Although superoxide dismutase (SOD) and malondialdehyde (MDA) affect Delayed Onset Muscle Soreness (DOMS), their effects are unclear in rectus femoris muscles (RFM) of rats with different eccentric exercise programs and time points. The purpose of this study is to investigate the effects of the various eccentric exercise programs at different time points on the SOD mRNA expression and MDA using rat as the animal model.
248 male rats were randomly divided into 4 groups: control group (CTL, n = 8), once-only exercise group (OEG, n = 80), continuous exercise group (CEG, n = 80), and intermittent exercise group (IEG, n = 80). Each exercise group was divided into 10 subgroups that exercised 0.5 h, 6 h, 12 h, 24 h, 48 h, 72 h, 96 h, 120 h, 144 h, or 168 h. Rats were sacrificed and their SOD mRNA expression, and MDA concentrations of skeletal muscle tissue were measured.
The specimen in all eccentric exercise programs showed increased RFM SOD1 mRNA expression levels at 0.5 h (P<0.05), and decreased RFM SOD3 mRNA expression at 0.5 h (P<0.05). The continuous eccentric exercise (CE) significantly enhanced muscle SOD2 mRNA level at 0.5 h (P<0.05). After once-only eccentric exercise (OE), SOD1, SOD2, and SOD3 mRNA expression significantly increased at 96 h, whereas MDA concentrations decreased at 96 h. After CE, the correlation coefficients of SOD1, SOD2, SOD3 mRNA expression levels and MDA concentrations were −0.814, −0.763, −0.845 (all P<0.05) at 12 h.
Regular eccentric exercise, especially CE could enhance SOD1 and SOD2 mRNA expression in acute stage and the SOD2 mRNA expression correlates to MDA concentration in vivo, which may improve the oxidative adaption ability of skeletal muscles.
Study of the human microbiota in relation to human health and disease is a rapidly expanding field. To fully understand the complex relationship between the human gut microbiota and disease risks, study designs that capture the variation within and between human subjects at the population level are required, but this has been hampered by the lack of cost-effective methods to characterize this variation. Illumina sequencing is inexpensive and produces millions of reads per run, but it is unclear whether short reads can adequately represent the microbial community of a human host. In this study, we examined the utility of a profiling method, microbial nucleotide signatures (MNS), focused on low-depth sampling of the human microbiota using Ilumina short reads. This method is intended to aid in human population-based studies where large sample sizes are required to adequately capture variation in disease or phenotype differences. We found that, by calculating the nucleotide diversities along the sequenced 16S rRNA gene region, which did not require assembly or phylogenetic identification, we were able to differentiate the gut microbial nucleotide signatures of 9 healthy individuals. When we further subsampled the reads down to 40,000 reads (51 bp long) per sample, the diversity profiles were relatively unchanged. Applying MNS to a public datasets showed that it could differentiate body site differences. The scalability of our approach offers rapid classification of study participants for studies with the sample sizes required for epidemiological studies. Using MNS to classify the microbiome associated with a disease state followed by targeted in-depth sequencing will give a comprehensive understanding of the role of the microbiome in human health.
The findings on the association between fish intake and the risk of heart failure (HF) have been inconsistent. The purpose of this study was to clarify this potential association. We searched for relevant studies in the PubMed database through January 2012 and manually reviewed references. Five independent prospective cohort studies involving 5,273 cases and 144,917 participants were included. The summary relative risk estimates (SRRE) based on the highest compared with the lowest category of fish consumption were estimated by variance-based meta-analysis. In addition, we performed sensitivity and dose-response analyses to examine the association. Overall, an absence of an association between fish intake and HF was observed (SRRE=1.00; 95% CI, 0.81–1.24). However, fried fish intake positively associated with HF (SRRE=1.40; 95% CI, 1.22–1.61). In addition, dose-response analysis of fried fish suggested that each increment of six fried fish per month corresponded to a 37% increase of HF rate (RR=1.37; 95% CI, 1.20–1.56). In conclusion, our findings suggest that there is no significant association between fish intake and risk of HF, with the exception of a possible positive correlation with individuals comsuming fried fish, based on a limited number of studies. Future studies are required to confirm these findings.
fish; nutrition; heart failure; meta-analysis
Artemisinin analogue SM934 was previously reported to possess immunosuppressive properties. The aim of this study was to determine the effects and the underlying mechanisms of SM934 in murine experimental autoimmune encephalomyelitis (EAE).
