Abstract Trimethyltin chloride (TMT) is known to produce neuronal damage in the rat hippocampus, especially in the CA1 /CA3 subfields, together with reactive astrogliosis. Previous studies indicate ...that in cultured rat hippocampal neurons the Ca2+ cytosolic increase induced by TMT is correlated with apoptotic cell death, although some molecular aspects of the hippocampal neurodegeneration induced by this neurotoxicant still remain to be clarified. Cathepsin D (Cat D) is a lysosomal aspartic protease involved in some neurodegenerative processes and also seems to play an important role in the processes that regulate apoptosis. We investigated the specific activity and cellular expression of Cat D in the rat hippocampus in vivo and in cultured organotypic rat hippocampal slices. The role of Cat D in cell death processes and the mechanisms controlling Cat D were also investigated. Cat D activity was assayed in hippocampus homogenates of control and TMT-treated rats. In order to visualize the distribution of Cat D immunoreactivity in the hippocampus, double-label immunofluorescence for Cat D and Neu N, GFAP, OX42 was performed. In addition, in order to clarify the possible relationship between Cat D activity, neuronal calcium overload and neuronal death processes, organotypic hippocampal cultures were also treated with a Cat D inhibitor (Pepstatin A) or Calpain inhibitor (Calpeptin) or an intracellular Ca2+ chelator (BAPTA-AM) in the presence of TMT. TMT treatment in rat hippocampus induced high levels of Cat D activity both in vivo and in vitro , in glial cells and in CA3 neurons, where a marked TMT-induced neuronal loss also occurred. Cat D is actively involved in CA3 neuronal death and the protease increase is a calcium-Calpain dependent phenomenon.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Highlights • AQP4 over-expression in perivascular astrocytes of the rat hippocampus and cortex. • IgG leakage in the hippocampal and cortical paravasal parenchyma of TMT-treated rats. • Enhanced ...neuronal VEGF/VEGFR-2 production and VEGFR-2 activation (VEGFR-2P).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Species that live in extreme conditions have specially adapted physiology and tissue/organ organisation. The adaptation of lymphoid organs to low temperatures in polar species could be an original ...field of study, indicating how the immune system works under extreme conditions. In fishes, the head kidney is a key organ for immunity and here the cytology of this organ is studied in two common Antarctic species:
Trematomus bernacchii and
Chionodraco hamatus. Ultrastructural analysis revealed heterogeneity of epithelial cells, with reticular cells, subcapsular- and perivascular-limiting cells. Differences in the size and morphology of epithelial cells were observed between the polar species and warm water species of fish. Intermingled with epithelial cell leucocytes, such as lymphocytes, thrombocytes and macrophages, had comparable morphology in both species, contrary to sharp differences observed in the morphology of erythrocytes and granulocytes. The functional adaptation of the head kidney to the low temperatures of polar water is discussed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Trimethyltin (TMT) intoxication is considered a suitable experimental model to study the molecular basis of selective hippocampal neurodegeneration as that occurring in several neurodegenerative ...diseases. We have previously shown that rat hippocampal neurons expressing the Ca²⁺-binding protein calretinin (CR) are spared by the neurotoxic action of TMT hypothetically owing to their ability to buffer intracellular Ca²⁺ overload. The present study was aimed at determining whether intracellular Ca²⁺ homeostasis dysregulation is involved in the TMT-induced neurodegeneration and if intracellular Ca²⁺-buffering mechanisms may exert a protective action in this experimental model of neurodegeneration. In cultured rat hippocampal neurons, TMT produced time- and concentration-dependent Ca²⁺i increases that were primarily due to Ca²⁺ release from intracellular stores although Ca²⁺ entry through Cav1 channels also contributed to Ca²⁺i increases in the early phase of TMT action. Cell pre-treatment with the Ca²⁺ chelator, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester) (2 μM) significantly reduced the TMT-induced neuronal death. Moreover, CR⁺ neurons responded to TMT with smaller Ca²⁺i increases. Collectively, these data suggest that the neurotoxic action of TMT is mediated by Ca²⁺ homeostasis dysregulation, and the resistance of hippocampal neurons to TMT (including CR⁺ neurons) is not homogeneous among different neuron populations and is related to their ability to buffer intracellular Ca²⁺ overload.