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In addition to cellular damage, ischemia-reperfusion (IR) injury induces substantial damage to the mitochondria and endoplasmic reticulum. In this study, we sought to determine whether impaired mitochondrial function owing to IR could be restored by transplanting mitochondria into the heart under ex vivo IR states. Additionally, we aimed to provide preliminary results to inform therapeutic options for ischemic heart disease (IHD). Healthy mitochondria isolated from autologous gluteus maximus muscle were transplanted into the hearts of Sprague-Dawley rats damaged by IR using the Langendorff system, and the heart rate and oxygen consumption capacity of the mitochondria were measured to confirm whether heart function was restored. In addition, relative expression levels were measured to identify the genes related to IR injury. Mitochondrial oxygen consumption capacity was found to be lower in the IR group than in the group that underwent mitochondrial transplantation after IR injury (p < 0.05), and the control group showed a tendency toward increased oxygen consumption capacity compared with the IR group. Among the genes related to fatty acid metabolism, Cpt1b (p < 0.05) and Fads1 (p < 0.01) showed significant expression in the following order: IR group, IR + transplantation group, and control group. These results suggest that mitochondrial transplantation protects the heart from IR damage and may be feasible as a therapeutic option for IHD.
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This study sought to develop a novel diagnostic tool for atopic dermatitis (AD). Mouse transcriptome data were obtained via RNA-sequencing of dorsal skin tissues of CBA/J mice affected with contact hypersensitivity (induced by treatment with 1-chloro-2,4-dinitrobenzene) or brush stimulation-induced AD-like skin condition. Human transcriptome data were collected from German, Swedish, and American cohorts of AD patients from the Gene Expression Omnibus database. edgeR and SAM algorithms were used to analyze differentially expressed murine and human genes, respectively. The FAIME algorithm was then employed to assign pathway scores based on KEGG pathway database annotations. Numerous genes and pathways demonstrated similar dysregulation patterns in both the murine models and human AD. Upon integrating transcriptome information from both murine and human data, we identified 36 commonly dysregulated differentially expressed genes, which were designated as a 36-gene signature. A severity score (AD index) was applied to each human sample to assess the predictive power of the 36-gene AD signature. The diagnostic power and predictive accuracy of this signature were demonstrated for both AD severity and treatment outcomes in patients with AD. This genetic signature is expected to improve both AD diagnosis and targeted preclinical research.
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Biomarcadores , Dermatitis Atópica/etiología , Perfilación de la Expresión Génica , Transcriptoma , Animales , Biología Computacional/métodos , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Perfilación de la Expresión Génica/métodos , Regulación de la Expresión Génica , Humanos , RatonesRESUMEN
Far-infrared rays (FIR) are known to have various effects on atoms and molecular structures within cells owing to their radiation and vibration frequencies. The present study examined the effects of FIR on gene expression related to glucose transport through microarray analysis in rat skeletal muscle cells, as well as on mitochondrial biogenesis, at high and low glucose conditions. FIR were emitted from a bio-active material coated fabric (BMCF). L6 cells were treated with 30% BMCF for 24 h in medium containing 25 or 5.5 mM glucose, and changes in the expression of glucose transporter genes were determined. The expression of GLUT3 (Slc2a3) increased 2.0-fold (p < 0.05) under 5.5 mM glucose and 30% BMCF. In addition, mitochondrial oxygen consumption and membrane potential (ΔΨm) increased 1.5- and 3.4-fold (p < 0.05 and p < 0.001), respectively, but no significant change in expression of Pgc-1a, a regulator of mitochondrial biogenesis, was observed in 24 h. To analyze the relationship between GLUT3 expression and mitochondrial biogenesis under FIR, GLUT3 was down-modulated by siRNA for 72 h. As a result, the ΔΨm of the GLUT3 siRNA-treated cells increased 3.0-fold (p < 0.001), whereas that of the control group increased 4.6-fold (p < 0.001). Moreover, Pgc-1a expression increased upon 30% BMCF treatment for 72 h; an effect that was more pronounced in the presence of GLUT3. These results suggest that FIR may hold therapeutic potential for improving glucose metabolism and mitochondrial function in metabolic diseases associated with insufficient glucose supply, such as type 2 diabetes.