Female C57BL/6 mice immunized with MOG35–55 were treated with or without SM934, then the clinical scores and other relevant parameters were assessed. Th1, Th17 and regulatory T (Treg) cell profiles were determined through ELISA, qRT-PCR, flow cytometry and BrdU incorporation assay. The effects of SM934 on Th1, Th17 and Treg cells differentiation were explored through intracellular staining and flow cytometry examination.
In vivo, administration of SM934 significantly inhibited the development of EAE and suppressed the elevation of serum IL-17. Ex vivo, upon antigen-recall stimulation, IL-2, IFN-γ, IL-17 and IL-6 production were decreased, whereas IL-10 and TGF-β production were increased from the splenocytes isolated from SM934-treated mice. Consistently, both flow cytometry and qRT-PCR results showed that SM934 treatment significantly increased the Treg, while strongly suppressed the Th17 and Th1, responses in the peripheral. Furthermore, in the spinal lesion, SM934 treatment dramatically decreased the infiltration of CD4+ T cells, within which the Treg cells percentage was enlarged, whereas the Th17, but not Th1 percentage, was significantly decreased comparing with the vehicle-treated groups. Finally, both BrdU incorporation and in vitro Treg differentiation assays revealed that SM934 treatment could directly promote the expansion of Treg cells in vivo and in vitro.
Taken together, this study demonstrated that SM934 treatment could ameliorate the murine EAE disease, which might be mediated by inducing Treg differentiation and expansion.
Somatic mutation of the tumor suppressor gene LKB1 occurs frequently in lung cancer where it causes tumor progression and metastasis, but the underlying mechanisms remain mainly unknown. Here, we show that the oncogene NEDD9 is an important downstream mediator of lung cancer progression evoked by LKB1 loss. In de novo mouse models, RNAi-mediated silencing of Nedd9 inhibited lung tumor progression, whereas ectopic NEDD9 expression accelerated this process. Mechanistically, LKB1 negatively regulated NEDD9 transcription by promoting cytosolic translocation of CRTC1 from the nucleus. Notably, ectopic expression of either NEDD9 or CRTC1 partially reversed the inhibitory function of LKB1 on metastasis of lung cancer cells. In clinical specimens, elevated expression of NEDD9 was associated with malignant progression and metastasis. Collectively, our results decipher the mechanism through which LKB1 deficiency promotes lung cancer progression and metastasis, and provide a mechanistic rationale for therapeutic attack of these processes.
To evaluate the effect of Chinese herbal medicine (CHM) on albuminuria levels in patients with diabetic nephropathy (DN), we performed comprehensive searches on Medline database, Cochrane Library, CNKI database, CBM database, Wanfang database, and VIP database up to December 2012. A total of 29 trials including 2440 participants with DN met the selection criteria. CHM was tested to be more effective in reducing urinary albumin excretion rate (UAER) (MD −82.95 μg/min, [−138.64, −27.26]) and proteinuria (MD −565.99 mg/24 h, [−892.41, −239.57]) compared with placebo. CHM had a greater beneficial effect on reduction of UAER (MD −13.41 μg/min, [−20.63, −6.19]) and proteinuria (MD −87.48 mg/24 h, [−142.90, −32.06]) compared with angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). Combination therapy with CHM and ACEI/ARB showed significant improvement in UAER (MD −28.18 μg/min, [−44.4, −11.97]), urinary albumin-creatinine ratio (MD −347.00, [−410.61, −283.39]), protein-creatinine ratio (MD −2.49, [−4.02, −0.96]), and proteinuria (MD −26.60 mg/24 h, [−26.73, −26.47]) compared with ACEI/ARB alone. No serious adverse events were reported. CHM seems to be an effective and safe therapy option to treat proteinuric patients with DN, suggesting that further study of CHM in the treatment of DN is warranted in rigorously designed, multicentre, large-scale trials with higher quality worldwide.
