Influence of ABC stroke score on late recurrence of paroxysmal atrial fibrillation following radiofrequency catheter ablation.

BACKGROUND: In this study we investigated the impact of ABC stroke score on the recurrence of paroxysmal atrial fibrillation (PAF) following radiofrequency catheter ablation (RFCA). METHODS: A total of 132 patients with PAF who underwent RFCA from October 2018 to September 2019 were included in this study. During the first phase of this study the patients were categorized into two groups based on late recurrence of atrial fibrillation after RFCA. In the second phase, the patients were further divided into two groups based on whether their ABC stroke score was ≥ 6.5. RESULT: The univariate analysis indicated that the risk factors for late recurrence of PAF included early recurrence, ABC stroke score, CHA2DS2-VASc score, and NT-proBNP (P < 0.05). Cox multivariate regression analysis revealed that ABC stroke score (P = 0.006) and early recurrence (P = 0.000) were independent predictors of late recurrence, and ABC stroke score ≥ 6.5 was a risk for predicting recurrence of PAF after RFCA with a sensitivity of 66.7% and specificity of 65.7%. After the completion of the 1:1 matching, the univariate Cox analysis indicated that an elevated score of ABC stroke (≥ 6.5) was an independent predictor of late recurrence of PAF (HR = 2.687, 95% CI: 1.036-6.971, P = 0.042). However, using an ABC stroke score cut off at 6.4 predicted the recurrence of atrial tachyarrhythmia with 85% sensitivity and 58.5% specificity. CONCLUSION: An ABC stroke score ≥ 6.4 is a predictor for late recurrence of PAF after RFCA.

Comparison of Second-Generation Cryoballoon Ablation and Quantitative Radiofrequency Ablation Guided by Ablation Index for Atrial Fibrillation.

We compared the efficacy and complication rates of quantitative radiofrequency ablation guided by ablation index (RFCA-AI) with those of second-generation cryoballoon ablation (CBA-2). Consecutive patients (n = 230) with symptomatic atrial fibrillation (AF) undergoing a first ablation CBA-2 (92 patients) or RFCA-AI (138 patients) procedure were enrolled in this study. The late recurrence rate in the CBA-2 group was higher than that in the RFCA-AI group (P = .012). Subgroup analysis showed the same result in patients with paroxysmal AF (PAF) (P = .039), but no difference was found in patients with persistent AF (P = .21). The average operation duration in the CBA-2 group (85 [75-99.5] minutes) was shorter than that in the RFCA-AI group (100 [84.5-120] minutes) (P < .0001), but the average exposure time (17.36(13.87-22.49) vs 5.49(4.00-8.24) minutes) in the CBA-2 group and X-ray dose (223.25(149.15-336.95) vs 109.15(80.75-168.7) mGym) were significantly longer than those in RFCA-AI group (P < .0001). Multivariate logistic regression analysis showed that left atrial diameter (LAD), early recurrence, and methods of ablation (cryoballoon ablation) were independent risk factors for late recurrence after AF ablation. Early recurrence of AF and LAD were independent risk factors for predicting late recurrence after AF ablation.

Effects of ivabradine on ventricular electrophysiological remodeling after myocardial infarction in rats.

Introduction: This study aims to investigate the effects of ivabradine (IVA) on ventricular electrophysiological remodeling after myocardial infarction (MI) in rats. Material and methods: A total of 60 male Sprague-Dawley rats were randomly divided into five groups: an MI group, an IVA group, a metoprolol (MET) group, an IVA + MET group, and a sham group. After a four-week intervention, the ventricular electrophysiological parameters were detected by multichannel electrophysiological polygraph. Then, the morphological characteristics were evaluated using hematoxylin and eosin (H&E) and Masson's staining, and the expression of phosphorylated connexin 43 (p-Cx43) in the left ventricular wall was detected through immunohistochemistry and the Western blot test. Results: The electrophysiological examination revealed that the induction rate and fatality rate of ventricular tachycardia (VT)/ventricular fibrillation (VF) were lower in both the IVA and the MET group, compared with the MI group (6/12, 6/12 vs. 10/11; and 1/12, 1/12 vs. 5/11; all p < 0.05), as well as the IVA + MET group (1/11 vs. 10/11, p < 0.01; and 1/11 vs. 5/11, p < 0.05). The induction rate of VT/VF was lower in the IVA + MET group, compared to the MET group (1/11 vs. 6/12, p < 0.05). H&E and Masson's staining revealed that compared with the MI group, the left ventricular infarction area was lower in the IVA, MET, and IVA + MET groups (p < 0.05, p < 0.05, and p < 0.01, respectively), while collagen volume fraction (CVF) also was lower in the other groups (all p < 0.01). The left ventricular infarction area and CVF both were lower in the IVA + MET group, compared to the MET group (p < 0.05 and p < 0.01, respectively). The immunohistochemistry and Western blot revealed that p-Cx43 expression was higher in the treatment groups, compared with the MI group (all p < 0.01). Conclusions: IVA can reduce the incidence of ventricular arrhythmia after MI in male rats by improving both structural and electrical remodeling, and the combination of IVA and MET is even more effective.

