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Lolli G.,Venetian Institute of Molecular Medicine
Cell Cycle | Year: 2010

Cyclin Dependent Kinases (CDKs) regulate the cell division cycle, apoptosis, transcription and differentiation in addition to functions in the nervous system. They are regulated by their cyclin partners and by a variety of additional protein effectors (inhibitors, kinases, phosphatases). Each CDK serves its function by means of specific protein recognition properties. These are also responsible for the differential regulation of CDKs/Cyclin couples involved in processes as different as cell cycle and transcription. The structural features determining general and specific properties for CDKs/Cyclin complexes are analyzed. They reside in an overall conserved architecture with divergent spots used by the complexes to present themselves to specific substrates or other protein effectors. © 2010 Landes Bioscience. Source


Carafoli E.,Venetian Institute of Molecular Medicine
Biochimica et Biophysica Acta - Bioenergetics | Year: 2010

A number of findings in the 1950s had offered indirect indications that mitochondria could accumulate Ca2+. In 1961, the phenomenon was directly demonstrated using isolated mitochondria: the uptake process was driven by respiratory chain activity or by the hydrolysis of added ATP. It could be accompanied by the simultaneous uptake of inorganic phosphate, in which case precipitates of hydroxyapatite were formed in the matrix, buffering its free Ca2+ concentration. The properties of the uptake process were established in the 1960s and 1970s: the uptake of Ca2+ occurred electrophoretically on a carrier that has not yet been molecularly identified, and was released from mitochondria via a Na+/Ca2+ antiporter. A H+/Ca2+ release exchanger was also found to operate in some mitochondrial types. The permeability transition pore was later also found to mediate the efflux of Ca2+ from mitochondria. In the mitochondrial matrix two TCA cycle dehydrogenases and pyruvate dehydrogenase phosphate phosphatase were found to be regulated in the matrix by the cycling of Ca2+ across the inner membrane. In conditions of cytoplasmic Ca2+ overload mitochondria could store for a time large amounts of precipitated Ca2+-phosphate, thus permitting cells to survive situations of Ca2+ emergency. The uptake process was found to have very low affinity for Ca2+: since the bulk concentration of Ca2+ in the cytoplasm is in the low to mid-nM range, it became increasingly difficult to postulate a role of mitochondria in the regulation of cytoplsmic Ca2+. A number of findings had nevertheless shown that energy linked Ca2+ transport occurred efficiently in mitochondria of various tissues in situ. The paradox was only solved in the 1990s, when it was found that the concentration of Ca2+ in the cytoplasm is not uniform: perimitochondrial micropools are created by the agonist-promoted discharge of Ca2+ from vicinal stores in which the concentration of Ca2+ is high enough to activate the low affinity mitochondrial uniporter. Mitochondria thus regained center stage as important regulators of cytoplasmic Ca2+ (not only of their own internal Ca2+). Their Ca2+ uptake systems was found to react very rapidly to cytoplasmic Ca2+ demands, even in the 150-200 msec time scale of processes like the contraction and relaxation of heart. An important recent development in the area of mitochondrial Ca2+ transport is its involvement in the disease process. Ca2+ signaling defects are now gaining increasing importance in the pathogenesis of diseases, e.g., neurodegenerative diseases. Since mitochondria have now regained a central role in the regulation of cytoplasmic Ca2+, dysfunctions of their Ca2+ controlling systems have expectedly been found to be involved in the pathogenesis of numerous disease processes. © 2010. Source


