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PURPOSE: The aim of this study was to assess the effectiveness of mind-body therapy (MBT) and/or physical training in alleviating depressive symptoms among adult cancer patients through a meta-analysis. METHODS: PubMed, Embase, EBSCO, Web of Science, and Cochrane Library databases were searched from up to October 21, 2023. Effect sizes, 95% confidence intervals, and other pertinent values were computed utilizing a random-effects model with Review Manager 5.3 and StataMP 14. The reporting of findings adhered to the guidelines for systematic reviews and meta-analyses. The PROSPERO registration code for this review is 4,203,477,316. RESULTS: 10 randomized controlled trials (11 datasets) involving a total of 620 participants were selected for analysis. The results demonstrated that complementary therapies, encompassing MBT and physical training, were effective in alleviating depressive symptoms in adult cancer patients (SMD= -0.47; 95%CI: -0.87, -0.08; P = 0.02). Subgroup analysis indicate that physical training may effectively alleviate depressive symptoms (SMD= -0.72; 95%CI: -1.31, -0.13; P = 0.02), demonstrating moderate effect sizes. Conversely, MBT does not seem to significantly influence depressive symptoms (P = 0.69). CONCLUSIONS: Complementary therapy lasting four weeks or more, incorporating physical training and MBT, has been shown to alleviate depressive symptoms in adult cancer patients. And physical training has a significant effect on depressive symptoms, while MBT has no effect. Nevertheless, given the constraints of the included studies, further research is required in the future to provide more robust evidence.
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Depressão , Terapias Mente-Corpo , Neoplasias , Humanos , Neoplasias/psicologia , Neoplasias/terapia , Depressão/terapia , Depressão/psicologia , Terapias Mente-Corpo/métodos , Adulto , Ensaios Clínicos Controlados Aleatórios como Assunto , Terapia por Exercício/métodosRESUMO
Circular RNAs (circRNAs) plays critical roles in non-small cell lung cancer (NSCLC) development. Herein, we illustrated the effects of circ_0007432 on malignant features of NSCLC. We found that circ_0007432 played a promoting role in NSCLC progression, lying in accelerating cell viability, migration and invasion of NSCLC cells, promoting M2 macrophage polarization, suppressing cell apoptosis of NSCLC cells, and enhancing tumor growth in vivo. Mechanistically, the interactions among circ_0007432, SRSF1, KLF12, and IL-8 were validated by RNA-binding protein immunoprecipitation (RIP), electrophoretic mobility shift assay (EMSA), RNA pull-down, dual luciferase reporter assay and chromatin immunoprecipitation (ChIP) assays. Circ_0007432 upregulated KLF12 by recruiting SRSF1. KLF12 facilitated IL-8 expression and release by binding to IL-8 promoter. Furthermore, the role of circ_0007432/SRSF1/KLF12/IL-8 axis in malignant phenotypes of tumor cells or macrophage polarization was investigated using rescue experiments. In conclusion, circ_0007432 bound with SRSF1 to stabilize KLF12 and then promote IL-8 release, thus promoting malignant behaviors of NSCLC cells and M2 macrophage polarization.
