Angiogenesis plays an important role in tumor growth, invasion, and eventually metastasis. Antiangiogenic strategies have been proven to be a promising approach for clinical therapy for a variety of tumors. As a potent inhibitor of tumor angiogenesis, pigment epithelium-derived factor (PEDF) has recently been studied and used as an anticancer agent in several tumor models.
A recombined adenovirus carrying PEDF gene (Ad-PEDF) was prepared, and its expression by infected cells and in treated animals was confirmed with Western blotting and ELISA, respectively. Its activity for inhibiting human umbilical vein endothelial cell (HUVEC) proliferation was tested using the MTT assay. C57BL/6 mice bearing B16-F10 melanoma were treated with i.v. administration of 5 × 108 IU/mouse Ad-PEDF, or 5 × 108 IU/mouse Ad-Null, or normal saline (NS), every 3 days for a total of 4 times. Tumor volume and survival time were recorded. TUNEL, CD31 and H&E stainings of tumor tissue were conducted to examine apoptosis, microvessel density and histological morphology changes. Antiangiogenesis was determined by the alginate-encapsulated tumor cell assay.
The recombinant PEDF adenovirus is able to transfer the PEDF gene to infected cells and successfully produce secretory PEDF protein, which exhibits potent inhibitory effects on HUVEC proliferation. Through inhibiting angiogenesis, reducing MVD and increasing apoptosis, Ad-PEDF treatment reduced tumor volume and prolonged survival times of mouse bearing B16-F10 melanoma.
Our data indicate that Ad-PEDF may provide an effective approach to inhibit mouse B16-F10 melanoma growth.
Metastasis in breast cancer is a vital concern in treatment because most women with primary breast cancer have micrometastases to distant sites at diagnosis. As a member of the inhibitor of apoptosis protein (IAP) family, survivin has been proposed as an attractive target for new anticancer interventions. In this study, we investigated the role of the plasmid encoding the phosphorylation-defective mouse survivin threonine 34→alanine mutant (Msurvivin T34A plasmid) in suppressing both murine primary breast carcinomas and pulmonary metastases.
In vitro study, induction of apoptosis by Msurvivin T34A plasmid complexed with cationic liposome (DOTAP/Chol) was examined by PI staining fluorescence microscopy and flow cytometric analysis. The anti-tumor and anti-metastases activity of Msurvivin T34A plasmid complexed with cationic liposome (DOTAP/Chol) was evaluated in female BALB/c mice bearing 4T1 s.c. tumors. Mice were treated twice weekly with i.v. administration of Msurvivin T34A plasmid complexed with cationic liposome (DOTAP/Chol), PORF-9 null plasmid complexed with cationic liposome (DOTAP/Chol), 0.9% NaCl solution for 4 weeks. Tumor volume was observed. After sacrificed, tumor net weight was measured and Lung metastatic nodules of each group were counted. Assessment of apoptotic cells by TUNEL assay was conducted in tumor tissue. Microvessel density within tumor tissue was determined by CD31 immunohistochemistry. Alginate-encapsulated tumor cells test was conducted to evaluate the effect on angiogenesis. By experiment of cytotoxicity T lymphocytes, we test whether Msurvivin T34A plasmid complexed with cationic liposome (DOTAP/Chol) can induce specific cell immune response.
Administration of Msurvivin T34A plasmid complexed with cationic liposome (DOTAP/Chol) resulted in significant inhibition in the growth and metastases of 4T1 tumor model. These anti-tumor and anti-metastases responses were associated with triggering the apoptosis of tumor cells directly, inhibiting angiogenesis and inducing specific cellular immune response.
The present findings suggest that the Msurvivin T34A plasmid complexed with cationic liposome may provide an effective approach to inhibit the growth and metastases of a highly metastatic mouse breast cancer model with minimal side effects.
