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Intracranial aneurysm (IA), is a localized dilation of the intracranial arteries, the rupture of which is catastrophic. Hypertension is major IA risk factor that mediates endothelial cell damage. Sox17 is highly expressed in intracranial vascular endothelial cells, and GWAS studies indicate that its genetic alteration is one of the major genetic risk factors for IA. Vascular endothelial cell injury plays a vital role in the pathogenesis of IA. The genetic ablation of Sox17 plus hypertension induced by AngII can lead to an increased incidence of intracranial aneurysms had tested in the previous animal experiments. In order to study the underlying molecular mechanisms, we established stable Sox17-overexpressing and knockdown cell lines in human brain microvascular endothelial cells (HBMECs) first. Then flow cytometry, western blotting, and immunofluorescence were employed. We found that the knockdown of Sox17 could worsen the apoptosis and autophagy of HBMECs caused by AngII, while overexpression of Sox17 had the opposite effect. Transmission electron microscopy displayed increased autophagosomes after the knockdown of Sox17 in HBMECs. The RNA-sequencing analysis shown that dysregulation of the Sox17 gene was closely associated with the autophagy-related pathways. Our study suggests that Sox17 could protect HBMECs from AngII-induced injury by regulating autophagy and apoptosis.
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Glioma is one of the most commonly observed tumours, representing approximately 75% of brain tumours in the adult population. Generally, glioma therapy includes surgical resection followed by radiotherapy and chemotherapy. The transcription factor STAT3 (signal transducer and activator of transcription 3) is a promising target for the treatment of cancer and several other diseases. At nanomolar concentrations, SD-36 induces rapid cellular degradation of STAT3 but cannot degrade other STAT proteins. The current study demonstrates the therapeutic efficacies of the STAT3 degraders SD-36 against glioma, as well as understanding the elucidating mechanisms and identifying molecular markers that determine cell sensitivity to STAT3 degraders. Glioma cell lines possessed similar response patterns to SD-36 but different responses to the STAT3 inhibitor Stattic. SD-36 potently induced apoptosis in glioma cells along with a reduction in Mcl-1 levels, which are critical for mediating the induction of apoptosis and enhancing TMZ-induced apoptosis. Accordingly, SD-36 sensitizes the antitumour effect of TMZ in patient-derived xenograft. In addition, the downregulation of Mcl-1 expression-mediated antitumour effect of SD-36 was analysed in cell-derived xenograft. These observations need to be validated clinically to confirm the efficacy of STAT3 degraders in glioma.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias do Sistema Nervoso Central , Glioma , Fator de Transcrição STAT3/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/metabolismo , Glioma/tratamento farmacológico , Glioma/metabolismo , Humanos , CamundongosRESUMO
In this paper, an optical fiber time transmission technology based on a double-fiber round-trip method is provided. In the system, the one-way transmission delay from the master station to the slave station can be calculated directly through the measurement of three time interval counters and their ratio relationship. The method eliminates the influence of fiber length expansion and round-trip transmission delay fluctuation, which is caused by ambient temperature change. The master and slave stations are connected by 100 km and 80 km optical fibers, respectively, and the temperature of the optical fiber link varies from -20∘C to 40°C. Compared with the single-fiber round-trip method, the time interval error of a double-fiber round-trip method is reduced from 1.4 ns to 80 ps when the wavelength is 1310-1550 nm, and from 320 to 80 ps when the wavelength is 1490-1550 nm.
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Glioma is a brain tumour that is often diagnosed, and temozolomide (TMZ) is a common chemotherapeutic drug used in glioma. Yet, resistance to TMZ is a chief hurdle towards curing the malignancy. The current work explores the pathways and involvement of miR-3116 in the TMZ resistance. miR-3116 and FGFR1 mRNA were quantified by real-time PCR in malignant samples and cell lines. Appropriate assays were designed for apoptosis, viability, the ability to form colonies and reporter assays to study the effects of the miR-3116 or FGFR1. The involvement of PI3K/AKT signalling was assessed using Western blotting. Tumorigenesis was evaluated in an appropriate xenograft mouse model in vivo. This work revealed that the levels of miR-3116 dipped in samples resistant to TMZ, while increased miR-3116 caused an inhibition of the tumour features mentioned above to hence augment TMZ sensitivity. miR-3116 was found to target FGFR1. When FGFR1 was overexpressed, resistance to TMZ was augmented and reversed the sensitivity caused by miR-3116. Our findings further confirmed PI3K/AKT signalling pathway is involved in this action. In conclusion, miR-3116 sensitizes glioma cells to TMZ through FGFR1 downregulation and the PI3K/AKT pathway inactivation. Our results provide a strategy to overcome TMZ resistance in glioma treatment.
