Degree Of Change In Expression Research Articles

Transcriptomic network analysis reveals key drivers of response to anti-TNF biologics in patients with rheumatoid arthritis.

Anti-TNF biologics have been widely used to ameliorate disease activity in patients with RA. However, a large fraction of patients show a poor response to these agents. Moreover, no clinically applicable predictive biomarkers have been established. This study aimed to identify response-associated biomarkers using longitudinal transcriptomic data in two independent RA cohorts. RNA sequencing data from peripheral blood cell samples of Korean and Caucasian RA cohorts before and after initial treatment with anti-TNF biologics were analysed to assess treatment-induced expression changes that differed between highly reliable excellent responders and null responders. Weighted correlation network, immune cell composition, and key driver analyses were performed to understand response-associated transcriptomic networks and cell types and their correlation with disease activity indices. In total, 305 response-associated genes showed significantly different treatment-induced expression changes between excellent and null responders. Co-expression network construction and subsequent key driver analysis revealed that 41 response-associated genes played a crucial role as key drivers of transcriptomic alteration in four response-associated networks involved in various immune pathways: type I IFN signalling, myeloid leucocyte activation, B cell activation, and NK cell/lymphocyte-mediated cytotoxicity. Transcriptomic response scores that we developed to estimate the individual-level degree of expression changes in the response-associated key driver genes were significantly correlated with the changes in clinical indices in independent patients with moderate or ambiguous response outcomes. This study provides response-specific treatment-induced transcriptomic signatures by comparing the transcriptomic landscape between patients with excellent and null responses to anti-TNF drugs at both gene and network levels.

Differential epigenetic profiles induced by sodium selenite in breast cancer cells

ObjectivesSelenium (Se) was a potential anticancer micronutrient with proposed epigenetic effect. However, the Se-induced epigenome in breast cancer cells was yet to be studied. MethodsThe profiles of DNA methylation, microRNA (miRNA), long non-coding RNA (lncRNA), and message RNA (mRNA) in breast cancer cells treated with sodium selenite were examined by microarrays. We verified the epigenetic modifications by integrating their predicted target genes and differentially expressed mRNAs. The epigenetically regulated genes were further validated in a breast cancer cohort by associating with tumor progression. We conducted a series of bioinformatics analyses to assess the biological function of these validated genes and identified the critical genes. ResultsThe Se-induced epigenome regulated the expression of 959 genes, and 349 of them were further validated in the breast cancer cohort. Biological function analyses suggested that these validated genes were enriched in several cancer-related pathways, such as PI3K/Akt and metabolic pathways. Based on the degrees of expression change, hazard ratio difference, and connectivity, NEDD4L and FMO5 were identified as the critical genes. ConclusionsThese results confirmed the epigenetic effects of sodium selenite and revealed the epigenetic profiles in breast cancer cells, which would help understand the mechanisms of Se against breast cancer.

Differential epigenetic and transcriptional profile in MCF-7 breast cancer cells exposed to cadmium

Cadmium (Cd) has been confirmed to be associated with breast carcinogenesis, but the mechanism was not clarified yet. Given that epigenetic modification was speculated as underlying mechanism, we examined the differential epigenome caused by Cd in breast cancer cells. Profiles of DNA methylation, microRNA (miRNA), long non-coding RNA (lncRNA), and message RNA (mRNA) were derived from Cd-treated and untreated MCF-7 breast cancer cells by microarray. We identified 997 target genes epigenetically regulated by Cd through cross-verification with the differential epigenome and transcriptome, and 400 of them were further validated in a breast cancer cohort. Biological function analyses suggested that several pathways were involved in Cd-induced breast carcinogenesis, such as Wnt signaling, metabolism, and human papilloma virus (HPV) infection. TXNRD1 and CCT3 were further identified as the critical genes based on the degree of expression change, hazard ratio difference, and connectivity. The present study revealed that Cd epigenetically regulated several pathways involving in breast carcinogenesis, particularly the Wnt signaling and metabolic pathways, among which TXNRD1 and CCT3 might play critical roles. It was also suggested that Cd and HPV infection might jointly participate in breast tumorigenesis.