Detection of acute kidney injury is undergoing a dynamic revolution of biomarker technology allowing greater, earlier, and more accurate determination of diagnosis, prognosis, and with powerful implication for management. Biomarkers can be broadly considered as any measurable biologic entity or process that allows differentiation between normal function and injury or disease. The ADQI (Acute Dialysis Quality Initiative) had its Ninth Consensus Conference dedicated to synthesis and formulation of the existing literature on biomarkers for the detection of acute kidney injury in a variety of settings. In the papers that accompany this summary, ADQI workgroups fully develop key concepts from a summary of the literature in the domains of early diagnosis, differential diagnosis, prognosis and management, and concurrent physiologic and imaging measures.
The past 5–10 years have brought significant advances in the identification and validation of novel biochemical biomarkers in the prevention and treatment of acute kidney injury (AKI). These biochemical biomarkers remain research tools but we anticipate that soon they will be employed in clinical practice. A Consensus Conference held by the Acute Dialysis Quality Initiative (ADQI) recently reviewed the evidence, and identified gaps and a research agenda. Furthermore, at this meeting was the birth of an initiative to comprehensively identify new opportunities to characterize the physiological changes during the course of AKI based upon a conceptual framework for the detection and monitoring of renal ischemia-reperfusion injury. This framework includes a transition from monitoring physiological biomarkers of adequate renal perfusion, to pathophysiologic biomarkers of renal hypoperfusion, and finally biomarkers of kidney cell structural injury/damage. Techniques to measure physiological changes in AKI include several physiological variables that might be used in an interactive way to supplement clinical information and biochemical damage biomarkers in the diagnosis and management of AKI. This review summarizes the spectrum of physiological parameters and potential new physiological methods that enable identification of high-risk patients for AKI, facilitate early diagnosis, and differential diagnosis to guide therapeutic management and prognostication. Finally, we propose a research agenda for the next 5 years to facilitate the development and validation of physiological biomarkers in AKI.
Diffraction imaging of polystyrene spheres and B16F10 mouse melanoma cells embedded in gel has been investigated with a microscope objective. The diffraction images acquired with the objective from a sphere have been shown to be comparable to the Mie theory based projection images of the scattered light if the objective is translated to defocused positions towards the sphere. Using a confocal imaging based method to reconstruct and analyze the 3D structure, we demonstrated that genetic modifications in these cells can induce morphological changes and the modified cells can be used as an experimental model for study of the correlation between 3D morphology features and diffraction image data.
Diffraction images of spheres (left column) and melanoma cells (right column) acquired with an objective.
diffraction imaging; light scattering; melanoma cells; cell morphology
One great challenge in our understanding of TGF-β cancer biology and the successful application of TGF-β targeted therapy is that TGF-β works as both a tumor suppressor and a tumor promoter. The underlying mechanisms for its functional change remain to be elucidated. Using 4T1 mammary tumor model that shares many characteristics with human breast cancer, particularly its ability to spontaneously metastasize to the lungs, we demonstrate that Gr-1+CD11b+ cells or myeloid derived suppressor cells (MDSCs) are important mediators in TGF-β regulation of mammary tumor progression. Depletion of Gr-1+CD11b+ cells diminished the anti-tumor effect of TGF-β neutralization. Two mechanisms were involved: first, treatment with TGF-β neutralization antibody (1D11) significantly decreased the number of Gr-1+CD11b+ cells in tumor tissues and premetastatic lung. This is mediated through increased Gr-1+CD11b+ cell apoptosis. In addition, 1D11 treatment significantly decreased the expression of Th2 cytokines & Arginase 1. Interestingly, the number and property of Gr-1+CD11b+ cells in peripheral blood/draining lymph nodes correlated with tumor size and metastases in response to 1D11 treatment. Our data suggest that the efficacy of TGF-β neutralization depends on the presence of Gr-1+CD11b+ cells, and these cells could be good biomarkers for TGF-β targeted therapy.