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Thyroid carcinoma (THCA) is the most common malignancy in the endocrine system. Long intergenic non-coding RNA 2454 (LINC02454) exhibits an HMGA2-like expression pattern, but their relationship and roles in THCA are largely unknown. The present purpose was to delineate the roles of LINC02454 in THCA progression and its molecular mechanisms. We collected THCA tissues from patients and monitored patient survival. THCA cell colony formation, migration, and invasion were evaluated. Metastasis was evaluated by examining EMT markers through Western blotting. Gene interaction was determined with ChIP, RIP, RNA pull-down, and luciferase activity assays. A mouse model of a subcutaneous tumor was used to determine the activity of LINC02454 knockdown in vivo. We found that LINC02454 was highly expressed in THCA, and its upregulation was associated with poor survival. The knockdown of LINC02454 repressed colony formation, migration, and invasion. Moreover, loss of LINC02454 inhibited tumor growth and metastasis in mice. HMGA2 promoted LINC02454 transcription via binding to the LINC02454 promoter, and silencing of HMGA2 suppressed malignant behaviors through downregulation of LINC02454. HMGA2 was a novel functional target of LINC02454 in THCA cells, and knockdown of LINC02454-mediated anti-tumor effects was reversed by HMGA2 overexpression. Mechanically, LINC02454 promoted CREB1 phosphorylation and nuclear translocation, and CREB1 was subsequently bound to the HMGA2 promoter to facilitate its expression. LINC02454 cis-regulates HMGA2 transcription via facilitating CREB1 phosphorylation and nuclear translocation, and, in turn, HMGA2 promotes LINC02454 expression, thus accelerating thyroid carcinoma progression. Our results support therapeutic targets of LINC02454 and HMGA2 for THCA.
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MicroRNAs , Neoplasias da Glândula Tireoide , Animais , Humanos , Camundongos , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Proteína HMGA2/genética , MicroRNAs/genética , Neoplasias da Glândula Tireoide/metabolismo , Ativação Transcricional , Regulação para CimaRESUMO
Candidiasis caused by Candida albicans infection has long been a serious human health problem. The pathogenicity of C. albicans is mainly due to its virulence factors, which are novel targets of antifungal drugs for low risk of resistance development. In this study, we identified a maleimide compound [1-(4-methoxyphenyl)-1hydro-pyrrole-2,5-dione, MPD] that exerts effective anti-virulence activity. It could inhibit the process of adhesion, filamentation, and biofilm formation in C. albicans. In addition, it exhibited low cytotoxicity, hemolytic activity, and drug resistance development. Moreover, in Galleria mellonella-C. albicans (in vivo) infection model, the survival time of infected larvae was significantly prolonged under the treatment of MPD. Further, mechanism research revealed that MPD increased farnesol secretion by upregulating the expression of Dpp3. The increased farnesol inhibited the activity of Cdc35, which then decreased the intracellular cAMP content resulting in the inhibition of virulence factors via the Ras1-cAMP-Efg1 pathway. In all, this study evaluated the inhibitory effect of MPD on various virulence factors of C. albicans and identified the underlying mechanisms. This suggests a potential application of MPD to overcome fungal infections in clinics.
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Candida albicans , Candidíase , Animais , Humanos , Candida albicans/metabolismo , Fatores de Virulência/metabolismo , Farneseno Álcool/farmacologia , Candidíase/microbiologia , Antifúngicos/uso terapêutico , Maleimidas/metabolismo , Maleimidas/farmacologia , Maleimidas/uso terapêutico , Biofilmes , HifasRESUMO
Increasing genetic and biochemical evidence has broadened our view of the pathomechanisms that lead to Spinal muscular atrophy (SMA) and Amyotrophic lateral sclerosis (ALS), two fatal neurodegenerative diseases with similar symptoms and causes. Stress granules are dynamic cytosolic storage hubs for mRNAs in response to stress exposures, that are evolutionarily conserved cytoplasmic RNA granules in somatic cells. A lot of previous studies have shown that the impaired stress granules are crucial events in SMA/ALS pathogenesis. In this review, we described the key stress granules related RNA binding proteins (SMN, TDP-43, and FUS) involved in SMA/ALS, summarized the reported mutations in these RNA binding proteins involved in SMA/ALS pathogenesis, and discussed the mechanisms through which stress granules dynamics participate in the diseases. Meanwhile, we described the applications and limitation of current therapies targeting SMA/ALS. We futher proposed the promising targets on stress granules in the future therapeutic interventions of SMA/ALS.