Paraganglioma of the urinary bladder is rare, accounting for <0.05% of all bladder tumors. Common clinical findings in patients with bladder paraganglioma include hematuria and intermittent hypertension during urination, along with generalized symptoms due to increased levels of catecholamines. Although unsuspected bladder paraganglioma may result in intraoperative hypertensive crises, these may be avoided if characteristic imaging signs are observed. The present study reports a case in which a patient with unsuspected paraganglioma experienced a severe hypertensive episode during cystoscopic tumor resection. Although this case had typical computed tomographic characteristics of the bladder paraganglioma, the possibility of the paraganglioma pre-operatively was not taken into account.
paraganglioma; pheochromocytoma; urinary bladder; computed tomography
To evaluate if the Apgar score remains pertinent in contemporary practice after more than 50 years of wide use, and to assess the value of the Apgar score in predicting infant survival, expanding from the neonatal to the post-neonatal period.
The U.S. linked live birth and infant death dataset was used, which included 25,168,052 singleton births and 768,305 twin births. The outcome of interest was infant death within 1 year after birth. Cox proportional hazard-model was used to estimate risk ratio of infant mortality with different Apgar scores.
Among births with a very low Apgar score at five minutes (1–3), the neonatal and post-neonatal mortality rates remained high until term (≥ 37 weeks). On the other hand, among births with a high Apgar score (≥7), neonatal and post-neonatal mortality rate decreased progressively with gestational age. Non-Hispanic White had a consistently higher neonatal mortality than non-Hispanic Black in both preterm and term births. However, for post-neonatal mortality, Black had significantly higher rate than White. The pattern of changes in neonatal and post-neonatal mortality by Apgar score in twin births is essentially the same as that in singleton births.
The Apgar score system has continuing value for predicting neonatal and post-neonatal adverse outcomes in term as well as preterm infants, and is applicable to twins and in various race/ethnic groups.
MicroRNAs (miRNAs) are endogenously encoded small RNAs that post-transcriptionally regulate gene expression and play essential roles in numerous developmental and physiological processes. Currently, little information on the transcriptome and tissue-specific expression of miRNAs is available in the model non-edible oilseed crop castor bean (Ricinus communis L.), one of the most important non-edible oilseed crops cultivated worldwide. Recent advances in sequencing technologies have allowed the identification of conserved and novel miRNAs in many plant species. Here, we used high-throughput sequencing technologies to identify and characterize the miRNAs in castor bean.
Five small RNA libraries were constructed for deep sequencing from root tips, leaves, developing seeds (at the initial stage, seed1; and at the fast oil accumulation stage, seed2) and endosperms in castor bean. High-throughput sequencing generated a large number of sequence reads of small RNAs in this study. In total, 86 conserved miRNAs were identified, including 63 known and 23 newly identified. Sixteen miRNA isoform variants in length were found from the conserved miRNAs of castor bean. MiRNAs displayed diverse organ-specific expression levels among five libraries. Combined with criteria for miRNA annotation and a RT-PCR approach, 72 novel miRNAs and their potential precursors were annotated and 20 miRNAs newly identified were validated. In addition, new target candidates for miRNAs newly identified in this study were proposed.
The current study presents the first high-throughput small RNA sequencing study performed in castor bean to identify its miRNA population. It characterizes and increases the number of miRNAs and their isoforms identified in castor bean. The miRNA expression analysis provides a foundation for understanding castor bean miRNA organ-specific expression patterns. The present study offers an expanded picture of miRNAs for castor bean and other members in the family Euphorbiaceae.
