Blood glycated hemoglobin (HbA1c) levels reflecting average glucose concentrations over the past three months are fundamental for the diagnosis, monitoring, and risk assessment of diabetes. It has been hypothesized that aptamers, which are single-stranded DNAs or RNAs that demonstrate high affinity to a large variety of molecules ranging from small drugs, metabolites, or proteins, could be used for the measurement of HbA1c. Aptamers are selected through an in vitro process called systematic evolution of ligands by exponential enrichment (SELEX), and they can be chemically synthesized with high reproducibility at relatively low costs. This study therefore aimed to select HbA1c- and hemoglobin (Hb)-specific single-stranded DNA aptamers using an on-chip SELEX protocol. A microfluidic SELEX chip was developed to continuously and automatically carry out multiple rounds of SELEX to screen specific aptamers for HbA1c and Hb. HbA1c and Hb were first coated onto magnetic beads. Following several rounds of selection and enrichment with a randomized 40-mer DNA library, specific oligonucleotides were selected. The binding specificity and affinity were assessed by competitive and binding assays. Using the developed microfluidic system, the incubation and partitioning times were greatly decreased, and the entire process was shortened dramatically. Both HbA1c- and Hb-specific aptamers selected by the microfluidic system showed high specificity and affinity (dissociation constant, Kd = 7.6 ± 3.0 nM and 7.3 ± 2.2 nM for HbA1c and Hb, respectively). With further refinements in the assay, these aptamers may replace the conventional antibodies for in vitro diagnostics applications in the near future.
Ca(2+) signaling has been increasingly implicated in cancer invasion and metastasis, and yet, the underlying mechanisms remained largely unknown. In this paper, we report that STIM1- and Orai1-mediated Ca(2+) oscillations promote melanoma invasion by orchestrating invadopodium assembly and extracellular matrix (ECM) degradation. Ca(2+) oscillation signals facilitate invadopodial precursor assembly by activating Src. Disruption of Ca(2+) oscillations inhibited invadopodium assembly. Furthermore, STIM1 and Orai1 regulate the proteolysis activity of individual invadopodia. Mechanistically, Orai1 blockade inhibited the recycling of MT1-matrix metalloproteinase (MMP) to the plasma membrane and entrapped MT1-MMP in the endocytic compartment to inhibit ECM degradation. STIM1 knockdown significantly inhibited melanoma lung metastasis in a xenograft mouse model, implicating the importance of this pathway in metastatic dissemination. Our findings provide a novel mechanism for Ca(2+)-mediated cancer cell invasion and shed new light on the spatiotemporal organization of store-operated Ca(2+) signals during melanoma invasion and metastasis.
BackgroundOsteopontin (OPN) is a pro-inflammatory cytokine which is expressed in various tissues. It participates in the bone remodeling process and stimulates bone resorption by osteoclasts. It is also a core protein of cholesterol gallstones. We hypothesized osteoporotic patients might have higher risk in developing gallstones and conducted a population-based study to examine the risk of developing gallstone in osteoporotic patients in Taiwan.MethodsA total of 1,638 patients diagnosed with osteoporosis between 2003 and 2005 were identified in the National Health Insurance Research Database. A comparison cohort without osteoporosis (n =6,552) was randomly matched to each osteoporosis patient at a ratio of 4: 1 based on age and sex. A Cox proportional-hazards regression analysis was performed to evaluate the 5-year gallstone-free survival rates for the 2 cohorts.ResultsDuring the 5-year follow-up period, 114 and 311 cases of gallstone occurred in the osteoporosis and comparison cohorts, respectively. After adjusting for the confounders, the Cox regression analysis of the risk of gallstone in the osteoporosis and comparison cohorts yielded a hazard ratio of 1.35 (95% confidence interval: 1.07 - 1.69; p < 0 .01).ConclusionPatients with osteoporosis in Taiwan have a higher risk of developing gallstone than the general population.
A high sensitive sensor is demonstrated by exploiting strong transverse magneto-optical Kerr effect on a ferromagnetic surface plasmon grating. The surface plasmon grating, made of a hybridized Au/Fe/Au layer, exhibits a very dispersive Kerr parameter variation near the surface plasmon polariton (SPP) wavelength via coherent scattering of the SPP on the grating structure. Interrogating this Kerr parameter can be utilized for detecting chemical or biological objects in a fluid medium. The experiment results show the minimal detectable mass concentration of sodium chloride in a saline solution is 4.27 × 10-3 %, corresponding to a refractive index change of 7.60 × 10-6 RIU. For an avidin-biotin interaction experiment, the sensitivity of avidin detection in PBS solution is 1.97 nM, which is limited by the index fluctuation of flowing media during measurement.
Many red algae-derived natural products are known to have anticancer effects. The biological functions of the red alga Solieria robusta from the Karachi coast (Pakistan) remain unclear. Here, we prepared a methanolic extracts of S. robusta (MESR) to examine its possible anti-oral cancer effects and the corresponding mechanism of action. Cell viability of MESR-incubated oral cancer Ca9-22 cells was dose-responsively decreased (p < 0.001). According to a propidium iodide (PI)-based assay the cell cycle distribution was dramatically changed, especially for subG1 accumulation. Annexin V/PI assay of apoptosis using flow cytometry also showed that MESR-incubated Ca9-22 cells were dose-responsively increased (p < 0.001). For evaluation of oxidative stress in MESR-incubated Ca9-22 cells, we found that reactive oxygen species (ROS) were overexpressed dose- and time-responsively and mitochondrial depolarization was also increased (p < 0.001). Taken together, MESR showed inhibitory effects on oral cancer proliferation coupled with apoptosis and oxidative stress.
Chronic amphetamine intake leads to neurogenic bladder and chronic urinary retention. The mechanism underlying persistent urinary retention is unclear. The pelvic-urethral reflex (PUR) is essential for the urethra to develop sufficient resistance to maintain urine continence, an important function of the urinary system. Recent studies on PUR activities have indicated that repetitive/tetanic stimulation of the pelvic afferent fibers induces spinal reflex potentiation (SRP) in PUR activities, which further increases urinary retention. In this study, results showed that test stimulation (TS, 1/30 Hz) evoked a baseline reflex activity, while repetitive stimulation (RS, 1 Hz) induced reflex potentiation in the external urethral sphincter. Intrathecal d-amphetamine (AMPH, 30 ?M) did not but higher AMPH concentration (100 ?M) induced SRP in TS-induced reflex activity. H89 (10 ?M, a protein kinase A inhibitor), but not chelerythrine chloride (CTC, 10 ?M, a protein kinase C inhibitor), prevented the 100 ?M AMPH-elicited SRP. At 30 ?M, forskolin, an activator of adenylyl cyclase, elicited SRP. The co-administration of 10 ?M forskolin and 30 ?M AMPH induced SRP in TS-induced reflex activity. These results implied that the repetitive/tetanic stimulation of the pelvic afferent fibers could induce SRP in PUR activities, so that the urethra can produce sufficient resistance and played a significant role in urinary retention. Findings in this study demonstrated that amphetamine could induce bladder dysfunction by triggering protein kinase A activation, and provide a practical basis for the development of treatment for amphetamine-associated urinary retention.
