Diabetic cardiomyopathy (DCM) is a cardiac dysfunction which affects approximately 12% of diabetic patients, leading to overt heart failure and death. However, there is not an efficient and specific ...methodology for DCM diagnosis, possibly because molecular mechanisms are not fully elucidated, and it remains asymptomatic for many years. Also, DCM frequently coexists with other comorbidities such as hypertension, obesity, dyslipidemia, and vasculopathies. Thus, human DCM is not specifically identified after heart failure is established. In this sense, echocardiography has been traditionally considered the gold standard imaging test to evaluate the presence of cardiac dysfunction, although other techniques may cover earlier DCM detection by quantification of altered myocardial metabolism and strain. In this sense, Phase-Magnetic Resonance Imaging and 2D/3D-Speckle Tracking Echocardiography may potentially diagnose and stratify diabetic patients. Additionally, this information could be completed with a quantification of specific plasma biomarkers related to related to initial stages of the disease. Cardiotrophin-1, activin A, insulin-like growth factor binding protein-7 (IGFBP-7) and Heart fatty-acid binding protein have demonstrated a stable positive correlation with cardiac hypertrophy, contractibility and steatosis responses. Thus, we suggest a combination of minimally-invasive diagnosis tools for human DCM recognition based on imaging techniques and measurements of related plasma biomarkers.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The term 'casein kinase' has been widely used for decades to denote protein kinases sharing the ability to readily phosphorylate casein in vitro. These fall into three main classes: two of them, ...later renamed as protein kinases CK1 (casein kinase 1, also known as CKI) and CK2 (also known as CKII), are pleiotropic members of the kinome functionally unrelated to casein, whereas G-CK, or genuine casein kinase, responsible for the phosphorylation of casein in the Golgi apparatus of the lactating mammary gland, has only been identified recently with Fam20C family with sequence similarity 20C; also known as DMP-4 (dentin matrix protein-4), a member of the four-jointed family of atypical protein kinases, being responsible for the phosphorylation of many secreted proteins. In hindsight, therefore, the term 'casein kinase' is misleading in every instance; in the case of CK1 and CK2, it is because casein is not a physiological substrate, and in the case of G-CK/Fam20C/DMP-4, it is because casein is just one out of a plethora of its targets, and a rather marginal one at that. Strikingly, casein kinases altogether, albeit representing a minimal proportion of the whole kinome, appear to be responsible for the generation of up to 40-50% of non-redundant phosphosites currently retrieved in human phosphopeptides database. In the present review, a short historical explanation will be provided accounting for the usage of the same misnomer to denote three unrelated classes of protein kinases, together with an update of our current knowledge of these pleiotropic enzymes, sharing the same misnomer while playing very distinct biological roles.
The oxidative modification hypothesis of atherosclerosis, which assigns to oxidized low-density lipoproteins (LDLs) a crucial role in atherosclerosis initiation and progression, is still debated. ...This review examines the role played by oxidized LDLs in atherogenesis taking into account data derived by studies based on molecular and clinical approaches. Experimental data carried out in cellular lines and animal models of atherosclerosis support the proatherogenic role of oxidized LDLs: (a) through chemotactic and proliferating actions on monocytes/macrophages, inciting their transformation into foam cells; (b) through stimulation of smooth muscle cells (SMCs) recruitment and proliferation in the tunica intima; (c) through eliciting endothelial cells, SMCs, and macrophages apoptosis with ensuing necrotic core development. Moreover, most of the experimental data on atherosclerosis-prone animals benefiting from antioxidant treatment points towards a link between oxidative stress and atherosclerosis. The evidence coming from cohort studies demonstrating an association between oxidized LDLs and cardiovascular events, notwithstanding some discrepancies, seems to point towards a role of oxidized LDLs in atherosclerotic plaque development and destabilization. Finally, the results of randomized clinical trials employing antioxidants completed up to date, despite demonstrating no benefits in healthy populations, suggest a benefit in high-risk patients. In conclusion, available data seem to validate the oxidative modification hypothesis of atherosclerosis, although additional proofs are still needed.
Synapse regulation exploits the capacity of actin to function as a stable structural component or as a dynamic filament. Beyond its well-appreciated role in eliciting visible morphological changes at ...the synapse, the emerging picture points to an active contribution of actin to the modulation of the efficacy of pre- and postsynaptic terminals. Moreover, by engaging distinct pools of actin and divergent signalling pathways, actin-dependent morphological plasticity could be uncoupled from modulation of synaptic strength. The aim of this Review is to highlight some of the recent progress in elucidating the role of the actin cytoskeleton in synaptic function.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Chronic kidney disease patient's progression to end-stage renal disease as well as their high mortality are linked to cardiovascular disease. However, the high incidence rate of cardiovascular ...morbidity and mortality in these patients is not fully accounted for by traditional cardiovascular risk factors such as diabetes, hypertension and obesity. Renal disease and CVD are associated with endothelial dysfunction, inflammation and oxidative stress and in this review we will examine what is known regarding their similar roles in both CVD and chronic kidney disease, specifically focusing on the interconnections between oxidative stress, inflammation and endothelial dysfunction. These interconnections are best visualized as a vicious circle wherein these entities coexist and communicate with each other, thereby exacerbating the processes underpinning these different entities with the end result of the high morbidity and mortality that characterize CKD patients. By exploring this vicious circle i.e. the mode and extent of the interrelationships as well as some of the underlying mechanisms involved, this review aims at outlining our current understanding as well as highlighting future avenues for research and potential targets for therapeutic intervention.