Ideal wound dressing materials should create a good healing environment, with immediate hemostatic effects and antimicrobial activity. In this study, chitosan/konjac glucomannan (CS/KGM) films embedded with gentamicin-loaded poly(dex-GMA/AAc) nanoparticles (giving GNP-CS/KGM films) were prepared as novel wound dressings. The results revealed that the modified CS/KGM films could be used as effective wound dressings and had significant hemostatic effects. With their microporous structure, the films could effectively absorb water from blood and trap blood cells. The gentamicinloaded poly(dex-GMA/AAc) nanoparticles (GNPs) also further promoted blood clotting, with their favorable water uptake capacity. Thus, the GNP-CS/KGM films had wound healing and synergistic effects that helped to stop bleeding from injuries, and also showed good antibiotic abilities by addition of gentamicin to the NPs. These GNPCS/KGM films can be considered as promising novel biodegradable and biocompatible wound dressings with hemostatic capabilities and antibiotic effects for treatment of external bleeding injuries.
The beet armyworm, Spodoptera exigua (Hübner), is a serious pest worldwide that causes significant losses in crops. Unfortunately, genetic resources for the beet armyworm is extremely scarce. To improve these resources we sequenced the transcriptome of S. exigua representing all stages including eggs, 1st to 5th instar larvae, pupae, male and female adults using the Illumina Solexa platform. We assembled the transcriptome with Trinity that yielded 31,414 contigs. Of these contigs, 18,592 were annotated as protein coding genes by Blast searches against the NCBI nr database. It has been shown that knockdown of important insect genes by dsRNAs or siRNAs is a feasible mechanism to control insect pests. The first key step towards developing an efficient RNAi-mediated pest control technique is to find suitable target genes. To screen for effective target genes in the beet armyworm, we selected nine candidate genes. The sequences of these genes were amplified using the RACE strategy. Then, siRNAs were designed and chemically synthesized. We injected 2 µl siRNA (2 µg/µl) into the 4th instar larvae to knock down the respective target genes. The mRNA abundance of target genes decreased to different levels (∼20–94.3%) after injection of siRNAs. Knockdown of eight genes including chitinase7, PGCP, chitinase1, ATPase, tubulin1, arf2, tubulin2 and arf1 caused a significantly high level of mortality compared to the negative control (P<0.05). About 80% of the surviving insects in the siRNA-treated group of five genes (PGCP, chitinase1, tubulin1, tubulin2 and helicase) showed retarded development. In chitinase1-siRNA and chitinase7-siRNA administered groups, 12.5% survivors exhibited “half-ecdysis”. In arf1-siRNA and arf2-siRNA groups, the body color of 15% became black 48 h after injections. In summary, the transcriptome could be a valuable genetic resource for identification of genes in S. exigua and this study provided putative targets for RNAi pest control.
Bronchiectasis is characterized by an irreversible dilatation of bronchi and is associated with lung fibrosis. MMP-1 polymorphism may alter its transcriptional activity, and differentially modulate bronchial destruction and lung fibrosis.
To investigate the association of MMP-1 polymorphisms with disease severity in non-cystic fibrosis (CF) bronchiectasis patients, 51 normal subjects and 113 patients with bronchiectasis were studied. The associations between MMP-1 polymorphisms, lung function, and disease severity evaluated by high resolution computed tomography (HRCT) were analyzed.
The frequency of MMP-1(-1607G) allele was significantly higher in patients with bronchiectasis than normal subjects (70.8% vs 45.1%, p<0.01). Forced expiratory volume in 1 second (FEV1) was decreased in bronchiectasis patients with 1G/1G (1.2±0.1 L, n = 14) and 1G/2G (1.3±0.1 L, n = 66) genotypes compared to the 2G/2G genotype (1.7±0.1 L, n = 33, p<0.01). Six minute walking distance was decreased in bronchiectasis patients with 1G/1G and 1G/2G compared to that of 2G/2G genotype. Disease severity evaluated by HRCT score significantly increased in bronchiectasis patients with 1G/1G and 1G/2G genotypes compared to that of 2G/2G genotype. Bronchiectasis patients with at least one MMP-1 (-1607G) allele showed increased tendency for hospitalization. Serum levels of pro-MMP-1, active MMP-1 and TGF-β1 were significantly increased in patients with bronchiectasis with 1G/1G and 1G/2G genotype compared with 2G/2G genotype or normal subjects. Under IL-1β stimulation, peripheral blood monocytes from subjects with 1G/2G or 1G/1G genotype secreted higher levels of TGF-β1compared to subjects with 2G/2G genotype.
