RESUMO
The autophagy process recycles dysfunctional cellular components and protein aggregates by sequestering them in autophagosomes directed to lysosomes for enzymatic degradation. A basal level of autophagy is essential for skeletal muscle maintenance. Increased autophagy occurs in several forms of muscular dystrophy and in the merosin-deficient congenital muscular dystrophy 1A mouse model (dy3k/dy3k) lacking the laminin-α2 chain. This pilot study aimed to compare autophagy marker expression and autophagosomes presence using light and electron microscopes and western blotting in diagnostic muscle biopsies from newborns affected by different congenital muscular myopathies and dystrophies. Morphological examination showed dystrophic muscle features, predominance of type 2A myofibers, accumulation of autophagosomes in the subsarcolemmal areas, increased number of autophagosomes overexpressing LC3b, Beclin-1 and ATG5, in the merosin-deficient newborn suggesting an increased autophagy. In Duchenne muscular dystrophy, nemaline myopathy, and spinal muscular atrophy the predominant accumulation of p62+ puncta rather suggests an autophagy impairment.
RESUMO
Several studies have provided interesting evidence about the role of the bidirectional communication between the gut and brain in the onset and development of several pathologic conditions, including inflammatory bowel diseases (IBDs), neurodegenerative diseases, and related comorbidities. Indeed, patients with IBD can experience neurologic disorders, including depression and cognitive impairment, besides typical intestinal symptoms. In parallel, patients with neurodegenerative disease, such as Parkinson disease and Alzheimer disease, are often characterized by the occurrence of functional gastrointestinal disorders. In this context, enteric glial cells and brain astrocytes are emerging as pivotal players in the initiation/maintenance of neuroinflammatory responses, which appear to contribute to the alterations of intestinal and neurologic functions observed in patients with IBD and neurodegenerative disorders. The present review was conceived to provide a comprehensive and critical overview of the available knowledge on the morphologic, molecular, and functional changes occurring in the enteric glia and brain astroglia in IBDs and neurologic disorders. In addition, our intent is to identify whether such alterations could represent a common denominator involved in the onset of comorbidities associated with the aforementioned disorders. This might help to identify putative targets useful to develop novel pharmacologic approaches for the therapeutic management of such disturbances.
RESUMO
Glioblastomas are among the deadliest human cancers and are highly vascularized. Angiogenesis is dynamic during brain development, almost quiescent in the adult brain but reactivated in vascular-dependent CNS pathologies, including brain tumors. The oncofetal axis describes the reactivation of fetal programs in tumors, but its relevance in endothelial and perivascular cells of the human brain vasculature in glial brain tumors is unexplored. Nucleolin is a regulator of cell proliferation and angiogenesis, but its roles in the brain vasculature remain unknown. Here, we studied the expression of Nucleolin in the neurovascular unit in human fetal brains, adult brains, and human gliomas in vivo as well as its effects on sprouting angiogenesis and endothelial metabolism in vitro. Nucleolin is highly expressed in endothelial and perivascular cells during brain development, downregulated in the adult brain, and upregulated in glioma. Moreover, Nucleolin expression correlated with glioma malignancy in vivo. In culture, siRNA-mediated Nucleolin knockdown reduced human brain endothelial cell (HCMEC) and HUVEC sprouting angiogenesis, proliferation, filopodia extension, and glucose metabolism. Furthermore, inhibition of Nucleolin with the aptamer AS1411 decreased brain endothelial cell proliferation in vitro. Mechanistically, Nucleolin knockdown in HCMECs and HUVECs uncovered regulation of angiogenesis involving VEGFR2 and of endothelial glycolysis. These findings identify Nucleolin as a neurodevelopmental factor reactivated in glioma that promotes sprouting angiogenesis and endothelial metabolism, characterizing Nucleolin as an oncofetal protein. Our findings have potential implications in the therapeutic targeting of glioma.