WITHDRAWN: Comparison of second-generation cryoballoon ablation and quantitative radiofrequency ablation guided by ablation index for atrial fibrillation.

Ahead of Print article withdrawn by publisher.

A promising Prognostic risk model for advanced renal cell carcinoma (RCC) with immune-related genes.

BACKGROUND: Renal cell carcinoma (RCC) is a third most common tumor of the urinary system. Nowadays, Immunotherapy is a hot topic in the treatment of solid tumors, especially for those tumors with pre-activated immune state. METHODS: In this study, we downloaded genomic and clinical data of RCC samples from The Cancer Genome Atlas (TCGA) database. Four immune-related genetic signatures were used to predict the prognosis of RCC by Cox regression analysis. Then we established a prognostic risk model consisting of the genes most related to prognosis from four signatures to value prognosis of the RCC samples via Kaplan-Meier (KM) survival analysis. An independent data from International Cancer Genome Consortium (ICGC) database were used to test the predictive stability of the model. Furthermore, we performed landscape analysis to assess the difference of gene mutant in the RCC samples from TCGA. Finally, we explored the correlation between the selected genes and the level of tumor immune infiltration via Tumor Immune Estimation Resource (TIMER) platform. RESULTS: We used four genetic signatures to construct prognostic risk models respectively and found that each of the models could divide the RCC samples into high- and low-risk groups with significantly different prognosis, especially in advanced RCC. A comprehensive prognostic risk model was constructed by 8 candidate genes from four signatures (HLA-B, HLA-A, HLA-DRA, IDO1, TAGAP, CIITA, PRF1 and CD8B) dividing the advanced RCC samples from TCGA database into high-risk and low-risk groups with a significant difference in cancer-specific survival (CSS). The stability of the model was verified by independent data from ICGC database. And the classification efficiency of the model was stable for the samples from different subgroups. Landscape analysis showed that mutation ratios of some genes were different between two risk groups. In addition, the expression levels of the selected genes were significantly correlated with the infiltration degree of immune cells in the advanced RCC. CONCLUSIONS: Sum up, eight immune-related genes were screened in our study to construct prognostic risk model with great predictive value for the prognosis of advanced RCC, and the genes were associated with infiltrating immune cells in tumors which have potential to conduct personalized treatment for advanced RCC.

Atrial High-Rate Event Incidence and Predictors in Patients With Permanent Pacemaker Implantation.

Objective: The present study aims to investigate the incidence and predictors of atrial high-rate events (AHREs) in patients with permanent pacemaker implants. Methods: A total of 289 patients who were implanted with a dual-chamber pacemaker due to complete atrioventricular block or symptomatic sick sinus syndrome (SSS) and had no previous history of atrial fibrillation were included in the present study. AHREs are defined as events with an atrial frequency of ≥175 bpm and a duration of ≥5 min. The patients were divided into two groups according to whether or not AHREs were detected during the follow-up: group A (AHRE+, n = 91) and group N (AHRE-, n = 198). Results: During the 12-month follow-up period, AHREs were detected in 91 patients (31.5%). The multivariate Cox regression analysis revealed that patient age [odds ratio [OR] = 1.041; 95% confidence interval [CI], 1.018-1.064; and P < 0.001], pacemaker implantation due to symptomatic SSS (OR = 2.225; 95% CI, 1.227-4.036; and P = 0.008), and the percentage of atrial pacing after pacemaker implantation (OR = 1.010; 95% CI, 1.002-1.017; and P = 0.016) were independent AHRE predictors. Conclusion: The AHRE detection rate in patients with pacemaker implants was 31.5%. Patient age, pacemaker implantation due to symptomatic SSS, and the percentage of atrial pacing after pacemaker implantation were independent AHRE predictors.