It is becoming more understandable that an existing challenge for translational research is the development of pharmaceuticals that appropriately target reactive oxygen species (ROS)-mediated molecular networks in cancer cells. In line with this approach, there is an overwhelmingly increasing list of many non-marine drugs and marine drugs reported to be involved in inhibiting and suppressing cancer progression through ROS-mediated cell death. In this review, we describe the strategy of oxidative stress-based therapy and connect the ROS modulating effect to the regulation of apoptosis and autophagy. Finally, we focus on exploring the function and mechanism of cancer therapy by the autophagy modulators including inhibitors and inducers from non-marine drugs and marine drugs.
Ankylosing spondylitis (AS) is a highly familial rheumatic disorder and is considered as a chronic inflammatory disease. Genetic factors are involved in the pathogenesis of AS. To identify genes which render people susceptible to AS in a Taiwanese population, we selected six single-nucleotide polymorphisms (SNPs) from previous genome-wide association studies (GWASs) which were associated with AS in European descendants and Han Chinese. To assess whether the six SNPs contributed to AS susceptibility and severity in Taiwanese population, 475 AS patients fulfilling the modified New York Criteria and 527 healthy subjects were recruited. We found that rs10865331 was significantly associated with AS susceptibility and with Bath AS Function Index (BASFI). The AA and AG genotypes of rs10865331 were also significantly associated with a higher erythrocyte sedimentation rate. Our findings provided evidence that rs10865331 is associated AS susceptibility and with disease activity (BASFI) in a Taiwanese population.
Genetic regulators and signaling pathways are important for the formation of blood vessels. Transcription factors controlling vein identity, intersegmental vessels (ISV) growth and caudal vein plexus (CVP) formation in zebrafish are little understood as yet. Here, we show the importance of the nuclear receptor subfamily member 1A (nr2f1a) in zebrafish vascular development. Amino acid sequence alignment and phylogenetic analysis of nr2f1a is highly conserved among the vertebrates. Our in situ hybridization results showed nr2f1a mRNA is expressed in the lateral plate mesoderm at 18 somite stage and in vessels at 24-30 hpf, suggesting its roles in vasculization. Consistent with this morpholino-based knockdown of nr2fla impaired ISV growth and failed to develop fenestrated vascular structure in CVP, suggesting that nr2f1a has important roles in controlling ISV and CVP growth. Consequently, nr2f1a morphants showed pericardial edema and circulation defects. We further demonstrated reduced ISV cells and decreased CVP endothelial cells sprouting in nr2f1a morphants, indicating the growth impairment of ISV and CVP is due to a decrease of cell proliferation and migration, but not results from cell death in endothelial cells after morpholino knockdown. To test molecular mechanisms and signals that are associated with nr2f1a, we examined the expression of vascular markers. We found that a loss of nr2f1a results in a decreased expression of vein/ISV specific markers, flt4, mrc1, vascular markers stabilin and ephrinb2. This indicates the regulatory role of nr2f1a in controlling vascular development. We further showed that nr2f1a likely interact with Notch signaling by examining nr2f1a expression in rbpsuh morphants and DAPT-treatment embryos. Together, we show nr2f1a plays a critical role for vascular development in zebrafish.
Kawasaki disease (KD) is a systemic vasculitis with unknown etiology mainly affecting children in Asian countries. Dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN, CD209) in humans was showed to trigger an anti-inflammatory cascade and associated with KD susceptibility. This study was conducted to investigate the association between genetic polymorphisms of CD209 and the risk KD.
This study estimates the risk of symptomatic nephrolithiasis within 5 years of newly diagnosed osteoporosis in a Taiwan population. This cohort study consisted of patients with a diagnosis of osteoporosis between Jan. 2003 and Dec. 2005 (N = 1634). Four age- and gender- matched patients for every patient in the study cohort were selected using random sampling as the comparison cohort (N = 6536). All patients were tracked for 5 years from the date of cohort entry to identify whether they developed symptomatic nephrolithiasis. Cox proportional hazard regressions were performed to evaluate the 5-year nephrolithiasis-free survival rates. During the 5-year follow-up period, 60 osteoporosis patients (3.7%) and 165 non- osteoporosis patients (2.5%) developed symptomatic nephrolithiasis. The adjusted HR of symptomatic nephrolithiasis was 1.38 times greater risk for patients with osteoporosis than for the comparison cohort (95% confidence interval (CI) 1.03-1.86; P < .05). Osteoporosis is very likely to be an independent risk factor for subsequent diagnosis of symptomatic nephrolithiasis.
Kawasaki disease (KD) is known to be associated with T help (Th) 2 reaction and subsequently allergic diseases. Interleukin-31 (IL-31) has also been reported to be involved in Th2 mediated diseases such as allergic diseases. However, the role of IL-31 in KD has not been previously reported. The aim of this study is to investigate whether IL-31 is associated with KD and its clinical outcome.
In daily life, humans are exposed to the extremely low-frequency electromagnetic fields (ELF-EMFs) generated by electric appliances, and public concern is increasing regarding the biological effects of such exposure. Numerous studies have yielded inconsistent results regarding the biological effects of ELF-EMF exposure. Here we show that ELF-EMFs activate the ATM-Chk2-p21 pathway in HaCaT cells, inhibiting cell proliferation. To present well-founded results, we comprehensively evaluated the biological effects of ELF-EMFs at the transcriptional, protein, and cellular levels. Human HaCaT cells from an immortalized epidermal keratinocyte cell line were exposed to a 1.5 mT, 60 Hz ELF-EMF for 144 h. The ELF-EMF could cause G1 arrest and decrease colony formation. Protein expression experiments revealed that ELF-EMFs induced the activation of the ATM/Chk2 signaling cascades. In addition, the p21 protein, a regulator of cell cycle progression at G1 and G2/M, exhibited a higher level of expression in exposed HaCaT cells compared with the expression of sham-exposed cells. The ELF-EMF-induced G1 arrest was diminished when the CHK2 gene expression (which encodes checkpoint kinase 2; Chk2) was suppressed by specific small interfering RNA (siRNA). These findings indicate that ELF-EMFs activate the ATM-Chk2-p21 pathway in HaCaT cells, resulting in cell cycle arrest at the G1 phase. Based on the precise control of the ELF-EMF exposure and rigorous sham-exposure experiments, all transcriptional, protein, and cellular level experiments consistently supported the conclusion. This is the first study to confirm that a specific pathway is triggered by ELF-EMF exposure.
Cryptocarya-derived natural products were reported to have several biological effects such as the antiproliferation of some cancers. The possible antioral cancer effect of Cryptocarya-derived substances was little addressed as yet. In this study, we firstly used the methanolic extracts of C. concinna Hance roots (MECCrt) to evaluate its potential function in antioral cancer bioactivity. We found that MECCrt significantly reduced cell viability of two oral cancer Ca9-22 and CAL 27 cell lines in dose-responsive manners (P < 0.01). The percentages of sub-G1 phase and annexin V-positive of MECCrt-treated Ca9-22 and CAL 27 cell lines significantly accumulated (P < 0.01) in a dose-responsive manner as evidenced by flow cytometry. These apoptotic effects were associated with the findings that intracellular ROS generation was induced in MECCrt-treated Ca9-22 and CAL 27 cell lines in dose-responsive and time-dependent manners (P < 0.01). In a dose-responsive manner, MECCrt also significantly reduced the mitochondrial membrane potential in these two cell lines (P < 0.01-0.05). In conclusion, we demonstrated that MECCrt may have antiproliferative potential against oral cancer cells involving apoptosis, ROS generation, and mitochondria membrane depolarization.