Assuntos
Neoplasias Encefálicas , Glioma , Adulto , Humanos , Glioma/metabolismo , Fosfoproteínas/metabolismo , Encéfalo/metabolismo , Neoplasias Encefálicas/patologia , NucleolinaRESUMO
Dermatomyositis (DM) and immune-mediated necrotizing myopathy (IMNM) are two rare diseases belonging to the group of idiopathic inflammatory myopathies (IIM). Muscle involvement in DM is characterized by perifascicular atrophy and poor myofiber necrosis, while IMNM is characterized by myofiber necrosis with scarce inflammatory infiltrates. Muscle biopsies and laboratory tests are helpful in diagnosis, but currently, few biomarkers of disease activity and progression are available. In this context, we conducted a cohort study of forty-one DM and IMNM patients, aged 40-70 years. In comparison with control subjects, in the muscle biopsies of these patients, there was a lower expression of FNDC5, the precursor of irisin, a myokine playing a key role in musculoskeletal metabolism. Expectedly, the muscle cross-sectional areas of these patients were reduced, while, surprisingly, serum irisin levels were higher than in CTRL, as were mRNA levels of ADAM10, a metalloproteinase recently shown to be the cleavage agent for FNDC5. We hypothesize that elevated expression of ADAM10 in the skeletal muscle of DM and IMNM patients might be responsible for the discrepancy between irisin levels and FNDC5 expression. Future studies will be needed to understand the mechanisms underlying exacerbated FNDC5 cleavage and muscle irisin resistance in these inflammatory myopathies.
Assuntos
Doenças Autoimunes , Miosite , Humanos , Fibronectinas/metabolismo , Estudos de Coortes , Músculo Esquelético/metabolismo , Miosite/metabolismo , Fatores de Transcrição/metabolismo , Doenças Autoimunes/metabolismo , Necrose/metabolismo , Proteína ADAM10/genética , Proteína ADAM10/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismoRESUMO
Vascular co-option is a non-angiogenic mechanism whereby tumor growth and progression move on by hijacking the pre-existing and nonmalignant blood vessels and is employed by various tumors to grow and metastasize.The histopathological identification of co-opted blood vessels is complex, and no specific markers were defined, but it is critical to develop new and possibly more effective therapeutic strategies. Here, in glioblastoma, we show that the co-opted blood vessels can be identified, by double immunohistochemical staining, as weak CD31+ vessels with reduced P-gp expression and proliferation and surrounded by highly proliferating and P-gp- or S100A10-expressing tumor cells. Results can be quantified by the Aperio Colocalization algorithm, which is a valid and robust method to handle and investigate large data sets.
Assuntos
Glioblastoma , Neovascularização Patológica , Formaldeído , Humanos , Neovascularização Patológica/patologia , Inclusão em Parafina , Coloração e RotulagemRESUMO
BACKGROUND: Vascular co-option is one of the main features of brain tumor progression. It is identified using histopathological analysis, but no antibody-specific markers were found, and no universally accepted histological features were defined. METHODS: We employed double immunohistochemical stainings for CD31, P-gp, S100A10, and mitochondria on formalin-fixed, paraffin-embedded human samples of IDH-WT glioblastoma, IDH-mutant astrocytoma, and meningioma to study vascular co-option across different brain tumors and across normal, peritumoral, and intratumoral areas using the Aperio colocalization algorithm, which is a valid and robust method to handle and investigate large data sets. RESULTS: The results have shown that (i) co-opted vessels could be recognized by the presence of metabolically overactive (evaluated as mitochondria expression) and P-gp+ or S100A10+ tumor cells surrounding CD31+ endothelial cells; (ii) vascular co-option occurs in the intratumoral area of meningioma and astrocytoma; and (iii) vascular co-option is prevalent in peritumoral glioblastoma area. CONCLUSIONS: The described approach identifies new markers for cellular components of the vessel wall and techniques that uncover the order and localization of vascularization mechanisms, which may contribute to developing new and possibly more effective therapeutic strategies.