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Esclerose Lateral Amiotrófica , Atrofia Muscular Espinal , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/terapia , Humanos , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/metabolismo , Atrofia Muscular Espinal/terapia , Mutação , Proteína FUS de Ligação a RNA/genética , Proteína FUS de Ligação a RNA/metabolismo , Grânulos de EstresseRESUMO
Nasopharyngeal carcinoma (NPC) is consistently associated with Epstein-Barr virus (EBV) latent infection and is common in Southern China and Southeast Asia. The viral latent membrane proteins LMP1 and LMP2 are persistently expressed in NPC tissues; the cytoplasmic domain of LMP1 (LMP1 C-terminal) and LMP2A (LMP2A N-terminal) proteins is essential for maintenance of latency and can alter host cell signaling to facilitate tumor growth and progression. Thus, targeting LMP1 or LMP2 oncoprotein has been an increasing interest for diagnosis and targeted therapy of NPC. Affibody molecules, a new class of small-affinity engineered scaffold proteins, have demonstrated high potential for therapeutics, diagnostics, and biotechnological applications. More recently, radiolabelled HER2-specific affibody molecules have demonstrated to be useful in imaging of HER2 expressing tumor. In this study, we report three novel EBV LMP1 C-terminal (EBV LMP1-C) domain affibody molecules (ZLMP1-C15, ZLMP1-C114, and ZLMP1-C277) were selected by biopanning from a random-peptide displayed phage library and used for molecular imaging in tumor-bearing nude mice. Surface plasmon resonance (SPR), indirect immunofluorescence, and immunohistochemistry (IHC) clearly showed that all three selected affibody molecules have high affinity and specificity in binding to EBV LMP1 protein. Moreover, in vivo tumor imaging revealed that Dylight-755-labeled affibody molecules accumulated rapidly in tumor site after injection (1 h) and then were continuously maintained for 24 h in EBV-positive NPC xenograft mice model. In conclusion, our findings highlight the potential use of ZLMP1-C affibody molecules as tumor-specific molecular imaging agents of EBV-associated NPC.Key points⢠We screened three novel affibody molecules (ZLMP1-C15, ZLMP1-C114, and ZLMP1-C277) targeting EBV LMP1-C terminal domain⢠ZLMP1-C recognize the recombinant and native LMP1-C with high affinity and specificity⢠ZLMP1-C can be used for molecular imaging.
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Infecções por Vírus Epstein-Barr , Neoplasias Nasofaríngeas , Animais , Infecções por Vírus Epstein-Barr/diagnóstico por imagem , Herpesvirus Humano 4 , Camundongos , Camundongos Nus , Imagem Molecular , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/diagnóstico por imagemRESUMO
BACKGROUND: To investigate the impact of protective measures and isolation on respiratory tract infections in children during the COVID-19 outbreak. METHODS: We extracted data on outpatient visits and respiratory infection visits, and tests of respiratory viruses (adenovirus (ADV), influenza A (FluA), influenza B (FluB) and respiratory syncytial virus (RSV)) from electronic healthcare records in Children's Hospital, Zhejiang University School of Medicine during the COVID-19 outbreak (January-April, 2020), compared with those in 2018 and 2019 during the same periods. RESULTS: We found that outpatient visits in January, 2020 was comparable with those in 2018 and 2019, but decreased by 59.9% (288,003 vs. 717,983) and 57.4% (288,003 vs. 676,704), respectively during the period of February-April, 2020, as compared with the same periods in 2018 and 2019. The total number of respiratory tract infections from January to April 2020 decreased by 65.7% (119,532 vs.348,762) and 59.0% (119,532 vs.291,557), respectively compared with the same periods in 2018 and 2019. The proportion of respiratory tract infections during the outbreak also dropped compared with the same periods in 2018 and 2019 (P<0.001). We also found significantly decreased number of completed tests for respiratory viruses and positive cases of ADV, FluA, FluB, and RSV during February-April, 2020. CONCLUSIONS: In this study, we found that outpatient visits and respiratory tract infections in children significantly decreased during COVID-19 outbreak. Adequate protective measures and isolation in children may help to prevent respiratory virus infections in children.