Past researches almost explored the relationship between a single gene with a single disease. Our study aims to investigate into the interaction of multi-gene with a single disease by using Genetic Algorithms.
We developed a HNO3-assisted polyol reduction method to synthesize ultralarge single-crystalline Ag microplates routinely. The edge length of the synthesized Ag microplates reaches 50 ?m, and their top facets are (111). The mechanism for dramatically enlarging single-crystalline Ag structure stems from a series of competitive anisotropic growths, primarily governed by carefully tuning the adsorption of Ag(0) by ethylene glycol and the desorption of Ag(0) by a cyanide ion on Ag(100). Finally, we measured the propagation length of surface plasmon polaritons along the air/Ag interface under 534 nm laser excitation. Our single-crystalline Ag microplate exhibited a propagation length (11.22 ?m) considerably greater than that of the conventional E-gun deposited Ag thin film (5.27 ?m).
Cancer stem cells (CSCs) are a subset of cancer cells in tumors or established cancer cell lines that can initiate and sustain the growth of tumors in vivo. Cancer stem cells can be enriched in serum-free, suspended cultures that allow the formation of tumorspheres over several days to weeks. Brefeldin A (BFA) is a mycotoxin that induces endoplasmic reticulum (ER) stress in eukaryotic cells. We found that BFA, at sub-microgram per milliliter concentrations, preferentially induced cell death in MDA-MB-231 suspension cultures (EC50: 0.016 µg/mL) compared to adhesion cultures. BFA also effectively inhibited clonogenic activity and the migration and matrix metalloproteinases-9 (MMP-9) activity of MDA-MB-231 cells. Western blotting analysis indicated that the effects of BFA may be mediated by the down-regulation of breast CSC marker CD44 and anti-apoptotic proteins Bcl-2 and Mcl-1, as well as the reversal of epithelial-mesenchymal transition. Furthermore, BFA also displayed selective cytotoxicity toward suspended MDA-MB-468 cells, and suppressed tumorsphere formation in T47D and MDA-MB-453 cells, suggesting that BFA may be effective against breast cancer cells of various phenotypes.
Dyregulation of autophagy has been reported in various human cancers including oral squamous cell carcinoma (OSCC). The objective of this study was to link expression of autophagy-related 16-like 1 (ATG16L1), a protein essential for autophagosome formation, to clinical outcome in a cohort of 90 OSCC patients. Expression level of ATG16L1 was assessed by immunohistochemistry and an immunoreactivity score (IRS), ranging from 0 to 9, was assigned to each case. The results were correlated with clinicopathological parameters and outcome of patients. Twenty-seven patients (30 %) exhibited ATG16L1 overexpression as indicated by an IRS of 9. Overexpression of ATG16L1 was significantly associated with disease stage (p?=?0.001), size (p?=?0.031) of the tumor, lymph node metastasis (p?=?0.004), and histological grade (p?=?0.038). ATG16L1 overexpression significantly affected the overall survival (p?=?0.020) and time to recurrence (p?=?0.031) of OSCC patients in Kaplan-Meier analysis. The present study suggested that ATG16L1 may be used as a biomarker for selecting OSCC patients with a more aggressive phenotype.
Ovarian cancer has emerged as a multifaceted and genomically complex disease. Genetic/epigenetic mutations, suppression of tumor suppressors, overexpression of oncogenes, rewiring of intracellular signaling cascades and loss of apoptosis are some of the deeply studied mechanisms. In vitro and in vivo studies have highlighted different molecular mechanisms that regulate tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mediated apoptosis in ovarian cancer. In this review, we bring to limelight, expansion in understanding systematical characterization of ovarian cancer cells has led to the rapid development of new drugs and treatments to target negative regulators of TRAIL mediated signaling pathway. Wide ranging synthetic and natural agents have been shown to stimulate mRNA and protein expression of death receptors. This review is compartmentalized into programmed cell death protein 4, platelet-derived growth factor signaling and miRNA control of TRAIL mediated signaling to ovarian cancer. Mapatumumab and PRO95780 have been tested for efficacy against ovarian cancer. Use of high-throughput screening assays will aid in dissecting the heterogeneity of this disease and increasing a long-term survival which might be achieved by translating rapidly accumulating information obtained from molecular and cellular studies to clinic researches.
Carbapenem-resistance in Acinetobacter baumannii has gradually become a global challenge. To identify the genes involved in carbapenem resistance in A. baumannii, the transcriptomic responses of the completely sequenced strain ATCC 17978 selected with 0.5 mg/L (IPM-2 m) and 2 mg/L (IPM-8 m) imipenem were investigated using RNA-sequencing to identify differences in the gene expression patterns.
Tobacco includes thousands of chemicals such as nicotine, which causes numerous diseases including oral cancer. We synthesized nicotinic acid based probes by chemical modification to identify the proteins expressed by the oral cancer cell line Ca9-22 that interact with the nicotinic functional group. Proteins belonging to human oral squamous cell carcinoma were pulled down by a probe carrier based on nicotinic acid, which was reacted with 3-aminopropyltriethoxysilane to compose nicotinic acid linked 3-aminopropyltriethoxysilane exposed on the SiO2 surface. Oral cancer cell lysates were incubated with the nicotinic acid chemical probes to identify the interactions between the nicotinic group and oral cancer cell line extracted proteins. The interactions between the chemical probes and proteins identified as their targets were confirmed by consulting chemicals databases. Interestingly, chaperone proteins (e.g., heat-shock proteins and endoplasmin) that were found to interact with nicotinic acid were identified as binding partners in ribosomal and nucleosome assembly complexes.
Bone loss is a recognized feature of ankylosing spondylitis (AS). The binding of microRNA-21 (miR-21) to programmed cell death 4 (PDCD4) could inhibit the expression of PDCD4 and further induce the activation of osteoclasts. In the present study, we compared the difference in miR-21 expression between patients with AS and healthy controls, and evaluated the relationships of miR-21, PDCD4 mRNA, and bone erosion in patients with AS. The influences of nonsteroidal antiinflammatory drugs (NSAID) and disease-modifying antirheumatic drugs (DMARD) on the expressions of miR-21 and PDCD4 mRNA in patients with AS were also assessed.
Gene-gene interaction studies focus on the investigation of the association between the single nucleotide polymorphisms (SNPs) of genes for disease susceptibility. Statistical methods are widely used to search for a good model of gene-gene interaction for disease analysis, and the previously determined models have successfully explained the effects between SNPs and diseases. However, the huge numbers of potential combinations of SNP genotypes limit the use of statistical methods for analysing high-order interaction, and finding an available high-order model of gene-gene interaction remains a challenge. In this study, an improved particle swarm optimization with double-bottom chaotic maps (DBM-PSO) was applied to assist statistical methods in the analysis of associated variations to disease susceptibility. A big data set was simulated using the published genotype frequencies of 26 SNPs amongst eight genes for breast cancer. Results showed that the proposed DBM-PSO successfully determined two- to six-order models of gene-gene interaction for the risk association with breast cancer (odds ratio > 1.0; P value <0.05). Analysis results supported that the proposed DBM-PSO can identify good models and provide higher chi-square values than conventional PSO. This study indicates that DBM-PSO is a robust and precise algorithm for determination of gene-gene interaction models for breast cancer.