RESUMO
BACKGROUND: In myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), several areas of demyelination are detectable in mouse cerebral cortex, where neuroinflammation events are associated with scarce inflammatory infiltrates and blood-brain barrier (BBB) impairment. In this condition, the administration of mesenchymal stem cells (MSCs) controls neuroinflammation, attenuating astrogliosis and promoting the acquisition of stem cell traits by astrocytes. To contribute to the understanding of the mechanisms involved in the pathogenesis of EAE in gray matter and in the reverting effects of MSC treatment, the neocortex of EAE-affected mice was investigated by analyzing the cellular source(s) of chemokine CCL2, a molecule involved in immune cell recruitment and BBB-microvessel leakage. METHODS: The study was carried out by immunohistochemistry (IHC) and dual RNAscope IHC/in situ hybridization methods, using astrocyte, NG2-glia, macrophage/microglia, and microglia elective markers combined with CCL2. RESULTS: The results showed that in EAE-affected mice, hypertrophic microglia are the primary source of CCL2, surround the cortex neurons and the damaged BBB microvessels. In EAE-affected mice treated with MSCs, microgliosis appeared diminished very soon (6 h) after treatment, an observation that was long-lasting (tested after 10 days). This was associated with a reduced CCL2 expression and with apparently preserved/restored BBB features. In conclusion, the hallmark of EAE in the mouse neocortex is a condition of microgliosis characterized by high levels of CCL2 expression. CONCLUSIONS: This finding supports relevant pathogenetic and clinical aspects of the human disease, while the demonstrated early control of neuroinflammation and BBB permeability exerted by treatment with MSCs may have important therapeutic implications.
Assuntos
Quimiocina CCL2 , Encefalomielite Autoimune Experimental , Neocórtex , Animais , Quimiocina CCL2/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Microglia , Doenças NeuroinflamatóriasRESUMO
Successful neuroprotection is only possible with contemporary microvascular protection. The prevention of disease-induced vascular modifications that accelerate brain damage remains largely elusive. An improved understanding of pericyte (PC) signalling could provide important insight into the function of the neurovascular unit (NVU), and into the injury-provoked responses that modify cell-cell interactions and crosstalk. Due to sharing the same basement membrane with endothelial cells, PCs have a crucial role in the control of endothelial, astrocyte, and oligodendrocyte precursor functions and hence blood-brain barrier stability. Both cerebrovascular and neurodegenerative diseases impair oxygen delivery and functionally impair the NVU. In this review, the role of PCs in central nervous system health and disease is discussed, considering their origin, multipotency, functions and also dysfunction, focusing on new possible avenues to modulate neuroprotection. Dysfunctional PC signalling could also be considered as a potential biomarker of NVU pathology, allowing us to individualize therapeutic interventions, monitor responses, or predict outcomes.