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Alnus sibirica extracts (ASex) have long been used in Oriental medicine to treat various conditions. To provide a scientific basis for this application and the underlying mechanism, we investigated the anti-inflammatory effects of ASex in vitro and in vivo. The in vitro model was established using human dermal fibroblasts (HDFs) treated with inflammatory stimulants (lipopolysaccharide, tumor necrosis factor-alpha, interferon-gamma). Lactate dehydrogenase and reverse transcription-polymerase chain reaction showed that ASex inhibited the increased expression of acute-phase inflammatory cytokines. The in vivo model was established by inducing skin inflammation in NC/Nga mice via the repeated application of house dust mite (HDM) ointment to the ears and back of the mice for eight weeks. HDM application increased the severity of skin lesions, eosinophil/mast cell infiltration, and serum immunoglobulin E levels, which were all significantly decreased by ASex treatment, demonstrating the same degree of protection as hydrocortisone. Overall, ASex showed excellent anti-inflammatory effects both in vitro and in vivo, suggesting its potential as an excellent candidate drug to reduce skin inflammation.
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Alnus/química , Antiinflamatorios/química , Antiinflamatorios/farmacología , Extractos Vegetales/química , Extractos Vegetales/farmacología , Animales , Biopsia , Cromatografía Líquida de Alta Presión , Citocinas/sangre , Citocinas/genética , Citocinas/metabolismo , Dermis/citología , Dermis/efectos de los fármacos , Dermis/metabolismo , Modelos Animales de Enfermedad , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Humanos , Inmunoglobulina E/sangre , Mediadores de Inflamación/metabolismo , RatonesRESUMEN
BACKGROUND: Leukocyte telomere length (LTL), an indicator of aging, is influenced by both genetic and environmental factors; however, its heritability is unknown. We determined heritability and inheritance patterns of telomere length across three generations of families. METHODS: We analyzed 287 individuals from three generations of 41 Korean families, including newborns, parents, and grandparents. LTL (the ratio of telomere repeat copy number to single gene copy number) was measured by quantitative real-time PCR. We estimated heritability using the SOLAR software maximum-likelihood variance component methods and a pedigree dataset. With adjustment for age and length of marriage, Pearson's partial correlation was performed for spousal pairs. RESULTS: Heritability of LTL was high in all participants (h2 = 0.64). There were no significant differences in correlation coefficients of telomere length between paternal and maternal lines. There was a positive LTL correlation in grandfather-grandmother pairs (r = 0.25, p = 0.03) but not in father-mother pairs. After adjusting for age and length of marriage, the relationship between telomere lengths in grandfathers and grandmothers disappeared. There were inverse correlations between spousal rank differences of telomere length and length of marriage. CONCLUSIONS: LTL is highly heritable without a sex-specific inheritance pattern and may be influenced by a shared environment.
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Pueblo Asiatico/genética , Familia , Patrón de Herencia , Homeostasis del Telómero , Acortamiento del Telómero , Telómero/genética , Ambiente , Familia/etnología , Femenino , Herencia , Humanos , Recién Nacido , Masculino , Matrimonio/etnología , Linaje , Seúl , Factores SexualesRESUMEN
Lung cancer is the most common cause of cancer deaths worldwide and several molecular signatures have been developed to predict survival in lung cancer. Increasing evidence suggests that proliferation and migration to promote tumor growth are associated with dysregulated ion channel expression. In this study, by analyzing high-throughput gene expression data, we identify the differentially expressed K+ channel genes in lung cancer. In total, we prioritize ten dysregulated K+ channel genes (5 up-regulated and 5 down-regulated genes, which were designated as K-10) in lung tumor tissue compared with normal tissue. A risk scoring system combined with the K-10 signature accurately predicts clinical outcome in lung cancer, which is independent of standard clinical and pathological prognostic factors including patient age, lymph node involvement, tumor size, and tumor grade. We further indicate that the K-10 potentially predicts clinical outcome in breast and colon cancers. Molecular signature discovered through K+ gene expression profiling may serve as a novel biomarker to assess the risk in lung cancer.
