Search results for "Transduction"

Immunoadhesins of interleukin-6 and the IL-6/soluble IL-6R fusion protein hyper-IL-6.

1999

Signal transduction in response to interleukin-6 (IL-6) results from homodimerization of gp130. This dimerization occurs after binding of IL-6 to its surface receptor (IL-6R) and can also be triggered by the complex of soluble IL-6R and IL-6. We fused IL-6 to the constant region of a human IgG1 heavy chain (Fc). IL-6Fc was expressed in COS-7 cells and purified via Protein A Sepharose. Using three different assays we found that the biological activity of this dimeric IL-6 protein is comparable with monomeric IL-6. Recently, we described the designer cytokine Hyper-IL-6 (H-IL-6) in which soluble IL-6R and IL-6 are connected via a flexible peptide linker. This molecule turned out to be 100-100…

Immune Control in Hepatocellular Carcinoma Development and Progression: Role of Stromal Cells

2014

Immune control of hepatocellular carcinoma (HCC) is executed by effector immune cells, which efficiently eliminate malignant transformed cells. However, progression of HCC clearly documents failure of tumor immune control, which led to the concept of immune subversion by the tumor environment. Particularly tumor-associated stromal cells cooperate within an inflammatory network, which is responsible for immune privilege. The stromal cell composition matures during tumor growth and is derived from surrounding noncancerous tissue or from circulating cells recruited to the tumor site. Therefore, immunosuppressive stromal cells represent heterogeneous cell lineages, including myeloid cells, lymp…

Molecular diagnosis and therapy of hepatocellular carcinoma (HCC): an emerging field for advanced technologies.

2011

Despite great progress in diagnosis and management of hepatocellular carcinoma (HCC), the exact biology of the tumor remains poorly understood overall limiting the patients' outcome. Detailed analysis and characterization of the molecular mechanisms and subsequently individual prediction of corresponding prognostic traits would revolutionize both diagnosis and treatment of HCC and is the key goal of modern personalized medicine. Over the recent years systematic approaches for the analysis of whole tumor genomes and transcriptomes as well as epigenomes became affordable tools in translational research. This includes simultaneous analyses of thousands of molecular targets using microarray-bas…

Deleting Full Length Titin Versus the Titin M-Band Region Leads to Differential Mechanosignaling and Cardiac Phenotypes

2019

Background: Titin is a giant elastic protein that spans the half-sarcomere from Z-disk to M-band. It acts as a molecular spring and mechanosensor and has been linked to striated muscle disease. The pathways that govern titin-dependent cardiac growth and contribute to disease are diverse and difficult to dissect. Methods: To study titin deficiency versus dysfunction, the authors generated and compared striated muscle specific knockouts (KOs) with progressive postnatal loss of the complete titin protein by removing exon 2 (E2-KO) or an M-band truncation that eliminates proper sarcomeric integration, but retains all other functional domains (M-band exon 1/2 [M1/2]-KO). The authors evaluated c…

Cardioprotection by gene therapy

2015

Ischemic heart disease remains the leading cause of death worldwide. Ischemic pre-, post-, and remote conditionings trigger endogenous cardioprotection that renders the heart resistant to ischemic-reperfusion injury (IRI). Mimicking endogenous cardioprotection by modulating genes involved in cardioprotective signal transduction provides an opportunity to reproduce endogenous cardioprotection with better possibilities of translation into the clinical setting. Genes and signaling pathways by which conditioning maneuvers exert their effects on the heart are partially understood. This is due to the targeted approach that allowed identifying one or a few genes associated with IRI and cardioprote…

Cardioprotective effects of phytopigments via multiple signaling pathways.

2021

Abstract Background Cardiovascular diseases (CVDs) are among the deadliest non-communicable diseases, and millions of dollars are spent every year to combat CVDs. Unfortunately, the multifactorial etiology of CVDs complicates the development of efficient therapeutics. Interestingly, phytopigments show significant pleiotropic cardioprotective effects both in vitro and in vivo. Purpose This review gives an overview of the cardioprotective effects of phytopigments based on in vitro and in vivo studies as well as clinical trials. Methods A literature-based survey was performed to collect the available data on cardioprotective activities of phytopigments via electronic search engines such as Pub…

Genetic abrogation of the fibronectin-α5β1 integrin interaction in articular cartilage aggravates osteoarthritis in mice.

2018

The balance between synthesis and degradation of the cartilage extracellular matrix is severely altered in osteoarthritis, where degradation predominates. One reason for this imbalance is believed to be due to the ligation of the α5β1 integrin, the classic fibronectin (FN) receptor, with soluble FN fragments instead of insoluble FN fibrils, which induces matrix metalloproteinase (MMP) expression. Our objective was to determine whether the lack of α5β1-FN binding influences cartilage morphogenesis in vivo and whether non-ligated α5β1 protects or aggravates the course of osteoarthritis in mice. We engineered mice (Col2a-Cre;Fn1RGE/fl), whose chondrocytes express an α5β1 binding-deficient FN, …

Current knowledge of pituitary adenylate cyclase activating polypeptide (PACAP) in articular cartilage

2020

Pituitary adenylate cyclase activating polypeptide (PACAP) is an evolutionally well conserved neuropeptide, mainly expressed by neuronal and peripheral cells. It proves to be an interesting object of study both for its trophic functions during the development of several tissues and for its protective effects against oxidative stress, hypoxia, inflammation and apoptosis in different degenerative diseases. This brief review summarises the recent findings concerning the role of PACAP in the articular cartilage. PACAP and its receptors are expressed during chondrogenesis and are shown to activate the pathways involved in regulating cartilage development. Moreover, this neuropeptide proves to be…

Transcriptional and post-transcriptional regulation of iNOS expression in human chondrocytes

2009

Chondrocytes are important for the development and maintenance of articular cartilage. However, both in osteoarthritis (OA) and rheumatoid arthritis (RA) chondrocytes are involved in the process of cartilage degradation and synthesize important immunomodulatory mediators, including nitric oxide (NO) generated by the inducible NO synthase (iNOS). To uncover the role of iNOS in the pathomechanisms of OA and RA, we analyzed the regulation of iNOS expression using immortalized human chondrocytes as a reproducible model. In C-28/I2 chondrocytes, iNOS expression was associated with the expression of the chondrocyte phenotype. Peak induction by a cytokine cocktail occurred between 6 and 8h and dec…

2020

Cilia are cellular organelles that project from the cell. They occur in nearly all non-hematopoietic tissues and have different functions in different tissues. In mesenchymal tissues primary cilia play a crucial role in the adequate morphogenesis during embryological development. In mature articular cartilage, primary cilia fulfil chemo- and mechanosensitive functions to adapt the cellular mechanisms on extracellular changes and thus, maintain tissue homeostasis and morphometry. Ciliary abnormalities in osteoarthritic cartilage could represent pathophysiological relationships between ciliary dysfunction and tissue deformation. Nevertheless, the molecular and pathophysiological relationships…