Assuntos
Células Endoteliais , Pericitos , Astrócitos , Barreira Hematoencefálica/patologia , Comunicação Celular , Células Endoteliais/fisiologia , Pericitos/patologiaRESUMO
OBJECTIVES: To study the phenotype of macrophage infiltrates and their role in angiogenesis in different idiopathic inflammatory myopathies (IIMs). METHODS: The density and distribution of the subpopulations of macrophages subsets (M1, inducible nitric oxide+, CD11c+; M2, arginase-1+), endomysial capillaries (CD31+, FLK1+), degenerating (C5b-9+) and regenerating (NCAM+) myofibres were investigated by immunohistochemistry in human muscle samples of diagnostic biopsies from a large cohort of untreated patients (n: 81) suffering from anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (anti-HMGCR)+ immune mediated necrotizing myopathy (IMNM), anti-signal recognition particle (anti-SRP)+ IMNM, seronegative IMNM, DM, PM, PM with mitochondrial pathology, sporadic IBM, scleromyositis, and anti-synthetase syndrome. The samples were compared with mitochondrial myopathy and control muscle samples. RESULTS: Compared with the other IIMs and controls, endomysial capillary density (CD) was higher in anti-HMGCR+ IMNM, where M1 and M2 macrophages, detected by confocal microscopy, infiltrated perivascular endomysium and expressed angiogenic molecules such as VEGF-A and CXCL12. These angiogenic macrophages were preferentially associated with CD31+ FLK1+ microvessels in anti-HMGCR+ IMNM. The VEGF-A+ M2 macrophage density was significantly correlated with CD (rS: 0.98; P: 0.0004). Western blot analyses revealed increased expression levels of VEGF-A, FLK1, HIF-1α and CXCL12 in anti-HMGCR+ IMNM. CD and expression levels of these angiogenic molecules were not increased in anti-SRP+ and seronegative IMNM, offering additional, useful information for differential diagnosis among these IIM subtypes. CONCLUSION: Our findings suggest that in IIMs, infiltrating macrophages and microvascular cells interactions play a pivotal role in coordinating myogenesis and angiogenesis. This reciprocal crosstalk seems to distinguish anti-HMGCR associated IMNM.
Assuntos
Doenças Autoimunes , Miosite , Anticorpos , Autoanticorpos , Quimiocina CXCL12 , Humanos , Hidroximetilglutaril-CoA Redutases , Macrófagos/patologia , Músculo Esquelético/patologia , Necrose , Partícula de Reconhecimento de Sinal , Fator A de Crescimento do Endotélio VascularRESUMO
Mounting evidence has linked the metabolic disease to neurovascular disorders and cognitive decline. Using a murine model of a high-fat high-sugar diet mimicking obesity-induced type 2 diabetes mellitus (T2DM) in humans, we show that pro-inflammatory mediators and altered immune responses damage the blood-brain barrier (BBB) structure, triggering a proinflammatory metabolic phenotype. We find that disruption to tight junctions and basal lamina due to loss of control in the production of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) causes BBB impairment. Together the disruption to the structural and functional integrity of the BBB results in enhanced transmigration of leukocytes across the BBB that could contribute to an initiation of a neuroinflammatory response through activation of microglia. Using a humanized in vitro model of the BBB and T2DM patient post-mortem brains, we show the translatable applicability of our results. We find a leaky BBB phenotype in T2DM patients can be attributed to a loss of junctional proteins through changes in inflammatory mediators and MMP/TIMP levels, resulting in increased leukocyte extravasation into the brain parenchyma. We further investigated therapeutic avenues to reduce and restore the BBB damage caused by HFHS-feeding. Pharmacological treatment with recombinant annexin A1 (hrANXA1) or reversion from a high-fat high-sugar diet to a control chow diet (dietary intervention), attenuated T2DM development, reduced inflammation, and restored BBB integrity in the animals. Given the rising incidence of diabetes worldwide, understanding metabolic-disease-associated brain microvessel damage is vital and the proposed therapeutic avenues could help alleviate the burden of these diseases.