TGF-β; Gr-1+CD11b+ cells; breast cancer; targeted therapy; biomarker
Processing of Aβ-precursor protein (APP) plays an important role in Alzheimer’s disease (AD) pathogenesis. The APP intracellular domain contains residues important in regulating APP function and processing, in particular the 682YENPTY687 motif. To dissect the functions of this sequence in vivo, we created an APP knock-in allele mutating Y682 to Gly (APPYG/YG mice). This mutation alters processing of APP and TrkA signaling, and leads to postnatal lethality and neuromuscular synapse defects when expressed on an APP-like protein 2 KO background. This evidence prompted us to characterize further the APPYG/YG mice. Here, we show that APPYG/YG mice develop aging-dependent decline in cognitive and neuromuscular functions, a progressive reduction in dendritic spines, cholinergic tone and TrkA levels in brain regions governing cognitive and motor functions. These data are consistent with our previous findings linking NGF and APP signaling and suggest a causal relationship between altered synaptic connectivity, cholinergic tone depression and TrkA signaling deficit, and cognitive and neuromuscular decline in APPYG/YG mice. The profound deficits caused by the Y682 mutation underscore the biological importance of APP and indicate that APPYG/YG are a valuable mouse model to study APP functions in physiological and pathological processes.
Amyloid Precursor Protein; YENTP domain; Alzheimer’s Disease; Dendritic spines; Cholinergic system; TrkA receptor; behavior
Compounds that modulate metabotropic glutamate subtype 2 (mGlu2) receptors have the potential to treat several disorders of the central nervous system (CNS) including drug dependence. Herein we describe the synthesis and structure-activity relationship (SAR) studies around a series of mGlu2 receptor positive allosteric modulators (PAMs). The effects of N-substitution (R1) and substitutions on the aryl ring (R2) were identified as key areas for SAR exploration (Figure 3). Investigation of the effects of varying substituents in both the isoindolinone (2) and benzisothiazolone (3) series led to compounds with improved in vitro potency and/or efficacy. In addition, several analogues exhibited promising pharmacokinetic (PK) properties. Furthermore, compound 2 was shown to dose-dependently decrease nicotine self-administration in rats following oral administration. Our data, showing for the first time efficacy of an mGlu2 receptor PAM in this in vivo model, suggest potential utility for the treatment of nicotine dependence in humans.
Metabotropic glutamate receptors; agonist; positive allosteric modulators; BINA; nicotine self-administration; rat model; addiction
Maintaining a balance between ATP synthesis and heat generation is crucial for adapting to changes in climate. Variation in the mitochondrial DNA (mtDNA), which encodes 13 subunits of the respiratory chain complexes, may contribute to climate adaptation by regulating thermogenesis and the use of bioenergy. However, studies looking for a relationship between mtDNA haplogroups and climate have obtained mixed results, leaving unresolved the role of mtDNA in climate adaptation. Since mtDNA content can regulate human bioenergy processes and is known to influence many physiological traits and diseases, it is possible that mtDNA content contributes to climate adaptation in human populations. Here, we analyze the distribution of mtDNA content among 27 Chinese ethnic populations residing across China and find a significant association between mtDNA content and climate, with northern populations having significantly higher mtDNA content than southern populations. Functional studies have shown that high mtDNA content correlates with an increase in the expression of energy metabolism enzymes, which may accelerate thermogenesis. This suggests that the significantly higher mtDNA content observed in northern populations may confer a selective advantage in adapting to colder northern climates
Objectives. This study investigated the association between polymorphisms in the receptor for advanced glycation end products (RAGE) gene and the susceptibility to diabetic retinopathy (DR) in a Chinese population and identified a correlation between serum-soluble RAGE (sRAGE) levels and DR risk. Materials and Methods. We enrolled 1040 patients with type 2 diabetes mellitus: 372 patients with DR and 668 without retinopathy (NDR). All polymorphisms were genotyped by time-of-flight mass spectrometry. Serum levels of sRAGE were assayed by enzyme-linked immunosorbent assays. The interaction of SNPs was analyzed by multifactor dimensionality reduction (MDR). Results. The frequency of the SS genotype for the G82S polymorphism was 12.4% in the DR group and 6.6% in the NDR group; this difference was significant. G82S was associated with sRAGE levels. Specifically, after adjustments for age, sex, duration, and glucose metabolism, serum sRAGE levels were significantly higher in DR subjects with the S/S genotype than in NDR subjects in general. In the DR group, subjects with the G/S genotype had lower sRAGE levels than subjects with the G/G or S/S genotype (P < 0.01). The best multilocus genetic interaction model was assessed using the MDR method; 2184A/G, 1704G/T, G82S, and −429T/C were identified. Conclusions. The findings suggest that the G82S polymorphism in the RAGE gene is associated with DR risk, and G82S was associated with circulating levels of sRAGE. The mechanism by which G82S polymorphism modulates the sRAGE levels remains to be elucidated.