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Although atopic dermatitis (AD) is known to be a representative skin disorder, it also affects the systemic immune response. In a recent study, myoblasts were shown to be involved in the immune regulation, but the roles of muscle cells in AD are poorly understood. We aimed to identify the relationship between mitochondria and atopy by genome-wide analysis of skeletal muscles in mice. We induced AD-like symptoms using house dust mite (HDM) extract in NC/Nga mice. The transcriptional profiles of the untreated group and HDM-induced AD-like group were analyzed and compared using microarray, differentially expressed gene and functional pathway analyses, and protein interaction network construction. Our microarray analysis demonstrated that immune response-, calcium handling-, and mitochondrial metabolism-related genes were differentially expressed. In the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology pathway analyses, immune response pathways involved in cytokine interaction, nuclear factor-kappa B, and T-cell receptor signaling, calcium handling pathways, and mitochondria metabolism pathways involved in the citrate cycle were significantly upregulated. In protein interaction network analysis, chemokine family-, muscle contraction process-, and immune response-related genes were identified as hub genes with many interactions. In addition, mitochondrial pathways involved in calcium signaling, cardiac muscle contraction, tricarboxylic acid cycle, oxidation-reduction process, and calcium-mediated signaling were significantly stimulated in KEGG and Gene Ontology analyses. Our results provide a comprehensive understanding of the genome-wide transcriptional changes of HDM-induced AD-like symptoms and the indicated genes that could be used as AD clinical biomarkers.
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The effects of Alnus sibirica (AS) extracts on cytokine expression induced by inflammatory stimulants were examined in human dermal fibroblasts (HDFs) and RAW264.7 cells. The anti-oxidative effect and effect on cell viability of AS extracts were evaluated, and four extracts with the highest anti-oxidative effects were selected. HDFs and RAW264.7 cells were treated with inflammatory stimulants, and the expression of cytokines involved in acute (IL-6 and IL-10) and chronic (IL-18) inflammation, the initiation of the immune response (IL-33), and non-specific immune responses (IL-1ß, IL-8, and TNF-α) were determined using a reverse-transcription polymerase chain reaction. LPS increased the expression of all the cytokines, except for IL-18; however, AS extracts, particularly AS2 and AS4, reduced this increase, and TNF-α treatment markedly increased the expression of cytokines related to non-specific immune responses. IFN-γ treatment induced no significant changes, except for increased IL-33 expression in HDFs. AS extracts inhibited the increase in the expression of IL-33 and other cytokines in HDFs. Thus, the exposure of HDFs and RAW264.7 cells to inflammatory stimulants increased the expression of cytokines related to all the inflammatory processes. HDFs are involved not only in simple tissue regeneration but also in inflammatory reactions in the skin. AS2 and AS4 may offer effective therapy for related conditions.
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Alnus/química , Citocinas/genética , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Mediadores de Inflamación/metabolismo , Extractos Vegetales/farmacología , Animales , Antioxidantes/química , Antioxidantes/farmacología , Supervivencia Celular/efectos de los fármacos , Citocinas/metabolismo , Humanos , Interferón gamma/metabolismo , Interferón gamma/farmacología , Lipopolisacáridos , Ratones , Fitoquímicos/química , Fitoquímicos/farmacología , Extractos Vegetales/química , Células RAW 264.7 , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
Despite increased evidence of bio-activity following far-infrared (FIR) radiation, susceptibility of cell signaling to FIR radiation-induced homeostasis is poorly understood. To observe the effects of FIR radiation, FIR-radiated materials-coated fabric was put on experimental rats or applied to L6 cells, and microarray analysis, quantitative real-time polymerase chain reaction, and wound healing assays were performed. Microarray analysis revealed that messenger RNA expressions of rat muscle were stimulated by FIR radiation in a dose-dependent manner in amount of 10% and 30% materials-coated. In 30% group, 1,473 differentially expressed genes were identified (fold change [FC] > 1.5), and 218 genes were significantly regulated (FC > 1.5 and p < 0.05). Microarray analysis showed that extracellular matrix (ECM)-receptor interaction, focal adhesion, and cell migration-related pathways were significantly stimulated in rat muscle. ECM and platelet-derived growth factor (PDGF)-mediated cell migration-related genes were increased. And, results showed that the relative gene expression of actin beta was increased. FIR radiation also stimulated actin subunit and actin-related genes. We observed that wound healing was certainly promoted by FIR radiation over 48 h in L6 cells. Therefore, we suggest that FIR radiation can penetrate the body and stimulate PDGF-mediated cell migration through ECM-integrin signaling in rats.