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Glioma/tratamento farmacológico , MicroRNAs/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Temozolomida/farmacologia , Animais , Apoptose/genética , Carcinogênese/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dacarbazina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioma/genética , Glioma/patologia , Humanos , Camundongos , Proteína Oncogênica v-akt/genética , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Mesenchymal stromal injection is a promising therapy for traumatic brain injury (TBI). The aim of this study was to explore the effects of the HIF-1α/SDF-1/CXCR4 axis on neuron repair in TBI rats through improving the bone marrow-derived mesenchymalstromal cells (BMSCs) migration. TBI rat models were established. The rats were treated with exogenous SDF-1, and then the neuronal apoptosis in TBI rats was measured. BMSCs from rats were collected, and the roles of NF-κB p65 expression in nuclei, overexpression of SDF-1 and HIF-1α, as well as downregulation of CXCR4 in BMSC migration were identified. HIF-1α- and SDF-1- treated BMSCs were transplanted into TBI rats, after which the neuronal apoptosis and activity of the HIF-1α/SDF-1/CXCR4 axis were detected. Consequently, we found SDF-1 elevated the HIF-1α/SDF-1/CXCR4 activity and presented protective roles in TBI rat hippocampal neurons with reduced neuronal apoptosis. SDF-1 promoted BMSC migration in vitro, and co-effects of SDF-1 and HIF-1α showed strong promotion, while CXCR4 inhibition suppressed BMSC migration. BMSC transplantation activated the HIF-1α/SDF-1/CXCR4 axis and reduced neuronal apoptosis in TBI rats. To conclude, our study demonstrated that the HIF-1α/SDF-1/CXCR4 axis could enhance BMSC migration and alleviate neuronal damage and apoptosis in TBI rats. This study provided novel options for TBI therapy.
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Lesões Encefálicas Traumáticas/genética , Quimiocina CXCL12/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Receptores CXCR4/genética , Animais , Apoptose/genética , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/patologia , Movimento Celular/genética , Modelos Animais de Doenças , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Neurônios/metabolismo , Neurônios/patologia , Ratos , Transdução de Sinais/genética , Células Estromais/metabolismo , Células Estromais/patologiaRESUMO
Coactivator-associated arginine methyltransferase 1 (CARM1) is involved in a variety of biological processes in different cell types and disease conditions, including myogenesis. However, the specific function of CARM1 in skeletal muscle wasting under pathologic conditions remains unclear. Here, we identify CARM1 as a novel participant in muscular atrophy. Increases in CARM1 protein levels correlated positively with the loss of muscle mass upon denervation in mice. Notably, the knockdown of CARM1 represses the progression of muscle wasting and the expression of the atrophy-related genes Atrogin-1 and MuRF1 in vivo and in vitro. With respect to the underlying mechanism, we show that CARM1 interacts with and asymmetrically dimethylates FoxO3 (a specific transcription factor that controls atrophy-related gene expression). This methylation modification by CARM1 is required for FoxO3-dependent transcription. Accordingly, a CARM1 methyltransferase inhibitor also restrains the expression of Atrogin-1 and MuRF1 and myotube atrophy. Furthermore, CARM1 knockdown induces a remarkable myofiber autophagic deficit during the atrophy process. Altogether, our study identifies a crucial regulator of skeletal muscle atrophy and suggests that CARM1 is a potential target for the prevention of muscle atrophy.