Scrub typhus is endemic to a 13,000,000-km2 area of the Asia-Pacific region, and causes an annual incidence of 1 million people. The mortality rate of scrub typhus ranges from 6.1% to 25% in Southeast Asia. Natural infection of Orientia tsutsugamushi has been identified in domestic rodents in Shandong Province. However, infestation of chiggers and ticks on the domestic rodents and prevalence and genotypes of O. tsutsugamushi in these Acarina remain unclear.
During September 2010 to March 2012, 3134 chiggers and 89 ticks were collected from domestic rodents captured in three counties of Shandong Province. We amplified and sequenced the 56-kDa type-specific antigen gene of O. tsutsugamushi from DNA samples of these Acarina and designated to genotype according to sequence analysis.
Overall, the infestation rate of chiggers on domestic rodents was 17.0%, and the chigger index was 5.38. The infestation rate of ticks on rodents was 3.1%. Natural infection of O. tsutsugamushi was found in Leptotrombidium taishanicum, L. linhuaikongense, L. intermedium, L. scutellare, L. palpale, and Ixodes spp., the minimum positive rates of which were 5.9%, 3.2%, 1.2%, 0.8%, 0.8%, and 2.2%, respectively. Kawasaki-like genotypes were predominant in chiggers and ticks on domestic rodents, which were detected from L. taishanicum, L. intermedium, L. scutellare, L. palpale, and Ixodes spp. Shimokoshi-like genotype was detected from L. palpale.
In the present study we investigated the infestation of chiggers and ticks on domestic rodents in Shandong Province, and identified the prevalence and genotypes of O. tsutsugamushi in the Acarina. Infestation of vector chiggers in domestic rodents, prevalence of O. tsutsugamushi in infested chiggers, and high nucleotide homologies among the O. tsutsugamushi sequences from the Acarina, their animal hosts and scrub typhus patients, implied that domestic rodents may play an important role in the transmission of scrub typhus in Shandong, China. Further studies are needed to verify the vector significance of chiggers and ticks that tested positive for O. tsutsugamushi, and to assess the risk of human exposure to chiggers and ticks on domestic rodents.
Scrub typhus; Orientia tsutsugamushi; Chigger; Tick; Rodents
Because of the importance of wood in many industrial applications, tremendous studies have been performed on wood formation, especially in lignin biosynthesis. MYB transcription factors (TFs), which consist of a large family of plant TFs, have been reported to directly regulate lignin biosynthetic genes in a number of plants. In this study, we describe the cloning and functional characterization of PtoMYB216, a cDNA isolated from Chinese white poplar (Populus tomentosa Carr.). PtoMYB216 encodes a protein belonging to the R2R3-MYB family and displays significant similarity with other MYB factors shown to regulate lignin synthesis in Arabidopsis. Gene expression profiling studies showed that PtoMYB216 mRNA is specifically expressed during secondary wall formation in wood. The 1.8-kb promoter sequence of PtoMYB216 was fused to the GUS coding sequence and introduced into wild-type A. thaliana. GUS expression was shown to be restricted to tissues undergoing secondary cell wall formation. Overexpression of PtoMYB216 specifically activated the expression of the upstream genes in the lignin biosynthetic pathway and resulted in ectopic deposition of lignin in cells that are normally unligninified. These results suggest that PtoMYB216 is specific transcriptional activators of lignin biosynthesis and involved in the regulation of wood formation in poplar.