Modulation of transport and metabolism of bile acids and bilirubin by chlorogenic acid against hepatotoxicity and cholestasis in bile duct ligation rats: involvement of SIRT1-mediated deacetylation of FXR and PGC-1α.

The purpose of the present study was to investigate the effect and potential mechanism of chlorogenic acid (CA) on liver injury induced by cholestasis in a rat model of bile duct ligation (BDL). Rats received vehicle or CA (20, 50, or 100mg/kg per day) orally for 3days. On the 4th day, the rats underwent sham or BDL surgery, and were orally administrated vehicle or CA for 3 or 7days. mRNA and protein expression levels were evaluated by qRT-PCR and western blot. After BDL, plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), and total bile acids (TBA) were increased and typical pathological changes were observed in liver morphology. Hepatic uptake transporters (Ntcp, Oatp 1a4, and Oatp 1b2) were downregulated, while efflux transporters (Bsep and Mrp 2/3/4) were upregulated. BDL inhibited the expressions of Cyp7a1, Cyp8b1, and Cyp27a1 and induced Ugt1a1. CA treatment decreased ALT, AST, TBIL, and TBA (P<0.05) and alleviated the liver pathological changes. The degree of expression changes in the transporters and enzymes was extended by CA (P<0.05). SIRT1 protein was induced after CA treatment in BDL rats. Chlorogenic acid attenuated hepatotoxicity and cholestasis by decreasing the uptake and synthesis of bilirubin and bile acids and accelerating the metabolism and efflux of bilirubin and bile acids.

Proteomic analysis of astaxanthin biosynthesis in Xanthophyllomyces dendrorhous in response to low carbon levels.

The ratio of carbon to nitrogen (C/N) in media plays a crucial role in the production of microbial carotenoids. However, the effects of a high C/N ratio on carotenoid production are ambiguous, and the mechanism of how C/N ratio affects astaxanthin accumulation in X. dendrorhous is unclear. In this study, the influence of C/N ratio on astaxanthin biosynthesis in X. dendrorhous at a fixed nitrogen concentration was investigated, and comparative proteomics were applied to address how C/N ratio affects cell growth and astaxanthin accumulation in X. dendrorhous. The results showed that cell growth and astaxanthin accumulation in X. dendrorhous were strongly related to the ratio of carbon to nitrogen with increasing C/N ratio in medium. However, the astaxanthin content per cell showed an inverse relationship, decreasing with an increasing C/N ratio. Differential proteomics showed the proteins with highest degree of change in expression under varying C/N ratios were mainly involved in carbohydrate metabolic pathways and carotenogenesis metabolism. In addition, several redox- and stress-associated proteins were up-regulated along with the carotenogenesis proteins, implying the environmental stress may affect metabolism and astaxanthin synthesis. A possible regulatory mechanism in response to glucose in X. dendrorhous is discussed.

Susceptibility to Acute Rheumatic Fever Based on Differential Expression of Genes Involved in Cytotoxicity, Chemotaxis, and Apoptosis

It is unknown why only some individuals are susceptible to acute rheumatic fever (ARF). We investigated whether there are differences in the immune response, detectable by gene expression, between individuals who are susceptible to ARF and those who are not. Peripheral blood mononuclear cells (PBMCs) from 15 ARF-susceptible and 10 nonsusceptible (control) adults were stimulated with rheumatogenic (Rh+) group A streptococci (GAS) or nonrheumatogenic (Rh-) GAS. RNA from stimulated PBMCs from each subject was cohybridized with RNA from unstimulated PBMCs on oligonucleotide arrays to compare gene expression. Thirty-four genes were significantly differentially expressed between ARF-susceptible and control groups after stimulation with Rh+ GAS. A total of 982 genes were differentially expressed between Rh+ GAS- and Rh- GAS-stimulated samples from ARF-susceptible individuals. Thirteen genes were differentially expressed in the same direction (predominantly decreased) between the two study groups and between the two stimulation conditions, giving a strong indication of their involvement. Seven of these were immune response genes involved in cytotoxicity, chemotaxis, and apoptosis. There was variability in the degree of expression change between individuals. The high proportion of differentially expressed apoptotic and immune response genes supports the current model of autoimmune and cytokine dysregulation in ARF. This study also raises the possibility that a "failed" immune response, involving decreased expression of cytotoxic and apoptotic genes, contributes to the immunopathogenesis of ARF.