Assuntos
Barreira Hematoencefálica/imunologia , Colagenases/imunologia , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 2/imunologia , Inibidores Teciduais de Metaloproteinases/imunologia , Animais , Anexina A1/farmacologia , Barreira Hematoencefálica/patologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/patologia , Humanos , Masculino , Camundongos , Proteínas Recombinantes/farmacologiaRESUMO
To date, pharmacological strategies designed to accelerate bone fracture healing are lacking. We subjected 8-week-old C57BL/6 male mice to closed, transverse, mid-diaphyseal tibial fractures and treated them with intraperitoneal injection of a vehicle or r-irisin (100 µg/kg/weekly) immediately following fracture for 10 days or 28 days. Histological analysis of the cartilaginous callus at 10 days showed a threefold increase in Collagen Type X (p = 0.0012) and a reduced content of proteoglycans (40%; p = 0.0018). Osteoclast count within the callus showed a 2.4-fold increase compared with untreated mice (p = 0.026), indicating a more advanced stage of endochondral ossification of the callus during the early stage of fracture repair. Further evidence that irisin induced the transition of cartilage callus into bony callus was provided by a twofold reduction in the expression of SOX9 (p = 0.0058) and a 2.2-fold increase in RUNX2 (p = 0.0137). Twenty-eight days post-fracture, microCT analyses showed that total callus volume and bone volume were increased by 68% (p = 0.0003) and 67% (p = 0.0093), respectively, and bone mineral content was 74% higher (p = 0.0012) in irisin-treated mice than in controls. Our findings suggest that irisin promotes bone formation in the bony callus and accelerates the fracture repair process, suggesting a possible use as a novel pharmacologic modulator of fracture healing.
Assuntos
Cartilagem/citologia , Fibronectinas/administração & dosagem , Consolidação da Fratura , Fraturas Ósseas/terapia , Osteoclastos/citologia , Osteogênese , Proteínas Recombinantes/administração & dosagem , Animais , Cartilagem/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Osteoclastos/metabolismoRESUMO
Central nervous system diseases involving the parenchymal microvessels are frequently associated with a 'microvasculopathy', which includes different levels of neurovascular unit (NVU) dysfunction, including blood-brain barrier alterations. To contribute to the understanding of NVU responses to pathological noxae, we have focused on one of its cellular components, the microvascular pericytes, highlighting unique features of brain pericytes with the aid of the analyses carried out during vascularization of human developing neocortex and in human gliomas. Thanks to their position, centred within the endothelial/glial partition of the vessel basal lamina and therefore inserted between endothelial cells and the perivascular and vessel-associated components (astrocytes, oligodendrocyte precursor cells (OPCs)/NG2-glia, microglia, macrophages, nerve terminals), pericytes fulfil a central role within the microvessel NVU. Indeed, at this critical site, pericytes have a number of direct and extracellular matrix molecule- and soluble factor-mediated functions, displaying marked phenotypical and functional heterogeneity and carrying out multitasking services. This pericytes heterogeneity is primarily linked to their position in specific tissue and organ microenvironments and, most importantly, to their ontogeny. During ontogenesis, pericyte subtypes belong to two main embryonic germ layers, mesoderm and (neuro)ectoderm, and are therefore expected to be found in organs ontogenetically different, nonetheless, pericytes of different origin may converge and colonize neighbouring areas of the same organ/apparatus. Here, we provide a brief overview of the unusual roles played by forebrain pericytes in the processes of angiogenesis and barriergenesis by virtue of their origin from midbrain neural crest stem cells. A better knowledge of the ontogenetic subpopulations may support the understanding of specific interactions and mechanisms involved in pericyte function/dysfunction, including normal and pathological angiogenesis, thereby offering an alternative perspective on cell subtype-specific therapeutic approaches.
Assuntos
Glioma/fisiopatologia , Neocórtex/irrigação sanguínea , Neocórtex/crescimento & desenvolvimento , Neovascularização Patológica/fisiopatologia , Neovascularização Fisiológica/fisiologia , Crista Neural/citologia , Pericitos/fisiologia , HumanosRESUMO
The myokine Irisin, produced during physical exercise, has an anabolic effect on bone, both in vitro and in vivo. Very recently, using a controlled in vitro 3D cell model to mimic the bone microenvironment aboard the International Space Station, it has been shown that Irisin treatment in microgravity prevents the down-regulation of the transcription factors Atf4, Runx2 and Osterix, as well as Collagen I and Osteoprotegerin proteins, crucial for osteoblast differentiation in physiologic conditions. Irisin action has also been investigated in human subjects, in which it correlates with bone health status, supporting its physiological importance also in human bone, both in healthy subjects and in patients suffering from diseases related to bone metabolism, such as hyperparathyroidism and type 1 diabetes. Low levels of circulating Irisin have been found in post-menopausal women affected by hyperparathyroidism. Furthermore, Irisin is positively correlated with bone strength in athletes and bone mineral density in football players. Moreover, in healthy children, Irisin is positively associated with bone mineral status and in children with type 1 diabetes, Irisin is positively correlated with improved glycemic control and skeletal health. In this review, we will focus on recent findings about Irisin action on microgravity induced bone loss and on osteocyte activity and survival through its αV/ß5 integrin receptor.