This is the first report to address the influence of MMP-1 polymorphisms on lung function and airway destruction in non-CF bronchiectasis patients. Bronchiectasis patients with MMP-1(-1607G) polymorphism may be more vulnerable to permanent lung fibrosis or airway destruction due to the enhanced MMP-1 and TGF-β1 activity. Upregulated MMP-1 activity results in proteolytic destruction of matrix, and leads to subsequent fibrosis.
The coercive fields (EC) of Pb(In0.5Nb0.5)O3-Pb(Mg1/3Nb2/3)O3-PbTiO3 (PIN-PMN-PT) ternary single crystals were found to be 5 kV/cm, double the value of binary Pb(Mg1/3Nb2/3)O3-PbTiO3 (PMNT) crystals, further increased to 6 to 9 kV/cm using Mn modifications. In addition to an increased EC, the acceptor modification resulted in the developed internal bias (Eint), on the order of ~1 kV/cm. The piezoelectric shear properties of unmodified and Mn-modified PIN-PMN-PT crystals with various domain configurations were investigated. The shear piezoelectric coefficients and electromechanical coupling factors for different domain configurations were found to be >2000 pC/N and >0.85, respectively, with slightly reduced properties observed in Mn-modified tetragonal crystals. Fatigue/cycling tests performed on shear-mode samples as a function of ac drive field level demonstrated that the allowable ac field levels (the maximum applied ac field before the occurrence of depolarization) were only ~2 kV/cm for unmodified crystals, less than half of their coercive field. Allowable ac drive levels were on the order of 4 to 6 kV/cm for Mn-modified crystals with rhombohedral/orthorhombic phase, further increased to 5 to 8 kV/cm in tetragonal crystals, because of their higher coercive fields. It is of particular interest that the allowable ac drive field level for Mn-modified crystals was found to be ≥60% of their coercive fields, because of the developed Eint, induced by the acceptor-oxygen vacancy defect dipoles.
Procainamide, a type I antiarrhythmic agent, is used to treat a variety of atrial and ventricular dysrhythmias. It was reported that long-term therapy with procainamide may cause lupus erythematosus in 25–30% of patients. Interestingly, procainamide does not induce lupus erythematosus in mouse models. To explore the differences in this side-effect of procainamide between humans and mouse models, metabolomic analysis using ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS) was conducted on urine samples from procainamide-treated humans, CYP2D6-humanized mice, and wild-type mice. Thirteen urinary procainamide metabolites, including nine novel metabolites, derived from P450-dependent, FMO-dependent oxidations and acylation reactions, were identified and structurally elucidated. In vivo metabolism of procainamide in CYP2D6-humanized mice as well as in vitro incubations with microsomes and recombinant P450s suggested that human CYP2D6 plays a major role in procainamide metabolism. Significant differences in N-acylation and N-oxidation of the drug between humans and mice largely account for the interspecies differences in procainamide metabolism. Significant levels of the novel N-oxide metabolites produced by FMO1 and FMO3 in humans might be associated with the development of procainamide-induced systemic lupus erythematosus. Observations based on this metabolomic study offer clues to understanding procainamide-induced lupus in humans and the effect of P450s and FMOs on procainamide N-oxidation.