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Pruritus (itching) is classically defined as an unpleasant cutaneous sensation that leads to scratching behavior. Although the scientific criteria of classification for pruritic diseases are not clear, it can be divided as acute or chronic by duration of symptoms. In this study, we investigated whether skin injury caused by chemical (contact hypersensitivity, CHS) or physical (skin-scratching stimulation, SSS) stimuli causes initial pruritus and analyzed gene expression profiles systemically to determine how changes in skin gene expression in the affected area are related to itching. In both CHS and SSS, we ranked the Gene Ontology Biological Process terms that are generally associated with changes. The factors associated with upregulation were keratinization, inflammatory response and neutrophil chemotaxis. The Kyoto Encyclopedia of Genes and Genomes pathway shows the difference of immune system, cell growth and death, signaling molecules and interactions, and signal transduction pathways. Il1a , Il1b and Il22 were upregulated in the CHS, and Tnf, Tnfrsf1b, Il1b, Il1r1 and Il6 were upregulated in the SSS. Trpc1 channel genes were observed in representative itching-related candidate genes. By comparing and analyzing RNA-sequencing data obtained from the skin tissue of each animal model in these characteristic stages, it is possible to find useful diagnostic markers for the treatment of itching, to diagnose itching causes and to apply customized treatment.
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This study investigated the expression of voltage-gated K⺠(KV) channels in human cardiac fibroblasts (HCFs), and the effect of nitric oxide (NO) on the KV currents, and the underlying phosphorylation mechanisms. In reverse transcription polymerase chain reaction, two types of KV channels were detected in HCFs: delayed rectifier K⺠channel and transient outward K⺠channel. In whole-cell patch-clamp technique, delayed rectifier K⺠current (IK) exhibited fast activation and slow inactivation, while transient outward K⺠current (Ito) showed fast activation and inactivation kinetics. Both currents were blocked by 4-aminopyridine. An NO donor, S-nitroso-N-acetylpenicillamine (SNAP), increased the amplitude of IK in a concentration-dependent manner with an EC50 value of 26.4 µM, but did not affect Ito. The stimulating effect of SNAP on IK was blocked by pretreatment with 1H-(1,2,4)oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) or by KT5823. 8-bromo-cyclic GMP stimulated the IK. The stimulating effect of SNAP on IK was also blocked by pretreatment with KT5720 or by SQ22536. Forskolin and 8-bromo-cyclic AMP each stimulated IK. On the other hand, the stimulating effect of SNAP on IK was not blocked by pretreatment of N-ethylmaleimide or by DL-dithiothreitol. Our data suggest that NO enhances IK, but not Ito, among KV currents of HCFs, and the stimulating effect of NO on IK is through the PKG and PKA pathways, not through S-nitrosylation.
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Miofibroblastos/metabolismo , Óxido Nítrico/metabolismo , Canales de Potasio con Entrada de Voltaje/metabolismo , Potenciales de Acción , Adenina/análogos & derivados , Adenina/farmacología , Carbazoles/farmacología , Células Cultivadas , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de GMP Cíclico/antagonistas & inhibidores , Proteínas Quinasas Dependientes de GMP Cíclico/metabolismo , Inhibidores Enzimáticos/farmacología , Humanos , Miofibroblastos/efectos de los fármacos , Miofibroblastos/fisiología , Oxadiazoles/farmacología , Pirroles/farmacología , Quinoxalinas/farmacología , S-Nitroso-N-Acetilpenicilamina/farmacologíaRESUMEN
We conducted a study on the relationship between leukocyte telomere length (LTL) and quality of life (QoL) in 82 couples aged 55 and older. LTL was measured by quantitative real-time PCR. QoL was evaluated using the physical component score (PCS) and mental component score (MCS) on the Korean version of the Short-Form Health Survey (SF-36). LTL was found to be independently associated with the SF-36 PCS in males (ß=0.014, p=0.03) and the SF-36 MCS in females (ß=1.16, p<0.01). Thus LTL is associated with QoL in gender-specific ways.
