Browsing by Subject "protein kinase"

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    Hypertrophic cardiomyopathy: Pathological features and molecular pathogenesis
    (2004) Çam F.S.; Cüray M.
    Hypertrophic cardiomyopathy (HCM) is a heterogeneous genetic cardiac disorder with various genotypic and phenotypic manifestations, and is often a diagnostic challenge. Although more than forty years have passed since the first description of HCM, a variety of mutations in genes encoding sarcomeric proteins, that cause the disease have been defined by laboratory and clinical studies over the past few years. The fact that HCM is the most common cause of sudden death in young competitive athletes and that it is actually an important cause of morbidity and mortality in people of all ages, has made the researchers to concentrate more on the molecular basis and treatment strategies of the disease. This study aims to summarize both pathological features and rapidly evolving molecular genetics of HCM, and so to understand this not infrequently seen, complex disorder better.
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    Ischemic preconditioning - Association of reperfusion and brain damage with metabolic state; [İskemik ön tanitim-reperfüzyon ve beyin hasarinin metabolik durumu ile ilişkisi]
    (2005) Tuǧlu I.; Vural K.; Cezayirli E.; Varol T.; Özbilgin K.
    Stroke and cardiac arrest, which are major causes of death and disability, affect millions of individuals around the world and are responsible for the leading health care costs of all diseases. The ischemia-induced neuronal death is an energy dependent process and is the result of activation of cascades of detrimental biochemical and histological events that include perturbion of calcium homeostasis leading to increased excitotoxicity, malfunction of endoplasmic reticulum and mitochondria, elevation of oxidative stress causing DNA damage, alteration in proapoptotic gene expression, and activation of the effector caspases and endonucleases leading to the final degradation of the genome. Ischemic preconditioning of the brain describes the neuroprotection induced by a short, conditioning ischemic episode to a subsequent severe ischemic episode. The tolerance of the brain to an ischemic injury depends not only on the duration and severity of insufficient blood flow but also on various pre- and post-ischemic factors that are able to influence the post ischemic outcome. Recent experimental studies focus on the preischemic factors, that can increase the ischemic tolerance, among which the suppression of metabolic rate, the increase of brain tissue energy reserves and the inhibition of membrane permeability of cations are of particular importance. During the induction phase, aspartate and adenosine receptors, and oxygen free radicals and conservation of energy metabolism are required. Protein kinases, transcription factors, and immediate early genes appear to transduce the signal into a tolerant response. The brain succumbs to ischemic injury as a result of loss of metabolic stores, excessive intracellular calcium accumulation, oxidative stress, and potentiation of the inflammatory response. Neurons can also die via necrotic or apoptotic mechanisms, depending on the nature and severity of the insult. While it has been widely held that ischemia is notable for cessation of protein synthesis, brain regions with marginal reduction in blood supply are especially capable of expressing a variety of genes, the functions of many of which are only beginning to be understood. Gene expression is also upregulated upon reperfusion and reoxygenation. Brain extracellular levels of glutamate, aspartate, GABA and glycine increase rapidly following the onset of ischemia, remain at an elevated level during the ischemia, and then decline following reperfusion. In the early stages neuronal responses to ischem ia are dependent on the modulation of ion channels. Reactive oxygen species generated during ische-mia-reperfusion contribute to the injury. Oxygen free-radicals serve as important signalling molecules that trigger inflammation and apoptosis. The use of appropriate animal models is essential to predict the value and effect of therapeutic approaches in human subjects. Animal models should be used to determine dosage and duration of therapy, which will vary with the pharmacokinetic properties of different agents. Finally, physiological monitoring for the metabolic condition such as cerebral blood flow, blood pressure and gazes, body temperature, glycemia, etc., should be performed to eliminate confounding variables and to observe adverse systemic effects. Therefore, it is very important to know the experimental process, survey of animals, neurologic scoring, histological methods which highly affect the explanation of the results. In this review, we discuss mechanisms of ischemic brain damage and reperfusion related to metabolic condition and histology.
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    Leishmania kinetoplast DNA contributes to parasite burden in infected macrophages: Critical role of the cGAS-STING-TBK1 signaling pathway in macrophage parasitemia
    (Frontiers Media S.A., 2022) Yilmaz I.C.; Dunuroglu E.; Ayanoglu I.C.; Ipekoglu E.M.; Yildirim M.; Girginkardesler N.; Ozbel Y.; Toz S.; Ozbilgin A.; Aykut G.; Gursel I.; Gursel M.
    Leishmania parasites harbor a unique network of circular DNA known as kinetoplast DNA (kDNA). The role of kDNA in leishmania infections is poorly understood. Herein, we show that kDNA delivery to the cytosol of Leishmania major infected THP-1 macrophages provoked increased parasite loads when compared to untreated cells, hinting at the involvement of cytosolic DNA sensors in facilitating parasite evasion from the immune system. Parasite proliferation was significantly hindered in cGAS- STING- and TBK-1 knockout THP-1 macrophages when compared to wild type cells. Nanostring nCounter gene expression analysis on L. major infected wild type versus knockout cells revealed that some of the most upregulated genes including, Granulysin (GNLY), Chitotriosidase-1 (CHIT1), Sialomucin core protein 24 (CD164), SLAM Family Member 7 (SLAMF7), insulin-like growth factor receptor 2 (IGF2R) and apolipoprotein E (APOE) were identical in infected cGAS and TBK1 knockout cells, implying their involvement in parasite control. Amlexanox treatment (a TBK1 inhibitor) of L. major infected wild type cells inhibited both the percentage and the parasite load of infected THP-1 cells and delayed footpad swelling in parasite infected mice. Collectively, these results suggest that leishmania parasites might hijack the cGAS-STING-TBK1 signaling pathway to their own advantage and the TBK1 inhibitor amlexanox could be of interest as a candidate drug in treatment of cutaneous leishmaniasis. Copyright © 2022 Yilmaz, Dunuroglu, Ayanoglu, Ipekoglu, Yildirim, Girginkardesler, Ozbel, Toz, Ozbilgin, Aykut, Gursel and Gursel.