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Autofagia , Proteína Forkhead Box O3/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Animais , Linhagem Celular , Dexametasona , Masculino , Metilação , Camundongos Endogâmicos C57BL , Modelos Biológicos , Denervação Muscular , Atrofia Muscular/patologia , Tamanho do Órgão , Ligação ProteicaRESUMO
Background Diabetic neuropathic pain is poorly controlled by analgesics, and the precise molecular mechanisms underlying hyperalgesia remain unclear. The KCNQ2/3/5 channels expressed in dorsal root ganglion neurons are important in pain transmission. The expression and activity of KCNQ2/3/5 channels in dorsal root ganglion neurons in rats with diabetic neuropathic pain were investigated in this study. Methods The mRNA levels of KCNQ2/3/5 channels were analyzed by real-time polymerase chain reaction. The protein levels of KCNQ2/3/5 channels were evaluated by Western blot assay. KCNQ2/3/5 channel expression in situ in dorsal root ganglion neurons was detected by double fluorescent labeling technique. M current (IM) density and neuronal excitability were determined by whole-cell voltage and current clamp recordings. Mechanical allodynia and thermal hyperalgesia were assessed by von Frey filaments and plantar analgesia tester, respectively. Results The mRNA and protein levels of KCNQ2/3/5 channels significantly decreased, followed by the reduction of IM density and elevation of neuronal excitability of dorsal root ganglion neurons from diabetic rats. Activation of KCNQ channels with retigabine reduced the hyperexcitability and inhibition of KCNQ channels with XE991 enhanced the hyperexcitability. Administration of retigabine alleviated both mechanical allodynia and thermal hyperalgesia, while XE991 augmented both mechanical allodynia and thermal hyperalgesia in diabetic neuropathic pain in rats. Conclusion The findings elucidate the mechanisms by which downregulation of the expression and reduction of the activity of KCNQ2/3/5 channels in diabetic rat dorsal root ganglion neurons contribute to neuronal hyperexcitability, which results in hyperalgesia. These data provide intriguing evidence that activation of KCNQ2/3/5 channels might be the potential new targets for alleviating diabetic neuropathic pain symptoms.
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Neuropatias Diabéticas/patologia , Gânglios Espinais/patologia , Canais de Potássio KCNQ/metabolismo , Neurônios/metabolismo , Animais , Antracenos/farmacologia , Carbamatos/farmacologia , Carbamatos/uso terapêutico , Células Cultivadas , Neuropatias Diabéticas/induzido quimicamente , Neuropatias Diabéticas/tratamento farmacológico , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Canais de Potássio KCNQ/genética , Moduladores de Transporte de Membrana/farmacologia , Moduladores de Transporte de Membrana/uso terapêutico , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Limiar da Dor/fisiologia , Técnicas de Patch-Clamp , Fenilenodiaminas/farmacologia , Fenilenodiaminas/uso terapêutico , Bloqueadores dos Canais de Potássio/farmacologia , RNA Mensageiro/metabolismo , Ratos , Estreptozocina/toxicidade , Canais de Cátion TRPV/metabolismoRESUMO
The communication between primary afferent neuron and skeletal muscle (SKM) is one of the important factors on maintaining the structure and function of SKM cells. Neuregulin-1ß (NRG-1ß) signaling is essential for regulating synaptic neurotransmission. Here, we established a neuromuscular coculture model of dorsal root ganglion (DRG) sensory neurons and SKM cells to explore the nerve-muscle communication in the presence of exogenous NRG-1ß. The expression of three distinct subtypes (TrkA, TrkB, and TrkC) of tyrosine kinase receptors was monitored for the phenotypical alterations of the neurons. The aggregation extent of acetylcholine receptor (AChR) represents the specific changes of SKM cells after NRG-1ß incubation in this neuromuscular coculture model. The results showed that NRG-1ß not only enhanced neurite outgrowth of DRG neurons but also increased the length and branches of SKM cells. NRG-1ß treatment not only induced expression of all the three subtypes of Trk receptors in neurons but also promoted AChR aggregation on the surface of SKM cells. The effects of NRG-1ß could be blocked by administration of ERK1/2 inhibitor PD98059, PI3K inhibitor LY294002, and JAK2 inhibitor AG490, respectively. These data imply that NRG-1ß is essential for the nerve-muscle communication by enhancing growth and modifying phenotypes of the two different kinds of cells. The specific effects produced by NRG-1ß add novel interpretation for nerve-muscle communication between sensory neurons and SKM cells.
