment and control groups was 16.67 and 13.33 %, respectively, but the difference was not significant (p > 0.05). Conclusion: Edaravone shows remarkable clinical efficacy and safety with no obvious adverse reactions in the treatment of ACH. Therefore, its use is recommended.

Proscillaridin A effects on histone acetylation and C-MYC degradation in acute lymphoblastic leukemia

La leucémie lymphoblastique aiguë (LLA) représente environ 25% des cancers pédiatriques diagnostiqués chaque année. Dans 80 % des cas, une rémission complète est observée. Cependant, les patients résistants aux traitements ainsi que les patients en rechute présentent un mauvais pronostique. Les altérations épigénétiques sont des facteurs essentiels dans le développement et la progression de la maladie, ainsi qu’à la résistance aux traitements. Lors d’un criblage de médicaments approuvés par la FDA, nous avons découvert des molécules ayant des caractéristiques anticancéreux et épigénétiques. Pour évaluer l’activité de ces molécules, nous avons procédé à un criblage secondaire sur plusieurs lignées cellulaires leucémiques. Nous avons découvert qu’une de ces molécules, un glucoside cardiotonique appelé la proscillaridine A, avait une activité anticancéreuse spécifique pour des cellules leucémiques. Nous faisons donc l’hypothèse que la proscillaridine A pourrait avoir des effets épigénétiques et anticancéreux dans des modèles précliniques de LLA. Pour tester cette hypothèse, nous avons traité deux lignées cellulaires de LLA Nalm-6 (LLA pre-B) et Molt-4 (T-LLA) in vitro pendant 2 à 96 heures à des doses pertinentes sur le plan clinique. Nous avons alors pu observer une inhibition de croissance qui était dépendante de la dose administrée dans les deux lignées cellulaires, avec des valeurs de 50% d’inhibition de croissance (CI50) de 3.0 nM pour les Nalm-6 et de et 2.3 nM pour les Molt-4. De plus, nos études sur le cycle cellulaire par BrdU démontrent un arrêt en phase G2/M. Nous avons également détecté par immunobuvardage de type western des baisses significatives de l’acétylation de résidus de l’histone 3. Les niveaux d’expression des enzymes responsables de cette acétylation, les histones acétyltransférases CBP, P300 et TIP60 ainsi que de l’oncogène C-MYC étaient également diminuées. Par des analyses de séquençage de l’ARN, nous avons observé une augmentation de l’expression des gènes impliquées dans les processus d’apoptose et de différentiation cellulaire, ainsi qu’une diminution des gènes impliqués dans la prolifération cellulaire comme en particulier les gènes cibles de C-MYC. Ces résultats prometteurs suggèrent le potentiel prometteur de la proscillaridine A comme nouvelle thérapie pour les patients atteints de LLA.

Proscillaridin A effects on histone acetylation and C-MYC degradation in acute lymphoblastic leukemia

La leucémie lymphoblastique aiguë (LLA) représente environ 25% des cancers pédiatriques diagnostiqués chaque année. Dans 80 % des cas, une rémission complète est observée. Cependant, les patients résistants aux traitements ainsi que les patients en rechute présentent un mauvais pronostique. Les altérations épigénétiques sont des facteurs essentiels dans le développement et la progression de la maladie, ainsi qu’à la résistance aux traitements. Lors d’un criblage de médicaments approuvés par la FDA, nous avons découvert des molécules ayant des caractéristiques anticancéreux et épigénétiques. Pour évaluer l’activité de ces molécules, nous avons procédé à un criblage secondaire sur plusieurs lignées cellulaires leucémiques. Nous avons découvert qu’une de ces molécules, un glucoside cardiotonique appelé la proscillaridine A, avait une activité anticancéreuse spécifique pour des cellules leucémiques. Nous faisons donc l’hypothèse que la proscillaridine A pourrait avoir des effets épigénétiques et anticancéreux dans des modèles précliniques de LLA. Pour tester cette hypothèse, nous avons traité deux lignées cellulaires de LLA Nalm-6 (LLA pre-B) et Molt-4 (T-LLA) in vitro pendant 2 à 96 heures à des doses pertinentes sur le plan clinique. Nous avons alors pu observer une inhibition de croissance qui était dépendante de la dose administrée dans les deux lignées cellulaires, avec des valeurs de 50% d’inhibition de croissance (CI50) de 3.0 nM pour les Nalm-6 et de et 2.3 nM pour les Molt-4. De plus, nos études sur le cycle cellulaire par BrdU démontrent un arrêt en phase G2/M. Nous avons également détecté par immunobuvardage de type western des baisses significatives de l’acétylation de résidus de l’histone 3. Les niveaux d’expression des enzymes responsables de cette acétylation, les histones acétyltransférases CBP, P300 et TIP60 ainsi que de l’oncogène C-MYC étaient également diminuées. Par des analyses de séquençage de l’ARN, nous avons observé une augmentation de l’expression des gènes impliquées dans les processus d’apoptose et de différentiation cellulaire, ainsi qu’une diminution des gènes impliqués dans la prolifération cellulaire comme en particulier les gènes cibles de C-MYC. Ces résultats prometteurs suggèrent le potentiel prometteur de la proscillaridine A comme nouvelle thérapie pour les patients atteints de LLA.