Previous epidemiological studies have demonstrated a correlation between fumonisin B1 (FB1) and human esophageal cancer in China, Iran and South Africa. The purpose of this study was to investigate the effects of FB1 on the proliferation, cell-cycle and apoptosis of normal human esophageal epithelial cells (HEECs) and to explore the molecular mechanisms of these effects. The proliferation of HEECs treated with FB1 was assessed using a colorimetric assay, while analyses of the cell cycle and apoptosis were performed using flow cytometry and the measurement of the protein expressions of genes associated with the cell cycle was conducted using western blotting. The results showed that FB1 stimulated the proliferation of HEECs, decreased the percentage of cells in the G0/G1 phase and reduced apoptosis. The western blotting results showed that FB1 significantly increased the protein expression of cyclin D1 and significantly decreased the protein expression of cyclin E, p21 and p27. The results indicated that FB1 stimulated the proliferation of HEECs by affecting the cell cycle and apoptosis. This mechanism was associated with changes in cyclin D1, cyclin E, p21 and p27 expression.
fumonisin B1; normal human esophageal epithelial cells; proliferation; cell cycle; apoptosis
Polo-like kinases (PLKs) have been reported to be essential components of anti-viral pathways. However, the role of PLKs in the production of pro-inflammatory cytokines induced by TLR activation is uncertain. We report here that monocytic THP-1 cells expressed PLK1, PLK2, PLK3 and PLK4. When THP-1 cells were treated with GW843682X, an inhibitor of PLK1 and PLK3, the results showed that GW843682X down-regulated Pam3CSK4- and LPS-induced TNF-α at both the gene and protein levels. GW843682X did not impact Pam3CSK4-induced IL-1β and IL-8 or LPS-induced IL-1β, but it down-regulated LPS-induced IL-8 significantly. Moreover, western blot results showed that TLRs activated PLK1, and PLK1 inhibition by RNA interference down-regulated Pam3CSK4-induced TNF-α production, suggesting the involvement of PLK1 in TNF-α up-regulation. In addition, GW843682X treatment for 12 to 24 h induced cell death and down-regulated MyD88, but neither of these roles contributed to the down-regulation of TNF-α, as TNF-α gene expression was up-regulated at 1 h. Furthermore, GW843682X inhibited Pam3CSK4-induced activation of ERK and NF-κB, which contributed to Pam3CSK4-induced up-regulation of TNF-α. GW843682X also inhibited LPS-induced activation of ERK, p38 and NF-κB, which contributed to LPS-induced up-regulation of TNF-α. Taken together, these results suggested that PLK1 is involved in TLR2- and TLR4-induced inflammation, and GW843682X may be valuable for the regulation of the inflammatory response.
The role of myeloid derived suppressor cells (MDSCs) in promoting tumorigenesis is well-established, and significant effort is being made to further characterize surface markers on MDSCs both for better diagnosis and as potential targets for therapy. Here we show that the B cell receptor adaptor molecule CD79a is unexpectedly expressed on immature bone marrow myeloid cells, and is upregulated on MDSCs generated in multiple different mouse models of metastatic but not non-metastatic cancer. CD79a on MDSCs is upregulated and activated in response to soluble factors secreted by tumor cells. Activation of CD79a on mouse MDSCs, by crosslinking with a specific antibody, maintained their immature phenotype (CD11b+Gr1+), enhanced their migration, increased their suppressive effect on T cell proliferation, and increased secretion of pro-tumorigenic cytokines such as IL-6 and CCL22. Furthermore, crosslinking CD79a on myeloid cells activated signaling through Syk, BLNK, ERK and STAT3 phosphorylation. In vivo, CD79+ myeloid cells showed enhanced ability to promote primary tumor growth and metastasis. Finally we demonstrate that CD79a is upregulated on circulating myeloid cells from lung cancer patients, and that CD79a+ myeloid cells infiltrate human breast tumors. We propose that CD79a plays a functional role in the tumor promoting effects of myeloid cells, and may represent a novel target for cancer therapy.
This study was conducted to determine whether the ratio of estrogen-DNA adducts to their respective metabolites and conjugates in serum differed between women with early-onset breast cancer and those with average or high risk of developing breast cancer.