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Gânglios Espinais/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Neuregulina-1/metabolismo , Células Receptoras Sensoriais/metabolismo , Animais , Cromonas/farmacologia , Técnicas de Cocultura , Flavonoides/farmacologia , Gânglios Espinais/citologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Morfolinas/farmacologia , Músculo Esquelético/citologia , Ratos , Ratos Wistar , Células Receptoras Sensoriais/citologia , Tirfostinas/farmacologiaRESUMO
Upregulation of the pro-inflammatory cytokine tumor necrosis factor α (TNF-α) is involved in the development and progression of numerous neurological disorders. Recent reports have challenged the concept that TNF-α exhibits only deleterious effects of pro-inflammatory destruction, and have raised the awareness that it may play a beneficial role in neuronal growth and function in particular conditions, which prompts us to further investigate the role of this cytokine. Insulin-like growth factor-1 (IGF-1) is a cytokine possessing powerful neuroprotective effects in promoting neuronal survival, neuronal differentiation, neurite elongation, and neurite regeneration. The association of IGF-1 with TNF-α and the biological effects, produced by interaction of IGF-1 and TNF-α, on neuronal outgrowth status of primary sensory neurons are still to be clarified. In the present study, using an in vitro model of primary cultured rat dorsal root ganglion (DRG) neurons, we demonstrated that TNF-α challenge at different concentrations elicited diverse biological effects. Higher concentration of TNF-α (10 ng/mL) dampened neurite outgrowth, induced activating transcription factor 3 (ATF3) expression, reduced growth-associated protein 43 (GAP-43) expression, and promoted GAP-43 and ATF3 coexpression, which could be reversed by IGF-1 treatment; while lower concentration of TNF-α (1 ng/mL) promoted neurite sprouting, decreased ATF3 expression, increased GAP-43 expression, and inhibited GAP-43 and ATF3 coexpression, which could be potentiated by IGF-1 supplement. Moreover, IGF-1 administration restored the activation of Akt and p70 S6 kinase (S6K) suppressed by higher concentration of TNF-α (10 ng/mL) challenge. In contrast, lower concentration of TNF-α (1 ng/mL) had no significant effect on Akt or S6K activation, and IGF-1 administration activated these two kinases. The effects of IGF-1 were abrogated by phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. These data imply that IGF-1 counteracts the toxic effect of higher concentration of TNF-α, while potentiates the growth-promoting effect of lower concentration of TNF-α, with the node for TNF-α and IGF-1 interaction being the PI3K/Akt/S6K signaling pathway. This study is helpful for interpretation of the association of IGF-1 with TNF-α and the neurobiological effects elicited by interaction of IGF-1 and TNF-α in neurological disorders.
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Fator 3 Ativador da Transcrição/biossíntese , Proteína GAP-43/biossíntese , Gânglios Espinais/metabolismo , Fator de Crescimento Insulin-Like I/farmacologia , Crescimento Neuronal/fisiologia , Fator de Necrose Tumoral alfa/farmacologia , Fator 3 Ativador da Transcrição/antagonistas & inibidores , Fator 3 Ativador da Transcrição/genética , Animais , Animais Recém-Nascidos , Células Cultivadas , Relação Dose-Resposta a Droga , Proteína GAP-43/antagonistas & inibidores , Proteína GAP-43/genética , Gânglios Espinais/efeitos dos fármacos , Expressão Gênica , Crescimento Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Proteína Oncogênica v-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Ratos , Ratos Wistar , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologiaRESUMO
A novel ultra-sensitive fluorescent sensor for monitoring microRNA (miRNA) in living cells was constructed by utilizing a hybridization chain reaction (HCR) as the signal amplification with a carbon nitride nanosheet (CNNS) as a carrier. The Cy5-labeled hairpin DNA could be adsorbed onto the surface of CNNS, resulting in fluorescence quenching of Cy5. When treated with complementary miRNA, the fluorescence was recovered because miRNA could efficiently trigger an HCR, which led to the release of the HCR products from the CNNS. This intracellular HCR strategy can be used for ultra-sensitive monitoring of intracellular miRNA. The main advantages of the proposed method are its simplicity, high sensitivity, high specificity and low toxicity for monitoring low-level biomarkers.
