Background: Immunoadsorption with subsequent IgG substitution (IA/IgG) represents a novel therapeutic approach in treatment of dilated cardiomyopathy (DCM) which leads to improvement of left ventricular ejection fraction (LVEF). However, response to this therapeutic intervention shows wide inter-individual variability. In this pilot study, we tested the value of clinical, biochemical and molecular parameters for prediction of the response of patients with DCM to IA/IgG.
Myocardial gene expression profiles and cardiodepressant autoantibodies predict response of patients with dilated cardiomyopathy to immunoadsorption therapy.
Sex, Age, Disease
View SamplesObjectives: We studied the signal transduction of atrial structural remodelling that contributes to
Rac1-induced connective tissue growth factor regulates connexin 43 and N-cadherin expression in atrial fibrillation.
Specimen part
View SamplesActivation of the immune system is a way for host tissue to defend itself against tumor growth. Hence, treatment strategies that are based on immunomodulation are on the rise. Conventional cytostatic drugs such as the anthracycline doxorubicin can also activate immune cell functions of macrophages and natural killer cells. In addition, cytotoxicity of doxorubicin can be enhanced by combining this drug with the cytokine IFN-alpha. Although doxorubicin is one of the most applied cytostatics, the molecular mechanisms of its immunomodulation ability are not investigated thoroughly. In microarray analyses of HeLa cells, a set of 19 genes related to interferon signaling was significantly overrepresented among genes regulated by doxorubicin exposure including STAT-1, -2, IRF9, NMI, and caspase 1. Regulation of these genes by doxorubicin was verified with Real-Time PCR and immunoblotting. An enhanced secretion of IFN-alpha was observed when HeLa cells were exposed to doxorubicin as compared to untreated cells. IFN-alpha neutralizing antibodies and inhibitors of JAK-STAT signaling (ATA and AG490) significantly abolished doxorubicin-stimulated expression of interferon signaling-related genes. Furthermore, inhibition of JAK-STAT signaling significantly reduced doxorubicin induced caspase 3 activation and desensitized HeLa cells to doxorubicin cytotoxicity. In conclusion, we demonstrate that doxorubicin induces interferon-responsive genes via IFN-alpha-JAK-STAT1 signaling and that this pathway is relevant for doxorubicins cytotoxicity in HeLa cells. As immunomodulation is a promising strategy in anticancer treatment, this novel mode of action of doxorubicin may help to further improve the use of this drug among different types of anticancer treatment strategies.
Regulation of interferon-inducible proteins by doxorubicin via interferon γ-Janus tyrosine kinase-signal transducer and activator of transcription signaling in tumor cells.
Cell line, Treatment
View SamplesDietary intervention constitutes a feasible approach for modulating metabolism and improving healthspan and lifespan. Methionine restriction (MR) delays the appearance of age-related diseases and increases longevity in normal mice. However, the effect of MR on premature aging remains to be elucidated. Here, we describe that MR extends lifespan in two different mouse models of Hutchinson-Gilford progeria syndrome (HGPS) by reversing the transcriptome alterations in inflammation and DNA-damage response genes present in this condition. Further, MR improves the lipid profile and alters the levels of bile acids, both in wild-type and in progeroid mice. Notably, treatment with the bile acid cholic acid improves healthspan and lifespan in vivo. These results suggest the existence of a metabolic pathway involved in the longevity extension achieved by MR and support the possibility of dietary interventions for treating progeria.
Methionine Restriction Extends Lifespan in Progeroid Mice and Alters Lipid and Bile Acid Metabolism.
Sex, Age, Specimen part
View SamplesThe identification of inflammatory bowel disease (IBD) susceptibility genes by genome-wide association has linked this pathology to autophagy, a lysosomal degradation pathway that is crucial for cell and tissue homeostasis. Here, we describe autophagin-1 (ATG4B) as an essential protein in the control of inflammatory response during experimental colitis. In this pathological condition, ATG4B protein levels increase paralleling the induction of autophagy. Moreover, ATG4B expression is significantly reduced in affected areas of the colon from IBD patients. Consistently, atg4b-/- mice present Paneth cell abnormalities, as well as an increased susceptibility to DSS-induced colitis. Atg4b-deficient mice exhibit significant alterations in proinflammatory cytokines and mediators of the immune response to bacterial infections, which are reminiscent of those found in patients with Crohns disease or ulcerative colitis. Additionally, antibiotic treatments and bone marrow transplantation from wild-type mice reduced colitis in atg4b-/- mice. Taken together, these results provide additional evidence on the importance of autophagy in intestinal pathologies and describe ATG4B as a novel protective protein in inflammatory colitis. Finally, we propose that Atg4b-null mice are a suitable model for in vivo studies aimed at testing new therapeutic strategies for intestinal diseases associated with autophagy deficiency
ATG4B/autophagin-1 regulates intestinal homeostasis and protects mice from experimental colitis.
Sex, Age, Specimen part, Treatment
View SamplesEmbryonic retinal development Overall design: Mouse retinas at different embryonic developmental stages were isolated and mRNA expression was determined by RNA sequencing
Programmed mitophagy is essential for the glycolytic switch during cell differentiation.
Specimen part, Cell line, Subject
View SamplesTransplanting renal allografts represents the major curative treatment of chronic renal failure. Despite recent advances in immunosuppressive therapy, long-term survival of allografts remains a major clinical problem. Kidney function depends in part on transport proteins such as MRP2 (ABCC2) which facilitates renal secretion of amphiphilic exogenous and endogenous compounds. Inherited variants of genes not related to the immune system have been shown to modify the outcome after renal transplantation. We investigated whether ABCC2 gene variants in the donor kidney affect renal graft function.
Multidrug resistance-related protein 2 genotype of the donor affects kidney graft function.
Sex
View SamplesPrimary pneumocytes from KRas;Atg5fl/+ and KRas;Atg5fl/fl littermates were cultured for 48 hours and infected with AdCre-GFP to induce expression of the KrasG12D oncogene and concomitant Atg5 deletion. The transcriptional profile of those cells was determined by mRNA sequencing and uncovered differential expression in cellular movement, inflammatory response and oxidative stress response. Overall design: Comparison of transcriptomes from KRas;Atg5fl/+ and KRas;Atg5fl/fl pneumocytes
A dual role for autophagy in a murine model of lung cancer.
Specimen part, Subject
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Critical role for TRIM28 and HP1β/γ in the epigenetic control of T cell metabolic reprograming and effector differentiation.
Specimen part
View SamplesCritical role for TRIM28 and HP1b/g in the epigenetic control of T cell metabolic reprogramming and effector differentiation
Critical role for TRIM28 and HP1β/γ in the epigenetic control of T cell metabolic reprograming and effector differentiation.
Specimen part
View Samples