Serum samples from women at average risk (n = 63) or high risk (n = 80) for breast cancer (using Gail model) and women newly diagnosed with early breast cancer (n = 79) were analyzed using UPLC-MS/MS. Adduct ratios were statistically compared among the three groups, and the Area Under the Receiver Operating Characteristic Curve (AUC) was used to identify a diagnostic cut-off point.
The median adduct ratio in the average-risk group was significantly lower than that of both the high-risk group and the breast cancer group (p values <0.0001), and provided good discrimination between those at average versus high risk of breast cancer (AUC = 0.84, 95% CI 0.77–0.90). Sensitivity and specificity were maximized at an adduct ratio of 77. For women in the same age and BMI group, the odds of being at high risk for breast cancer was 8.03 (95% CI 3.46–18.7) times higher for those with a ratio of at least 77 compared to those with a ratio less than 77.
The likelihood of being at high risk for breast cancer was significantly increased for those with a high adduct ratio relative to those with a low adduct ratio. These findings suggest that estrogen-DNA adducts deserve further study as potential biomarkers for risk of developing breast cancer.
breast cancer; depurinating estrogen-DNA adducts; biomarker; breast cancer prevention
Despite expanding sexually transmitted epidemics in South China, the majority of patients presenting to sexually transmitted infection (STI) clinics are not routinely screened for HIV infection. Identifying barriers to offering HIV testing among STI care providers is an important public health priority. The aim of this study was to investigate the frequency of offering HIV testing among STI care providers in South China and reported physician barriers to offering HIV testing. More detailed operational data regarding HIV test offer frequency and barriers to testing may enhance routine HIV testing at STI clinics. A sample of 62 STI care providers within the Pearl River Delta Region of South China completed a survey including socio-demographic and training background information (including sex, age, medical education, year of terminal medical degree, HIV-specific training), reasons for not offering HIV testing routinely, and physical examination and sexual history taking practices. Frequency of offering HIV testing was calculated based on reports from research assistants and operational data. STI care providers offered HIV testing to 3011/10592 (28.4%) of their patients. There was substantial variability across providers in the frequency of offering testing, ranging from 3% to 100%. None of the identified physician factors were associated with offering HIV testing 100% of the time in the multivariate model. The most commonly physician reported barriers to HIV testing included: 1) low perceived prevalence of disease; and 2) not recommended by current guidelines. Forty-seven providers (76%) reported asking about same sex behaviors rarely or never. Further research on HIV screening practices of STI care providers may help scale up HIV provider-initiated testing and counseling programs.
Impaired consciousness in epilepsy has a major negative impact on quality of life. Prior work suggests that complex partial seizures (CPS) and generalized tonic-clonic seizures (GTCS), which both cause loss of consciousness, affect similar fronto-parietal networks. Milder involvement in CPS than in GTCS may spare some simple behavioral responses, resembling the minimally conscious state. However, this difference in responses has not been rigorously tested previously. During video/EEG monitoring, we administered a standardized prospective testing battery including responses to questions and commands, as well as tests for reaching/grasping a ball and visual tracking in 27 CPS (14 patients) and 7 GTCS (6 patients). Behavioral results were analyzed in the ictal and post-ictal periods based on video review. During both CPS and GTCS, patients were unable to respond to questions or commands. However, during CPS patients often retain minimally conscious ball grasping and visual tracking responses. Patients were able to successfully grasp a ball in 60% or to visually track in 58% of CPS, and could carry out both activities in 52% of CPS. In contrast, during GTCS preserved ball grasp (10%), visual tracking (11%) or both (7%) were all significantly less than in CPS. Post-ictal ball grasping and visual tracking were also somewhat better following CPS than GTCS. These findings suggest that impaired consciousness in CPS is more similar to minimally conscious state than to coma. Further work may elucidate the specific brain networks underlying relatively spared functions in CPS, ultimately leading to improved treatments aimed at preventing impaired consciousness.
Consciousness; Epilepsy; Complex Partial Seizures; Generalized Tonic-Clonic Seizures; Visual Tracking; Minimally Conscious State; Vegetative State
The aim of this study was to evaluate whether frequent premature ventricular contractions originating from the right ventricular outflow tract remodel the cardiac structure and function in patients with a “seemingly normal heart” and whether radiofrequency ablation can reverse this remodeling.