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Leucocitos , Calidad de Vida , Telómero , Anciano , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Gestational vitamin D insufficiency is related with increased risks of various diseases and poor health outcomes later in life. Telomere length at birth or early in life is known to be a predictor of individual health. Both vitamin D and telomere length are related with various health conditions, and vitamin D concentrations are associated with leukocyte telomere lengths in women. We investigated the association between maternal vitamin D concentrations and newborn leukocyte telomere lengths. This cross-sectional study included 106 healthy pregnant women without adverse obstetric outcomes and their offspring. We examined the maternal age, weight before pregnancy, health behaviours, and nutritional intakes, along with each newborn's sex and birthweight, and we measured maternal height, telomere length, total white blood cell count, and glycosylated haemoglobin as covariates. Pearson's correlation coefficients were calculated to evaluate the relationship between the baseline variables and newborn leukocyte telomere lengths. To confirm that there was an independent association between newborn leukocyte telomere lengths and maternal vitamin D concentrations, we performed a stepwise multiple linear regression analysis. Newborn leukocyte telomere lengths correlated positively with maternal leukocyte telomere lengths (r = .76, p < .01), maternal 25-hydroxyvitamin D concentrations (r = .72, p < .01), maternal energy intakes (r = .22, p = .03), and newborn body weights (r = .51, p < .01). In the multivariate model, newborn leukocyte telomere lengths were associated with maternal vitamin D concentrations (ß = .33, p < .01). These findings suggest that the maternal vitamin D concentration during pregnancy may be a significant determinant of the offspring's telomere length.
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Leucocitos/patología , Fenómenos Fisiologicos Nutricionales Maternos , Estado Nutricional , Complicaciones del Embarazo/patología , Acortamiento del Telómero , Deficiencia de Vitamina D/patología , Vitamina D/sangre , 25-Hidroxivitamina D 2/sangre , Peso al Nacer , Calcifediol/sangre , Estudios Transversales , Femenino , Sangre Fetal/citología , Sangre Fetal/metabolismo , Humanos , Recién Nacido , Leucocitos/citología , Leucocitos/metabolismo , Masculino , Análisis Multivariante , Embarazo , Complicaciones del Embarazo/sangre , Complicaciones del Embarazo/epidemiología , Complicaciones del Embarazo/fisiopatología , Tercer Trimestre del Embarazo , Prevalencia , República de Corea/epidemiología , Índice de Severidad de la Enfermedad , Deficiencia de Vitamina D/sangre , Deficiencia de Vitamina D/epidemiología , Deficiencia de Vitamina D/fisiopatologíaRESUMEN
Several human diseases have been associated with mitochondrial voltage-dependent anion channel-1 (VDAC1) due to its role in calcium ion transportation and apoptosis. Recent studies suggest that VDAC1 may interact with endothelium-dependent nitric oxide synthase (eNOS). Decreased VDAC1 expression may limit the physical interaction between VDAC1 and eNOS and thus impair nitric oxide production, leading to cardiovascular diseases, including pulmonary arterial hypertension (PAH). In this report, we conducted meta-analysis of genome-wide expression data to identify VDAC1 influenced genes implicated in PAH pathobiology. First, we identified the genes differentially expressed between wild-type and Vdac1 knockout mouse embryonic fibroblasts in hypoxic conditions. These genes were deemed to be influenced by VDAC1 deficiency. Gene ontology analysis indicates that the VDAC1 influenced genes are significantly associated with PAH pathobiology. Second, a molecular signature derived from the VDAC1 influenced genes was developed. We suggest that, VDAC1 has a protective role in PAH and the gene expression signature of VDAC1 influenced genes can be used to i) predict severity of pulmonary hypertension secondary to pulmonary diseases, ii) differentiate idiopathic pulmonary artery hypertension (IPAH) patients from controls, and iii) differentiate IPAH from connective tissue disease associated PAH.