Long-term benefit of early pre-reperfusion metoprolol administration in patients with acute myocardial infarction: Results from the Metocard-CNIC trial (Effect of Metoprolol in Cardioprotection during an Acute Myocardial Infarction)

The goal of this trial was to study the long-term effects of intravenous (IV) metoprolol administration before reperfusion on left ventricular (LV) function and clinical events. Early IV metoprolol during ST-segment elevation myocardial infarction (STEMI) has been shown to reduce infarct size when used in conjunction with primary percutaneous coronary intervention (pPCI). The METOCARD-CNIC (Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction) trial recruited 270 patients with Killip class ≤II anterior STEMI presenting early after symptom onset (<6 h) and randomized them to pre-reperfusion IV metoprolol or control group. Long-term magnetic resonance imaging (MRI) was performed on 202 patients (101 per group) 6 months after STEMI. Patients had a minimal 12-month clinical follow-up. Left ventricular ejection fraction (LVEF) at the 6 months MRI was higher after IV metoprolol (48.7 ± 9.9% vs. 45.0 ± 11.7% in control subjects; adjusted treatment effect 3.49%; 95% confidence interval [CI]: 0.44% to 6.55%; p = 0.025). The occurrence of severely depressed LVEF (≤35%) at 6 months was significantly lower in patients treated with IV metoprolol (11% vs. 27%, p = 0.006). The proportion of patients fulfilling Class I indications for an implantable cardioverter-defibrillator (ICD) was significantly lower in the IV metoprolol group (7% vs. 20%, p = 0.012). At a median follow-up of 2 years, occurrence of the pre-specified composite of death, heart failure admission, reinfarction, and malignant arrhythmias was 10.8% in the IV metoprolol group versus 18.3% in the control group, adjusted hazard ratio (HR): 0.55; 95% CI: 0.26 to 1.04; p = 0.065. Heart failure admission was significantly lower in the IV metoprolol group (HR: 0.32; 95% CI: 0.015 to 0.95; p = 0.046). In patients with anterior Killip class ≤II STEMI undergoing pPCI, early IV metoprolol before reperfusion resulted in higher long-term LVEF, reduced incidence of severe LV systolic dysfunction and ICD indications, and fewer heart failure admissions.

Characteristics of microRNAs and their potential relevance for the diagnosis and therapy of the acute respiratory distress syndrome: from bench to bedside

Acute respiratory distress syndrome (ARDS) is a complex disease associated with high morbidity and mortality. Biomarkers and specific pharmacologic treatment of the syndrome are lacking. MicroRNAs (miRNAs) are small (∼19–22 nucleotides) noncoding RNA molecules whose function is the regulation of gene expression. Their uncommon biochemical characteristics (eg, their resistance to degradation because of extreme temperature and pH fluctuations, freeze-thaw cycles, long storage times in frozen conditions, and RNAse digestion) and their presence in a wide range of different biological fluids and the relatively low number of individual miRNAs make these molecules good biomarkers in different clinical conditions. In addition, miRNAs are suitable therapeutic targets as their expression can be modulated by different available strategies. The aim of the present review is to offer clinicians a global perspective of miRNA, covering their structure and nomenclature, biogenesis, effects on gene expression, regulation of expression, and features as disease biomarkers and therapeutic targets, with special attention to ARDS. Because of the early stage of research on miRNAs applied to ARDS, attention has been focused on how knowledge sourced from basic and translational research could inspire future clinical studies.

