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1.
Arch Biochem Biophys ; 562: 1-8, 2014 Nov 15.
Article in English | MEDLINE | ID: mdl-25151305

ABSTRACT

Elevation in [Ca(2+)]i and activation of calpain-1 occur in central nervous system of SOD1(G93A) transgenic mice model of amyotrophic lateral sclerosis (ALS), but few data are available about the early stage of ALS. We here investigated the level of activation of the Ca(2+)-dependent protease calpain-1 in spinal cord of SOD1(G93A) mice to ascertain a possible role of the protease in the aetiology of ALS. Comparing the events occurring in the 120 day old mice, we found that [Ca(2+)]i and activation of calpain-1 were also increased in the spinal cord of 30 day old mice, as indicated by the digestion of some substrates of the protease such as nNOS, αII-spectrin, and the NR2B subunit of NMDA-R. However, the digestion pattern of these proteins suggests that calpain-1 may play different roles depending on the phase of ALS. In fact, in spinal cord of 30 day old mice, activation of calpain-1 produces high amounts of nNOS active species, while in 120 day old mice enhanced-prolonged activation of calpain-1 inactivates nNOS and down-regulates NR2B. Our data reveal a critical role of calpain-1 in the early phase and during progression of ALS, suggesting new therapeutic approaches to counteract its onset and fatal course.


Subject(s)
Amyotrophic Lateral Sclerosis/genetics , Calcium/metabolism , Calpain/metabolism , Nitric Oxide Synthase Type I/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Spinal Cord/metabolism , Amyotrophic Lateral Sclerosis/physiopathology , Animals , Disease Models, Animal , Disease Progression , Humans , Mice , Mice, Transgenic , Motor Neurons/metabolism , Nitric Oxide Synthase Type I/genetics , Proteolysis , Receptors, N-Methyl-D-Aspartate/genetics , Superoxide Dismutase/genetics , Superoxide Dismutase-1
2.
J Neurochem ; 103(2): 590-603, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17666052

ABSTRACT

High mobility group proteins are chromatin binding factors with key roles in maintenance of nuclear homeostasis. The evidence indicates that extracellularly released high mobility group box 1 (HMGB1) protein behaves as a cytokine, promoting inflammation and participating to the pathogenesis of several disorders in peripheral organs. In this study, we have investigated the expression levels and relocation dynamics of HMGB1 in neural cells, as well as its neuropathological potential. We report that HMGB1 is released in the culture media of neurons and astrocytes challenged with necrotic but not apoptotic stimuli. Recombinant HMGB1 prompts induction of pro-inflammatory mediators such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2, interleukin-1beta, and tumor necrosis factor alpha, and increases excitotoxic as well as ischemic neuronal death in vitro. Dexamethasone reduces HMGB1 dependent immune glia activation, having no effect on the protein's neurotoxic effects. HMGB1 is expressed in the nucleus of neurons and astrocytes of the mouse brain, and promptly (1 h) translocates into the cytoplasm of neurons within the ischemic brain. Brain microinjection of HMGB1 increases the transcript levels of pro-inflammatory mediators and sensitizes the tissue to the ischemic injury. Together, data underscore the neuropathological role of nuclear HMGB1, and point to the protein as a mediator of post-ischemic brain damage.


Subject(s)
Brain Ischemia/metabolism , Brain Ischemia/pathology , HMGB1 Protein/metabolism , Nerve Degeneration/metabolism , Nerve Degeneration/pathology , Neurons/metabolism , Stress, Physiological/metabolism , Animals , Blotting, Western , Cells, Cultured , Female , Glucose/deficiency , HMGB1 Protein/administration & dosage , HMGB1 Protein/pharmacology , Hypoxia, Brain/metabolism , Image Processing, Computer-Assisted , Immunohistochemistry , Infarction, Middle Cerebral Artery/pathology , Inflammation/metabolism , Inflammation/pathology , Inflammation Mediators/physiology , Mice , Mice, Inbred C57BL , Microinjections , Pregnancy , RNA/biosynthesis , RNA/genetics , Reverse Transcriptase Polymerase Chain Reaction , Stress, Physiological/pathology , Tumor Necrosis Factor-alpha/metabolism
3.
Biochem J ; 357(Pt 2): 569-74, 2001 Jul 15.
Article in English | MEDLINE | ID: mdl-11439110