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Nitric oxide (NO) is an important signaling molecule and a component of the inflammatory cascade. Besides, it is also involved in tumorigenesis. Aberrant upregulation and activation of the ERK cascade by NO often leads to tumor cell development. However, the role of ERK inactivation induced by the negative regulation of NO during apoptosis is not completely understood. In this study, treatment of A549 and PC9 human lung adenocarcinoma cell lines with cordycepin led to a reduction in their viability. Analysis of the effect of cordycepin treatment on ERK/Slug signaling activity in the A549 cell line revealed that LPS-induced inflammatory microenvironments could stimulate the expression of TNF-α, CCL5, IL-1ß, IL-6, IL-8 and upregulate NO, phospho-ERK (p-ERK), and Slug expression. In addition, constitutive expression of NO was observed. Cordycepin inhibited LPS-induced stimulation of iNOS, NO, p-ERK, and Slug expression. L-NAME, an inhibitor of NOS, inhibited p-ERK and Slug expression. It was also found that cordycepin-mediated inhibition of ERK downregulated Slug, whereas overexpression of ERK led to an upregulation of Slug levels in the cordycepin-treated A549 cells. Inhibition of Slug by siRNA induced Bax and caspase-3, leading to cordycepin-induced apoptosis. Cordycepin-mediated inhibition of ERK led to a reduction in phospho-GSK3ß (p-GSK3ß) and Slug levels, whereas LiCl, an inhibitor of GSK3ß, upregulated p-GSK3ß and Slug. Overall, the results obtained indicate that cordycepin inhibits the ERK/Slug signaling pathway through the activation of GSK3ß which, in turn, upregulates Bax, leading to apoptosis of the lung cancer cells.
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Human cardiac fibroblasts (HCFs) have various voltage-dependent K(+) channels (VDKCs) that can induce apoptosis. Hydrogen peroxide (H2O2) modulates VDKCs and induces oxidative stress, which is the main contributor to cardiac injury and cardiac remodeling. We investigated whether H2O2 could modulate VDKCs in HCFs and induce cell injury through this process. In whole-cell mode patch-clamp recordings, application of H2O2 stimulated Ca(2+)-activated K(+) (KCa) currents but not delayed rectifier K(+) or transient outward K(+) currents, all of which are VDKCs. H2O2-stimulated KCa currents were blocked by iberiotoxin (IbTX, a large conductance KCa blocker). The H2O2-stimulating effect on large-conductance KCa (BKCa) currents was also blocked by KT5823 (a protein kinase G inhibitor) and 1 H-[1, 2, 4] oxadiazolo-[4, 3-a] quinoxalin-1-one (ODQ, a soluble guanylate cyclase inhibitor). In addition, 8-bromo-cyclic guanosine 3', 5'-monophosphate (8-Br-cGMP) stimulated BKCa currents. In contrast, KT5720 and H-89 (protein kinase A inhibitors) did not block the H2O2-stimulating effect on BKCa currents. Using RT-PCR and western blot analysis, three subtypes of KCa channels were detected in HCFs: BKCa channels, small-conductance KCa (SKCa) channels, and intermediate-conductance KCa (IKCa) channels. In the annexin V/propidium iodide assay, apoptotic changes in HCFs increased in response to H2O2, but IbTX decreased H2O2-induced apoptosis. These data suggest that among the VDKCs of HCFs, H2O2 only enhances BKCa currents through the protein kinase G pathway but not the protein kinase A pathway, and is involved in cell injury through BKCa channels.