Sixty-eight patients with idiopathic frequent premature ventricular contractions originating from the right ventricular outflow tract and normal heart structure and function were enrolled in this study. The patients were divided into three groups according to the therapeutic method: radiofrequency ablation group (24 cases), anti-arrhythmia drug group (26 cases), and control group (18 cases without any treatment). Clinical Registration number: ChiCTR-ONRC-12002834
The basic patient characteristics were comparable between the three groups, except for the premature ventricular contraction rate, which was significantly lower in the control group. After six months of follow up, the premature ventricular contraction rate was significantly reduced in the radiofrequency ablation group, which was accompanied by a significant decrease in the following cardiac cavity inner diameters, as determined by echocardiography: right atrium (33.33±3.78 vs. 30.05±2.60 mm, p = 0.001), right ventricle (23.24±2.40 vs. 21.05±2.16 mm, p = 0.020), and left ventricle (44.76±4.33 vs. 41.71±3.44 mm, p = 0.025). These results were similar in the anti-arrhythmia drug group, although this group exhibited a smaller extent of change (right atrium: 33.94±3.25 vs. 31.27±3.11 mm, p = 0.024; right ventricle: 22.97±3.09 vs. 21.64±2.33 mm, p = 0.049; left ventricle: 45.92±6.38 vs. 43.84±5.67 mm, p = 0.039), but not in the control group (p>0.05). There was a tendency toward improvement in the cardiac functions in both the radiofrequency ablation and anti-arrhythmia drug groups. However, these differences were not statistically significant (p>0.05).
These results indicate that radiofrequency ablation can potentially reverse the cardiac remodeling caused by frequent premature ventricular contractions even in structurally normal hearts and that frequent premature ventricular contractions should be abated even in structurally normal hearts.
Cardiac Remodeling; Radiofrequency Ablation; Idiopathic Frequency Premature Ventricular Contraction; Right Ventricular Outflow Tract
Acidosis is a biochemical hallmark of the tumor microenvironment. Here, we report that acute acidosis decreases c-Myc oncogene expression in U937 human lymphoma cells. The level of c-Myc transcripts, but not mRNA or protein stability, contributes to c-Myc protein reduction under acidosis. The pH-sensing receptor TDAG8 (GPR65) is involved in acidosis-induced c-Myc downregulation. TDAG8 is expressed in U937 lymphoma cells, and the overexpression or knockdown of TDAG8 further decreases or partially rescues c-Myc expression, respectively. Acidic pH alone is insufficient to reduce c-Myc expression, as it does not decrease c-Myc in H1299 lung cancer cells expressing very low levels of pH-sensing G protein-coupled receptors (GPCRs). Instead, c-Myc is slightly increased by acidosis in H1299 cells, but this increase is completely inhibited by ectopic overexpression of TDAG8. Interestingly, TDAG8 expression is decreased by more than 50% in human lymphoma samples in comparison to non-tumorous lymph nodes and spleens, suggesting a potential tumor suppressor function of TDAG8 in lymphoma. Collectively, our results identify a novel mechanism of c-Myc regulation by acidosis in the tumor microenvironment and indicate that modulation of TDAG8 and related pH-sensing receptor pathways may be exploited as a new approach to inhibit Myc expression.
