Methylcyclopentadienyl Manganese Tricarbonyl Alter Behavior and Cause Ultrastructural Changes in the Substantia Nigra of Rats: Comparison with Inorganic Manganese Chloride.

The antiknock additive methylcyclopentadienyl manganese tricarbonyl (MMT) is an organic manganese(Mn) compound. Mn neurotoxicity caused by occupational Mn exposure (mostly inorganic MnCl2) is associated with motor and cognitive disturbances, referred to as Manganism. However, the impact of environmentally relevant Mn exposure on MMT-induced Manganism is poorly understood. In this investigation, we studied the effects of MMT on motor function and brain structure, and compared its effects with those of inorganic MnCl2. After adaptive feeding for 7 days, male and female Sprague-Dawley (SD) rats in the MMT-treated groups and positive control group were treated for 8 weeks with MMT (1, 2 and 4 mg/kg/i.g.) or MnCl2·4H2O (200 mg/kg/i.g.). Mn content in blood, liver, spleen and distinct brain regions was determined by inductively coupled plasma-mass spectrometer (ICP-MS). We found that MMT and MnCl2 exposure led to slower body-weight-gain in female rats, impaired motor and balance function and spatial learning and memory both in male and female rats. HE staining showed that MMT and MnCl2 led to altered structure of the substantia nigra pars compacta (SNpc), and Nissl staining corroborated MMT's propensity to damage the SNpc both in male and female rat. In addition, Immunostaining of the SNpc showed decreased TH-positive neurons in MMT- and MnCl2-treated rats, concomitant with Iba1 activation in microglia. Moreover, no statistically significant difference was noted between the rats in the H-MMT and MnCl2 groups. In summary, these findings suggest that MMT and MnCl2 exposure cause ultrastructural changes in the SNpc neurons culminating in altered motor behavior and cognition, suggesting that altered SNpc structure and function may underline the motor and cognitive deficits inherent to Manganism, and accounting for MMT and MnCl2's manifestations of atypical parkinsonism.

Elevated N-terminal pro C-type natriuretic peptide is associated with mortality in patients undergoing transcatheter aortic valve replacement.

BACKGROUND: Unlike N-terminal pro-B-type natriuretic peptide (NT-proBNP), which have been extensively studied, little is known about the role of N-terminal pro-C-type natriuretic peptide (NT-proCNP) for predicting survival post transcatheter aortic valve replacement (TAVR). METHODS: A total of 309 patients were included in the analysis. Patients were grouped into quartiles (Q1-4) according to the baseline NT-proCNP value. Blood for NT-proCNP analysis was obtained prior to TAVR procedure. The primary endpoint was mortality after a median follow-up of 32 months. Multivariable Cox proportional hazards regression models analyzed prognostic factors. The predictive capability was compared between NT-proBNP and NT-proCNP using receiver operator curve (ROC) analysis. RESULTS: A total of 309 subjects with the mean age of 76.8 ± 6.3 years, among whom 58.6% were male, were included in the analysis. A total of 58 (18.8%) patients died during follow-up. Cox multivariable analyses indicated society of thoracic surgeons (STS)-score was a strong independent predictor for mortality (hazard ratio (HR) 1.08, 95% confidential interval (CI) 1.05-1.12, P < 0.001). Elevated NT-proCNP was associated with a higher risk of cardiovascular mortality (HR 1.02, 95% CI 1.00-1.03, P = 0.025) and All-cause mortality (HR 1.01, 95% CI 1.00-1.03, P = 0.027), whereas NT-proBNP showed a small effect size on mortality. ROC analysis indicated that NT-proCNP was superior to NT-proBNP for TAVR risk evaluation in patients with left ventricular ejection fraction (LVEF) < 50% [(Area under the curve (AUC)-values of 0.79 (0.69; 0.87) vs. 0.59 (0.48; 0.69), P = 0.0453]. CONCLUSIONS: NT-proCNP and STS-Score were the independent prognostic factors of mortality among TAVR patients. Furthermore, NT-proCNP was superior to NT-proBNP for TAVR risk evaluation in patients with LVEF < 50%. Trial registration NCT02803294, 16/06/2016.

Anemia and risk of periprocedural cerebral injury detected by diffusion-weighted magnetic resonance imaging in patients undergoing transcatheter aortic valve replacement.