The impact of echocardiographic parameter ratio of E/E' on the late recurrence paroxysmal atrial fibrillation in patients accepted radiofrequency catheter ablation: A retrospective clinical study.

This study aimed to evaluate the impact of the echocardiographic parameter ratio E/E' on the late recurrence of paroxysmal atrial fibrillation in patients after receiving radiofrequency catheter ablation.We retrospectively examined total of 288 paroxysmal atrial fibrillation (PAF) patients that underwent a preliminary radiofrequency catheter ablation (RFCA) in our hospital. During the first phase in this study, the patients were divided into 2 groups upon AF recurrence after RFCA: Recurrent group, n = 67 patients with rapid trial arrhythmia that lasted for more than 30 seconds at 3 months after RFCA and the Nonrecurrent group, n = 221. The clinical conditions were compared between the 2 groups. During the second phase of this study, based on the results in the first phase, the patients were divided into another 2 groups according to whether the ratio of E/E' ≥13 .45: Higher ratio of E/E' group, n = 55 and Lower ratio of E/E' group n = 233. The late AF recurrent rates were also compared between the 2 groups.During the first phase, the univariate analysis indicated that the risk factors(P < .05)for PAF late recurrence included early recurrence, E', and the ratio E/E'. The Cox multivariate analysis showed that the ratio of E/E' and early recurrence were the independent predictors for late PAF recurrence. The ratio of E/E' that was cut off at 13.45 also predicted atrial tachyarrhythmia recurrence with 40.3% sensitivity and 87.3% specificity. In the second phase, after completing the 1:1 matching, the Kaplan-Meier analysis indicated that the ratio of E/E' ≥ 13.45 was associated with further recurrences after RFCA (log-rank P = .009), compared to the patients with a ratio of E/E' < 13.45. The univariate Cox analysis indicated that an elevated ratio of E/E'(≥13.45) was the independent predictor for late PAF recurrence (HR = 3.322, 95%CI: 1.560-7.075, P = .002). However, the ratio of E/E' cut off at 13.25 predicted atrial tachyarrhythmia recurrence with 75% sensitivity and 62.2% specificity.The ratio of E/E' ≥ 13.25 is an important predictor of the late recurrence of paroxysmal atrial fibrillation (PAF) after radiofrequency catheter ablation (RFCA).

Combining current of injury and P-wave sensing optimized right atrial active-fixation leads implantation.

BACKGROUND: Pacing parameters may influence pacing lead life and pacemaker life. This study sought to determine whether different right atrial active-fixation lead implantation parameters are associated with chronic pacing performance. METHODS: A retrospective observational study was conducted on all consecutive patients implanted with an active-fixation atrial lead at our institution from July 2014 to October 2016. Atrial leads with a P-wave sensing of ≥2.0 mV, a pacing threshold of ≤1.0 V, and a lead impedance of 300-1,000 ohms were assigned as the optimized group, while atrial leads that did not meet these specifications were assigned as the conventional group. A total of 98 patients who received active-fixation atrial leads (55 patients were male, mean age was 63±12 years old) were studied, and the lead performance of 67 of these patients were optimized in 3 months. RESULTS: In the multivariate analysis, current of injury [COI; COI10min, odds ratio (OR): 0.296, 95% confidence interval (CI): 0.093-0.939, P=0.039] and P-wave sensing (P10min, OR: 0.449, 95% CI: 0.265-0.762, P=0.003) were recorded at 10 minutes after lead fixation, and were considered predictors of lead optimized performance. The cut-off value of COI10min and P10min was 1.04 mV (sensitivity: 0.58 and specificity: 0.77) and 3.3 mV (sensitivity: 0.67 and specificity: 0.74), respectively, for predicting lead optimized performance after 3 months. COI10min ≥1.04 mV and P10min ≥3.3 mV were combined and considered as the predictable criteria, and the area under the ROC curve was 0.806 (sensitivity =0.70 and specificity =0.77). CONCLUSIONS: Optimized atrial lead performance at 3 months was predictable from COI10min ≥1.04 mV and P10min ≥3.3 mV.

The correlation of pulmonary arterial hypertension with late recurrence of paroxysmal atrial fibrillation after catheter ablation.

