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Early diagnosis and pharmacological treatment of central nervous system (CNS) diseases has been a long-standing challenge for clinical research due to the presence of the blood-brain barrier. Specific proteins and RNAs in brain-derived extracellular vesicles (EVs) usually reflect the corresponding state of brain disease, and therefore, EVs can be used as diagnostic biomarkers for CNS diseases. In addition, EVs can be engineered and fused to target cells for delivery of cargo, demonstrating the great potential of EVs as a nanocarrier platform. We review the progress of EVs as markers and drug carriers in the diagnosis and treatment of neurological diseases. The main areas include visual imaging, biomarker diagnosis and drug loading therapy for different types of CNS diseases. It is hoped that increased knowledge of EVs will facilitate their clinical translation in CNS diseases.
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Doenças do Sistema Nervoso Central , Vesículas Extracelulares , Humanos , Encéfalo , Vesículas Extracelulares/metabolismo , Barreira Hematoencefálica , Biomarcadores/metabolismo , Doenças do Sistema Nervoso Central/diagnóstico , Doenças do Sistema Nervoso Central/terapia , Doenças do Sistema Nervoso Central/metabolismoRESUMO
The neuronal differentiation of mesenchymal stem cells offers a new strategy for the treatment of neurological disorders. Thus, there is a need to identify a noninvasive and sensitive in vivo imaging approach for real-time monitoring of transplanted stem cells. Our previous study confirmed that magnetic resonance imaging, with a focus on the ferritin heavy chain 1 reporter gene, could track the proliferation and differentiation of bone marrow mesenchymal stem cells that had been transduced with lentivirus carrying the ferritin heavy chain 1 reporter gene. However, we could not determine whether or when bone marrow mesenchymal stem cells had undergone neuronal differentiation based on changes in the magnetic resonance imaging signal. To solve this problem, we identified a neuron-specific enolase that can be differentially expressed before and after neuronal differentiation in stem cells. In this study, we successfully constructed a lentivirus carrying the neuron-specific enolase promoter and expressing the ferritin heavy chain 1 reporter gene; we used this lentivirus to transduce bone marrow mesenchymal stem cells. Cellular and animal studies showed that the neuron-specific enolase promoter effectively drove the expression of ferritin heavy chain 1 after neuronal differentiation of bone marrow mesenchymal stem cells; this led to intracellular accumulation of iron and corresponding changes in the magnetic resonance imaging signal. In summary, we established an innovative magnetic resonance imaging approach focused on the induction of reporter gene expression by a neuron-specific promoter. This imaging method can be used to noninvasively and sensitively detect neuronal differentiation in stem cells, which may be useful in stem cell-based therapies.
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To combine both electride and alkalide characteristics in one molecular switch, it is shown herein that the phenalenyl radical and the M3 ring (M3-PHY, M = Li, Na, and K) stacked with parallel and vertical geometries are good candidates. The former geometry is the superalkali electride e-â¯M3+-PHY while the latter geometry is the superalkalide Mδ--M2(1-δ)+-PHY-. The superalkalide Mδ--M2(1-δ)+-PHY- may isomerize to the superalkali electride e-â¯M3+-PHY (M = Li, Na, and K) using suitable long-wavelength irradiation, while the latter may isomerize to the former with suitable short-wavelength irradiation. Also, applying suitable oriented external electric fields can drive the superalkalide Mδ-M2(1-δ)+-PHY- to change into the superalkali electride e-â¯M3+-PHY (M = Li, Na, and K). The differences in the static and dynamic first hyperpolarizability (ß0) values between them were also studied.
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BACKGROUND: Primitive neuroectodermal tumors (PNETs) are rare, sporadic malignant tumors of the peripheral nervous system, bone, or soft tissues. However, to the best of our knowledge, only three cases of PNET in the pericardium have been reported in the English literature, and their magnetic resonance imaging findings have not previously been described. CASE SUMMARY: A 3-year-old boy was hospitalized with a 1-wk history of recurrent vomiting and weakness. Detailed history-taking revealed no evidence of heart disease. Computed tomography demonstrated a soft tissue mass in the left pericardial cavity with heterogeneous contrast enhancement. The border between the mass and the heart was poorly defined. Thoracotomy revealed a mass invading the left ventricle, with a high risk of bleeding. The mass was considered inoperable. A biopsy was performed, and the histological and immunohistochemical findings confirmed the diagnosis of primary PNET of the pericardium. The patient received four cycles of standard chemotherapy. Chest magnetic resonance imaging 3 mo after the initiation of chemotherapy revealed that the tumor in the pericardium still existed, but its volume had slightly decreased. The patient was lost to follow-up, and the final outcome was therefore unknown. CONCLUSION: Medical imaging plays an important role in defining the pericardial origin of PNET and understanding its characteristics. Magnetic resonance imaging can provide more information on the tumor than computed tomography and may thus aid therapeutic planning.