Assuntos
Osso e Ossos/efeitos dos fármacos , Fibronectinas/farmacologia , Animais , Densidade Óssea/efeitos dos fármacos , Doenças Ósseas Metabólicas/etiologia , Doenças Ósseas Metabólicas/metabolismo , Doenças Ósseas Metabólicas/patologia , Osso e Ossos/citologia , Diferenciação Celular/efeitos dos fármacos , Criança , Feminino , Fibronectinas/metabolismo , Fibronectinas/fisiologia , Humanos , Pessoa de Meia-Idade , Osteócitos/citologia , Osteócitos/efeitos dos fármacos , Osteócitos/fisiologiaRESUMO
Irisin is a myokine produced by skeletal muscle during exercise in both mice and humans. We previously showed that irisin treatment ameliorates immobility-induced osteoporosis and muscular atrophy in mice. Data in humans showed a positive association between irisin and bone mineral density (BMD) in athletes and a population of healthy children. However, the role of this myokine regarding the state of muscle and bone in the same population remained to be determined. For this purpose, 62 patients (age 68.71 ± 12.31 years) undergoing total hip or knee replacement were recruited. Our results showed that irisin serum levels negatively correlated with age (R = -0.515; p = .000018) and positively correlated with femoral BMD (R = 0.619; p = .001) and vertebral BMD (R = 0.201; p = .0001). Irisin was also positively associated with Fndc5 mRNA in muscle biopsies (R = 0.248; p = .016), as well as with Osteocalcin (Ocn) mRNA in bone biopsies (R = 0.708; p = .006). In skeletal muscle, FNDC5 positive fibers positively correlate with BMD of total femur (R = 0.765; p = .0014) and BMD of femoral neck (R = 0.575; p = .031), Interestingly, by analyzing patients divided by their T-score, we found lower irisin levels (p = .0011) in patients with osteopenia/osteoporosis (OP) compared to healthy controls matched for age and sex. By analyzing the senescence marker p21, we found a significant increase of its mRNA expression in the bone biopsies of OP patients compared to control ones. Therefore, we investigated in vitro whether rec-irisin had a direct effect on this senescence marker, showing that p21 mRNA expression was significantly downregulated in osteoblasts by the treatment with irisin. Overall, these results indicate that higher irisin levels are associated with a lower rate of age-related osteoporosis and that irisin could be effective in delaying the osteoblast aging process, suggesting a potential senolytic action of this myokine. © 2020 American Society for Bone and Mineral Research (ASBMR).
Assuntos
Densidade Óssea , Fibronectinas , Idoso , Animais , Inibidor de Quinase Dependente de Ciclina p21 , Colo do Fêmur , Fibronectinas/genética , Humanos , Camundongos , Atrofia Muscular , OsteoblastosRESUMO
Pericytes are integral part of neurovascular unit and play a role in the maintenance of blood-brain barrier integrity, angiogenesis, and cerebral blood flow regulation. Despite their important functional roles, a univocal phenotypic identification is still emerging also for the lack of a "pan-pericyte" marker. In the present study, we describe in detail the method for performing fluorescence immunohistochemistry on thick free-floating sections from human fetal brain in high resolution laser confocal microscopy. This method enables to obtain three-dimensional images of pericytes and provides insights about their distribution and localization in the microvessels of human developing brain.