BACKGROUND: Anemia is prevalent in patients undergoing transcatheter aortic valve replacement (TAVR) and has been linked to impaired outcomes after the procedure. Few studies have evaluated the impact of anemia and new ischemic lesions post TAVR. METHODS: We prospectively enrolled 158 patients who received TAVR in our center. Anemia was defined according to the World Health Organization criteria as hemoglobin <12 g/dL in women and <13 g/dL in men. All patients underwent diffusion-weighted magnetic resonance imaging (DW-MRI) procedure before and within 4-7 days after TAVR. RESULTS: Anemia was present in 85 (53.8%) patients who underwent TAVR, and 126 (79.7%) patients had 718 new DW-MRI positive lesions with a mean of 4.54±5.26 lesions per patient. The incidence of new ischemic lesions was 81.2% in patients with anemia versus 78.1% in patients without anemia (P=0.629). Moreover, anemic patients had bigger total volume/lesions in the anterior cerebral artery/middle cerebral artery (ACA/MCA) and MCA regions compared to the non-anemic patients (31.89±55.78 mm3 vs. 17.08±37.39 mm3, P=0.049; and 54.54±74.72 mm3 vs. 33.75±46.03 mm3, P=0.034). Anemia was independently associated with the volume/lesion in the ACA/MCA (ß=16.796, 95% confidence interval [95% CI] 2.001 to 31.591, P=0.026) and in the MCA zone (ß=0.020, 95% CI 0.001 to 0.040, P=0.041). CONCLUSIONS: Patients with pre-procedural anemia may have bigger total volume/lesions in the ACA/MCA and MCA regions compared to the non-anemic patients. Whether the consequences of bigger total volume/lesions impact neurological and cognitive outcomes remains to be investigated.

Ascending aortic dilatation rate after transcatheter aortic valve replacement in patients with bicuspid and tricuspid aortic stenosis: A multidetector computed tomography follow-up study.

BACKGROUND: Current data is lacking about the progression of ascending aortic dilatation after transcatheter aortic valve replacement (TAVR) in aortic stenosis (AS) patients with bicuspid aortic valve (BAV) and tricuspid aortic valve (TAV). This study aims to assess the ascending aortic dilatation rate (mm/year) after TAVR in patients with BAV versus TAV using a multidetector computed tomography (MDCT) follow-up and to determine the predictors of ascending aortic dilatation rate. METHODS: Severe AS patients undergoing TAVR from March 2013 to March 2018 at our center with MDCT follow-ups were included. BAV and TAV were identified using baseline MDCT. Baseline and follow-up MDCT images were analyzed, and the diameters of ascending aorta were measured. Study end point is ascending aortic dilatation rate (mm/year). Furthermore, factors predicting ascending aortic dilatation rate were also investigated. RESULTS: Two hundred and eight patients were included, comprised of 86 BAV and 122 TAV patients. Five, 4, 3, 2, and 1-year MDCT follow-ups were achieved in 7, 9, 30, 46, and 116 patients. The ascending aortic diameter was significantly increased after TAVR in both BAV group (43.7±4.4 mm vs. 44.0±4.5 mm; P<0.001) and TAV group (39.1±4.8 mm vs. 39.7±5.1 mm; P<0.001). However, no difference of ascending aortic dilatation rate was found between BAV and TAV group (0.2±0.8 mm/year vs. 0.3±0.8 mm/year, P=0.592). Multivariate linear regression revealed paravalvular leakage (PVL) grade was independently associated with ascending aortic dilatation rate in the whole population and BAV group, but not TAV group. No aortic events occurred during follow-ups. CONCLUSION: Ascending aortic size continues to grow after TAVR in BAV patients, but the dilatation rate is mild and comparable to that of TAV patients. PVL grade is associated with ascending aortic dilatation rate in BAV patients post-TAVR.

A hospital-based survey of patients with severe valvular heart disease in China.