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Corantes Fluorescentes/química , MicroRNAs/análise , Nanoestruturas/química , Nitrilas/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Corantes Fluorescentes/farmacologia , Nitrilas/farmacologia , Hibridização de Ácido Nucleico , Células PC12 , Ratos , Espectrometria de Fluorescência , Relação Estrutura-AtividadeRESUMO
Polybrominated diphenyl ethers (PBDEs) exist extensively in the environment as contaminants, in which 2,2',3,3',4,4',5,5',6,6'-decabrominated diphenyl ether (BDE-209) is the most abundant PBDE found in human samples. BDE-209 has been shown to cause neurotoxicity of primary sensory neurons with few effective therapeutic options available. Here, cultured dorsal root ganglion (DRG) neurons were used to determine the therapeutic effects of insulin-like growth factor-1 (IGF-1) on BDE-209-induced neurotoxicity. The results showed that IGF-1 promoted neurite outgrowth and cell viability of DRG neurons with BDE-209-induced neurotoxicity. IGF-1 inhibited oxidative stress and apoptotic cell death caused by BDE-209 exposure. IGF-1 could reverse the decrease in growth-associated protein-43 (GAP-43) and calcitonin gene-related peptide (CGRP), but not neurofilament-200 (NF-200), expression resulting from BDE-209 exposure. The effects of IGF-1 could be blocked by the extracellular signal-regulated protein kinase (ERK1/2) inhibitor PD98059 and the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002, either alone or in combination. IGF-1 may play an important role in neuroprotective effects on DRG neurons with BDE-209-induced neurotoxicity through inhibiting oxidative stress and apoptosis and regulating GAP-43 and CGRP expression of DRG neurons. Both ERK1/2 and PI3K/Akt signaling pathways were involved in the effects of IGF-1. Thus, IGF-1 might be one of the therapeutic agents on BDE-209-induced neurotoxicity.
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Poluentes Ambientais/toxicidade , Retardadores de Chama/toxicidade , Gânglios Espinais/efeitos dos fármacos , Éteres Difenil Halogenados/toxicidade , Fator de Crescimento Insulin-Like I/metabolismo , Neurônios/efeitos dos fármacos , Neuroproteção/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Peptídeo Relacionado com Gene de Calcitonina/agonistas , Peptídeo Relacionado com Gene de Calcitonina/antagonistas & inibidores , Peptídeo Relacionado com Gene de Calcitonina/genética , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Proteína GAP-43/agonistas , Proteína GAP-43/antagonistas & inibidores , Proteína GAP-43/genética , Proteína GAP-43/metabolismo , Gânglios Espinais/citologia , Gânglios Espinais/metabolismo , Gânglios Espinais/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/antagonistas & inibidores , Crescimento Neuronal/efeitos dos fármacos , Neurônios/citologia , Neurônios/metabolismo , Neurônios/patologia , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Estresse Oxidativo/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Ratos Wistar , Transdução de Sinais/efeitos dos fármacosRESUMO
Osteosarcoma is the most common malignant tumor of bone. Recent studies have proven long non-coding RNAs (lncRNAs) play important roles in the tumorigenesis and progression of cancer. However, few lncRNAs have been investigated in osteosarcoma. Here, we reported a novel lncRNA, tumor suppressor candidate 7 (TUSC7), was significantly downregulated in osteosarcoma tissues compared with paired non-tumor tissues and low expression of TUSC7 indicated poor survival (HR = 0.313, 95 % confidence interval (CI) 0.092-0.867) of osteosarcoma patients. Further analysis revealed that loss copy number of TUSC7 was correlated with low expression of TUSC7, and additionally, loss of TUSC7 copy number also indicated poor prognosis (HR = 3.994, 95 % CI 1.147-13.91) of osteosarcoma patients. Two osteosarcoma cell lines, HOS and MG63, were utilized to investigate biological function of TUSC7. Cell counting kit 8 (CCK-8) assay revealed that after silence of TUSC7, cell proliferation ability increased and the colony formation ability also increased. Further results showed that cell cycle was not affected by treatment of si-TUSC7, while the percentage of apoptotic cells decreased. Western blot showed that after silence of TUSC7, the proapoptotic Bcl2 expression was downregulated. Finally, we established xenograft tumor models in nude mice with MG63 cells. Compared with negative control group, silence of TUSC7 significantly promoted tumor growth in vivo. Thus, we demonstrated that TUSC7 could be a potential tumor suppressor in osteosarcoma.
