1,721,026 research outputs found
Diabetic cardiomyopathy: a “cardiac stem cell disease” involving p66Shc, an attractive novel molecular target for heart failure therapy
No full textA spectrophotometric method for the determination of 5-phosphoribosyl-1-pyrophosphate.
No full textA new, sensitive, specific and simple spectrophotometric method for the determination of 5-phosphoribosyl-l-pyrophosphate (PRPP) is presented. PRPP is reacted with excess hypoxanthine in the presence of hypoxanthine-guanine phosphoribosyltransferase. At the end of the reaction, PRPP concentration is measured from the extent of conversion of hypoxanthine to inositate. The concentration of the purine base is determined spectrophotometrically in the presence of xanthine oxidase
Guanine nucleotide depletion induces differentiation and aberrant neurite outgrowth in human dopaminergic neuroblastoma lines: a model for basal ganglia dysfunction in Lesch-Nyhan disease.
No full textLesch-Nyhan disease (LND), caused by complete deficiency of hypoxanthine guanine phosphoribosyltransferase (HPRT), is characterized by a neurological deficit, the etiology of which is unknown. Evidence has accumulated indicating that it might be related to dys A function of the basal ganglia with a prominent loss of striatal dopamine fibers. Guanine nucleoftide depletion has been shown to occur in cells from Lesch-Nyhan patients. In this study we demonstrate that chronic guanine nucleotide depletion induced by inhibition of inosine monophosphate dehydrogenase with low levels (50 nM) of mycophenolic acid (MPA) lead human neuroblastoma cell lines to differentiate toward the neuronal phenotype. The MPA-induced morphological changes were more evident in the dopaminergic line LAN5, than in the cholinergic line IMR32. MPA-induced differentiation, unlike that induced, by retinoic acid, caused a less extensive neurite outgrowth and branching (similar to that observed in cultured HPRT-deficient dopaminergic neurons) and involved up-regulation of p53, p21 and bax, and bcl-2 down-regulation without p27 protein accumulation. These results suggest that guanine nucleotide depletion following HPRT deficiency, might lead to earlier and abnormal brain development mainly affecting the basal ganglia, displaying the highest HPRT activity, and could be responsible for the specific neurobehavioral features of LN
Biochemistry and biology. Heart-to-heart to investigate cardiac progenitor cells
No full textBackground: Cardiac regenerative medicine is a rapidly evolving field, with promising future developments for effective personalized treatments. Several stem/progenitor cells are candidates for cardiac cell therapy, and emerging evidence suggests how multiple metabolic and biochemical pathways strictly regulate their fate and renewal. Scope of review: In this review, we will explore a selection of areas of common interest for biology and biochemistry concerning stem/progenitor cells, and in particular cardiac progenitor cells. Numerous regulatory mechanisms have been identified that link stem cell signaling and functions to the modulation of metabolic pathways, and vice versa. Pharmacological treatments and culture requirements may be exploited to modulate stem cell pluripotency and self-renewal, possibly boosting their regenerative potential for cell therapy. Major conclusions: Mitochondria and their many related metabolites and messengers, such as oxygen, ROS, calcium and glucose, have a crucial role in regulating stem cell fate and the balance of their functions, together with many metabolic enzymes. Furthermore, protein biochemistry and proteomics can provide precious clues on the definition of different progenitor cell populations, their physiology and their autocrine/paracrine regulatory/signaling networks. General significance: Interdisciplinary approaches between biology and biochemistry can provide productive insights on stem/progenitor cells, allowing the development of novel strategies and protocols for effective cardiac cell therapy clinical translation. This article is part of a Special Issue entitled Biochemistry of Stem Cells. © 2012 Elsevier B.V
Cardiac mechanoperception: A life-long story from early beats to aging and failure
No full textThe life-long story of the heart starts concomitantly with primary differentiation events occurring in multipotent progenitors located in the so-called heart tube. This initially tubular structure starts a looping process, which leads to formation of the final four-chambered heart with a primary contribution of geometric and position-associated cell sensing. While this establishes the correct patterning of the final cardiac structure, it also provides feedbacks to fundamental cellular machineries controlling proliferation and differentiation, thus ensuring a coordinated restriction of cell growth and a myocyte terminal differentiation. Novel evidences provided by embryological and cell engineering studies have clarified the relevance of mechanics-supported position sensing for the correct recognition of cell fate inside developing embryos and multicellular aggregates. One of the main components of this pathway, the Hippo-dependent signal transduction machinery, is responsible for cell mechanics intracellular transduction with important consequences for gene transcription and cell growth control. Being the Hippo pathway also directly connected to stress responses and altered metabolism, it is tempting to speculate that permanent alterations of mechanosensing may account for modifying self-renewal control in tissue homeostasis. In the present contribution, we translate these concepts to the aging process and the failing of the human heart, two pathophysiologic conditions that are strongly affected by stress responses and altered metabolism