OBJECTIVES: Due to increasing aging, the epidemiology of VHD may have changed in China. This study aimed to provide contemporary information on the prevalence, distribution patterns, and etiology of severe VHD in China. METHODS: This was a retrospective survey at Second Affiliated Hospital of Zhejiang University, which included all consecutive patients between 2010 and 2015. RESULTS: In all, 139,496 patients were enrolled. Among severe valve diseases, MR was the most frequent (n=946, 0.68%) followed by MS (n=524, 0.38%), AS (n=392, 0.28%), and AR (n=371, 0.27%). Severe MR and AS prevalence rates increased strikingly with age. Rheumatic heart disease had an prevalence of 1.56% (n=2179), and remained one of the most common causes of severe VHD in patients younger than 65years old (99.5% of MS with rheumatic; 27.6% of MR with rheumatic; 25.7% of AS with rheumatic; 31.6% of AR with rheumatic). Aortic valve calcification was the predominant AS etiology, and its prevalence greatly increased with age. In severe AR, rheumatic fever was the most common etiology in patients below 65; in those above 65, etiology was mostly degenerative. In severe primary MR, mitral valve prolapse was the most common cause. Prevalence of secondary MR increased with age, from 16.4% in 18-44years old to 51.7% in individuals ≥75. CONCLUSIONS: Severe valvular diseases are very common; rheumatic fever and degenerative valvular changes remain predominant causes in patients below 65 and older ones, respectively. Young adults present mainly with primary MR, while secondary MR is more common in elderly ones.

[Design, synthesis and biological evaluation of novel [1,3] dioxolo [4,5-f]isoindolone derivatives].

A series of [1,3]dioxolo[4,5-f]isoindolone derivatives were designed, synthesized and evaluated as inhibitors of acetylcholinesterases (AChE). Furthermore, their effects on memory impairment of mice induced by scopolamine were investigated with step-through test. The results suggested that most of the target compounds exhibited potential inhibition on AChE with IC50 values at micromolar range. Compounds I1 (IC50 value of 0.086 µmol · L(-1)) and I2 (IC50 value of 0.080 µmol · L(-1)) showed the strongest AChE inhibitory activity, which are equipotent to donepezil (IC50 value of 0.094 µmol · L(-1)). Moreover, compounds I1-I4 could improve the memory impairment induced by scopolamine in mice.

Catunarosides I-L, four new triterpenoid saponins from the stem bark of Catunaregam spinosa.

Four new triterpenoid saponins, Catunaroside I [3-O-ß-D-glucopyranosyl-(1→3)-ß-D-glucopyranosyl-arjunic acid 28-O-ß-D-glucopyranoside] (1), Catunaroside J [3-O-ß-D-glucopyranosyl-(1→2)-[ß-D-glucopyranosyl-(1→3)]-ß-D-glucopyranosyl-arjunic acid 28-O-ß-D-glucopyranoside] (2), Catunaroside K [3-O-ß-D-glucopyranosyl-(1→2)-[ß-D-glucopyranosyl-(1→3)]-ß-D-glucopyranosyl-tormentic acid] (3), and Catunaroside L [3-O-ß-D-glucopyranosyl-(1→2)-[ß-D-glucopyranosyl-(1→3)]-ß-D-glucopyranosyl-pomolic acid] (4), and two known triterpenoid saponin Arjunetoside (5) and Randiasaponin VII (6), were isolated from the stem bark of Catunaregam spinosa. Their structures were elucidated on the basis of their spectral data and chemical evidence.

[Design, synthesis and biological evaluation of novel 4-substituted-3-nitrobenzamide derivatives].

A series of novel 4-substituted-3-nitrobenzamide derivatives were designed and synthesized. The structures of the target compounds were confirmed with 1H NMR, 13C NMR, MS and element analysis. Anti-tumor activities against HCT-116, MDA-MB435 and HL-60 cell lines in vitro were evaluated by SRB assay. The results indicated most of the target compounds exhibited potent anti-tumor activity. Compound 4a showed the most potent inhibitory activities against three cancer cell lines with the GI50 values of 1.904-2.111 micromol x L(-1). Compounds 4g, 41-4n exhibited more potent inhibitory activities against MDA-MB435 and HL-60 cell lines with the GI50 values of 1.008-3.586 micromol x L(-1) and 1.993-3.778 micromol x L(-1), respectively. The structure-activity relationship of these compounds is discussed preliminarily.

In vitro antitumour activity of stearic acid-g-chitosan oligosaccharide polymeric micelles loading podophyllotoxin.