ABSTRACT

The release of amphoterin by murine erythroleukaemia cells exposed to the chemical inducer hexamethylenebisacetamide represents an essential step for the process of their terminal differentiation. Once exported in the culture medium, amphoterin undergoes limited proteolysis, catalysed by a serine proteinase also secreted by stimulated cells. The isolated proteinase is responsible for degradation of amphoterin, with the production of a 10-amino-acid-residue fragment, specifically retaining the cell-differentiation-stimulating activity of the native protein molecule. This peptide does not express other properties of amphoterin, such as protein kinase C-stimulating activity or systemic toxicity. These findings define a selective mechanism accounting for extracellular amphoterin functional maturation.


Subject(s)
Carrier Proteins/metabolism , Cell Differentiation/drug effects , High Mobility Group Proteins/metabolism , Peptide Fragments/metabolism , Peptide Fragments/pharmacology , Animals , Biomarkers, Tumor/metabolism , Cations, Divalent/pharmacology , HMGB1 Protein , Kinetics , Leukemia, Erythroblastic, Acute , Metals/pharmacology , Mice , Protease Inhibitors/pharmacology , Protein Kinase C/metabolism , Recombinant Proteins/metabolism , Tumor Cells, Cultured
4.
Biochem Biophys Res Commun ; 279(2): 589-94, 2000 Dec 20.
Article in English | MEDLINE | ID: mdl-11118330

ABSTRACT

Neuroblastoma LAN-5 cells exposed to retinoic acid cease to multiply and extend neurite outgrowths acquiring a neuronal phenotype. We now report that protein kinase C-theta; (PKC-theta;) isozyme is involved in this differentiation process due to the following findings: (i) PKC-theta; is expressed by LAN-5 cells as a nuclear and perinuclear protein; (ii) cell stimulation with retinoic acid promotes in a large increase in the expression level of the kinase and its intracellular redistribution; and (iii) a PKC-theta; antisense oligonucleotide reduces at the same time the expression level of the kinase and the cell response to retinoic acid. Altogether these data are consistent with a specific role played by PKC-theta; in the differentiation program of neuronal cells.


Subject(s)
Cell Differentiation/physiology , Isoenzymes/genetics , Isoenzymes/metabolism , Oligodeoxyribonucleotides, Antisense/pharmacology , Protein Kinase C/genetics , Protein Kinase C/metabolism , Cell Differentiation/drug effects , Cell Nucleus/enzymology , Gene Expression Regulation, Enzymologic/drug effects , Humans , Neuroblastoma , Polymerase Chain Reaction , Protein Kinase C-theta , RNA, Messenger/genetics , Transcription, Genetic/drug effects , Tretinoin/pharmacology , Tumor Cells, Cultured
5.
Biochem Biophys Res Commun ; 275(1): 149-53, 2000 Aug 18.
Article in English | MEDLINE | ID: mdl-10944456

ABSTRACT

In this study we demonstrate that the rat pheochromocytoma PC12 cell line expresses the novel protein kinase C isozyme designated PKC-θ. The isozyme is almost completely localized in the nuclear compartment of proliferating cells. Following stimulation with the nerve growth factor, PKC-θ is redistributed into the cytoplasm and the outgrowing neurite processes, mostly as a cytoskeletal associated kinase. This event is accompanied by an eightfold increase in the expression level and by the appearance of specific modifications of PKC-θ molecule. Conversely, the kinase is down-regulated once cells reach the terminally differentiated state displaying a neuron-like phenotype. These data suggest a functional role for the kinase in the regulation of cytoskeletal modeling along the multistage differentiation process of PC12 cells.


Subject(s)
Cell Differentiation , Isoenzymes/metabolism , Neurons/cytology , Neurons/enzymology , Protein Kinase C/metabolism , Animals , Biological Transport/drug effects , Blotting, Western , Cell Differentiation/drug effects , Cell Nucleus/drug effects , Cell Nucleus/enzymology , Cell Nucleus/metabolism , Cytochalasin B/pharmacology , Cytoskeleton/drug effects , Cytoskeleton/enzymology , Cytoskeleton/metabolism , Down-Regulation/drug effects , Fluorescent Antibody Technique , Nerve Growth Factor/pharmacology , Neurites/drug effects , Neurites/enzymology , Neurons/drug effects , PC12 Cells , Protein Kinase C-theta , Rats
6.
FEBS Lett ; 453(3): 249-53, 1999 Jun 25.
Article in English | MEDLINE | ID: mdl-10405154