Jia-wei-xiao-yao-san (JWXYS) is a traditional Chinese herbal medicine that is widely used to treat neuropsychological disorders. Only a few of the hepatoprotective effects of JWXYS have been studied. The aim of this study was to investigate the hepatoprotective effects of JWXYS on dimethylnitrosamine- (DMN-) induced chronic hepatitis and hepatic fibrosis in rats and to clarify the mechanism through which JWXYS exerts these effects. After the rats were treated with DMN for 3 weeks, serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) levels were significantly elevated, whereas the albumin level decreased. Although DMN was continually administered, after the 3 doses of JWXYS were orally administered, the SGOT and SGPT levels significantly decreased and the albumin level was significantly elevated. In addition, JWXYS treatment prevented liver fibrosis induced by DMN. JWXYS exhibited superoxide-dismutase-like activity and dose-dependently inhibited DMN-induced lipid peroxidation and xanthine oxidase activity in the liver of rats. Our findings suggest that JWXYS exerts antifibrotic effects against DMN-induced chronic hepatic injury. The possible mechanism is at least partially attributable to the ability of JWXYS to inhibit reactive-oxygen-species-induced membrane lipid peroxidation.
Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer that does not express estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (Her2/neu). TNBC has worse clinical outcomes than other breast cancer subtypes. However, the key molecules and mechanisms of TNBC migration remain unclear. In this study, we compared two normalized microarray datasets from GEO database between Asian (GSE33926) and non-Asian populations (GSE46581) to determine the molecules and common pathways in TNBC migration. We demonstrated that 16 genes in non-Asian samples and 9 genes in Asian samples are related to TNBC migration. In addition, our analytic results showed that 4 genes, PIK3R3, ITGB1, ITGAL, and ITGA6, were involved in the regulation of actin cytoskeleton. Our results indicated potential genes that link to TNBC migration. This study may help identify novel therapeutic targets for drug development in cancer therapy.
ORAI1 channels play an important role for breast cancer progression and metastasis. Previous studies indicated the strong correlation between breast cancer and individual single nucleotide polymorphisms (SNPs) of ORAI1 gene. However, the possible SNP-SNP interaction of ORAI1 gene was not investigated.
Mild traumatic brain injury (mTBI) is one of the most common neurological disorders. Most patients diagnosed with mTBI could fully recover, but 15% of patients suffer from persistent symptoms. In recent studies, genetic factors were found to be associated with recovery and clinical outcomes after TBI. In addition, results from our previous research have demonstrated that the bone marrow tyrosine kinase gene in chromosome X (BMX), a member of the Tec family of kinases, is highly expressed in rats with TBI. Therefore, our aim in this study was to identify the association between genetic polymorphisms of BMX and clinical symptoms following mTBI. Four tagging single nucleotide polymorphisms (tSNPs) of BMX with minimum allele frequency (MAF) >1% were selected from the HapMap Han Chinese database. Among these polymorphisms, rs16979956 was found to be associated with the Beck anxiety inventory (BAI) and dizziness handicap inventory (DHI) scores within the first week after head injury. Additionally, another SNP, rs35697037, showed a significant correlation with dizziness symptoms. These findings suggested that polymorphisms of the BMX gene could be a potential predictor of clinical symptoms following mTBI.
Hypoxia plays an important role in the development of solid tumors. Intermittent hypoxia is the hallmark of sleep apnea (SA). We tested the hypothesis that SA may increase the risk of breast cancer in Taiwan by using a population-based data set.
Most species of penguins are sexual monomorphic and therefore it is difficult to visually identify their genders for monitoring population stability in terms of sex ratio analysis. In this study, we evaluated the suitability using melting curve analysis (MCA) for high-throughput gender identification of penguins. Preliminary test indicated that the Griffiths's P2/P8 primers were not suitable for MCA analysis. Based on sequence alignment of Chromo-Helicase-DNA binding protein (CHD)-W and CHD-Z genes from four species of penguins (Pygoscelis papua, Aptenodytes patagonicus, Spheniscus magellanicus, and Eudyptes chrysocome), we redesigned forward primers for the CHD-W/CHD-Z-common region (PGU-ZW2) and the CHD-W-specific region (PGU-W2) to be used in combination with the reverse Griffiths's P2 primer. When tested with P. papua samples, PCR using P2/PGU-ZW2 and P2/PGU-W2 primer sets generated two amplicons of 148- and 356-bp, respectively, which were easily resolved in 1.5% agarose gels. MCA analysis indicated the melting temperature (Tm) values for P2/PGU-ZW2 and P2/PGU-W2 amplicons of P. papua samples were 79.75°C-80.5°C and 81.0°C-81.5°C, respectively. Females displayed both ZW-common and W-specific Tm peaks, whereas male was positive only for ZW-common peak. Taken together, our redesigned primers coupled with MCA analysis allows precise high throughput gender identification for P. papua, and potentially for other penguin species such as A. patagonicus, S. magellanicus, and E. chrysocome as well.
Rheumatoid arthritis (RA), a chronic inflammatory disease usually occurring in synovial tissues and joints, is highly associated with genetic and environmental factors. ORAI1, a gene related to cellular immune system, has been shown to be involved in the pathogenesis of chronic inflammatory diseases and immune diseases. To identify whether ORAI1 gene contributes to RA susceptibility, we enrolled 400 patients with RA and 621 healthy individuals for a case-control genetic association study. Five tagging single nucleotides polymorphisms (tSPNs) within ORAI1 gene were selected for genotyping. An SNP, rs7135617, showed a significant correlation with the risk of RA. Our results indicated that genetic polymorphism of ORAI1 gene is involved in the susceptibility of RA in a Taiwanese population.
All-trans retinoic acid (ATRA), a derivative of retinoid, is involved in the onset of differentiation and apoptosis in a wide variety of normal and cancer cells. MicroRNAs (miRNAs) are small non-coding RNAs that control gene expression. Several miRNAs were identified to participate in ATRA-mediated cell differentiation. However, no studies have demonstrated whether miRNA can enhance ATRA cytotoxicity, thereby resulting in cell apoptosis. This study investigated the effects of ATRA-mediated miRNA expression in activating apoptotic pathways in glioblastoma. First, we found that high-dose ATRA treatment significantly reduced cell viability, caspase-dependent apoptosis, endoplasmic reticular (ER) stress activation, and intracellular reactive oxygen species accumulation. From microarray data, miR-302b was analyzed as a putative downstream regulator upon ATRA treatment. Furthermore, we found that ATRA up-regulated miR-302b expression in a dose- and time-dependent manner through retinoic acid receptor ?-mediated pathway. Overexpression and knockdown of miR-302b significantly influenced ATRA-mediated cytotoxicity. E2F3, an important transcriptional regulator of glioma proliferation, was validated to be a direct target gene of miR-302b. The miR-302b-reduced E2F3 levels were also identified to be associated with ATRA-mediated glioma cell death. These results emphasize that an ATRA-mediated miR-302b network may provide novel therapeutic strategies for glioblastoma therapy. We propose that high-dose all-trans retinoic acid (ATRA) treatment, a derivative of retinoid, significantly induces glioblastoma cell apoptosis via caspase-dependent apoptosis, endoplasmic reticular (ER) stress, and intracellular reactive oxygen species (ROS) accumulation. The miR-302b overexpression enhanced by ATRA-mediated retinoic acid receptor (RAR)? pathway was also identified. The E2F3 repression, a novel target gene of miR-302b, was involved in ATRA-induced glioblastoma cell cytotoxicity.
The association between Kawasaki disease and autism has rarely been studied in Asian populations. By using a nationwide Taiwanese population-based claims database, we tested the hypothesis that Kawasaki disease may increase the risk of autism in Taiwan.