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Chronic infantile neurological, cutaneous and articular (CINCA) syndrome is a rare autoinflammatory disease caused by monogenic defects in the NLRP3 gene. Pro-inflammatory cytokines such as interleukin (IL)-1ß play a crucial role in the pathogenesis, and IL-1 receptor antagonists have been regarded as the mainstay therapy. Endogenous tumor necrosis factor (TNF)-α was found recently to be involved in the onset of the disease. Here, we report two Chinese children with CINCA syndrome who had elevated serum levels of TNF-α, with one carrying a novel mutation of c.1330T/G (p.444Phe/Val) in exon 3 of the NLRP3 gene. Anti-TNF-α (etanercept) therapy successfully alleviated both clinical symptoms and systemic inflammation after 6 months. These results suggest the complexity of the mechanisms of the disease and that TNF-α blockade will broaden the therapeutic approach for a subset of patients.
Assuntos
Síndromes Periódicas Associadas à Criopirina , Fator de Necrose Tumoral alfa , Criança , Síndromes Periódicas Associadas à Criopirina/diagnóstico , Síndromes Periódicas Associadas à Criopirina/tratamento farmacológico , Síndromes Periódicas Associadas à Criopirina/genética , Citocinas , Humanos , Inflamação , PeleRESUMO
Surgical resection remains the preferred approach for some patients with glioblastoma (GBM), and eradication of the residual tumour niche after surgical resection is very helpful for prolonging patient survival. However, complete surgical resection of invasive GBM is difficult because of its ambiguous boundary. Herein, a novel targeting material, c(RGDyk)-poloxamer-188, was synthesized by modifying carboxyl-terminated poloxamer-188 with a glioma-targeting cyclopeptide, c(RGDyk). Quantum dots (QDs) as fluorescent probe were encapsulated into the self-assembled c(RGDyk)-poloxamer-188 polymer nanoparticles (NPs) to construct glioma-targeted QDs-c(RGDyk)NP for imaging-guided surgical resection of GBM. QDs-c(RGDyk)NP exhibited a moderate hydrodynamic diameter of 212.4 nm, a negative zeta potential of -10.1 mV and good stability. QDs-c(RGDyk)NP exhibited significantly lower toxicity against PC12 and C6 cells and HUVECs than free QDs. Moreover, in vitro cellular uptake experiments demonstrated that QDs-c(RGDyk)NP specifically targeted C6 cells, making them display strong fluorescence. Combined with ultrasound-targeted microbubble destruction (UTMD), QDs-c(RGDyk)NP specifically accumulated in glioma tissue in orthotropic tumour rats after intravenous administration, evidenced by ex vivo NIR fluorescence imaging of bulk brain and glioma tissue sections. Furthermore, fluorescence imaging with QDs-c(RGDyk)NP guided accurate surgical resection of glioma. Finally, the safety of QDs-c(RGDyk)NP was verified using pathological HE staining. In conclusion, QDs-c(RGDyk)NP may be a potential imaging probe for imaging-guided surgery.
Assuntos
Glioma/cirurgia , Nanopartículas/química , Peptídeos Cíclicos/química , Pontos Quânticos/administração & dosagem , Cirurgia Assistida por Computador/instrumentação , Administração Intravenosa , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Corantes Fluorescentes/administração & dosagem , Corantes Fluorescentes/química , Corantes Fluorescentes/uso terapêutico , Glioma/diagnóstico por imagem , Glioma/patologia , Humanos , Microbolhas/uso terapêutico , Nanopartículas/administração & dosagem , Peptídeos Cíclicos/administração & dosagem , Poloxâmero/administração & dosagem , Poloxâmero/química , Pontos Quânticos/química , Ratos , Ondas UltrassônicasRESUMO
Tumor necrosis factor-alpha (TNFα) plays a crucial role in inflammatory diseases such as rheumatoid arthritis and postmenopausal osteoporosis. Recently, it has been demonstrated that hydrogen gas, known as a novel antioxidant, can exert therapeutic anti-inflammatory effect in many diseases. In this study, we investigated the effect of treatment with hydrogen molecule (H(2)) on TNFα-induced cell injury in osteoblast. The osteoblasts isolated from neonatal rat calvariae were cultured. It was found that TNFα suppressed cell viability, induced cell apoptosis, suppressed Runx2 mRNA expression, and inhibited alkaline phosphatase activity, which was reversed by co-incubation with H(2). Incubation with TNFα-enhanced intracellular reactive oxygen species (ROS) formation and malondialdehyde production increased NADPH oxidase activity, impaired mitochondrial function marked by increased mitochondrial ROS formation and decreased mitochondrial membrane potential and ATP synthesis, and suppressed activities of antioxidant enzymes including SOD and catalase, which were restored by co-incubation with H(2). Treatment with H(2) inhibited TNFα-induced activation of NFκB pathway. In addition, treatment with H(2) inhibited TNFα-induced nitric oxide (NO) formation through inhibiting iNOS activity. Treatment with H(2) inhibited TNFα-induced IL-6 and ICAM-1 mRNA expression. In conclusion, treatment with H(2) alleviates TNFα-induced cell injury in osteoblast through abating oxidative stress, preserving mitochondrial function, suppressing inflammation, and enhancing NO bioavailability.