Carafoli E.,Venetian Institute of Molecular Medicine
Cell Calcium | Year: 2012

Indirect findings in the 1950s had indicated that mitochondria could accumulate Ca2+, but only in 1961 isolated mitochondria were directly shown to take it up in a process driven by the activity of the respiratory chain or by the hydrolysis of added ATP. The uptake of Ca2+ could be accompanied by the simultaneous uptake of inorganic phosphate, leading to the precipitation of hydroxyapatite in the matrix and to the effective buffering of the free Ca2+ concentration in it. The uptake of Ca2+ occurred via an electrophoretic uniporter that has been molecularly identified only recently. Ca2+ was then released through a Na+/Ca2+ exchanger that has also been identified very recently (a H+/Ca2+ antiporter has also been described in some mitochondrial types). In the matrix two TCA cycle dehydrogenases and pyruvate dehydrogenase phosphate phosphatase were found to be regulated by Ca2+, providing a rationale for the Ca2+ cycling process. The affinity of the uptake uniporter was found to be too low to efficiently regulate Ca2+ in the low to mid nM concentration in the cytosol. However, a number of findings showed that energy linked transport of Ca2+ did nevertheless occur in mitochondria in situ. The enigma was solved in the 1990s, when it was found that perimitochondrial Ca2+ pools are created by the discharge of Ca2+ from vicinal endoplasmic reticulum stores in which the concentration of Ca2+ is high enough to satisfy the poor affinity of the uniporter. Thus, mitochondria have now regained a key role in the regulation of cytosolic Ca2+ (not only of their own internal Ca2+). © 2012. Source


Fadini G.P.,University of Padua | Fadini G.P.,Venetian Institute of Molecular Medicine
Diabetologia | Year: 2014

Traditionally, the development of diabetic complications has been attributed to the biochemical pathways driving hyperglycaemic cell damage, while reparatory mechanisms have been long overlooked. A more comprehensive view of the balance between damage and repair suggests that an impaired regenerative capacity of bone marrow (BM)-derived cells strongly contributes to defective re-endothelisation and neoangiogenesis in diabetes. Although recent technological advances have redefined the biology and function of endothelial progenitor cells (EPCs), interest in BM-derived vasculotropic cells in the setting of diabetes and its complications remains high. Several circulating cell types of haematopoietic and non-haematopoietic origin are affected by diabetes and are potentially involved in the pathobiology of chronic complications. In addition to classical EPCs, these include circulating (pro-)angiogenic cells, polarised monocytes/macrophages (M1 and M2), myeloid calcifying cells and smooth muscle progenitor cells, having disparate roles in vascular biology. In parallel with the study of elusive progenitor cell phenotypes, it has been recognised that diabetes induces a profound remodelling of the BM stem cell niche. The alteration of circulating (progenitor) cells in the BM is now believed to be the link among distant end-organ complications. The field is rapidly evolving and interest is shifting from specific cell populations to the complex network of interactions that orchestrate trafficking of circulating vasculotropic cells. © 2013 Springer-Verlag Berlin Heidelberg. Source


Avogaro A.,Venetian Institute of Molecular Medicine
Diabetes, Obesity and Metabolism | Year: 2012

Type 2 diabetes mellitus (T2DM) is a progressive disease characterized by worsening hyperglycaemia. Lowering haemoglobin A1c to below or around 7% has been shown to reduce microvascular and neuropathic complications of diabetes. The ongoing uncertainty regarding whether intensive glycaemic control can reduce the increased risk of cardiovascular disease (CVD) in people with T2DM stirred the launch of the recent long-term megatrials. These trials compared the effects of intensive vs. standard control on vascular complications in relatively high CV risk participants with T2DM. While in Veterans Affairs Diabetes Trial, and Action to Control Cardiovascular Risk in Diabetes, the effect of glucose optimization resulted either in no protection or in an excessive CVD death, the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation trial showed that intensive glycaemic control reduced the risk of combined major macrovascular and microvascular events. In this trial, the glucose control strategy was based on gliclazide MR at randomization in all patients and then further sequential addition of other glucose-lowering drugs. Several studies showed that gliclazide has antioxidant properties, reduces markers of endothelial inflammation, and prevents glucose-induced apoptosis of endothelial cells. These positive antioxidant effects are not confined to the vascular wall but they are effective also in the β cells. These properties are important because (i) in patients with atherosclerotic process, microvascular abnormalities may hasten disease progression and (ii) slowing the microvascular complications may have a potentially remarkable effect on the natural history of macrovascular disease. © 2011 Blackwell Publishing Ltd. Source

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