Procainamide; Systemic lupus erythematosus; Metabolomics; N-Oxidation; Ultra-performance liquid chromatography; Time-of-flight mass spectrometry
The gas-phase fragmentation pathways of deprotonated diacylhydrazine derivatives (R1(C = O)-N(t-Bu)NH(C = O)R2, Compounds 1–6) were investigated by the combination of electrospray ionization tandem mass spectrometry (ESI-MS/MS) and theoretical calculations. Upon collisional activation, the deprotonated molecular ions [M – H]− dissociate in two reaction channels, both of which involve intramolecular rearrangement. The main product ion is confirmed to be an anionic acid species, [R1-CO2]−, generated through intramolecular rearrangement of [M – H]− initiated by the nucleophilic attack of the amide O6 on the carbonyl C2 (Path-1). The minor fragment channel (Path-2) involves methylpropene elimination of the precursor ion, followed by a similar nucleophilic displacement reaction to produce another acid anion [R2-CO2]−. Density functional theory calculations at the B3LYP/6-31+G(d,p) level indicate that Path-1 is more favorable than Path-2 for dissociation of the deprotonated halofenozide.
Rheological disorders of red blood cells (RBC) and decreased RBC deformability have been involved in the development of diabetic microangiopathy. However, few studies have evaluated the association of RBC count with microvascular complications in patients with type 2 diabetes mellitus (T2DM). The purpose of this study was to investigate the association of RBC count with microvascular complications in patients with T2DM.
This study involved 369 patients with T2DM: 243 with one or more microvascular complications and 126 without microvascular complications. Anticoagulated blood was collected and analyzed in an automated blood cell counter. The presence of risk factors for microvascular complications was determined.
The proportion of patients with microvascular complications increased as the RBC count decreased (P < 0.001). After adjustment for known risk factors for microvascular complications by logistic regression analysis, lower quartiles of RBC count were associated with a higher risk of microvascular complications compared with the reference group composed of the highest quartile (first quartile, odds ratio 4.98, 95% confidence interval 1.54–6.19, P = 0.008; second quartile, odds ratio 3.21, 95% confidence interval 1.17–5.28, P = 0.024).
A decreased RBC count is associated with microvascular complications in Chinese patients with T2DM. The RBC count is a potential marker to improve further the ability to identify diabetic patients at high risk of microvascular complications.
red blood cell count; microvascular complication; type 2 diabetes mellitus
The treatment of thymoma or thymic carcinoma with pleural dissemination remains controversial due to the unpredictable natural history of this tumor. Our study discusses the combination of cytoreductive surgery with hyperthermic intrapleural chemotherapy to treat thymoma or thymic carcinoma with pleural dissemination.
From February 2008 to January 2010, there were four patients with pleural thymoma metastases undergoing cytoreductive surgery and intrathoracic hyperthermic perfusion with chemotherapy at our department. After video-assisted thoracoscopic surgery, the hyperthermic perfusion system was set up for hyperthermic intrapleural chemotherapy. The thoracic cavity was perfused at a speed of approximately 1.8–2.3 L/min with 0.9% normal saline. The intrathoracic temperature remained between 42°C and 43°C. The perfusion process lasted for 2 hours.
There were no perioperative deaths. During the hyperthermic perfusion, the patient’s core temperature varied from 36.3°C and 39.3°C and pulse varied from 59 beats/min and 126 beats/min. Intraoperative sinus tachycardia occurred in two elderly patients. No hematologic toxicity and nephrotoxicity was observed within 1 week after surgery. Postoperative pneumonia occurred in one elderly patient. Patients were followed up for 1–4 years. One elderly patient died of heart failure 1 year after surgery. There were no patients with local recurrence or metastases to distant sites.
Cytoreductive surgery and intrathoracic hyperthermic perfusion with chemotherapy may be effective in treating thymoma or thymic carcinoma with pleural dissemination and has an encouraging impact on the patients’ long-term survival.
thymoma; pleural dissemination; surgery; hyperthermia; chemotherapy
A number of studies have shown that the outer membrane protein FomA found in Fusobacterium nucleatum demonstrates great potential as an immune target for combating periodontitis. Lactobacillus acidophilus is a useful antigen delivery vehicle for mucosal immunisation, and previous studies by our group have shown that L. acidophilus acts as a protective factor in periodontal health. In this study, making use of the immunogenicity of FomA and the probiotic properties of L. acidophilus, we constructed a recombinant form of L. acidophilus expressing the FomA protein and detected the FomA-specific IgG in the serum and sIgA in the saliva of mice through oral administration with the recombinant strains. When serum containing FomA-specific antibodies was incubated with the F. nucleatum in vitro, the number of Porphyromonas gingivalis cells that coaggregated with the F. nucleatum cells was significantly reduced. Furthermore, a mouse gum abscess model was successfully generated, and the range of gingival abscesses in the immune mice was relatively limited compared with the control group. The level of IL-1β in the serum and local gum tissues of the immune mice was consistently lower than in the control group. Our findings indicated that oral administration of the recombinant L. acidophilus reduced the risk of periodontal infection with P. gingivalis and F. nucleatum.