BACKGROUND: Paroxysmal atrial fibrillation (PAF) is one of the most common clinical arrhythmias. Although radiofrequency catheter ablation (RFCA) for the treatment of atrial fibrillation has continuously matured and developed in recent years, some patients treated with RFCA continued to have atrial fibrillation recurrence, and the recurrence rate was high. Determining indicators to predict the recurrence of PAF after RFCA is significantly important for improving the surgical success rate and guiding clinical work. This study aimed to investigate the influence of pulmonary arterial hypertension (PAH) on the late recurrence of PAF after RFCA. METHODS: A total of 300 patients with PAF, who underwent RFCA for the first time at the Department of Cardiology of Fujian Union Medical College Hospital from January 2013 to October 2016, were retrospectively studied. These patients were regularly followed-up from 3 months at least to 3 years and clinical data were collected. In order to observe the 100 PAF patients with PAH were assigned into the observation group, and 200 PAF patients without PAH were assigned as the control group. PAH and its related clinical characteristics were evaluated by univariate analysis of variance (ANOVA) and logistic regression analysis. RESULTS: The follow-up results revealed that 34 patients had early recurrence, and the early arrhythmia recurrence rate was 11.3%. Furthermore, 22 patients had late recurrence, including 19 patients with atrial fibrillation and three patients with atrial flutter; and the late recurrence rate was 7.3%. The univariate ANOVA revealed that PAH (P=0.001), early recurrence (P=0.014) and Left atrial diameter (LAD) (P=0.023) had significant effects on late recurrence after PAF ablation. Furthermore, logistic regression analysis revealed that PAH (P=0.049, OR =1.053, 95% CI: 1.000-1.109) was independently correlated to late recurrence of PAF. CONCLUSIONS: PAH is a predictive factor for late recurrence of PAF after RFCA.

System Pharmacology-Based Dissection of the Synergistic Mechanism of Huangqi and Huanglian for Diabetes Mellitus.

The rapidly increasing diabetes mellitus (DM) is becoming a major global public health issue. Traditional Chinese medicine (TCM) has a long history of the treatment of DM with good efficacy. Huangqi and Huanglian are one of the most frequently prescribed herbs for DM, and the combination of them occurs frequently in antidiabetic formulae. However, the synergistic mechanism of Huangqi (Radix Astragali) and Huanglian (Rhizoma Coptidis) has not been clearly elucidated. To address this problem, a feasible system pharmacology model based on chemical, pharmacokinetic and pharmacological data was developed via network construction approach to clarify the synergistic mechanisms of these two herbs. Forty-three active ingredients of Huangqi (mainly astragalosides and isoflavonoids) and Huanglian (primarily isoquinoline alkaloids) possessing favorable pharmacokinetic profiles and biological activities were selected, interacting with 50 DM-related targets to provide potential synergistic therapeutic actions. Systematic analysis of the constructed networks revealed that these targets such as GLUT2, NOS2, PTP1B, and IGF1R were mainly involved in PI3K-Akt signaling pathway, insulin resistance, insulin signaling pathway, and HIF-1 signaling pathway, and were mainly located in retina, pancreatic islet, smooth muscle, immunity-related organ tissues, and whole blood. The contribution index of every active ingredient also indicated five compounds, including berberine (BBR), astragaloside IV (AIV), quercetin, palmatine, and astragalus polysaccharides, as the principal components of this herb combination. These results successfully explained the polypharmcological and synergistic mechanisms underlying the efficiency of Huangqi and Huanglian for the treatment of DM and its complications.

Predictable Chronic Mild Stress during Adolescence Promotes Fear Memory Extinction in Adulthood.

Early-life stress in adolescence has a long-lasting influence on brain function in adulthood, and it is mostly recognized as a predisposing factor for mental illnesses, such as anxiety and posttraumatic stress disorder. Previous studies also indicated that adolescent predictable chronic mild stress (PCMS) in early life promotes resilience to depression- and anxiety-like behaviors in adulthood. However, the role of PCMS in associated memory process is still unclear. In the present study, we found that adolescent PCMS facilitated extinction and inhibited fear response in reinstatement and spontaneous recovery tests in adult rats, and this effect was still present 1 week later. PCMS in adolescence increased the activity of brain-derived neurotrophic factor (BDNF)-extracellular signal-regulated kinase 1/2 (ERK1/2) signaling in infralimbic cortex (IL) but not prelimbic cortex in adulthood. Intra-IL infusion of BDNF antibody and the ERK1/2 inhibitor U0126 reversed PCMS-induced enhancement of fear extinction. Moreover, we found that PCMS decreased DNA methylation of the Bdnf gene at exons IV and VI and elevated the mRNA levels of Bdnf in the IL. Our findings indicate that adolescent PCMS exposure promotes fear memory extinction in adulthood, which reevaluates the traditional notion of adolescent stress.