Cancer stem cells are a subset of cancer cells that initiate the growth of tumors. Low levels of cancer stem cells also exist in established cancer cell lines, and can be enriched in serum-free tumorsphere cultures. Since cancer stem cells have been reported to be resilient to common chemotherapeutic drugs in comparison to regular cancer cells, screening for compounds selectively targeting cancer stem cells may provide an effective therapeutic strategy. We found that 5-azacytidine (5-AzaC) selectively induced anoikis of MCF-7 in suspension cultures with an EC?? of 8.014 µM, and effectively inhibited tumorsphere formation, as well as the migration and matrix metalloproteinases-9 (MMP-9) activity of MCF-7 cells. Furthermore, 5-AzaC and radiation collaboratively inhibited MCF-7 tumorsphere formation at clinically relevant radiation doses. Investigating the underlying mechanism may provide insight into signaling pathways crucial for cancer stem cell survival and pave the way to novel potential therapeutic targets.
Protein methylation is a kind of post-translational modification (PTM), and typically takes place on lysine and arginine amino acid residues. Protein methylation is involved in many important biological processes, and most recent studies focused on lysine methylation of histones due to its critical roles in regulating transcriptional repression and activation. Histones possess highly conserved sequences and are homologous in most species. However, there is much less sequence conservation among non-histone proteins. Therefore, mechanisms for identifying lysine-methylated sites may greatly differ between histones and non-histone proteins. Nevertheless, this point of view was not considered in previous studies. Here we constructed two support vector machine (SVM) models by using lysine-methylated data from histones and non-histone proteins for predictions of lysine-methylated sites. Numerous features, such as the amino acid composition (AAC) and accessible surface area (ASA), were used in the SVM models, and the predictive performance was evaluated using five-fold cross-validations. For histones, the predictive sensitivity was 85.62% and specificity was 80.32%. For non-histone proteins, the predictive sensitivity was 69.1% and specificity was 88.72%. Results showed that our model significantly improved the predictive accuracy of histones compared to previous approaches. In addition, features of the flanking region of lysine-methylated sites on histones and non-histone proteins were also characterized and are discussed. A gene ontology functional analysis of lysine-methylated proteins and correlations of lysine-methylated sites with other PTMs in histones were also analyzed in detail. Finally, a web server, MethyK, was constructed to identify lysine-methylated sites. MethK now is available at http://csb.cse.yzu.edu.tw/MethK/.
Microarrays are widely used to assess gene expressions. Most microarray studies focus primarily on identifying differential gene expressions between conditions (e.g., cancer versus normal cells), for discovering the major factors that cause diseases. Because previous studies have not identified the correlations of differential gene expression between conditions, crucial but abnormal regulations that cause diseases might have been disregarded. This paper proposes an approach for discovering the condition-specific correlations of gene expressions within biological pathways. Because analyzing gene expression correlations is time consuming, an Apache Hadoop cloud computing platform was implemented. Three microarray data sets of breast cancer were collected from the Gene Expression Omnibus, and pathway information from the Kyoto Encyclopedia of Genes and Genomes was applied for discovering meaningful biological correlations. The results showed that adopting the Hadoop platform considerably decreased the computation time. Several correlations of differential gene expressions were discovered between the relapse and nonrelapse breast cancer samples, and most of them were involved in cancer regulation and cancer-related pathways. The results showed that breast cancer recurrence might be highly associated with the abnormal regulations of these gene pairs, rather than with their individual expression levels. The proposed method was computationally efficient and reliable, and stable results were obtained when different data sets were used. The proposed method is effective in identifying meaningful biological regulation patterns between conditions.
Alzheimer's disease (AD) is the main cause of dementia for older people. Although several antidementia drugs such as donepezil, rivastigmine, galantamine, and memantine have been developed, the effectiveness of AD drug therapy is still far from satisfactory. Recently, the single nucleotide polymorphisms (SNPs) have been chosen as one of the personalized medicine markers. Many pharmacogenomics databases have been developed to provide comprehensive information by associating SNPs with drug responses, disease incidence, and genes that are critical in choosing personalized therapy. However, we found that some information from different sets of pharmacogenomics databases is not sufficient and this may limit the potential functions for pharmacogenomics. To address this problem, we used approximate string matching method and data mining approach to improve the searching of pharmacogenomics database. After computation, we can successfully identify more genes linked to AD and AD-related drugs than previous online searching. These improvements may help to improve the pharmacogenomics of AD for personalized medicine.
Nephrolithiasis is a multifactorial disease caused by environmental, hormonal, and genetic factors. Genetic polymorphisms of ORAI1, which codes for the main subunit of the store-operated calcium (SOC) channel, were reported to be associated with the risk and recurrence of calcium nephrolithiasis. Inositol 1,4,5-trisphosphate (IP3) 3-kinase C (ITPKC) is a negative regulator of the SOC channel-mediated signaling pathway. We investigated the association between calcium containing nephrolithiasis and genetic variants of ITPKC gene in Taiwanese patients. 365 patients were recruited in this study. Eight tagging single nucleotide polymorphisms of ITPKC were selected for genotyping. ITPKC genotypes were determined by TaqMan assay. ITPKC plasmids were transfected into cells to evaluate the intracellular calcium mobilization. Our results indicated that rs2607420 CC genotype in the intron region of the ITPKC gene is associated with a lower eGFR by both Modification of Diet in Renal Diseases (P = 0.0405) and Cockcroft-Gault (P = 0.0215) equations in patients with calcium nephrolithiasis. Our results identify a novel polymorphism for renal function and highlight the importance of ITPKC as a key molecule to regulate calcium signaling.
The anticancer effects of ceramide have been reported in many types of cancers but less in lung cancer. In this study, we used C2-ceramide to further investigate its possible anticancer effects and mechanisms on non-small cell lung cancer (NSCLC) H1299 cells. The result of cell proliferation in terms of trypan blue assay showed high dose of C2-ceramide inhibited cell survival after 24 h treatment. The flow cytometry-based assays indicated the effect of apoptosis, chromatin condensation, and G1 arrest in terms of Annexin V/propidium iodide (PI), DAPI, and PI stainings, respectively. Moreover, the decreased protein level of p-Akt, p-NF?B, survivin and cyclin A2 were detected by Western blot assay. Taken together, these results indicated the antiproliferative effect of C2-ceramide is majorly responsible for cell apoptosis in lung cancer H1299 cells.
Following an increase in the use of electric appliances that can generate 50 or 60 Hz electromagnetic fields, concerns have intensified regarding the biological effects of extremely low-frequency electromagnetic fields (ELF-EMFs) on human health. Previous epidemiological studies have suggested the carcinogenic potential of environmental exposure to ELF-EMFs, specifically at 50 or 60 Hz. However, the biological mechanism facilitating the effects of ELF-EMFs remains unclear. Cellular studies have yielded inconsistent results regarding the biological effects of ELF-EMFs. The inconsistent results might have been due to diverse cell types. In our previous study, we indicated that 1.5 mT, 60 Hz ELF-EMFs will cause G1 arrest through the activation of the ATM-Chk2-p21 pathway in human keratinocyte HaCaT cells. The aim of the current study was to investigate whether ELF-EMFs cause similar effects in a distinct epidermal keratinocyte, primary normal human epidermal keratinocytes (NHEK), by using the same ELF-EMF exposure system and experimental design. We observed that ELF-EMFs exerted no effects on cell growth, cell proliferation, cell cycle distribution, and the activation of ATM signaling pathway in NHEK cells. We demonstrated that the 2 epidermal keratinocytes responded to ELF-EMFs differently. To further validate this finding, we simultaneously exposed the NHEK and HaCaT cells to ELF-EMFs in the same incubator for 168 h and observed the cell growths. The simultaneous exposure of the two cell types results showed that the NHEK and HaCaT cells exhibited distinct responses to ELF-EMFs. Thus, we confirmed that the biological effects of ELF-EMFs in epidermal keratinocytes are cell type specific. Our findings may partially explain the inconsistent results of previous studies when comparing results across various experimental models.