Calcium channels in chromaffin cells: focus on L and T types

Voltage-gated Ca2+ channels (Cav) are highly expressed in the adrenal chromaffin cells of mammalian species. Besides shaping action potential waveforms, they are directly involved in the excitation-secretion coupling underlying catecholamine release and, possibly, control other Ca2+-dependent events that originate near the membrane. These functions are shared by a number of Cav channel types (L, N, P/Q, R and T) which have different structure-function characteristics and whose degree of expression changes remarkably among mammalian species. Understanding precisely the functioning of each voltage-gated Ca2+ channels is a crucial task that helps clarifying the Ca2+-dependent mechanisms controlling exocytosis during physiological and pathological conditions. In this paper, we focus on classical and new roles that L- and T-type channels play in the control of chromaffin cell excitability and neurotransmitter release. Interestingly, L-type channels are shown to be implicated in the spontaneous autorhythmicity of chromaffin cells, while T-type channels, which are absent in adult chromaffin cells, are coupled with secretion and can be recruited following long-term beta-adrenergic stimulation or chronic hypoxia. This suggests that like other cells, adrenal chromaffin cells undergo effective remodelling of membrane ion channels and cell functioning during prolonged stress conditions.

Expression of activation markers on basophils in a controlled model of anaphylaxis

Anaphylaxis has variable clinical presentations and lacks reliable biomarkers. Expression of activation markers on basophils has been useful in assessing sensitization in IgE-mediated diseases but has not been examined in vivo in anaphylaxis. The study's goals were to assess the baseline expression of activation markers on basophils in individuals with a sting reaction history, the degree of change in expression of these markers after intentional sting challenge, and the relationship between in vitro and in vivo activation marker expression. Patients allergic to insect venom were enrolled and grouped by clinical category defined by a history of a systemic or large local reaction and use of venom immunotherapy. Blood was collected before and after sting challenge. Enriched basophils were analyzed for activation marker expression. In select subjects, basophils were examined after in vitro stimulation with insect venom for activation marker expression and histamine release. Of 35 sting-challenge participants, 21 provided adequate samples for analysis. Pre-sting basophil CD63 expression was significantly higher in systemic reactors on immunotherapy. Following sting challenge, the rise in basophil CD69 expression and CD203c was significantly higher in systemic reactors on immunotherapy. Levels of activation markers on basophils were greater after in vitro venom stimulation than after in vivo challenge. Broader shifts in expression of basophil activation markers after in vivo challenge occurred among subjects with a history of in vivo systemic anaphylaxis despite venom immunotherapy. Basophil activation markers may be potential biomarkers for anaphylaxis.

Cloning and expression of DnaJ homolog in carrot somatic embryo*

Abstract As the co-chaperone of DnaK/Hsp70 protein, DnaJ/Hsp40 protein influences the synthesis and assembly of the protein complex by regulating ATPase activity of DnaK/Hsp70 protein. By employing the modified method of cDNA representational difference analysis, a homologous fragment of DnaJ was isolated from the deregulated carrot somatic embryos and it was further used as the probe to screen the cDNA library of carrot somatic embryo deregulated for 12 h. As the result. DcJ1 gene, the homologous gene of DnaJ, was isolated from carrot. Sequence analysis showed that its coding region is 1257 bp, which codes 418 amino acids and comprises 3 highly-conserved characteristic domains. Southern blot analysis suggested that the DcJ1 gene seems to be a single copy in the genome, while Northern blot result indicated that DcJ1 expresses only in roots and its degree of expression changes obviously with the regulation-deregulation process. These results suggest that DcJ1 is correlated with the early development of car...