Epigenetic modification of PKMζ rescues aging-related cognitive impairment.

Cognition is impacted by aging. However, the mechanisms that underlie aging-associated cognitive impairment are unclear. Here we showed that cognitive decline in aged rats was associated with changes in DNA methylation of protein kinase Mζ (PKMζ) in the prelimbic cortex (PrL). PKMζ is a crucial molecule involved in the maintenance of long-term memory. Using different behavioral models, we confirmed that aged rats exhibited cognitive impairment in memory retention test 24 h after training, and overexpression of PKMζ in the PrL rescued cognitive impairment in aged rats. After fear conditioning, the protein levels of PKMζ and the membrane expression of GluR2 increased in the PrL in young and adult rats but not in aged rats, and the levels of methylated PKMζ DNA in the PrL decreased in all age groups, whereas the levels of unmethylated PKMζ DNA increased only in young and adult rats. We also found that environmentally enriched housing reversed the hypermethylation of PKMζ and restored cognitive performance in aged rats. Inactivation of PKMζ prevented the potentiating effects of environmental enrichment on memory retention in aged rats. These results indicated that PKMζ might be a potential target for the treatment of aging-related cognitive impairment, suggesting a potential therapeutic avenue.

Reversal of P-gp and BCRP-mediated MDR by tariquidar derivatives.

With an aim to generate non-toxic, specific and highly potent multidrug resistance (MDR) modulators, a novel series of anthranilic acid amide-substituted tariquidar derivatives were synthesized. The new compounds were evaluated for their cytotoxicity toward normal human colon fibroblasts (CCD18-Co), human gastric epithelial cell line (HFE) and primary rat liver cells, and for their ability to inhibit P-gp/BCRP-mediated drug efflux and reversal of P-gp and BCRP-mediated MDR in parental and drug-resistant cancer cell lines (LCC6 MDR1, MCF-7 FLV1000, R-HepG2, SW620-Ad300). While tariquidar is highly toxic to normal cells, the new derivatives exhibited much lower or negligible cytotoxicity. Some of the new tariquidar derivatives inhibited both P-gp and BCRP-mediated drug efflux whereas a few of them bearing a sulfonamide functional group (1, 5, and 16) are specific to P-gp. The new compounds were also found to potentiate the anticancer activity of the transporter substrate anticancer drugs in the corresponding transporter-overexpressing cell lines. The extent of resistance reversal was found to be consistent with the transporter inhibitory effect of the new derivatives. To further understand the mechanism of P-gp and BCRP inhibition, the tariquidar derivatives were found to interact with the transporters using an antibody-based UIC2 or 5D3 shift assay. Moreover, the transporters-inhibiting derivatives were found to modulate the ATPase activities of the two MDR transporters. Our data thus advocate further development of the new compounds for the circumvention of MDR.

Telmisartan reduces atrial arrhythmia susceptibility through the regulation of RAS-ERK and PI3K-Akt-eNOS pathways in spontaneously hypertensive rats.

Telmisartan is an angiotensin II receptor blocker that displays unique PPAR-γ modulating activity. PPAR-γ agonists have been shown to decrease susceptibility to atrial fibrillation through their antioxidant and antiapoptotic effects. The aim of this study was to determine whether telmisartan would have a greater effect on susceptibility to atrial arrhythmia in a hypertensive rat model than valsartan, which is a traditional angiotensin II receptor blocker. In this study, spontaneously hypertensive rats were treated with 10 mg·(kg body mass)(-1)·d(-1) telmisartan (TEL group), 10 mg·(kg body mass)(-1)·d(-1) valsartan (VAL group), or vehicle (saline; SHR group) for 4 weeks. Age-matched Wistar-Kyoto rats (WKY) were used as normotensive controls. After 4 weeks of treatment, we performed echocardiographic assessment, electrophysiological analysis, histological evaluation, and Western blot analysis. Telmisartan decreased systolic blood pressure to a similar extent as valsartan. Relative to the WKY controls, atrial arrhythmia susceptibility was significantly increased in the SHR group, and was significantly decreased by both telmisartan and valsartan, albeit to a greater extent with telmisartan. Arrhythmogenic atrial remodeling, including enlargement of the left atrium, myocyte hypertrophy, interstitial fibrosis, and myocyte apoptosis, was observed in the SHR group, and was accompanied by activated RAS-ERK signaling and suppressed PI3K-Akt-eNOS signaling. The results suggest that telmisartan reduced susceptibility to atrial arrhythmia to a greater extent than valsartan, ameliorated atrial remodeling, and reversed imbalances in the RAS-ERK and PI3K-Akt-eNOS pathways.

