TY - JOUR AB - BACKGROUND: Experimental nephrotic syndrome in mice leads to proteolytic activation of the epithelial sodium channel ENaC, possibly involving the distal polybasic tract of its γ-subunit (183RKRK). OBJECTIVE: We sought to determine if urine samples from both nephrotic mice and a cohort of patients with acute nephrotic syndrome contain a specific proteolytic activity against this region of γ- Method: A peptide substrate consisting of amino acids 180-194 of murine γ-ENaC was N-terminally coupled to a fluorophore, yielding AMCA-FTGRKRKISGKIIHK. The substrate was incubated with nephrotic urine samples from mice as well as patients and with or without the serine protease inhibitor aprotinin. The digested peptides were separated on a reverse phase HPLC and detected with a fluorescence detector (350/450 nm). Peptide masses of the peaks were determined with a MALDI-TOF mass spectrometer. In addition, urinary proteolytic activity was quantitated using AMC-coupled substrates reflecting different cleavage sites within the polybasic tract. RESULTS: No significant proteolytic activity against the substrate was found in the urine of healthy humans or mice. Incubation with urine samples of nephrotic patients (n=8) or mice subjected to three different models of experimental nephrotic syndrome (n=4 each) led to cleavage of the substrate within the polybasic tract which was prevented by the serine protease inhibitor aprotinin. The most dominant cleavage product was FTGRKR in both species which was confirmed using quantitative measurements with FTGRKR-AMC. CONCLUSION: Nephrotic urine from both humans and mice contains aprotinin-sensitive proteolytic activity against the distal polybasic tract of γ-ENaC, reflecting excretion of active proteases in the urine or proteasuria. AU - Wörn, M.* AU - Kalbacher, H.* AU - Artunc, F. C1 - 65451 C2 - 52688 SP - 6433-6445 TI - Proteolytic activity against the distal polybasic tract of the gamma subunit of the epithelial sodium channel ENaC in nephrotic urine. JO - Curr. Med. Chem. VL - 29 IS - 42 PY - 2022 SN - 0929-8673 ER - TY - JOUR AB - IRS1 and IRS2 are the most important representatives of the IRS protein family and critical nodes in insulin/IGF1-signaling. Although they are quite similar in their structural and functional features they show tissue-specific differences. In this review, we outline the functions of IRS1 and IRS2 in skeletal muscle and liver with regard to their importance for metabolism, growth and differentiation. Mechanisms contributing to IRS1 and IRS2 dysregulation in disease states as well as consequences thereof are discussed. IRS1 plays the dominant role in skeletal muscle. It is crucial for normal growth and differentiation of myofibers, insulin- dependent glucose uptake and glycogen synthesis. The presence of IRS2 in skeletal muscle is negligible for insulin-induced glucose uptake and the general role of IRS2 in muscle is still not fully understood. In liver IRS1 and IRS2 are important to mediate insulindependent regulation of glucose and lipid metabolism and complement each other in the diurnal regulation thereof. IRS1 in the liver is more important for signaling in the late refeeding period, whereas IRS2 signaling is mostly dominating in the period directly after food intake and during fasting. Importantly, the expression level of IRS1 and IRS2 is different within the liver lobule, which could be an explanation for the phenomenon of selective insulin resistance. Dysregulated muscular or hepatic abundance and/or phosphorylation status of IRS1 and IRS2 are important factors in the pathogenesis of insulin resistance, type 2 diabetes and muscle wasting. AU - Eckstein, S.S.* AU - Weigert, C. AU - Lehmann, R. C1 - 51557 C2 - 43245 CY - Sharjah SP - 1827-1852 TI - Divergent roles of IRS (Insulin receptor substrate) 1 and 2 in liver and skeletal muscle. JO - Curr. Med. Chem. VL - 24 IS - 17 PB - Bentham Science Publ Ltd PY - 2017 SN - 0929-8673 ER - TY - JOUR AB - During the last decade, a multitude of experimental evidence has accumulated showing that low-dose radiation therapy (single dose 0.5-1 Gy) functionally modulates a variety of inflammatory processes and cellular compounds including endothelial (EC), mononuclear (PBMC) and polymorphonuclear (PMN) cells, respectively. These modulations comprise a hampered leukocyte adhesion to EC, induction of apoptosis, a reduced activity of the inducible nitric oxide synthase, and a lowered oxidative burst in macrophages. Moreover, irradiation with a single dose between 0.5-0.7 Gy has been shown to induce the expression of X-chromosome linked inhibitor of apoptosis and transforming growth factor beta 1, to reduce the expression of E-selectin and L-selectin from EC and PBMC, and to hamper secretion of Interleukin-1, or chemokine CCL20 from macrophages and PMN. Notably, a common feature of most of these responses is that they display discontinuous or biphasic dose dependencies, shared with "non-targeted" effects of low-dose irradiation exposure like the bystander response and hyper-radiosensitivity. Thus, the purpose of the present review is to discuss recent developments in the understanding of low-dose irradiation immune modulating properties with special emphasis on discontinuous dose response relationships. AU - Rödel, F.* AU - Frey, B.* AU - Gaipl, U.* AU - Keilholz, L.* AU - Fournier, C.* AU - Manda, K.* AU - Schöllnberger, H. AU - Hildebrandt, G.* AU - Rödel, C.* C1 - 7450 C2 - 29717 SP - 1741-1750 TI - Modulation of inflammatory immune reactions by low-dose ionizing radiation: Molecular mechanisms and clinical application. JO - Curr. Med. Chem. VL - 19 IS - 12 PB - Bentham Science Publishers PY - 2012 SN - 0929-8673 ER - TY - JOUR AB - ogether with surgery and chemotherapy, ionizing irradiation is one of the key therapeutic approaches to treat cancer. More than 50 percent of all cancer patients will receive radiotherapeutic intervention at some stage of their disease. The more precise instrumentation for delivery of radiotherapy and the emphasis on hypofractionation technologies have drastically improved loco-regional tumor control within the last decades. However, the appearance of distant metastases often requires additional systemic treatment modalities such as chemotherapy. High dose chemotherapy is generally considered as immunosuppressive and can cause severe adverse effects. Therefore, we want to elucidate the effects of ionizing irradiation on the immune system and provide immunological treatment strategies which are induced by the host's stress response. Similar to other stressors, ionizing irradiation is known to enhance the synthesis of a variety of immune-stimulatory and -modulating molecules such as heat shock proteins (HSP), high mobility group box 1 (HMGB1) and survivin. Herein, we focus on HSP that exhibit an unusual cell membrane localization and release mechanism in tumor cells. These tumor-specific characteristics render HSP as ideal targets for therapeutic interventions. Depending on their intra/membrane and extracellular localization HSP have the ability to protect tumor cells from stress-induced lethal damage by interfering with antiapoptotic pathways or to elicit anti-cancer immunity. AU - Schmid, T.E.* AU - Multhoff, G. C1 - 7273 C2 - 29633 SP - 1765-1770 TI - Radiation-induced stress proteins - the role of heat shock proteins (HSP) in anti-tumor responses. JO - Curr. Med. Chem. VL - 19 IS - 12 PB - Bentham Science Publishers PY - 2012 SN - 0929-8673 ER - TY - JOUR AU - Balakin, K.V.* AU - Savchuk, N.P.* AU - Tetko, I.V. C1 - 4445 C2 - 24032 SP - 223-241 TI - In Silico approaches to prediction of aqueous and DMSO solubility of drug-like compounds: Trends, problems and solutions. JO - Curr. Med. Chem. VL - 13 PY - 2006 SN - 0929-8673 ER -