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract The specific functional and pathological alterations observed in Alzheimer's disease are less severe in the cerebellum than in other brain areas, particularly the entorhinal cortex and ...hippocampus. Since dense core amyloid-beta plaque formation has been associated with an acetylcholinesterase heterogeneous nucleator action, we examined if an acetylcholinesterase imbalance was involved in cerebellum plaque deposition. By using the canine counterpart of senile dementia of the Alzheimer's type, a promising model of human brain aging and early phases of Alzheimer's disease, we investigated how cerebellar pathology and acetylcholinesterase density could be related with cognitive dysfunction. As in Alzheimer's disease, the late affectation of the cerebellum was evidenced by its lack of amyloid-beta plaque and the presence of diffuse deposition throughout all cortical grey matter layers. The highest acetylcholinesterase optic density corresponded to cerebellar islands of the granular layer and was predominantly associated with synaptic glomeruli and the somata of Golgi cells. Its reduction correlated with aging and loss of granule cells, whereas cognitive deficit only correlated with loss of Purkinje cells. The observed Bergmann glia alterations may correspond to a reactive response to the loss and damage of the Purkinje cells, their specific neuronal partner. Regarding the role of acetylcholinesterase mediation in amyloid-beta deposition, our data argue against an interaction between these two proteins because acetylcholinesterase reduction correlates with aging but not with cognitive deficit. Finally, our data support the use of companion dogs of all breeds to study aging and early phases of Alzheimer's disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Lymphomyeloid organs of two common species of Antarctic fish, Trematomus nicolai and Chionodraco hamatus, were studied with the aim of analysing some morphological aspects of these organs in relation ...to adaptation to low environmental temperature. The thymuses of T. nicolai and C. hamatus were flattened, incompletely lobated, with numerous Hassall-like bodies, which were mainly located in the central part of the organ in C. hamatus. In T. nicolai, thymocytes, erythroid and reticular epithelial cells filled the organ. In C. hamatus, the thymocytes intermingled with reticular epithelial cells were often close to groups of melano-macrophages. In both species, the thymus did not show distinct compartmentalisation; however, the thymocytes had significantly different sizes in the outer and inner portions of the thymus. The head kidney of both species was completely filled by haematopoietic tissue, highly vascularised and mainly lymphopoietic in T. nicolai, while both erythropoietic and lymphopoietic in C. hamatus. The spleen appeared mainly erythropoietic in T. nicolai and mainly lymphopoietic in C. hamatus. Solitary melano-macrophages in T. nicolai were close to numerous small vascular ellipsoids where erythroid and lymphoid cells were intermingled without the formation of red and white pulp areas. In C. hamatus, large lymphoid areas were organised around the capillaries. The possible adaptation of lymphoid organs to the low temperature of polar water is discussed.PUBLICATION ABSTRACT
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Lymphomyeloid organs of three common Antarctic fish species, Trematomus bernacchii, Trematomus nicolai and Chionodraco hamatus, were analysed.
Contrary to species living in temperate sea water, the ...thymus of polar fishes were flattened, incompletely lobated and scarcely distinguishable by normal histology into cortical and medullary regions. Functional regionalisation, however, was suggested by differences in the sizes of thymocytes from the outer to the inner thymus zone. Another particularity was observed in the thymus of Trematomus species: next to lymphocytes, numerous erythroid cells circulated and differentiated in the parenchyma. Only two main types of epithelial cells could be found by cytological analysis: (i) limiting cells that surround the haematopoietic tissue and (ii) reticular cells that constitute the frame where the lymphoid and erythroid cells can proliferate and differentiate. The reticular cells could not be distinguished in cortical and medullary subtypes as observed in temperate-water fish. Numerous Hassall's corpuscles, probably with a scavenging role, were also observed in the thymus.
The head kidney housed haematopoietic tissue, lacked any excretory tubules, and had a huge blood supply, characteristic of polar fish species. It appeared mainly lymphopoietic in C. hamatus but contemporary erythropoietic and lymphopoietic in Trematomus species. The ultrastructural analysis revealed the presence of both reticular and limiting epithelial cells. Reticular epithelial cells (REC) characteristically showed numerous vesicles with a granular content and cell debris. Numerous lymphoblasts, lymphocytes and plasma cells were observed among the REC. Erythropoiesis occurred in all polar species analysed, but in C. hamatus the erythroblasts did not differentiate because they had a fast senescence.
The spleen appeared mainly erythropoietic, with scarcely developed areas of white pulp, in Trematomus species; the erythropoiesis was scarcely evident in C. hamatus. Small vascular ellipsoids showed numerous melano-macrophages in Trematomus, while large haematopoietic areas were organised around the capillaries in C. hamatus. Utrastructural analysis revealed, in all species examined, two main types of epithelial cells: reticular, close to the ellipsoids, and limiting-subcapsular, which surround the organ. A large blood supply and extended capillary frame were also observed in polar species. The possible adaptation of lymphoid organs to the low temperatures of polar water is discussed.