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Biomarcadores Tumorais/genética , Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Recidiva Local de Neoplasia/patologia , Osteossarcoma/patologia , RNA Longo não Codificante/genética , Adolescente , Animais , Apoptose , Western Blotting , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Estudos de Casos e Controles , Proliferação de Células , Feminino , Citometria de Fluxo , Seguimentos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Metástase Neoplásica , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Estadiamento de Neoplasias , Osteossarcoma/genética , Osteossarcoma/metabolismo , Prognóstico , Estudos Retrospectivos , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Advanced glycation endproducts (AGEs)-induced cytotoxicity is regarded as one of the main mechanisms responsible for neurological disorders. Although erythropoietin (EPO) is demonstrated to have neuroprotective effects in neurodegenerative diseases, the effects of EPO on AGEs-induced toxicity of Schwann cells (SCs) remain open for investigation. Primary cultured SCs isolated from 4 day-old Wistar rats were exposed to AGEs with or without EPO treatment for 5 days. AGEs decreased cell viability, increased apoptotic rate, elevated intracellular reactive oxygen species levels, and reduced total glutathione levels of SCs. The AGEs-induced toxic effects on SCs were partially blocked by AGER siRNA or AGER inhibitor FPS-ZM1. SCs exposed to AGEs exhibited higher mRNA and protein levels of receptor for AGEs (AGER), EPO, and EPO receptor (EPOR). Exogenous EPO treatment attenuated AGEs-induced oxidative stress and apoptosis probably by reducing the mRNA and protein expression of AGER. The protective effect of EPO against AGEs-induced toxicity was blocked by EPOR siRNA. The data of the present study gives, for the first time, evidence of the protective effects of EPO on SCs with AGEs-induced oxidative stress and apoptosis. These results imply that EPO might be a novel valuable agent for treating AGEs-induced toxicity.
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Eritropoetina/farmacologia , Produtos Finais de Glicação Avançada/toxicidade , Células de Schwann/efeitos dos fármacos , Animais , Apoptose , Células Cultivadas , Eritropoetina/genética , Glutationa/metabolismo , Técnicas In Vitro , RNA Mensageiro/genética , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Receptor para Produtos Finais de Glicação Avançada/genética , Receptores da Eritropoetina/genética , Células de Schwann/citologia , Células de Schwann/metabolismoRESUMO
Inflammatory damage plays an important role in cerebral ischemic pathogenesis and represents a new target for treatment of stroke. Shikonin has gained attention for its prominent anti-inflammatory property, but up to now little is known about shikonin treatment in acute ischemic stroke. The aim of this study was to evaluate the potential neuroprotective role of shikonin in cerebral ischemic injury, and investigate whether shikonin modulated inflammatory responses after stroke. Focal cerebral ischemia in male ICR mice was induced by transient middle cerebral artery occlusion. Shikonin (10 and 25 mg/kg) was administered by gavage once a day for 3 days before surgery and another dosage after operation. Neurological deficit, infarct volume, brain edema, blood-brain barrier (BBB) dysfunction, and inflammatory mediators were evaluated at 24 and 72 h after stroke. Compared with vehicle group, 25 mg/kg shikonin significantly improved neurological deficit, decreased infarct volume and edema both at 24 and 72 h after transient ischemic stroke, our data also showed that shikonin inhibited the pro-inflammatory mediators, including TLR4, TNF-α, NF-κB, and phosphorylation of p38MAPK in ischemic cortex. In addition, shikonin effectively alleviated brain leakage of Evans blue, up-regulated claudin-5 expression, and inhibited the over-expressed MMP-9 in ischemic brain. These results suggested that shikonin effectively protected brain against ischemic damage by regulating inflammatory responses and ameliorating BBB permeability.