Assuntos
Encéfalo/irrigação sanguínea , Microscopia Confocal/métodos , Microvasos/citologia , Pericitos/citologia , Barreira Hematoencefálica/citologia , Circulação Cerebrovascular/fisiologia , Humanos , Imageamento Tridimensional/métodos , Imuno-Histoquímica/métodos , Neovascularização Fisiológica/fisiologiaRESUMO
Transplanted mesenchymal stromal/stem cells (MSC) ameliorate the clinical course of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS), reducing inflammation and demyelination. These effects are mediated by instructive cross-talk between MSC and immune and neural cells. Astroglial reaction to injury is a prominent feature of both EAE and MS. Astrocytes constitute a relevant target to control disease onset and progression and, based on their potential to acquire stem cell properties in situ, to foster recovery in the post-acute phase of pathology. We have assessed how MSC impact astrocytes in vitro and ex vivo in EAE. Expression of astroglial factors implicated in EAE pathogenesis was quantified by real-time PCR in astrocytes co-cultured with MSC or isolated from EAE cerebral cortex; astrocyte morphology and expression of activation markers were analyzed by confocal microscopy. The acquisition of neural stem cell properties by astrocytes was evaluated by neurosphere assay. Our study shows that MSC prevented astrogliosis, reduced mRNA expression of inflammatory cytokines that sustain immune cell infiltration in EAE, as well as protein expression of endothelin-1, an astrocyte-derived factor that inhibits remyelination and contributes to neurodegeneration and disease progression in MS. Moreover, our data reveal that MSC promoted the acquisition of progenitor traits by astrocytes. These data indicate that MSC attenuate detrimental features of reactive astroglia and, based on the reacquisition of stem cell properties, also suggest that astrocytes may be empowered in their protective and reparative actions by MSC.
Assuntos
Encefalomielite Autoimune Experimental , Células-Tronco Mesenquimais , Esclerose Múltipla , Animais , Astrócitos , Camundongos , Camundongos Endogâmicos C57BL , FenótipoRESUMO
Vanadium, a transition series metal released during some industrial activities, induces oxidative stress and lipid peroxidation. Ameliorative effect of a pure compound from the methanolic extract of Moringa oleifera leaves, code-named MIMO2, in 14-day old mice administered with vanadium (as sodium metavanadate 3 mg/kg) for 2 weeks was assessed. Results from body weight monitoring, muscular strength, and open field showed slight reduction in body weight and locomotion deficit in vanadium-exposed mice, ameliorated with MIMO2 co-administration. Degeneration of the Purkinje cell layer and neuronal death in the hippocampal CA1 region were observed in vanadium-exposed mice and both appeared significantly reduced with MIMO2 co-administration. Demyelination involving the midline of the corpus callosum, somatosensory and retrosplenial cortices was also reduced with MIMO2. Microglia activation and astrogliosis observed through immunohistochemistry were also alleviated. Immunohistochemistry for myelin, axons and oligodendrocyte lineage cells were also carried out and showed that in vanadium-treated mice brains, oligodendrocyte progenitor cells increased NG2 immunolabelling with hypertrophy and bushy, ramified appearance of their processes. MIMO2 displayed ameliorative and antioxidative effects in vanadium-induced neurotoxicity in experimental murine species. This is likely the first time MIMO2 is being used in vivo in an animal model.