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Integrins are extracellular matrix receptors that mediate biochemical and mechanical bi‐directional signals between the extracellular and intracellular environment of a cell thanks to allosteric ...conformational changes. In the brain, they are found in both neurons and glial cells, where they play essential roles in several aspects of brain development and function, such as cell migration, axon guidance, synaptogenesis, synaptic plasticity and neuro‐inflammation. Although there are many successful examples of how regulating integrin adhesion and signaling can be used for therapeutic purposes, for example for halting tumor progression, this is not the case for the brain, where the growing evidence of the importance of integrins for brain pathophysiology has not translated yet into medical applications. Here, we review recent literature showing how alterations in integrin structure, expression and signaling may be involved in the etiology of autism spectrum disorder, epilepsy, schizophrenia, addiction, depression and Alzheimer's disease. We focus on common mechanisms and recurrent signaling pathways, trying to bridge studies on the genetics and molecular structure of integrins with those on synaptic physiology and brain pathology. Further, we discuss integrin‐targeting strategies and their potential benefits for therapeutic purposes in neuropsychiatric disorders.
Integrins are extracellular matrix receptors mediating biochemical and mechanical signals at the cell surface. In the brain, they regulate development and function of neurons and glial cells. Defects in integrin expression or signaling contribute to autism spectrum disorder, epilepsy, schizophrenia, addiction, depression and Alzheimer's disease. We review how genetics and structure of integrins affect synaptic physiology and brain pathology, and discuss integrin‐targeting strategies for therapies in neuropsychiatric disorders.
Gitelman syndrome (GS) is a rare, salt-losing tubulopathy characterized by hypokalemic metabolic alkalosis with hypomagnesemia and hypocalciuria. The disease is recessively inherited, caused by ...inactivating mutations in the SLC12A3 gene that encodes the thiazide-sensitive sodium-chloride cotransporter (NCC). GS is usually detected during adolescence or adulthood, either fortuitously or in association with mild or nonspecific symptoms or both. The disease is characterized by high phenotypic variability and a significant reduction in the quality of life, and it may be associated with severe manifestations. GS is usually managed by a liberal salt intake together with oral magnesium and potassium supplements. A general problem in rare diseases is the lack of high quality evidence to inform diagnosis, prognosis, and management. We report here on the current state of knowledge related to the diagnostic evaluation, follow-up, management, and treatment of GS; identify knowledge gaps; and propose a research agenda to substantiate a number of issues related to GS. This expert consensus statement aims to establish an initial framework to enable clinical auditing and thus improve quality control of care.
Hypertensive kidney disease classically entails nephroangiosclerosis and hyalinosis with glomerular damage. However, in recent years, several evidences showed that high blood pressure also injures ...tubular cells, inducing epithelial-to-mesenchymal transition and tubulointerstitial fibrosis. Recently investigated mechanisms are also podocyte effacement and loss, which lead to denudation of the glomerular basement membrane and focal adhesion of the tufts to the Bowmanʼs capsule, with reduced filtration and scars. Starting from the classic concept of nephroangiosclerosis, this review examines the recently emerged knowledge of new biochemical and molecular mechanisms underlying the kidney damage in hypertension and discusses how viable podocytes or podocyte-deriving proteins are promising tools for early diagnosis of renal remodelling in hypertension.
At variance with most oncogenic protein kinases whose malignancy is generally due to genetic alterations conferring constitutive activity, CK2 is a highly pleiotropic Ser/Thr protein kinase naturally ...endowed with constitutive activity and lacking gain-of-function mutants. Nonetheless CK2 is abnormally elevated in a wide variety of tumors and there is strong evidence that it operates as a cancer driver by creating a cellular environment favorable to neoplasia: notably, CK2 plays a global role as an anti-apoptotic and pro-survival agent, it enhances the multi-drug resistance (MDR) phenotype, it assists the chaperone machinery which protects the “onco-kinome” and it promotes neo-angiogenesis. Based on this scenario we propose that the implication of CK2 in neoplasia is an example of “non oncogene addiction”, i.e. over reliance of the perturbed cellular signaling network on high CK2 level for its own maintenance. Consistent with this, an ample spectrum of diverse types of cancer cells have been already shown to rely on high CK2 level for their survival, as judged from their response to specific CK2 inhibitors and silencing of endogenous CK2 catalytic subunits. Remarkably, among these are cells whose cancer phenotype arises from the genetic alteration of onco-kinases (e.g. Abl and Alk) different from CK2 and insensitive to the CK2 inhibitors used in those experiments. Based on these premises, CK2 could represent a “multi-purpose” target for the treatment of different kinds of tumors.
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