FomA; Lactobacillus acidophilus; Fusobacterium nucleatum; Porphyromonas gingivalis; periodontal infection
Direct current electric fields (DCEFs) can induce directional migration for many cell types through activation of intracellular signaling pathways. However, the mechanisms that bridge extracellular electrical stimulation with intracellular signaling remain largely unknown. In the current study, we found that a DCEF can induce the directional migration of U87, C6 and U251 glioma cells to the cathode and stimulate the production of hydrogen peroxide and superoxide. Subsequent studies demonstrated that the electrotaxis of glioma cells were abolished by the superoxide inhibitor N-acetyl-l-cysteine (NAC) or overexpression of mitochondrial superoxide dismutase (MnSOD), but was not affected by inhibition of hydrogen peroxide through the overexpression of catalase. Furthermore, we found that the presence of NAC, as well as the overexpression of MnSOD, could almost completely abolish the activation of Akt, extracellular-signal-regulated kinase (Erk)1/2, c-Jun N-terminal kinase (JNK), and p38, although only JNK and p38 were affected by overexpression of catalase. The presenting of specific inhibitors can decrease the activation of Erk1/2 or Akt as well as the directional migration of glioma cells. Collectively, our data demonstrate that superoxide may play a critical role in DCEF-induced directional migration of glioma cells through the regulation of Akt and Erk1/2 activation. This study provides novel evidence that the superoxide is at least one of the “bridges” coupling the extracellular electric stimulation to the intracellular signals during DCEF-mediated cell directional migration.
PURPOSE: The inherent treatment resistance of glioblastoma (GBM) can involve multiple mechanisms including checkpoint kinase (Chk1/2)-mediated increased DNA repair capability, which can attenuate the effects of genotoxic chemotherapies and radiation. The goal of this study was to evaluate diffusion-weighted magnetic resonance imaging (DW-MRI) as a biomarker for Chk1/2 inhibitors in combination with radiation for enhancement of treatment efficacy in GBM. EXPERIMENTAL DESIGN: We evaluated a specific small molecule inhibitor of Chk1/2, AZD7762, in combination with radiation using in vitro human cell lines and in vivo using a genetically engineered GBM mouse model. DW-MRI and T1-contrast MRI were used to follow treatment effects on intracranial tumor cellularity and growth rates, respectively. RESULTS: AZD7762 inhibited clonal proliferation in a panel of GBM cell lines and increased radiosensitivity in p53-mutated GBM cell lines to a greater extent compared to p53 wild-type cells. In vivo efficacy of AZD7762 demonstrated a dose-dependent inhibitory effect on GBM tumor growth rate and a reduction in tumor cellularity based on DW-MRI scans along with enhancement of radiation efficacy. CONCLUSION: DW-MRI was found to be a useful imaging biomarker for the detection of radiosensitization through inhibition of checkpoint kinases. Chk1/2 inhibition resulted in antiproliferative activity, prevention of DNA damage-induced repair, and radiosensitization in preclinical GBM tumor models, both in vitro and in vivo. The effects were found to be maximal in p53-mutated GBM cells. These results provide the rationale for integration of DW-MRI in clinical translation of Chk1/2 inhibition with radiation for the treatment of GBM.