Preparation and characterization of injectable Mitoxantrone poly (lactic acid)/fullerene implants for in vivo chemo-photodynamic therapy.

Fullerene (C60) L-phenylalanine derivative attached with poly (lactic acid) (C60-phe-PLA) was developed to prepare injectable Mitoxantrone (MTX) multifunctional implants. C60-phe-PLA was self-assembled to form microspheres consisting of a hydrophilic antitumor drug (MTX) and a hydrophobic block (C60) by dispersion-solvent diffusion method. The self-assembled microspheres showed sustained release pattern almost 15days in vitro release experiments. According to the tissue distribution of C57BL mice after intratumoral administration of the microspheres, the MTX mainly distributed in tumors, and rarely in heart, liver, spleen, lung, and kidney. Photodynamic antitumor efficacy of blank microsphere was realized. Microspheres afforded high antitumor efficacy without obvious toxic effects to normal organs, owing to its significantly increased MTX tumor retention time, low MTX levels in normal organs and strong photodynamic activity of PLA-phe-C60. These C60-phe-PLA microspheres may be promising for the efficacy with minimal side effects in future treatment of solid tumors.

Therapeutic effects of fucoidan in 6-hydroxydopamine-lesioned rat model of Parkinson's disease: Role of NADPH oxidase-1.

AIMS: To explore the effect of fucoidan treatment on oxidative stress-mediated dopaminergic neuronal damage and its potential mechanisms. METHODS: The effect of fucoidan was investigated in a 6-hydroxydopamine (6-OHDA) rat model of PD, an animal model considered appropriate for preclinical studies of PD therapy. The effects of fucoidan treatment on animal behavior and the survival ratio of dopaminergic neurons were investigated. We further observed the effect of fucoidan on microglia and the NADPH oxidases-1 (Nox1), a family of enzymes generating reactive oxygen species (ROS). RESULTS: We found that chronic fucoidan administration mitigated the motor dysfunction induced by 6-OHDA. Similarly, fucoidan reduced the loss of DA neurons in the SNc and DA fibers in the striatum in 6-OHDA-lesioned rats. Moreover, we found that fucoidan inhibited the 6-OHDA-stimulating expression of Nox1 in both tyrosine hydroxylase (TH)-positive neurons and non-TH-positive neurons, prevented Nox1-sensitive oxidative stress and cell damage in SNc neurons. Fucoidan also effectively inhibited nigral microglial activation. CONCLUSION: These results support the beneficial effect of fucoidan in 6-OHDA-lesioned rat model of PD. Fucoidan may suppress the Nox1-triggered oxidative stress in the SNc to protect DA neurons from 6-OHDA-induced toxicity and achieve its beneficial effect.

5-Aminolevulinic acid-loaded fullerene nanoparticles for in vitro and in vivo photodynamic therapy.

This report explores some properties of 80-200 nm nanoparticles containing 5-aminolevulinic acid (ALA) and fullerene (C60) for photodynamic therapy (PDT). Compared with ALA, the nanoparticles yielded more protoporphyrin IX (PpIX) formation in cells and tissues and to a significant improvement in antitumor efficacy in tumor-bearing mice. Maximum levels of PpIX were obtained 4 h after administration and selective PpIX formation in tumor was observed. These nanoparticles appear to be a useful vehicle for drug delivery purposes. In this study, a procedure for preparing fullerene nanoparticles containing ALA was developed. The product alone exhibited no detectable toxicity in the dark and was superior to ALA alone in promoting PpIX biosynthesis and PDT efficacy both in culture and in a murine tumor model. These results suggest that this procedure could be the basis for an improved PDT protocol for cancer control.

Evaluation and SAR analysis of the cytotoxicity of tanshinones in colon cancer cells.