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COVID-19 , Infecções por Vírus Respiratório Sincicial , Vírus Sincicial Respiratório Humano , Infecções Respiratórias , Criança , Surtos de Doenças , Humanos , Lactente , Infecções por Vírus Respiratório Sincicial/epidemiologia , Infecções Respiratórias/epidemiologia , SARS-CoV-2RESUMO
Hirschsprung's disease (HSCR) is a common congenital defect. It occurs when bowel colonization by neural crest-derived enteric nervous system (ENS) precursors is incomplete during the first trimester of pregnancy. Several sources of candidate cells have been previously studied for their capacity to regenerate the ENS, including enteric neural crest stem cells (En-NCSCs) derived from native intestine or those simulated from human pluripotent stem cells (hPSCs). However, it is not yet known whether the native NCSCs other than En-NCSCs would have the potential of regenerating functional enteric neurons and producing neuron dependent motility under the intestinal environment. The present study was designed to determine whether premigratory NCSCs (pNCSCs), as a type of the nonenteric NCSCs, could form enteric neurons and mediate the motility. pNCSCs were firstly transplanted into the colon of adult mice, and were found to survive, migrate, differentiate into enteric neurons, and successfully integrate into the adult mouse colon. When the mixture of pNCSCs and human intestinal organoids was implanted into the subrenal capsule of nude mice and grown into the mature tissue-engineered intestine (TEI), the pNCSCs-derived neurons mediated neuron-dependent peristalsis of TEI. These results show that the pNCSCs that were previously assumed to not be induced by intestinal environment or cues can innervate the intestine and establish neuron-dependent motility. Future cell candidates for ENS regeneration may include nonenteric NCSCs.
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Intestinos/fisiologia , Crista Neural , Células-Tronco Neurais , Neurônios , Peristaltismo , Animais , Colo , Humanos , Camundongos , Camundongos Nus , Crista Neural/citologia , Células-Tronco Neurais/transplante , Neurônios/citologia , Engenharia TecidualRESUMO
ß-Catenin is a key component of the canonical Wnt signaling pathway. It has been shown to have an important role in formation of the neuromuscular junction. Our previous studies showed that in the absence of ß-catenin, the resting membrane potential (RMP) is depolarized in muscle cells and expression of the α2 subunit of sodium/potassium adenosine triphosphatase (α2NKA) is reduced. To understand the underlying mechanisms, we investigated the electrophysiologic properties of a primary cell line derived from mouse myoblasts (C2C12 cells) that were transfected with small-interfering RNAs and over-expressed plasmids targeting ß-catenin. We found that the RMP was depolarized in ß-catenin knocked-down C2C12 cells and was unchanged in ß-catenin over-expressed muscle cells. An action potential (AP) was not released by knockdown or over-expression of ß-catenin. α2NKA expression was reduced by ß-catenin knockdown, and increased by ß-catenin over-expression. We showed that ß-catenin could interact physically with α2NKA (but not with α1NKA) in muscle cells. NKA activity and α2NKA content in the cell membranes of skeletal muscle cells were modulated positively by ß-catenin. These results suggested that ß-catenin (at least in part) regulates the RMP and AP in muscle cells, and does so by regulating α2NKA.
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Epstein-Barr virus (EBV) is widespread and is associated with nasopharyngeal carcinoma (NPC). Serological detection of EBV is commonly used for screening, diagnosis and epidemiological surveys of NPC. In the present study, a novel B cell multi-epitope peptide fusion protein (EBV-LMP2-3B), which is composed of three B cell linear epitopes (RIEDPPFNSLL, TLNLT and KSLSSTEFIPN) of EBV latent membrane protein 2 (LMP2), was expressed in a prokaryotic expression system and purified using Ni2+-nitrilotriacetate-Sepharose. The immunogenicity and binding specificity of EBV-LMP2-3B were evaluated on the basis of antibody responses in immunized BALB/c mice, western blotting and indirect immunofluorescence assay. Evaluation of EBV-LMP2-3B as a serological diagnostic reagent was performed using an indirect ELISA in 198 patients with NPC and 102 healthy adults. These results revealed that EBV-LMP2-3B was able to eliminate the high-titer serum antibody response in BALB/c mice. Western blot analysis and indirect immunofluorescence assay confirmed that the mouse immune sera recognized the native LMP2. Compared with healthy adults, patients with NPC demonstrated significantly greater reactivity to EBV-LMP2-3B (P<0.05). Furthermore, it was possible to effectively detect specific IgG in sera from patients with NPC, with a sensitivity of 91.91% and specificity of 93.14%, representing an improvement over the traditional viral capsid antigen-IgA-based detection method with 59.59% sensitivity and 75.49% specificity. In conclusion, the EBV-LMP2-3B protein may be used as a serological diagnostic reagent to screen for and diagnose NPC.