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Anti-Inflamatórios não Esteroides/uso terapêutico , Isquemia Encefálica/patologia , Naftoquinonas/uso terapêutico , Receptor 4 Toll-Like/biossíntese , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Claudina-5/biossíntese , Regulação para Baixo , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Metaloproteinase 9 da Matriz/biossíntese , Camundongos , Camundongos Endogâmicos ICR , NF-kappa B/biossíntese , Fármacos Neuroprotetores/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Fator de Necrose Tumoral alfa/biossíntese , Regulação para Cima , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
The development of heterogeneous chiral dirhodium catalysts for fabricating important bioactive substances and reducing the loss of noble metals has long been of significant interest. However, there still remains formidable synthetic challenges since it requires multiple steps of the synthetic process, and rhodium is easily leached from solid materials during the reaction. Here, we demonstrated a self-supported strategy based on the Suzuki-Miyaura coupling reaction to construct two chiral dirhodium organic frameworks for heterogeneous asymmetric catalysis. The synthetic approach is simple and efficient since it requires only a small number of preparation steps and does not require any catalyst supporting materials. The obtained chiral dirhodium materials can be highly efficient and recyclable heterogeneous catalysts for asymmetric cyclopropanation between diazooxindole and alkenes. Importantly, Rh2-MOCP-2 exhibited almost similar catalytic performance compared to homogeneous catalyst Rh2(S-Br-NTTL)4. The afforded catalytic performance (93.9% yield with 80.9% ee) highly surpasses previous heterogeneous dirhodium catalysts reported to date.
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[This corrects the article DOI: 10.3389/fcimb.2022.1021320.].
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Background: Currently, ischemic stroke is the leading cause of death in China. To compare regional differences of ischemic stroke, we analyzed the clinical characteristics of patients with ischemic stroke in four regionally representative hospitals in China. Methods: We conducted a retrospective study at four tertiary hospitals in east China, with regionally representative patients. The associated factors include hypertension, diabetes mellitus, coronary heart disease, hyperlipidemia and a combination of these factors. The standardized ratio (SR), estimated as the observed number divided by the expected number, computed as the sum of predicted probabilities from a multivariable logistic regression model derived using data from all other cities, was used to compare to average levels. Results: A total of 34,707 patients were included. The number of patients increased with age in all four hospitals and patients were predominantly male. The number of ischemic stroke cases with related factors increased with age, except for hyperlipidemia. There was no significant gender difference when multiple related factors existed simultaneously. Coronary heart disease had a more significant impact on ischemic stroke in Qingdao Municipal Hospital and the First Hospital of Qinhuangdao, while hyperlipidemia had a significant influence on ischemic stroke in the First Hospital of Qinhuangdao. Conclusions: At four hospitals in east China, with the increase of age, the risk factors associated with ischemic stroke increased, and the distribution of ischemic stroke-related factors showed regional differences.
RESUMO
Selection for phomopsis stem blight disease (PSB) resistance is one of the key objectives in lupin (Lupinus angustifolius L.) breeding programs. A cross was made between cultivar Tanjil (resistant to PSB) and Unicrop (susceptible). The progeny was advanced into F(8) recombinant inbred lines (RILs). The RIL population was phenotyped for PSB disease resistance. Twenty plants from the RIL population representing disease resistance and susceptibility was subjected to next-generation sequencing (NGS)-based restriction site-associated DNA sequencing on the NGS platform Solexa HiSeq2000, which generated 7,241 single nucleotide polymorphisms (SNPs). Thirty-three SNP markers showed the correlation between the marker genotypes and the PSB disease phenotype on the 20 representative plants, which were considered as candidate markers linked to a putative R gene for PSB resistance. Seven candidate markers were converted into sequence-specific PCR markers, which were designated as PhtjM1, PhtjM2, PhtjM3, PhtjM4, PhtjM5, PhtjM6 and PhtjM7. Linkage analysis of the disease phenotyping data and marker genotyping data on a F(8) population containing 187 RILs confirmed that all the seven converted markers were associated with the putative R gene within the genetic distance of 2.1 CentiMorgan (cM). One of the PCR markers, PhtjM3, co-segregated with the R gene. The seven established PCR markers were tested in the 26 historical and current commercial cultivars released in Australia. The numbers of "false positives" (showing the resistance marker allele band but lack of the putative R gene) for each of the seven PCR markers ranged from nil to eight. Markers PhtjM4 and PhtjM7 are recommended in marker-assisted selection for PSB resistance in the Australian national lupin breeding program due to its wide applicability on breeding germplasm and close linkage to the putative R gene. The results demonstrated that application of NGS technology is a rapid and cost-effective approach in development of markers for molecular plant breeding.