AIM: This study was designed to evaluate the anti-cancer actions of tanshinone I and tanshinone IIA, and six derivatives of tanshinone IIA on normal and cancerous colon cells. Structure activity relationship (SAR) analysis was conducted to delineate the significance of the structural modifications of tanshinones for improved anti-cancer action. METHOD: Tanshinone derivatives were designed and synthesized according to the literature. The cytotoxicity of different compounds on colon cancer cells was determined by the MTT assay. Apoptotic activity of the tanshinones was measured by flow cytometry (FCM). RESULTS: Tanshinone I and tanshinone IIA both exhibited significant cytotoxicity on colon cancer cells. They are more effective in p53(+/+) colon cancer cell line. It was also noted that the anti-cancer activity of tanshinone I was more potent and selective. Two of the derivatives of tanshinone IIA (N1 and N2) also exhibited cytotoxicity on colon cancer cells. CONCLUSION: The anti-colon cancer activity of tanshinone I was more potent and selective than tanshinone IIA, and is p53 dependent. The derivatives obtained by structural modifications of tanshinone IIA exhibited lower cytotoxicity on both normal and colon cancer cells. From steric and electronic characteristics point of view, it was concluded that structural modifications of ring A and furan or dihydrofuran ring D on the basic structure of tanshinones influences the activity. An increase of the delocalization of the A and B rings could enhance the cytotoxicity of such compounds, while a non-planar and small sized D ring region would provide improved anti-cancer activity.

Preparation and characterization of fullerene (C60) amino acid nanoparticles for liver cancer cell treatment.

The properties of an ideal photosensitizer are water solubility, low cytotoxicity in the dark, high ability to produce reactive oxygen species (ROS). The characteristics of water-soluble fullerene (C60) amino acid nanoparticles as a photosensitizer were evaluated. C60 modified with l-phenylalanine (C60-phe) or glycine (C60-gly) was very efficient to carry out photodynamic activity leading to cleavage of plasmid DNA in vitro. These C60 amino acid nanoparticles were the most active photosensitizer against human Liver cancer cells and induced cancer cells apoptosis after illumination. However, these derivatives exhibited no significant cytotoxicity in dark. It produced diffuse intracellular fluorescence when 2',7'-dichlorfluorescein-diacetate (DCFH-DA) was added as an ROS probe, suggesting phototoxicity of these derivatives related with the generation of intracellular ROS. These findings indicate that these fullerene derivatives may be excellent candidate PDT enhancing agents.

[Time course of myocardial NF-kappaB activation post coronary microembolization].

OBJECTIVE: To investigate the time course of myocardial NF-kappaB activation and association with cardiac function and other pro-inflammation cytokines following coronary microembolization (CME). METHODS: CME was induced by homologous microthrombotic particle suspension injection into left ventricle with simultaneous short-term ascending aorta clamping. The CME rats were randomized to untreated group and pyrrolidine dithiocarbamate (PDTC, a specific NF-kappaB inhibitor) treated group (n = 32 respectively). The rats were sacrificed on day 1, 3, 7 and 14 post-operationally (n = 8 each). Twenty-four rats were sham-operated and served as controls. NF-kappaB DNA-binding activity was evaluated by electrophoretic mobility shift assay (EMSA), protein expressions of TNFalpha, IL-6 and ICAM-1 were analyzed by Western blotting, the dynamic alterations of TNFalpha, IL-6 and ICAM-1 mRNA were quantitatively assessed by Real-time PCR post hemodynamic measurements. RESULTS: NF-kappaB DNA-binding activity in CME group was significantly increased than that of sham group on day 1, peaked at day 3 and was similar as that in sham rats on day 14. The protein and mRNA expressions of TNFalpha, IL-6 and ICAM-1 were significantly increased in CME group at various time points compared those in sham rats. NF-kappaB DNA-binding activity positively correlated with mRNA expressions of TNFalpha, IL-6, ICAM-1, respectively (r = 0.72, P < 0.05; r = 0.94, P < 0.01; r = 0.62, P < 0.05). PDTC significantly suppressed protein and mRNA expressions of TNFalpha, IL-6 and ICAM-1 (P < 0.05) and improved left ventricular function. CONCLUSION: NF-kappaB activation post CME could upregulate the gene transcriptions of TNFalpha, IL-6, ICAM-1 and enhance inflammatory responses and aggravate left ventricular dysfunction.