RESUMO
P-Glycoprotein (P-gp) is a 170-kDa transmembrane glycoprotein that works as an efflux pump and confers multidrug resistance (MDR) in normal tissues and tumors, including nervous tissues and brain tumors. In the developing telencephalon, the endothelial expression of P-gp, and the subcellular localization of the transporter at the luminal endothelial cell (EC) plasma membrane are early hallmarks of blood-brain barrier (BBB) differentiation and suggest a functional BBB activity that may complement the placental barrier function and the expression of P-gp at the blood-placental interface. In early fetal ages, P-gp has also been immunolocalized on radial glia cells (RGCs), located in the proliferative ventricular zone (VZ) of the dorsal telencephalon and now considered to be neural progenitor cells (NPCs). RG-like NPCs have been found in many regions of the developing brain and have been suggested to give rise to neural stem cells (NSCs) of adult subventricular (SVZ) neurogenic niches. The P-gp immunosignal, associated with RG-like NPCs during cortical histogenesis, progressively decreases in parallel with the last waves of neuroblast migrations, while 'outer' RGCs and the deriving astrocytes do not stain for the efflux transporter. These data suggest that in human glioblastoma (GBM), P-gp expressed by ECs may be a negligible component of tumor MDR. Instead, tumor perivascular astrocytes may dedifferentiate and resume a progenitor-like P-gp activity, becoming MDR cells and contribute, together with perivascular P-gpexpressing glioma stem-like cells (GSCs), to the MDR profile of GBM vessels. In conclusion, the analysis of Pgp immunolocalization during brain development may contribute to identify the multiple cellular sources in the GBM vessels that may be involved in P-gp-mediated chemoresistance and can be responsible for GBM therapy failure and tumor recurrence.
Assuntos
Glioblastoma , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Adulto , Barreira Hematoencefálica , Encéfalo/fisiologia , Feminino , Glioblastoma/tratamento farmacológico , Humanos , Recidiva Local de Neoplasia , GravidezRESUMO
Aims: Systemic Lupus Erythematosus (SLE) is a connective tissue disease characterized by a wide range of pleomorphic pictures, including mucocutaneous, renal, musculoskeletal and neurological symptoms. It involves oral tissues, with hyposalivation, tooth decay, gingivitis, angular cheilitis, ulcers and glossitis. Temporomandibular disorders represent a heterogeneous group of inflammatory or degenerative diseases of the stomatognatic system, with algic and/or dysfunctional clinical features involving temporomandibular joint (TMJ) and related masticatory muscles. The aim of this study was to investigate the prevalence of oral manifestations and temporomandibular disorders (TMD) in SLE patients (Lp) compared with a control group. Methods: Fifty-five patients (9 men and 46 women) with diagnosed Lupus were recruited in the study group. A randomly selected group of 55 patients, matched by sex and age, served as control group. The examination for TMD symptoms and signs was based on the standardized Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) through a questionnaire and clinical examination. Results: Lupus patients complained more frequently (95.8%) of oral and TMJ symptoms (dysgeusia, stomatodynia, masticatory muscle pain during function, neck and shoulder muscles pain and presence of tinnitus) but only xerostomia (χ2=4,1548 p=0,0415), temple headache (χ2=4,4542 p=0,035) and the sensation of a stuck jaw (Mid-p-test p=0,043) were significant. About signs, cheilitis (p=0,0284) oral ulcers (χ2=4,0104 p=0,045) and fissured tongue are significantly more frequent in study group. The salivary flow was significantly decreased in the study group respect to the control one (p<0.0001). As regard to the oral kinematics, restricted movements (RM) in protrusion and left lateral movement were significantly different between study group and controls. In particular, 85,2% of Lp showed limited protrusion versus 56,4% of controls (χ2= 10,91 p<0,001); 59,3% of Lp had also a limitation during left lateral movement versus 47,3% of controls (T=2,225 p=0,0282). About bruxism, only the indentations on the lateral edges of the tongue were found in Lp group (72,7%), with a significant difference respect to controls (χ2=7,37 p=0,007). Conclusions: While masticatory muscles have an overlapping behavior in both groups, the findings collected show a more severe TMJ kinematic impairment in Lp than in controls, with protrusion and left lateral movements significantly different. In addition, a remarkable reduction of salivary flow has been detected in Lp compared to controls. In conclusion, this autoimmune disease seems to play a role in oral manifestations and TMJ disorders, causing an increase in orofacial pain and an altered chewing function.