Potential role of mycophenolate mofetil in the management of neuroblastoma patients
No full textIn human neuroblastoma cell lines (LAN5, SHEP and IMR32), mycophenolic acid (MPA) at concentrations (10(-7) -10(-6) M) readily attainable during immunosuppressive therapy with mycophenolate mofetil (Cellcept), induces guanine nucleotide depletion leading to cell cycle arrest and apoptosis through a p53 mediated pathway (up-regulation of p53, p21 and bax and down-regulation of bcl-2 and survivin). MPA-induced apoptosis is also associated to a marked decrease of p27 protein. In the same cell lines MPA, at lower concentrations (50 nM), corresponding to the plasma levels of the active free drug during Cellcept therapy, induces differentiation toward the neuronal phenotype by causing a partial chronic guanine nucleotide depletion. MPA-induced differentiation is not associated to p27 accumulation as occurs using retinoic acid. At a fixed concentration of MPA a higher percentage of apoptotic or differentiated cells is obtained when non dialysed serum substitutes for the dialysed one, due to the higher hypoxanthine concentration in the former (about 10 muM) leading to competition on HPRT-mediated salvage of guanine. At hypoxanthine or oxypurinol concentrations higher than 1 muM (up to 100 mu) no further enhancement of MPA effects was obtained, in agreement with the recently described safety of the allopurinol-mycophenolate mofetil combination in the treatment of hyperuricemia of kidney transplant recipients. The apoptotic effects of MPA do not appear to be significantly increased by the UDP-glucuronosyltransferase inhibitor niflumic acid
Endogenous cardiac stem cells.
No full textAbstract In the past few years it has been established that the heart contains a reservoir of stem and progenitor cells. These cells are positive for various stem/progenitor cell markers (Kit, Sca-1, Isl-1, and Side Population (SP) properties). The relationship between the various cardiac stem cells (CSC) and progenitor cells described awaits clarification. Furthermore, they may open a new therapeutic strategies of cardiac repair based on the regeneration potential of cardiac stem cells. Currently, cellular cardiomyoplasty is actively explored as means of regenerating damaged myocardium using several different cell types. CSCs seem a logical cell source to exploit for cardiac regeneration therapy. Their presence into the heart, the frequent co-expression of early cardiac progenitor transcription factors, and the capability for ex vivo and in vivo differentiation toward the cardiac lineages offer promise of enhanced cardiogenicity compared to other cell sources. CSCs, when isolated from various animal models by selection based on c-Kit, Sca-1, and/or MDR1, have shown cardiac regeneration potential in vivo following injection in the infracted myocardium. Recently, we have successfully isolated CSCs from small biopsies of human myocardium and expanded them ex vivo by many folds without losing differentiation potential into cardiomyocytes and vascular cells, bringing autologous transplantation of CSCs closer to clinical evaluation. These cells are spontaneously shed from human surgical specimens and murine heart samples in primary culture. This heterogeneous population of cells forms multi-cellular clusters, dubbed cardiospheres (CSs), in suspension culture. CSs are composed of clonally-derived cells, consist of proliferating c-Kit positive cells primarily in their core and differentiating cells expressing cardiac and endothelial cell markers on their periphery. Although the intracardiac origin of adult myocytes has been unequivocally documented, the potential of an extracardiac source of cells, able to repopulate the lost CSCs in pathological conditions (infarct) cannot be excluded and will be discussed in this review. The delivery of human CSs or of CSs-derived cells into the injured heart of the SCID mouse resulted in engraftment, migration, myocardial regeneration and improvement of left ventricular function. Our method for ex vivo expansion of resident CSCs for subsequent autologous transplantation back into the heart, may give these cell populations, the resident and the transplanted one, the combined ability to mediate myocardial regeneration to an appreciable degree, and may change the way in which cardiovascular disease will be approached in the future
Cardiac stem cell populations for repair of cardiac tissue
No full textMethod for the isolation, expansion and preservation of cardiac stem cells from human or animal tissue biopsy samples to be employed in cell transplantation and functional repair of the myocardium or other organs. Cells may also be used in gene therapy for treating cardiomyopathies, for treating ischemic heart diseases and for setting in vitro models to study drugs.Method for the isolation, expansion and preservation of cardiac stem cells from human or animal tissue biopsy samples to be employed in cell transplantation and functional repair of the myocardium or other organs. Cells may also be used in gene therapy for treating cardiomyopathies, for treating ischemic heart diseases and for setting in vitro models to study drug
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