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PURPOSE: This study aims to understand the clinical characteristics of preterm neonatal necrotizing enterocolitis (NEC) to improve the medical management level. METHODS: The clinical characteristics of preterm NEC infants with low birth weight (LBW, ≥ 1500 g) and very low birth weight (VLBW, < 1500 g) were compared. Then, clinical information, including demographics, surgical interventions and morbidity, were collected. RESULTS: A total of 149 preterm NEC infants (60 with VLBW and 89 with LBW) were enrolled. Their median birth weight and gestational age were 1600 g and 31 weeks, respectively. Respiratory support and surfactant therapy were more frequent in VLBW infants (90% vs. 38% and 75% vs. 21.3%) than in LBW infants. In addition, 70.5% of these infants were fed by formula before the NEC occurred. Prematurity-associated morbidities were significantly higher in VLBW infants. Furthermore, 12.8% of all NEC infants died at discharge, and mortality was more prevalent in VLBW infants (21.7% vs. 6.7%). The most frequently received surgeries were enterostomy (n = 58), primary anastomosis (n = 42), and peritoneal drainage (n = 2). Multifocal, localized and pan-intestinal disease occurred in 77.5%, 19.6% and three infants, respectively. Furthermore, postoperative complications occurred more frequently in VLBW infants. CONCLUSION: The overall mortality was 12.8% for infants who had a larger mean gestational age and birth weight, when compared to that in developed countries. Higher rate of formula feeding might be an important risk factor for NEC development. Furthermore, mortality and morbidities, especially nutrition-associated complications, were more frequent in VLBW infants.
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Enterocolite Necrosante/mortalidade , Recém-Nascido de Baixo Peso , Recém-Nascido Prematuro , Recém-Nascido de muito Baixo Peso , Anastomose Cirúrgica/estatística & dados numéricos , China/epidemiologia , Drenagem/estatística & dados numéricos , Enterocolite Necrosante/terapia , Enterostomia/estatística & dados numéricos , Feminino , Idade Gestacional , Humanos , Lactente , Fórmulas Infantis/estatística & dados numéricos , Recém-Nascido , Masculino , Oxigenoterapia/estatística & dados numéricos , Complicações Pós-Operatórias , Surfactantes Pulmonares/uso terapêutico , Estudos RetrospectivosRESUMO
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease that varies greatly in its expression. The current study reports a novel case of TSC caused by a TSC2 mutation (TSC2c.1642_1643insA or TSC2p.K549fsX589), in which multiple cardiac rhabdomyomas were detected by fetal echocardiography in week 31 of pregnancy. The infant was delivered successfully; however, seizures began 16 days following birth. Subsequent genetic tests confirmed a diagnosis of TSC. Rapamycin treatment resulted in regression of cardiac rhabdomyomas and controlled seizures. The current study demonstrates the value of fetal echocardiography in the diagnosis of TSC and suggests that inhibition of the mammalian target of the rapamycin (mTOR) signaling pathway may be considered as a potential antiepileptogenic therapy for neonatal TSC. In addition, it was demonstrated that rapamycin treatment was therapeutically beneficial for preventing disorders caused by abnormal mTOR signaling, such as cancer. According to the literature, cardiac rhabdomyomas, seizures and skin lesions are well established markers for TSC in neonates. MRI scans of the brain and genetic screening of TSC1 and TSC2 genes may facilitate an early diagnosis of TSC.