Detecting periodicity signals from time-series microarray data is commonly used to facilitate the understanding of the critical roles and underlying mechanisms of regulatory transcriptomes. However, time-series microarray data are noisy. How the temporal data structure affects the performance of periodicity detection has remained elusive. We present a novel method based on empirical mode decomposition (EMD) to examine this effect. We applied EMD to a yeast microarray dataset and extracted a series of intrinsic mode function (IMF) oscillations from the time-series data. Our analysis indicated that many periodically expressed genes might have been under-detected in the original analysis because of interference between decomposed IMF oscillations. By validating a protein complex coexpression analysis, we revealed that 56 genes were newly determined as periodic. We demonstrated that EMD can be used incorporating with existing periodicity detection methods to improve their performance. This approach can be applied to other time-series microarray studies.
Hypoxia inducible factor 1? (HIF-1?) is a stress-responsive transcription factor to hypoxia and its expression is correlated to tumor progression and angiogenesis. Several single nucleotide polymorphisms (SNPs) of HIF-1? gene in the oxygen-dependent degradation (ODD) domain was reportedly associated with increased HIF-1? activity.
Mitochondria form a reticulum network dynamically fuse and divide in the cell. The balance between mitochondria fusion and fission is correlated to the shape, activity and integrity of these pivotal organelles. Resveratrol is a polyphenol antioxidant that can extend life span in yeast and worm. This study examined mitochondria dynamics in replicative senescent yeast cells as well as the effects of resveratrol on mitochondria fusion and fission. Collecting cells by biotin-streptavidin sorting method revealed that majority of the replicative senescent cells bear fragmented mitochondrial network, indicating mitochondria dynamics favors fission. Resveratrol treatment resulted in a reduction in the ratio of senescent yeast cells with fragmented mitochondria. The readjustment of mitochondria dynamics induced by resveratrol likely derives from altered expression profiles of fusion and fission genes. Our results demonstrate that resveratrol serves not only as an antioxidant, but also a compound that can mitigate mitochondria fragmentation in replicative senescent yeast cells.
Facial emotion perception (FEP) can affect social function. We previously reported that parts of five tested single-nucleotide polymorphisms (SNPs) in the MET and AKT1 genes may individually affect FEP performance. However, the effects of SNP-SNP interactions on FEP performance remain unclear.
Unique characteristics of tumor microenvironments can be used as targets of cancer therapy. The aryl hydrocarbon receptor nuclear translocator (ARNT) is an important mediator of tumor progression. However, the functional role of ARNT in chemotherapeutic drug-treated cancer remains unclear.
Prostate cancer is a gland tumor in the male reproductive system. It is a multifaceted and genomically complex disease. Transmembrane protease, serine 2 and v-ets erythroblastosis virus E26 homolog (TMPRSS2-ERG) gene fusions are the common molecular signature of prostate cancer. Although tremendous advances have been made in unraveling various facets of TMPRSS2-ERG-positive prostate cancer, many research findings must be sequentially collected and re-interpreted. It is important to understand the activation or repression of target genes and proteins in response to various stimuli and the assembly in signal transduction in TMPRSS2-ERG fusion-positive prostate cancer cells. Accordingly, we divide this multi-component review ofprostate cancer cells into several segments: 1) The role of TMPRSS2-ERG fusion in genomic instability and methylated regulation in prostate cancer and normal cells; 2) Signal transduction cascades in TMPRSS2-ERG fusion-positive prostate cancer; 3) Overexpressed genes in TMPRSS2-ERG fusion-positive prostate cancer cells; 4) miRNA mediated regulation of the androgen receptor (AR) and its associated protein network; 5) Quantitative control of ERG in prostate cancer cells; 6) TMPRSS2-ERG encoded protein targeting; In conclusion, we provide a detailed understanding of TMPRSS2-ERG fusion related information in prostate cancer development to provide a rationale for exploring TMPRSS2-ERG fusion-mediated molecular network machinery.
The association between liver cirrhosis (LC) and herpes zoster has rarely been studied. We investigated the hypothesis that LC, known as an immunodeficiency disease, may increase the risk of herpes zoster using a national health insurance database in Taiwan.
Sleep apnea (SA) is a common sleep disorder characterized by chronic intermittent hypoxia (IH). Chronic IH induces systemic inflammatory processes, which can cause tissue damage and contribute to prostatic enlargement. The purpose of this study was to evaluate the association between benign prostate hyperplasia (BPH) and SA in a Taiwanese population.
Kawasaki disease (KD) is a multi-systemic vasculitis that preferentially affects children. A single nucleotide polymorphism (SNP) in inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) has been identified to be an important polymorphism in the risk of KD. This study was conducted to comprehensively investigate the associations between all tagging SNPs of ITPKC in the risk of KD in a Taiwanese population. A total of 950 subjects (381 KD patients and 569 controls) were recruited. Seven tagging SNPs (rs11673492, rs7257602, rs7251246, rs890934, rs10420685, rs2607420, rs2290692) were selected for TaqMan allelic discrimination assay. Clinical data of coronary artery lesions (CAL) and aneurysms were collected for analysis. A significant association was found between rs7251246 in ITPKC and CAL formation. Haplotype analysis for ITPKC polymorphisms also confirmed this association in the patients with CAL and aneurysm formation. This is the first study to identify that SNP rs7251246 in ITPKC is associated with the severity of KD.
Patients with Type 2 diabetes (T2DM) are prone to develop dementia. Results from a recent study indicated that statin users had lower chance of developing incident dementia. However there is little information on the potential benefits of statin use on dementia in patients with T2DM cohort.
In addition to the previous investigations of bioactivity of aqueous extract of the edible Gracilaria tenuistipitata (AEGT) against H2O2-induced DNA damage and hepatitis C virus replication, the purpose of this study is to evaluate the potential therapeutic properties of AEGT against inflammation and hepatotoxicity using lipopolysaccharide (LPS)-stimulated mouse RAW 264.7 cells, primary rat peritoneal macrophages and carbon tetrachloride (CCl4)-induced acute hepatitis model in rats. AEGT concentration-dependently inhibited the elevated RNA and protein levels of inducible nitric oxide synthase and cyclooxygenase-2, thereby reducing nitric oxide and prostaglandin E2 levels, respectively. Moreover, AEGT significantly suppressed the production of LPS-induced proinflammatory cytokines, including interleukin (IL)-1?, IL-6 and tumor necrosis factor-?. These inhibitory effects were associated with the suppression of nuclear factor-kappa B activation and mitogen-activated protein kinase phosphorylation by AEGT in LPS-stimulated cells. In addition, we highlighted the hepatoprotective and curative effects of AEGT in a rat model of CCl4-intoxicated acute liver injury, which was evident from reduction in the elevated serum aspartate aminotransferase and alanine aminotransferase levels as well as amelioration of histological damage by pre-treatment or post-treatment of AEGT. In conclusion, the results demonstrate that AEGT may serve as a potential supplement in the prevention or amelioration of inflammatory diseases.