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Genetic variation arising from single nucleotide polymorphisms (SNPs) is ubiquitously found among human populations. While disease-causing variants are known in some cases, identifying functional or causative variants for most human diseases remains a challenging task. Rare SNPs, rather than common ones, are thought to be more important in the pathology of most human diseases. We propose that rare SNPs should be divided into two categories dependent on whether the minor alleles are derived or ancestral. Derived alleles are less likely to have been purified by evolutionary processes and may be more likely to induce deleterious effects. We therefore hypothesized that the rare SNPs with derived minor alleles would be more important for human diseases and predicted that these variants would have larger functional or structural consequences relative to the rare variants for which the minor alleles are ancestral. We systematically investigated the consequences of the exonic SNPs on protein function, mRNA structure, and translation. We found that the functional and structural consequences are more significant for the rare exonic variants for which the minor alleles are derived. However, this pattern is reversed when the minor alleles are ancestral. Thus, the rare exonic SNPs with derived minor alleles are more likely to be deleterious. Age estimation of rare SNPs confirms that these potentially deleterious SNPs are recently evolved in the human population. These results have important implications for understanding the function of genetic variations in human exonic regions and for prioritizing functional SNPs in genome-wide association studies of human diseases.
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Exones , Genoma Humano , Polimorfismo de Nucleótido Simple , Alelos , Evolución Biológica , Codón , Enfermedad/genética , Evolución Molecular , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Variación Genética , Estudio de Asociación del Genoma Completo , Humanos , ARN MensajeroRESUMEN
Ion channels are important regulators in cell proliferation, migration, and apoptosis. The malfunction and/or aberrant expression of ion channels may disrupt these important biological processes and influence cancer progression. In this study, we investigate the expression pattern of ion channel genes in glioma. We designate 18 ion channel genes that are differentially expressed in high-grade glioma as a prognostic molecular signature. This ion channel gene expression based signature predicts glioma outcome in three independent validation cohorts. Interestingly, 16 of these 18 genes were down-regulated in high-grade glioma. This signature is independent of traditional clinical, molecular, and histological factors. Resampling tests indicate that the prognostic power of the signature outperforms random gene sets selected from human genome in all the validation cohorts. More importantly, this signature performs better than the random gene signatures selected from glioma-associated genes in two out of three validation datasets. This study implicates ion channels in brain cancer, thus expanding on knowledge of their roles in other cancers. Individualized profiling of ion channel gene expression serves as a superior and independent prognostic tool for glioma patients.
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Glioma/genética , Canales Iónicos/genética , Biomarcadores de Tumor/genética , Bases de Datos Genéticas , Regulación Neoplásica de la Expresión Génica , Glioma/mortalidad , Glioma/patología , Humanos , Canales Iónicos/metabolismo , Estimación de Kaplan-Meier , Pérdida de Heterocigocidad , Clasificación del Tumor , Pronóstico , Modelos de Riesgos ProporcionalesRESUMEN
This study surveys the improvement characteristics in old-aged muscular mitochondria by bio-active materials coated fabric (BMCF). To observe the effects, the fabric (10 and 30%) was worn to old-aged rat then the oxygen consumption efficiency and copy numbers of mitochondria, and mRNA expression of apoptosis- and mitophagy-related genes were verified. By wearing the BMCF, the oxidative respiration significantly increased when using the 30% materials coated fabric. The mitochondrial DNA copy number significantly decreased and subsequently recovered in a dose-dependent manner. The respiratory control ratio to mitochondrial DNA copy number showed a dose-dependent increment. As times passed, Bax, caspase 9, PGC-1α and ß-actin increased, and Bcl-2 decreased in a dose-dependent manner. However, the BMCF can be seen to have had no effect on Fas receptor. PINK1 expression did not change considerably and was inclined to decrease in control group, but the expression was down-regulated then subsequently increased with the use of the BMCF in a dose-dependent manner. Caspase 3 increased and subsequently decreased in a dose-dependent manner. These results suggest that the BMCF invigorates mitophagy and improves mitochondrial oxidative respiration in skeletal muscle, and in early stage of apoptosis induced by the BMCF is not related to extrinsic death-receptor mediated but mitochondria-mediated signaling pathway.