Development of successful formulations for poorly water-soluble drugs remains a longstanding critical and challenging issue in cancer therapy. The stearic acid-g-chitosan oligosaccharide (CSO-SA) micelles have been presented as potential candidates for intracellular antitumour agent delivery carrier. Herein, podophyllotoxin (PPT) loaded CSO-SA micelles (CSO-SA/PPT) were prepared by a dialysis method. The drug encapsulation efficiency could reach a higher level, the micellar size and the zeta potential increased with increasing charged amounts of drug. The cumulative release percentage of PPT drug from micelles enhanced with decreasing PPT content in the micelles. The cytotoxicities of CSO-SA/PPT micelles against human breast carcinoma (MCF-7) cells, human lung cancer cells (A549) and human hepatoma cell line (Bel-7402) were higher than that of free PPT formulation. The higher cytotoxicities were due to the faster PPT transport into tumour cells mediated by CSO-SA micelles. Overall, CSO-SA micelles might be a promising carrier for PPT delivery in cancer therapy.

[Relation between beta-amyloid peptide-25-35 inducing cell cycle change and apoptosis of serum-deprived PC12 cell].

OBJECTIVE: To study the relation between cell cycle change and apoptosis of serum-deprived PC12 cell, which are induced by beta-amyloid peptide-25-35 (alpha beta(25-35)). METHODS: PC12 cells were synchronized by cultured in deprivation of serum for 24 h and treated with different concentration of alpha beta(25-35) (0-45 micromol/L) for another 24 h,and the cell survival rate was evaluated by MTT assay. The cell apoptosis was analyzed by Hoechst fluorescence staining and DNA agarose gel electrophoresis. The relation between cell cycle redistribution and apoptosis was analyzed by flow cytometry (FCM). RESULTS: alpha beta(25-35) decreased the survival rate of PC12 cells in dose-dependent manner. The typical apoptotic cells were showed by fluorescence staining when treated with 25 micromol/L alpha beta(25-35) for 24 h;the obvious DNA-Ladder was showed by DNA agarose electrophoresis. About 90% PC12 cells were found to arrest on G0/G1 by FCM being deprived serum. Treated with 25 micromol/L alpha beta(25-35) for 8, 16, 24 h, the percent of S phase cells was raised remarkably (P < 0.01) at 8 h, but the percent of S phase cells was declined gradually after treated for 16 h. Meanwhile the apoptotic rate was detected being increased obviously between 16 h and 24 h (P < 0.01), the obvious hypodiploid peak could be observed ahead of G0/G1 phase(Ap). CONCLUSION: alpha beta(25-35) decreases the survival rate of synchronized PC12 cell and induces the synchronized PC12 cells attempting to reenter cell cycle,which appear the apoptotic peak subsequently. This indicates that the cell apoptosis may be related to the abnormal cell cycle distribution induced by alpha beta(25-35), which means there may be a close relationship between cell cycle and apoptosis.

Efflux of potassium ion is an important reason of HL-60 cells apoptosis induced by tachyplesin.

AIM: To investigate the role of intercellular potassium in tachyplesin-induced HL-60 cells apoptosis. METHODS: The concentration of intercellular potassium, cell volume and mitochondrial membrane potential were examined by flow cytometry. RESULTS: The concentration of intercellular potassium reduced in a time-dependent manner in tachyplesin-treated HL-60 cells. In addition, the loss of mitochondrial membrane potential was tightly coupled with the shrinkage of cell volume. Different caspase inhibitors protected against DNA degradation but did not prevent the loss of HL-60 cell viability induced by tachyplesin. Ba2+, which was a kind of blocker of volume-regulatory K+ channels, increased the viability of tachyplesin-treated HL-60 cells and maintained mitochondrial membrane potential and cell volume. CONCLUSION: Efflux of K+ was an important reason for apoptosis in tachyplesin-treated HL-60 cells. Efflux of K+ affected the viability of tachyplesin-treated HL-60 cells independent of the process of caspase activation.

[Effects of polyporus polysaccharide on activity and mRNA expression of inducible nitric oxide synthase in peritoneal macrophages of mice].

OBJECTIVE: To study the mechanisms of the antitumor and immunoregulation functions of polyporus polysaccharide (PPS). METHODS: The production of nitric oxide (NO), the activity and mRNA expression of inducible nitric oxide synthase (iNOS) in peritoneal macrophages of mice administered with different dose of PPS were observed by Griess reaction, fluorimetry assay and RT-PCR, respectively. RESULTS: PPS could elevate the iNOS activity with dose-dependence and stimulate the iNOS mRNA expression of peritoneal macrophages in mice. CONCLUSION: The regulation of PPS on the production of NO in peritoneal macrophages of mice may occur at transcriptional level of iNOS. This indicates that the mechanism of PPS's antitumor and immunoregulation functions may be related to increasing NO output of macrophages through stimulating iNOS's denovo synthesis.