Aim: To evaluate the expression and prognostic value of two autophagy-related (Atg) proteins, Beclin-1 and Atg5, in human oral squamous cell carcinoma (OSCC) and to correlate findings with clinical outcomes.
Objective: Osteoporosis and periodontitis are both considered as the global health issues which threaten postmenopausal women and elder population. However, the correlation between osteoporosis and periodontitis is still unclear. Materials and methods: Using a nationwide Taiwanese population-based database, data from osteoporosis patients (year 2003 to 2005; N = 2527) and 7575 individuals who were matched to each patient by their age and gender were analyzed. All participates were tracked for 5 years from the date of enrollment to observe the percentage of patients who developed periodontitis. Cox proportional hazard regressions were performed to evaluate 5-year periodontitis-free survival rates. Results: Among the total sample, 3060 individuals were diagnosed with periodontitis during the 5-year follow-up period: 792 in the study cohort and 2268 in the comparison cohort. The adjusting hazard ratio (HR) for periodontitis in patients with osteoporosis compared to the non-osteoporosis subjects during the 5-year follow-up was 1.14 (95% confidence interval [CI] = 1.05-1.24, p < 0.01). Conclusions: This population-based study indicated that osteoporosis patients may have an increased risk of periodontitis.
Genetic association is a challenging task for the identification and characterization of genes that increase the susceptibility to common complex multifactorial diseases. To fully execute genetic studies of complex diseases, modern geneticists face the challenge of detecting interactions between loci. A genetic algorithm (GA) is developed to detect the association of genotype frequencies of cancer cases and noncancer cases based on statistical analysis. An improved genetic algorithm (IGA) is proposed to improve the reliability of the GA method for high-dimensional SNP-SNP interactions. The strategy offers the top five results to the random population process, in which they guide the GA toward a significant search course. The IGA increases the likelihood of quickly detecting the maximum ratio difference between cancer cases and noncancer cases. The study systematically evaluates the joint effect of 23 SNP combinations of six steroid hormone metabolisms, and signaling-related genes involved in breast carcinogenesis pathways were systematically evaluated, with IGA successfully detecting significant ratio differences between breast cancer cases and noncancer cases. The possible breast cancer risks were subsequently analyzed by odds-ratio (OR) and risk-ratio analysis. The estimated OR of the best SNP barcode is significantly higher than 1 (between 1.15 and 7.01) for specific combinations of two to 13 SNPs. Analysis results support that the IGA provides higher ratio difference values than the GA between breast cancer cases and noncancer cases over 3-SNP to 13-SNP interactions. A more specific SNP-SNP interaction profile for the risk of breast cancer is also provided.
The identification of molecular pathways in cancer cells is important for understanding the cells underlying biology and for designing effective cancer therapies. We demonstrate that the expression of aryl hydrocarbon receptor nuclear translocator (ARNT) is critical during the development of cisplatin resistance. The reduced expression of ARNT was correlated with cisplatin-induced cell death in drug-sensitive cells. In addition, suppression of ARNT reversed the characteristics of cisplatin-resistant cells, making these cells cisplatin-sensitive, and significantly enhanced caspase-3 activation, DNA fragmentation, and apoptosis. The inhibition of colony formation, regulated by cisplatin, was more significant in ARNT-knockdown cells than in parental cells. In a xenograft analysis of severe combined immunodeficiency mice, cisplatin also efficiently inhibited ARNT-deficient c4 tumors but not ARNT-containing vT2 tumor formation. Furthermore, the downregulation of multidrug resistance 1 (MDR1) expression and retention of drugs in cells caused by suppression of ARNT, resulting in the resensitization of drug-resistant cells to cisplatin, was observed. When overexpressed, ARNT interacted with Sp1 to enhance the expression of MDR1 through Sp1-binding sites on the MDR1 promoter, resulting in a reversal of the effect of cisplatin on cell death. In addition, ARNT-induced MDR1 expression was inhibited in Sp1-knockdown cells. These results reveal previously unrecognized, multifaceted functions of ARNT in establishing the drug-resistant properties of cancer cells by the upregulation of MDR1, highlighting ARNTs potential as a therapeutic target in an important subset of cancers.
Apoptosis is a key mechanism for enhanced cellular radiosensitivity in radiation therapy. Studies suggest that Akt signaling may play a role in apoptosis and radioresistance. This study evaluates the possible modulating role of amiloride, an antihypertensive agent with a modulating effect to alternative splicing for regulating apoptosis, in the antiproliferative effects induced by ionizing radiation (IR) in glioblastoma multiforme (GBM) 8401 cells. Analysis of cell viability showed that amiloride treatment significantly inhibited cell proliferation in irradiated GBM8401 cells (p<0.05) in a time-dependent manner, especially in cells treated with amiloride with IR post-treatment. In comparison with GBM8401 cells treated with amiloride alone, with GBM8401 cells treated with IR alone, and with human embryonic lung fibroblast control cells (HEL 299), GBM8401 cells treated with IR combined with amiloride showed increased overexpression of phosphorylated Akt, regardless of whether IR treatment was performed before or after amiloride administration. The alternative splicing pattern of apoptotic protease-activating factor-1 (APAF1) in cells treated with amiloride alone, IR alone, and combined amiloride-IR treatments showed more consistent cell proliferation compared to that in other apoptosis-related genes such as baculoviral IAP repeat containing 5 (BIRC5), Bcl-X, and homeodomain interacting protein kinase-3 (HIPK3). In GBM8401 cells treated with amiloride with IR post-treatment, the ratio of prosurvival (-XL,-LC) to proapoptotic (-LN,-S) splice variants of APAF1 was lower than that seen in cells treated with amiloride with IR pretreatment, suggesting that proapoptotic splice variants of APAF1 (APAF1-LN,-S) were higher in the glioblastoma cells treated with amiloride with IR post-treatment, as compared to glioblastoma cells and fibroblast control cells that had received other treatments. Together, these results suggest that amiloride modulates cell radiosensitivity involving the Akt phosphorylation and the alternative splicing of APAF1, especially for the cells treated with amiloride with IR post-treatment. Therefore, amiloride may improve the effectiveness of radiation therapy for GBMs.
Abstract Background and aims: Single nucleotide polymorphism (SNP) interaction analysis can simultaneously evaluate the complex SNP interactions present in complex diseases. However, it is less commonly applied to evaluate the predisposition of chronic dialysis and its computational analysis remains challenging. In this study, we aimed to improve the analysis of SNP-SNP interactions within the mitochondrial D-loop in chronic dialysis. Material & method: The SNP-SNP interactions between 77 reported SNPs within the mitochondrial D-loop in chronic dialysis study were evaluated in terms of SNP barcodes (different SNP combinations with their corresponding genotypes). We propose a genetic algorithm (GA) to generate SNP barcodes. The ?(2) values were then calculated by the occurrences of the specific SNP barcodes and their non-specific combinations between cases and controls. Results: Each SNP barcode (2- to 7-SNP) with the highest value in the ?(2) test was regarded as the best SNP barcode (11.304 to 23.310; p?0.001). The best GA-generated SNP barcodes (2- to 7-SNP) were significantly associated with chronic dialysis (odds ratio [OR]?=?1.998 to 3.139; p?0.001). The order of influence for SNPs was the same as the order of their OR values for chronic dialysis in terms of 2- to 7-SNP barcodes. Conclusion: Taken together, we propose an effective algorithm to address the SNP-SNP interactions and demonstrated that many non-significant SNPs within the mitochondrial D-loop may play a role in jointed effects to chronic dialysis susceptibility.