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BFBNIB, DOBA, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Macroautophagy/autophagy occurs at basal levels in all eukaryotic cells and plays an important role in maintaining bio-energetic homeostasis through the control of molecule degradation and organelle ...turnover. It can be induced by environmental conditions such as starvation, and is deregulated in many diseases including autoimmune diseases, neurodegenerative disorders, and cancer. Interestingly, the modulation of autophagy in mesenchymal stem cells (MSCs) represents a possible mechanism which, affecting MSC properties, may have an impact on their regenerative, therapeutic potential. Furthermore, the ability of MSCs to modulate autophagy of cells in injured tissues/organs has been recently proposed to be involved in the regeneration of damaged tissues and organs. In particular, MSCs can affect autophagy in immune cells involved in injury-induced inflammation reducing their survival, proliferation, and function and favoring the resolution of inflammation. In addition, MSCs can affect autophagy in endogenous adult or progenitor cells, promoting their survival, proliferation and differentiation supporting the restoration of functional tissue. This review provides, for the first time, an overview of the studies which highlight a possible link between the therapeutic properties of MSCs and their ability to modulate autophagy, and it summarizes examples of disorders where these therapeutic properties have been correlated with such modulation. A better elucidation of the mechanism(s) through which MSCs can modulate the autophagy of target cells and how autophagy can affect MSCs therapeutic properties, can provide a wider perspective for the clinical application of MSCs in the treatment of many diseases.
Abbreviations: 3-MA: 3-methyladenine; AD: Alzheimer disease; ATG: autophagy-related; BECN1: beclin 1; BM: bone marrow; CD: cluster of differentiation; EAE: experimental autoimmune encephalomyelitis; IL: interleukin; INF: interferon; LAP: LC3-associated phagocytosis; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MSCs: mesenchymal stem cells; MTOR: mechanistic target of rapamycin kinase; PD: Parkinson disease; PtdIns3K: class III phosphatidylinositol 3-kinase; ROS: reactive oxygen species; SLE: systemic lupus erythematosus; SQSTM1: sequestosome 1; TBI: traumatic brain injury; TGF: transforming growth factor; TNF: tumor necrosis factor
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
The fibula free flap represents the gold standard for mandibular reconstruction. However, when harvested as a single barrel, this flap does not allow the native mandibular height to be restored, ...which is required for implant-supported dental rehabilitation of the patient. The aim of this study was to present a new design for a patient-specific three-dimensionally printed reconstructive plate (3DBO-PSI) that positions the fibula bone at the height of the resected mandibular alveolar bone while restoring the mandibular profile to ensure a correct morphological outcome. Twenty patients were enrolled prospectively between January 2019 and May 2022. All patients underwent a segmental mandibular resection and prosthetically guided reconstruction making use of a fibula free flap supported by the 3DBO-PSI. The mean follow-up period was 20 months. All microvascular and implant-related complications were recorded. Microvascular failure occurred in two patients. No PSI-related complications were recorded during the postoperative follow-up. The proposed reconstructive method was found to be reliable and reproducible. In all treated patients, the bony flap appeared to be adequately positioned to maintain the preoperative intermaxillary relationship, as planned. To date, dental rehabilitation has been completed in seven patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Multiple Sclerosis (MS) is a chronic inflammatory disease that affects the brain and spinal cord. Inflammation, demyelination, synaptic alteration, and neuronal loss are hallmarks detectable in MS. ...Experimental autoimmune encephalomyelitis (EAE) is an animal model widely used to study pathogenic aspects of MS. Autophagy is a process that maintains cell homeostasis by removing abnormal organelles and damaged proteins and is involved both in protective and detrimental effects that have been seen in a variety of human diseases, such as cancer, neurodegenerative diseases, inflammation, and metabolic disorders. This study is aimed at investigating the autophagy signaling pathway through the analysis of the main autophagic proteins including Beclin-1, microtubule-associated protein light chain (LC3, autophagosome marker), and p62 also called sequestosome1 (SQSTM1, substrate of autophagy-mediated degradation) in the hippocampus of EAE-affected mice. The expression levels of Beclin-1, LC3, and p62 and the Akt/mTOR pathway were examined by Western blot experiments. In EAE mice, compared to control animals, significant reductions of expression levels were detectable for Beclin-1 and LC3 II (indicating the reduction of autophagosomes), and p62 (suggesting that autophagic flux increased). In parallel, molecular analysis detected the deregulation of the Akt/mTOR signaling. Immunofluorescence double-labeling images showed co-localization of NeuN (neuronal nuclear marker) and Beclin-1, LC3, and p62 throughout the CA1 and CA3 hippocampal subfields. Taken together, these data demonstrate that activation of autophagy occurs in the neurons of the hippocampus in this experimental model.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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