ABSTRACT

Protein kinase C-theta is a member of the n-protein kinase C subfamily that in mitotic cells translocates to centrosomes and kinetochores. Although this kinase is expressed in comparable amounts in murine erythroleukaemia cells during the interphase or metaphase, when localized in the mitotic structures, it selectively phosphorylates a 66 kDa protein, also associated to chromosomes. Moreover, protein kinase C-theta immunoprecipitated from cells at the metaphase results four times more active in the absence of lipid cofactors as compared with the kinase obtained from cells in the interphase. This activation is accomplished by interaction of protein kinase C-theta with a protein factor which also promotes an increased autophosphorylation of the kinase. These findings indicate that in the mitotic phase of the cell cycle, protein kinase C-theta recognizes a protein factor which operates as a positive modulator of the kinase activity in the absence lipids.


Subject(s)
Isoenzymes/metabolism , Leukemia, Erythroblastic, Acute/enzymology , Mitosis/physiology , Protein Kinase C/metabolism , Animals , Chromosomes/enzymology , Mice , Nuclear Proteins/isolation & purification , Phosphorylation , Protein Kinase C-theta , Spindle Apparatus/enzymology , Tumor Cells, Cultured
7.
J Gen Orthod ; 8(1): 5-16, 1997 Mar.
Article in English | MEDLINE | ID: mdl-9508861

ABSTRACT

Tongue thrust is involved in nearly all open bites. An open bite can be created by tongue thrust, tongue posture or mandibular posture. Tongue is an unusual muscle in that its contraction allows it to assume many shapes; its influence in the swallow can create an open bite in the area dictated by the contraction, thrust or rest position. Once space has been created between the upper and lower teeth by the tongue it continues to enter the space created, consequently enlarging the space. Skeletal open bites do not occur in patients whose masseter muscles are active during the swallow (an open bite can develop in these individuals due to habit or during orthodontic therapy). In these individuals the masseters fully contract during the swallow. The weaker the masseter muscles, the more likely an open bite will either be present or may develop during orthodontic treatment. Orthodontic movement will always result in occlusal interferences at some point in treatment. Occlusal interferences during orthodontic treatment make it difficult for patients to find a comfortable biting position. At this point they do not fully contract--"squeeze"--the masseters during the swallow to avoid traumatizing the teeth. Once the masseter squeeze is reduced, the tongue must contribute more to the swallow than when the masseters were more actively involved. The tongue becomes the cushion for the dentition during the swallow. The tongue now positions itself between the teeth during the swallow and the open bite during orthodontic treatment is born. Once the open bite occurs it is best to treat it immediately as the open bite thus created will only worsen with time. If the patient was originally a counterclockwise grower (brachycephalic), it is easier to correct. A clockwise grower (dolichocephalic) is hardest to correct, but can be corrected with patience, perseverance, exercise and a properly constructed tongue thrust appliance. While it is true that some skeletal configurations (i.e. clockwise growers, dolichocephalic facial types) lend themselves to the development of an open bite, the skeletal configuration itself seldom produces an open bite. The tongue is the main progenitor of open bites and it is also responsible for perpetuating the open bite. Dolichocephalic facial types lend themselves to open bite development as any orthodontic treatment which either distalizes molars or allows molars to extrude will tend to wedge the mandible and dentition open. (In this type of patient the masseter muscles develop insufficient force on closure to intrude the molars.) Once the bite opens, the tongue now enters the picture in order to complete the swallow. The open bite immediately worsens. The open bite thus created may require several months to correct. In the clockwise growth patient it is imperative that all precautions be taken during treatment to counteract open bite development. It is also imperative that an open bite, once detected, be treated immediately as the longer it persists the more difficult it becomes to treat. If left untreated, it becomes a habit and the more engrained a habit the more effort needed to change it.


Subject(s)
Malocclusion/therapy , Adolescent , Child , Deglutition/physiology , Dental Occlusion , Female , Humans , Male , Malocclusion/diagnosis , Malocclusion/etiology , Malocclusion/physiopathology , Maxillofacial Development , Orthodontics, Corrective/methods , Vertical Dimension
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