Cancer stem cells (CSCs) are a small subset of cancer cells with indefinite potential for self-renewal and the capacity to drive tumorigenesis. Brefeldin A (BFA) is an antibiotic that is known to block protein transport and induce endoplasmic reticulum (ER) stress in eukaryotic cells, but its effects on colorectal CSCs are unknown. We investigated the inhibitory effect of BFA on human colorectal cancer Colo 205 cells. We found that BFA effectively reduced the survival of suspension Colo 205 cells (IC?? = ~15 ng/mL) by inducing apoptosis, and inhibited the clonogenic activity of Colo 205 CSCs in tumorsphere formation assay and soft agar colony formation assay in the same nanogram per milliliter range. We also discovered that at such low concentrations, BFA effectively induced endoplasmic reticulum (ER) stress response as indicated by the increased mRNA expression of ER stress-related genes, such as glucose-regulated protein 78 (GRP78), X-box binding protein 1 (XBP1), and C/EBP homologous protein (CHOP). Finally, we found that BFA reduced the activity of matrix metallopeptidase 9 (MMP-9). These findings suggest that BFA can effectively suppress the progression of colorectal cancer during the tumorigenesis and metastasis stages. These results may lead to the development of novel therapies for the treatment of colorectal cancer.
This study computationally determines the contribution of clinicopathologic factors correlated with 5-year survival in oral squamous cell carcinoma (OSCC) patients primarily treated by surgical operation (OP) followed by other treatments. From 2004 to 2010, the program enrolled 493 OSCC patients at the Kaohsiung Medical Hospital University. The clinicopathologic records were retrospectively reviewed and compared for survival analysis. The Apriori algorithm was applied to mine the association rules between these factors and improved survival. Univariate analysis of demographic data showed that grade/differentiation, clinical tumor size, pathology tumor size, and OP grouping were associated with survival longer than 36 months. Using the Apriori algorithm, multivariate correlation analysis identified the factors that coexistently provide good survival rates with higher lift values, such as grade/differentiation = 2, clinical stage group = early, primary site = tongue, and group = OP. Without the OP, the lift values are lower. In conclusion, this hospital-based analysis suggests that early OP and other treatments starting from OP are the key to improving the survival of OSCC patients, especially for early stage tongue cancer with moderate differentiation, having a better survival (>36 months) with varied OP approaches.
Ferulic acid (FA), a phenolic compound, is an abundant dietary antioxidant and exerts the mitogenic effect on cells. Recently, we isolated an active FA derivative, namely feruloyl-L-arabinose (FAA), from coba husk. The aim of this study was to investigate the effects of FAA on the proliferation, migration and invasion of H1299 human lung cancer cells. Our results showed a strong antioxidant potential of FAA. Additionally, FAA inhibited the migration and invasion ability, while causing a significant accumulation of G2/M-population, of H1299 tumor cells in a dose-dependent manner, whereas no significant change on cell proliferation was observed. Results from the wound healing assay revealed that cell migration ability was markedly inhibited by FAA treatments. Similarly, results of gelatin zymography study showed that FAA treatments significantly decreased the activities of matrix metalloproteinase (MMP)-2 and MMP-9, suggesting that FAA-mediated inhibition on migration and invasion of lung cancer cells may be achieved by the down-regulation of the MMPs activities. Taken together, our present work provides a new insight into the novel inhibitory function of FAA on cell migration in H1299 cells, suggesting its promising role in the chemoprevention of lung cancer.
Epidermal growth factor receptor (EGFR) is overexpressed in many types of cancer cells. EGFR-mediated signaling involves inflammatory gene expression including cyclooxygenase (COX)-2 and interleukin (IL)-8, and is associated with cancer pathogenesis. In a search of phytochemicals with anti-inflammatory activity, the COX-2 and IL-8 inhibitory activities of some marine compounds were examined. After screening these compounds 11-episinulariolide acetate (1) from soft coral exhibited the most potent activity. Reverse-transcription PCR; western blotting; ELISA and luciferase assays were used to test the effect of compound 1 on EGF-stimulated expressions of COX-2 and IL-8 in A431 human epidermoid carcinoma cells. After exposure to 10 ?M of compound 1, expression levels of COX-2 and IL-8 were reduced. In addition; intracellular Ca²? increase and Ca²?-dependent transcription factor activation were blocked by compound 1. Thus, compound 1 can potentially serve as a lead compound for targeting Ca²? signaling-dependent inflammatory diseases.
For their various bioactivities, biomaterials derived from marine algae are important ingredients in many products, such as cosmetics and drugs for treating cancer and other diseases. This mini-review comprehensively compares the bioactivities and biological functions of biomaterials from red, green, brown, and blue-green algae. The anti-oxidative effects and bioactivities of several different crude extracts of algae have been evaluated both in vitro and in vivo. Natural products derived from marine algae protect cells by modulating the effects of oxidative stress. Because oxidative stress plays important roles in inflammatory reactions and in carcinogenesis, marine algal natural products have potential for use in anti-cancer and anti-inflammatory drugs.
Although an increasing number of RNA adenosine-to-inosine (A-to-I) editing sites are being discovered, how the editing frequencies of these sites are modulated to fine-tune protein function in adaptive responses is not well understood. A previous study screening for heat tolerance in Drosophila mutants discovered a hypnos-2 mutant strain that was later found to be defective in dADAR, the Drosophila gene encoding the A-to-I editing enzyme. This supports the hypothesis that cells and organisms respond to stressful environments by ADAR (adenosine deaminase acting on RNA)-mediated RNA editing. Here, we investigated changes in the RNA A-to-I editing frequencies of 30 Drosophila nervous system targets in response to heat shock, a stress acclimatization that requires the dADAR function. To our surprise, most of these nervous system editing targets showed reduced editing. Our results suggest that a change in RNA editing pattern is a mechanism by which organisms acclimate to drastic environmental change. However, how RNA editing confers heat resistance is more complicated and requires further investigation.
In this study, a genetic algorithm (GA) is developed to detect the association of genotype frequencies of cancer cases and non-cancer cases based on statistical analysis. An improved genetic algorithm (IGA) is proposed to improve the reliability of the GA method for high-dimensional SNP-SNP interactions. The strategy offers the top five results to the random population process, in which they guide the GA toward a significant search course. IGA increases the likelihood of quickly detecting the maximum ratio difference between cancer cases and non-cancer cases. The study systematically evaluates the joint effect of 23 SNP combinations of six steroid hormone metabolisms and signaling-related genes involved in breast carcinogenesis pathways were systematically evaluated, with IGA success fully detecting significant ratio differences between breast cancer cases and non-cancer cases. The possible breast cancer risks were subsequently analyzed by odds-ratio (OR) and risk-ratio (RR) analysis. The estimated OR of the best SNP barcode is significantly higher than 1 (between 1.15 and 7.01) for specific combinations of two to 13 SNPs. Analysis results support that IGA provides higher ratio difference values than GA between breast cancer cases and non-cancer cases over 3-SNP to 13-SNP interactions. A more specific SNP-SNP interaction profile for the risk of breast cancer is also provided.
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