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Anti-Inflamatórios/farmacologia , Hidrogênio/farmacologia , Osteoblastos/efeitos dos fármacos , Fator de Necrose Tumoral alfa/fisiologia , Fosfatase Alcalina/metabolismo , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Inativação Gênica/efeitos dos fármacos , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Osteoblastos/enzimologia , Osteoblastos/imunologia , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Ativação Transcricional/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
In the title polymeric complex, [Ni(C(2)H(6)NO(3)S)(2)](n), the Ni(II) ion occupies a special position on an inversion centre and displays a slightly distorted octa-hedral coordination geometry, being linked to four sulfonate O atoms and to two N atoms of the taurine ligands. The sulfonate groups doubly bridge symmetry-related Ni(II) centers, forming polymeric chains along the a axis.
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In the polymeric title compound, [[Cu(C(10)H(7)NO(5))(H(2)O)].H(2)O](n), the Cu atom adopts a square-based pyramidal coordination involving a N,O,O'-tridentate glycine dianionic ligand, a water O atom and an apical bridging carboxylate O atom from an adjacent ligand. The title compound also adopts a carboxylate-bridged chain structure. The molecular chain propagates in a helical fashion along the b axis of the monoclinic unit cell. Neighbouring chains are linked together to form a three-dimensional network via hydrogen-bonding interactions between coordinated and uncoordinated water molecules and O atoms of the bridging carboxylate groups.
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OBJECTIVE: To trace magnetically labeled MSCs transplanted into the rat livers by magnetic resonance imaging (MRI). METHODS: Feridex and DAPI labeled rat mesenchymal stem cells (MSCs) were injected via portal veins into carbon tetrachloride treated rats. MRI was performed with a clinical 1.5 T MRI machine immediately before the MSCs injection and at h 1, d 3, d 7, and d 14 after the injection, and then the signal-to-noise ratio (SNR) was measured. MRI findings were compared with the liver histopathologies after the slides were stained with fluorescence dye and Prussian blue. RESULTS: The SNR for liver was 1.10+/-0.26 at hour 1, 8.18+/-1.55 at day 3, 11.08+/-1.30 at day 7, and 14.15+/-1.02 at day 14 respectively. Within 7 days after the MSCs transplantation, the SNRs of the livers were significantly lower than those before the transplantation (P less than 0.05). Histologically, the blue fluorescent particles under the fluorescence microscopy matched in distribution with the iron particles on the Prussian blue stained slides. CONCLUSION: The magnetically labeled MSCs transplanted into livers give rise to an obvious signal decrease, and can be tracked with a 1.5 T clinical MRI machine for up to 7 days after MSCs transplantation.
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Fígado/patologia , Imageamento por Ressonância Magnética , Transplante de Células-Tronco Mesenquimais , Animais , Aumento da Imagem/métodos , Masculino , Traçadores Radioativos , Ratos , Ratos WistarRESUMO
BACKGROUND: A hyperdense line on the ilium that runs roughly parallel to the sacroiliac joint (we called it "iliac hyperdense line sign") was frequently observed on pelvic radiographs of patients with gluteal muscle contracture (GMC). A literature search revealed no description of this sign. OBJECTIVE: To determine the relationship between the iliac hyperdense line sign and GMC and to explore how this sign is formed. MATERIALS AND METHODS: Pelvic plain films of 103 cases of GMC and those of 200 control individuals were reviewed for the presence or absence of the iliac hyperdense line sign. Pelvic CT scans in 8 of 103 cases and 13 of 200 controls were analyzed with relation to the plain films. RESULTS: The iliac hyperdense line sign was visualized in 85 of 103 (82.5%) cases of GMC and none of the 200 controls. In the GMC group, pelvic CT scans showed a deformity of the posterior ilium. The lateral cortex of the posterior ilium took on a partly or completely anteroposterior course, while in the control group the course appeared as an oblique orientation from posteromedial to anterolateral. CONCLUSION: The iliac hyperdense line on pelvic plain film can be used as a radiographic sign to suggest a diagnosis of GMC. This sign might be a result of the long and persistent pulling effect of the contracted gluteus maximus muscle, which deforms the lateral cortex of the posterior ilium from an oblique course to an anteroposterior course tangential to the X-ray beam.