Assuntos
Ascomicetos/fisiologia , Resistência à Doença/genética , Genes de Plantas/genética , Marcadores Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Lupinus/genética , Doenças das Plantas/genética , Caules de Planta/genética , Ascomicetos/patogenicidade , Sequência de Bases , Mapeamento Cromossômico , Cromossomos de Plantas/genética , Cruzamentos Genéticos , Ligação Genética/genética , Lupinus/imunologia , Lupinus/microbiologia , Dados de Sequência Molecular , Fenótipo , Doenças das Plantas/imunologia , Doenças das Plantas/microbiologia , Caules de Planta/imunologia , Caules de Planta/microbiologia , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único/genética , Locos de Características QuantitativasRESUMO
INTRODUCTION: Both target skeletal muscle (SKM) cells and neurotrophins (NTs) are essential for the maintenance of neuronal function and nerve-muscle communication. The effects of different NTs and SKM cells on growth-associated protein-43 (GAP-43) expression in dorsal root ganglion (DRG) neurons have not been clarified. METHODS: The morphological relationship between DRG neurons and SKM cells in neuromuscular cocultures was observed by scanning electron microscopy. The levels of GAP-43 and its mRNA were determined after administration of different NTs. RESULTS: DRG neurons demonstrated dense neurite outgrowth in the presence of NTs. Distinct NTs promoted GAP-43 and its mRNA expression in neuromuscular cocultures of DRG neurons and SKM cells. CONCLUSIONS: These results offer new clues for a better understanding of the effects of distinct NTs on GAP-43 expression in DRG sensory neurons in the presence of target SKM cells and implicate NTs and target SKM cells in DRG neuronal regeneration.
Assuntos
Proteína GAP-43/metabolismo , Gânglios Espinais/citologia , Fibras Musculares Esqueléticas/fisiologia , Fatores de Crescimento Neural/farmacologia , Células Receptoras Sensoriais/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/farmacologia , Células Cultivadas , Técnicas de Cocultura , Proteína GAP-43/efeitos dos fármacos , Proteína GAP-43/fisiologia , Microscopia Eletrônica de Varredura , Fator de Crescimento Neural/farmacologia , Neuritos/efeitos dos fármacos , Neuritos/ultraestrutura , Neurotrofina 3/farmacologia , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/ultraestruturaRESUMO
This study aimed to explore the characteristics of sleep disorders and their relationship with abnormal white-matter integrity in patients with sporadic amyotrophic lateral sclerosis. One hundred and thirty-six patients and 80 healthy controls were screened consecutively, and 56 patients and 43 healthy controls were ultimately analyzed. Sleep disorders were confirmed using the Pittsburgh sleep quality index, the Epworth sleepiness scale, and polysomnography; patients were classified into those with poor and good sleep quality. White-matter integrity was assessed using diffusion tensor imaging and compared between groups to identify the white-matter tracts associated with sleep disorders. The relationship between scores on the Pittsburgh sleep quality index and impaired white-matter tracts was analyzed using multiple regression. Poor sleep quality was more common in patients (adjusted odds ratio, 4.26; p = 0.005). Compared to patients with good sleep quality (n = 30), patients with poor sleep quality (n = 26; 46.4%) showed decreased fractional anisotropy, increased mean diffusivity, and increased radial diffusivity of projection and commissural fibers, and increased radial diffusivity of the right thalamus. The Pittsburgh score showed the best fit with the mean fractional anisotropy of the right anterior limb of the internal capsule (r = - 0.355, p = 0.011) and the mean radial diffusivity of the right thalamus (r = 0.309, p = 0.028). We conclude that sleep disorders are common in patients with sporadic amyotrophic lateral sclerosis and are associated with reduced white-matter integrity. The pathophysiology of amyotrophic lateral sclerosis may contribute directly to sleep disorders.