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The overexpression of heat shock protein 70 (HSP70), a major stress-inducible heat shock protein, has been identified to enhance the proliferation, survival, invasion and metastasis of diverse types of human cancer. However, its role in hepatocellular carcinoma (HCC) remains poorly understood. The present study demonstrated that HSP70 expression was higher in tested HCC cell lines, compared with the normal hepatocyte LO2, and the suppression of HSP70 significantly inhibited the proliferation of SMMC-7721 and Hep3B cells. The growth inhibitory effect was mediated by cell cycle arrest at the G1/S phase with reduced cyclin D1 and increased p27Kip1 expression. Furthermore, HSP70 knockdown significantly inhibited the migration and invasion abilities of HCC cells. In conclusion, HSP70 is a key regulator involved in the proliferation, migration and invasion of HCC, and it may be used as a potential therapeutic target for HCC.
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Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Src is involved in multiple processes of cancer metastasis; however, its significance in HCC is not well defined. In the present study, overexpression of Src phosphorylation (Y416) was observed in the highly metastatic MHCC97H cell line; additionally, through inhibition of Src kinase activation, HCC cell proliferation, migration, invasion and colony formation were significantly reduced in vitro. Tumour growth was not affected in the orthotopic xenograft HCC model, but the metastasic potential was inhibited as revealed by reduced lung metastasic foci after administration of saracatinib. Phosphorylation level of Src pathway signalling molecules, such as Src, FAK and Stat3, were also reduced in vitro and in vivo, as a result of the anti-metastasic effects caused by saracatinib treatment. In conclusion, we demonstrated the pro-metastasic role of Src in HCC, and further experiments suggest the use of the Src inhibitor in combination with cytotoxic agents and other anticancer treatments to improve HCC prognosis.
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Benzodioxóis/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Metástase Neoplásica/tratamento farmacológico , Quinazolinas/farmacologia , Animais , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica/patologia , Metástase Neoplásica/patologia , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Quinases da Família src/metabolismoRESUMO
BACKGROUND AND PURPOSE: Thrombin and lipocalin-2 (LCN2) contribute to intracerebral hemorrhage-induced brain injury. Thrombin-induced brain damage is partially through a thrombin receptor, protease-activated receptor-1. LCN2 is involved in cellular iron transport and neuroinflammation. This study investigated the role of LCN2 in thrombin-induced brain injury. METHODS: There were 3 parts in this study. First, male adult C57BL/6 wild-type or LCN2 knockout (LCN2 KO) mice had an intracaudate injection of thrombin (0.4 U) or saline. Second, LCN2 KO mice had an injection of thrombin (0.4 U) with recombinant mouse LCN2 protein (1 µg) into the right caudate. Third, protease-activated receptor-1 KO or wild-type mice had an intracaudate injection of thrombin or saline. All mice had T2-weighted magnetic resonance imaging and behavioral tests. Brains were used for histology, immunohistochemistry, and Western blotting. RESULTS: Intracerebral thrombin injection caused LCN2 upregulation and brain injury in mice. Thrombin-induced brain swelling, blood-brain barrier disruption, neuronal death, and neurological deficits were markedly less in LCN2 KO mice (P<0.05) and were exacerbated by exogenous LCN2 coinjection. In addition, thrombin injection resulted in less LCN2 expression and brain injury in protease-activated receptor-1 KO mice. CONCLUSIONS: Thrombin upregulates LCN2 through protease-activated receptor-1 activation and causes brain damage.