This study aimed to investigate the efficacy and safety of echinacoside (ECH) using an osteopenia rat model. Forty-eight 6-month-old female Sprague-Dawley rats were randomly divided into one sham-operated group (SHAM) and five OVX (ovariectomized) subgroups: SHAM with vehicle 0.5% carboxymethylcellulose sodium (0.5% CMC-Na) and OVX with vehicle (OVX), OVX with 17β-estradiol (E2), and OVX with ECH of graded doses (ECH-L, ECH-M, and ECH-H). The effects of ECH and E2 on serum biochemical parameters, bone mineral density (BMD), bone biomechanical properties, bone microarchitecture, and immunohistochemistry were examined, and safety assessments were also evaluated. The results showed that ECH treatments improved total femur BMD, bone microarchitecture, and biomechanical properties and decreased serum marker levels in comparison to OVX group. Moreover, ECH administration significantly increased osteoprotegerin (OPG) level, and decreased receptor activator of nuclear factor-κB ligand (RANKL) level in serum, as well as in proximal femur. Importantly, ECH treatment ameliorated the lipid
parameters without the overall incidences of adverse events of uterus and mammary gland compared to OVX and SHAM groups. This study demonstrated that administration of ECH for 12 weeks can effectively and safely prevent OVX-induced osteoporosis in rats via increasing the OPG/RANKL ratio.
The title compound, [Ba(C12H6O4)(H2O)2]n, is represented by a layer-like structure built of BaO8 polyhedra. The asymmetric unit contains a Ba2+ ion, half a coordinating water molecule and half a μ4-bridging naphthalene-1,8-dicarboxylate (1,8-nap) ligand, the whole structure being generated by twofold rotational symmetry. The carboxylate groups of the 1,8-nap ligands act as bridges linking four Ba2+ ions, while each Ba2+ ion is eight-coordinated by O atoms from four 1,8-nap ligands and two coordinating water molecules. In the crystal, there are O—H⋯O hydrogen bonds involving the water molecules and carboxylate O atoms in the BaO8 polyhedra. Each BaO8 polyhedron is connected via corner-sharing water O atoms or edge-sharing ligand O atoms, forming a sheet parallel to the bc plane. These sheets stack along the a-axis direction and are connected via van der Waals forces only. The naphthalene groups protrude above and below the layers of the BaO8 polyhedra and there are voids of ca 208 Å3 bounded by these groups. No residual electron density was found in this region. The crystal studied was twinned by pseudo-merohedry, with a refined twin component ratio of 0.5261 (1):0.4739 (1).
Exercise training is of benefit for patients with restrictive lung disease. However, it tends to be intolerable for those with severe disease. We examined whether providing ventilatory assistance by using negative pressure ventilators (NPV) during exercise training is feasible for such patients and the effects of training.
36 patients with restrictive lung disease were prospectively enrolled for a 12-week multidisciplinary rehabilitation program. During this program, half of them (n:18; 60.3 ± 11.6 years; 6 men; FVC: 32.5 ± 11.7% predicted ) received regular sessions of exercise training under NPV, whilst the 18 others (59.6 ± 12.3 years; 8 men; FVC: 37.7 ± 10.2% predicted) did not. Exercise capacity, pulmonary function, dyspnea and quality of life were measured. The primary endpoint was the between-group difference in change of 6 minute-walk distance (6MWD) after 12 weeks of rehabilitation.
All patients in the NPV-exercise group were able to tolerate and completed the program. The between-group differences were significantly better in the NPV-exercise group in changes of 6MWD (34.1 ± 12.7 m vs. -32.5 ± 17.5 m; P = 0.011) and St George Score (−14.5 ± 3.6 vs. 11.8 ± 6.0; P < 0.01). There was an improvement in dyspnea sensation (Borg’s scale, from 1.4 ± 1.5 point to 0.8 ± 1.3 point, P = 0.049) and a small increase in FVC (from 0.85 ± 0.09 L to 0.91 ± 0.08 L, P = 0.029) in the NPV-exercise group compared to the control group.
Exercise training with NPV support is feasible for patients with severe restrictive lung diseases, and improves exercise capacity and health-related quality of life.
Restrictive lung disease; Negative pressure ventilation; Exercise training; Exercise capacity; Health-related quality of life