acidosis; tumor microenvironment; TDAG8; GPR65; c-Myc
This study was carried out to investigate the protective effects of chitosan nanoparticles (CNP) against hydrogen peroxide (H2O2)-induced oxidative damage in murine macrophages RAW264.7 cells. After 24 h pre-incubation with CNP (25–200 μg/mL) and chitosan (CS) (50–200 μg/mL, as controls), the viability loss in RAW264.7 cells induced by H2O2 (500 μM) for 12 h was markedly restored in a concentration-dependent manner as measured by MTT assay (P < 0.05) and decreased in cellular LDH release (P < 0.05). Moreover, CNP also exerted preventive effects on suppressing the production of lipid peroxidation such as malondialdehyde (MDA) (P < 0.05), restoring activities of endogenous antioxidant including superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) (P < 0.05), along with increasing total antioxidant capacity (T-AOC) (P < 0.05). In addition, pre-incubation of CNP with RAW264.7 cells for 24 h resulted in the increase of the gene expression level of endogenous antioxidant enzymes, such as MnSOD and GSH-Px (P < 0.05). At the same concentration, CNP significantly decreased LDH release and MDA (P < 0.05) as well as increased MnSOD, GSH-Px, and T-AOC activities (P < 0.05) as compared to CS. Taken together, our findings suggest that CNP can more effectively protect RAW264.7 cells against oxidative stress by H2O2 as compared to CS, which might be used as a potential natural compound-based antioxidant in the functional food and pharmaceutical industries.
chitosan nanoparticles; antioxidant activity; stress injury; RAW264.7 cells
Anoectochilus formosanus is an herb well known in Asian countries. The polysaccharide isolated from A. formosanus consists of type II arabinogalactan (AGAF), with branched 3,6-Gal as the major moiety. In this study, AGAF was examined for the granulocyte colony-stimulating factor (G-CSF) production and related protein expression in RAW 264.7 murine macrophages. The signaling pathway of G-CSF production involves AGAF and mitogen-activated protein kinases (MAPKs) inhibitors and pattern-recognition receptor antibodies. AGAF was evaluated to ease the leukopenia in CT26-colon-cancer-bearing mice treated with 5-fluorouracil (5-FU). The results of this study showed that AGAF was a stimulant for Toll-like receptor 2 and Dectin-1 and that it induced G-CSF production, through p38 and ERK MAPK, and NF-κB pathways. In vivo examination showed that the oral administration of AGAF mitigated the side effects of leukopenia caused by 5-FU in colon-cancer-bearing mice. In conclusion, the botanic type II AGAF in this study was a potent G-CSF inducer in vivo and in vitro.
The dynamic responses of honeycomb sandwich panels (HSPs) subjected to in-plane projectile impact were studied by means of explicit nonlinear finite element simulations using LS-DYNA. The HSPs consisted of two identical aluminum alloy face-sheets and an aluminum honeycomb core featuring three types of unit cell configurations (regular, rectangular-shaped, and reentrant hexagons). The ballistic resistances of HSPs with the three core configurations were first analyzed. It was found that the HSP with the reentrant auxetic honeycomb core has the best ballistic resistance, due to the negative Poisson's ratio effect of the core. Parametric studies were then carried out to clarify the influences of both macroscopic (face-sheet and core thicknesses, core relative density) and mesoscopic (unit cell angle and size) parameters on the ballistic responses of the auxetic HSPs. Numerical results show that the perforation resistant capabilities of the auxetic HSPs increase as the values of the macroscopic parameters increase. However, the mesoscopic parameters show nonmonotonic effects on the panels' ballistic capacities. The empirical equations for projectile residual velocities were formulated in terms of impact velocity and the structural parameters. It was also found that the blunter projectiles result in higher ballistic limits of the auxetic HSPs.
Fibroblasts, far frombeing merely bystander cells, are known to play a specific role in inflammation resolution after an acute injury. As the endogenous “braking signal,” resolvins possess potent anti-inflammatory and proresolution actions. We demonstrated that the expression of COX-2 protein was significantly peaked initially at 6 hours but then also at 48 hours after LPS stimulation in lung fibroblasts. PGE2 levels also peaked at 6 hours, and PGD2 levels were increased and peaked at 48 hours. However, no significant change in the protein expression of COX-1 was observed after treatment with LPS in lung fibroblasts. Exogenous resolvin D1 inhibited the first peak of COX-2 expression as well as the production of PGE2 induced by LPS. In contrast, exogenous resolvin D1 increased the second peak of COX-2 expression as well as the production of PGD2 induced by LPS. In addition, resolvin D1 inhibited COX-2 expression at 6 hours, which was partly through PI3K/AKT and ERK2 signalling pathways.