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1.
Mol Neurobiol ; 45(3): 596-604, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22648535

ABSTRACT

Phospholipases (PLA2s) are a superfamily of enzymes characterized by the ability to specifically hydrolyze the sn-2 ester bond of phospholipids generating arachidonic acid, utilized in inflammatory responses, and lysophospholipids involved in the control of cell membrane remodeling and fluidity. PLA2s have been so far considered a crucial element in the etiopathogenesis of several neurological diseases such as cerebral ischemia, multiple sclerosis, Parkinson's disease, and Alzheimer's disease (AD). In AD, the role of beta-amyloid (Aß) fragments is well established although still more elusive are the molecular events of the cascade that from the Aß accumulation leads to neurodegeneration with its clinical manifestations. However, it is well known that inflammation and alteration of lipid metabolism are common features of AD brains. Findings obtained from in vitro studies, animal models, and human brain imaging analysis point towards cPLA2 as a key molecule in the onset and maintenance of the neurodegenerative mechanism(s) of AD. In this review, we have focused on the molecular and biological evidence of the involvement of cPLA2s in the pathogenesis of AD. An insight into the molecular mechanism(s) underlying the action and the regulation of cPLA2 is of tremendous interest in the pharmaceutical and biotechnology industry in developing selective and potent inhibitors able to modulate the onset and/or the outcome of AD.


Subject(s)
Alzheimer Disease/enzymology , Alzheimer Disease/etiology , Calcium/metabolism , Phospholipases A2, Cytosolic/metabolism , Alzheimer Disease/pathology , Alzheimer Disease/therapy , Animals , Central Nervous System/enzymology , Central Nervous System/pathology , Humans , Models, Biological , Molecular Targeted Therapy , Phospholipases A2, Cytosolic/antagonists & inhibitors
2.
Neurol Sci ; 27(4): 266-70, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16998731

ABSTRACT

Until the 1990s, neurologists were practising their profession under the doctrine established in the late 19th to early 20th century by the prominent histologist Ramon y Cajal: "Once the development was ended, the founts of growth and regeneration of the axons and dendrites dried up irrevocably. In the adult centers, the nerve paths are something fixed, ended, and immutable. Everything may die, nothing may be regenerated. It is for the science of the future to change, if possible, this harsh decree." Similarly, Giulio Bizzozero, the most prominent Italian histologist and mentor of Camillo Golgi, classified the tissues of the human body into "labile, stable and perennial". Among the latter were the nerve cells, believed to be unable to proliferate in the postnatal brain. This classification was taught until a few years ago to generations of medical students and biologists all over the world. We have investigated the historical, methodological and technical reasons why this "central dogma of neurology", so influential in clinical and experimental neurology, has lasted so long. We examined how this dogma was broken and who contributed, and the difficulties encountered by the "heretical" researchers who contributed to this goal, especially between the 1960s and the early 1990s, when at last neurogenesis in the adult brain could no longer be denied. Finally, we propose that the understanding of the mechanisms underlying various neurological diseases and the interpretations of clinical syndromes, as well as the design of new therapies, are being revolutionised by the breaking of this dogma and the discovery of the presence of neural stem cells in the adult brain.


Subject(s)
Cell Differentiation/physiology , Central Nervous System/physiology , Nerve Regeneration/physiology , Neurobiology/history , Stem Cells/physiology , Central Nervous System/cytology , Central Nervous System/surgery , History, 18th Century , History, 19th Century , Humans , Stem Cell Transplantation
3.
Cancer Res ; 60(5): 1365-70, 2000 Mar 01.
Article in English | MEDLINE | ID: mdl-10728700

ABSTRACT

Pheochromocytomas are tumors originating from chromaffin cells, the large majority of which are sporadic neoplasms. The genetic and molecular events determining their tumorigenesis continue to remain unknown. On the other hand, RET germ-line mutations cause the inheritance of familial tumors in multiple endocrine neoplasia (MEN)-2 diseases, which account for a minority of pheochromocytomas. We investigated the expression of the RET gene in 14 sporadic tumors harboring no activating mutations. A subset of highly RET-expressing tumors (50%) could be distinguished. They showed RET transcript, protein amounts as well as Ret-associated phosphotyrosine levels similar to those measured in MEN-2A-associated pheochromocytomas. We also determined the GDNF and GDNF family receptor alpha (GFRalpha)-1 transcript levels in tumors and in normal tissues. Whereas the GFRalpha-1 transcripts were detected at similar levels in normal tissues and in tumors, GDNF was frequently found expressed in sporadic tumors at levels several times higher than in controls. These results led us to propose the existence of an autocrine or paracrine loop leading to chronic stimulation of the Ret signaling pathway, which could participate in the pathogenesis of a number of sporadic pheochromocytomas.


Subject(s)
Adrenal Gland Neoplasms/metabolism , Drosophila Proteins , Nerve Growth Factors , Pheochromocytoma/metabolism , Proto-Oncogene Proteins/metabolism , Receptor Protein-Tyrosine Kinases/metabolism , Adrenal Gland Neoplasms/genetics , Gene Expression Regulation, Neoplastic , Glial Cell Line-Derived Neurotrophic Factor , Glial Cell Line-Derived Neurotrophic Factor Receptors , Humans , Nerve Tissue Proteins/biosynthesis , Nerve Tissue Proteins/genetics , Pheochromocytoma/genetics , Phosphorylation , Proto-Oncogene Proteins/biosynthesis , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins c-ret , Receptor Protein-Tyrosine Kinases/biosynthesis , Receptor Protein-Tyrosine Kinases/genetics , Signal Transduction , Tyrosine
4.
Biochem Biophys Res Commun ; 165(1): 506-11, 1989 Nov 30.
Article in English | MEDLINE | ID: mdl-2590241

ABSTRACT

Thyrotropin (TSH) is the primary hormone regulating the activity of the thyroid gland. We have recently shown that TSH stimulates H-ferritin mRNA levels in rat thyroid. Ferritin plays a key role in determining the intracellular fate of iron. The induction of ferritin synthesis by iron in liver is regulated both at transcriptional and translational levels. Here we present evidence that the mechanisms by which TSH regulates the mRNA levels are mediated by a diffusible product acting in trans on its own promoter. In fact, the H-ferritin promoter mediates increased CAT activity in response to hormone induction. Our results identify transcription as an important regulatory step of TSH action. They suggest that TSH induces expression of the ferritin gene, and that continuous protein synthesis is required to maintain basal ferritin gene expression in the absence of hormone.


Subject(s)
Ferritins/genetics , Genes/drug effects , Promoter Regions, Genetic/drug effects , Thyrotropin/pharmacology , Transcription, Genetic/drug effects , Animals , Blotting, Northern , Cell Division/drug effects , Cell Line , Kinetics , Macromolecular Substances , RNA, Messenger/drug effects , RNA, Messenger/genetics , Rats , Thyroid Gland
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