Mechanochemical treatment of kaolinite

Kaolinite surfaces were modified by mechanochemical treatment for periods of time up to 10 h. X-ray diffraction shows a steady decrease in intensity of the d(001) spacing with mechanochemical treatment, resulting in the delamination of the kaolinite and a subsequent decrease in crystallite size with grinding time. Thermogravimetric analyses show the dehydroxylation patterns of kaolinite are significantly modified. Changes in the molecular structure of the kaolinite surface hydroxyls were followed by infrared spectroscopy. Hydroxyls were lost after 10 h of grinding as evidenced by a decrease in intensity of the OH stretching vibrations at 3695 and 3619 cm−1 and the deformation modes at 937 and 915 cm−1. Concomitantly an increase in the hydroxyl stretching vibrations of water is found. The water-bending mode was observed at 1650 cm−1, indicating that water is coordinating to the modified kaolinite surface. Changes in the surface structure of the OSiO units were reflected in the SiO stretching and OSiO bending vibrations. The decrease in intensity of the 1056 and 1034 cm−1 bands attributed to kaolinite SiO stretching vibrations were concomitantly matched by the increase in intensity of additional bands at 1113 and 520 cm−1 ascribed to the new mechanically synthesized kaolinite surface. Mechanochemical treatment of the kaolinite results in a new surface structure.

Thermal treatment of weddellite—a Raman and infrared emission spectroscopic study

Thermal transformations of natural calcium oxalate dihydrate known in mineralogy as weddellite have been undertaken using a combination of Raman microscopy and infrared emission spectroscopy. The vibrational spectroscopic data was complimented with high resolution thermogravimetric analysis combined with evolved gas mass spectrometry. TG–MS identified three mass loss steps at 114, 422 and 592 °C. In the first mass loss step water is evolved only, in the second and third steps carbon dioxide is evolved. The combination of Raman microscopy and a thermal stage clearly identifies the changes in the molecular structure with thermal treatment. Weddellite is the phase in the temperature range up to the pre-dehydration temperature of 97 °C. At this temperature, the phase formed is whewellite (calcium oxalate monohydrate) and above 114 °C the phase is the anhydrous calcium oxalate. Above 422 °C, calcium carbonate is formed. Infrared emission spectroscopy shows that this mineral decomposes at around 650 °C. Changes in the position and intensity of the C=O and C---C stretching vibrations in the Raman spectra indicate the temperature range at which these phase changes occur.

Radiobiological model comparison of 3D conformal radiotherapy and IMRT plans for the treatment of prostate cancer

The main aim of radiotherapy is to deliver a dose of radiation that is high enough to destroy the tumour cells while at the same time minimising the damage to normal healthy tissues. Clinically, this has been achieved by assigning a prescription dose to the tumour volume and a set of dose constraints on critical structures. Once an optimal treatment plan has been achieved the dosimetry is assessed using the physical parameters of dose and volume. There has been an interest in using radiobiological parameters to evaluate and predict the outcome of a treatment plan in terms of both a tumour control probability (TCP) and a normal tissue complication probability (NTCP). In this study, simple radiobiological models that are available in a commercial treatment planning system were used to compare three dimensional conformal radiotherapy treatments (3D-CRT) and intensity modulated radiotherapy (IMRT) treatments of the prostate. Initially both 3D-CRT and IMRT were planned for 2 Gy/fraction to a total dose of 60 Gy to the prostate. The sensitivity of the TCP and the NTCP to both conventional dose escalation and hypo-fractionation was investigated. The biological responses were calculated using the Källman S-model. The complication free tumour control probability (P+) is generated from the combined NTCP and TCP response values. It has been suggested that the alpha/beta ratio for prostate carcinoma cells may be lower than for most other tumour cell types. The effect of this on the modelled biological response for the different fractionation schedules was also investigated.