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Proteínas de Fase Aguda/metabolismo , Edema Encefálico/metabolismo , Encéfalo/metabolismo , Hemorragia Cerebral/metabolismo , Lipocalinas/metabolismo , Proteínas Oncogênicas/metabolismo , Proteínas de Fase Aguda/genética , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Edema Encefálico/induzido quimicamente , Edema Encefálico/patologia , Morte Celular/efeitos dos fármacos , Hemorragia Cerebral/induzido quimicamente , Hemorragia Cerebral/patologia , Lipocalina-2 , Lipocalinas/genética , Imageamento por Ressonância Magnética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Oncogênicas/genética , Receptor PAR-1/metabolismo , Trombina , Regulação para Cima/efeitos dos fármacosRESUMO
BACKGROUND: Reversible bilateral striatal necrosis associated with Mycoplasma pneumoniae (M. pneumoniae) infection is a rare neurological disease. The exact pathogenic mechanism remains unknown. PATIENT: We report reversible bilateral striatal lesions with a favorable outcome secondary to M. pneumoniae infection in an 8-year-old Chinese girl. Cranial MRI showed abnormal signals in bilateral striatum, which disappeared 8 months later. To better understand the pathogenesis of this encephalopathy, we examined cytokines levels in serum and cerebrospinal fluid from this patient. The results revealed the concentrations of interleukin-6 and interleukin-8 increased significantly in serum (26 pg/mL and 66 pg/mL, respectively) and cerebrospinal fluid (122 pg/mL and 325 pg/mL, respectively), and were reduced markedly after the therapy. Intrathecal production of interleukin-6 and interleukin-8 is probably related to the pathogenesis of striatal lesions caused by M. pneumoniae. These cytokines may cause local vascular injury, and finally leading to local vascular occlusion. CONCLUSION: Our results suggest that interleukin-6 and interleukin-8 may play important roles in the pathogenesis of this disease. This is the first report to describe the role of cytokines in this condition and relevant literature is reviewed. Our findings may lead to better understanding of the pathogenesis of M. pneumoniae-associated striatal lesions.
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Corpo Estriado/patologia , Interleucina-6/sangue , Interleucina-8/sangue , Infecções por Mycoplasma/sangue , Infecções por Mycoplasma/patologia , Mycoplasma pneumoniae , Criança , China , Feminino , Humanos , Imageamento por Ressonância Magnética , Infecções por Mycoplasma/terapia , Resultado do TratamentoRESUMO
BACKGROUND: Wilson's disease (WD) is an autosomal recessive genetic disorder of copper metabolism, caused by mutations in the ATP7B gene, resulting in copper accumulation in the liver, brain, kidney, and cornea and leading to significant disability or death if untreated. Early diagnosis and proper therapy usually predict a good prognosis, especially in pre-symptomatic WD. Genetic testing is the most accurate and effective diagnostic method for early diagnosis. METHODS: The clinical and biochemical features of three unrelated Han Chinese families with pre-symptomatic WD were reported. The molecular defects in these families were investigated by polymerase chain reaction and DNA sequencing. Hundred healthy children with the same ethnic background served as controls. Bioinformatic tools (polymorphism phenotyping-2, sorting intolerant from tolerant, protein analysis through evolutionary relationships, and predictor of human deleterious single nucleotide polymorphisms) were combined and used to predict the functional effects of mutations. RESULTS: We identified 2 novel ATP7B mutations (p.Leu692Pro and p.Asn728Ser) and 3 known mutations (p.Met769fs, p.Arg778Leu and p.Val1216Met) in these Chinese WD families. These mutations were not observed in the 100 normal controls. The bioinformatic method showed that p.Leu692Pro and p.Asn728Ser mutations are pathogenic. CONCLUSIONS: Our research enriches the mutation spectrum of the ATP7B gene worldwide and provides valuable information for studying the mutation types and mode of inheritance of ATP7B in the Chinese population. Liver function analysis and genetic testing in young children with WD are necessary to shorten the time to the initiation of therapy, reduce damage to the liver and brain, and improve prognosis.
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Adenosina Trifosfatases/genética , Proteínas de Transporte de Cátions/genética , Predisposição Genética para Doença , Degeneração Hepatolenticular/diagnóstico , Degeneração Hepatolenticular/genética , Linhagem , Pré-Escolar , China , Estudos de Coortes , Cobre/uso terapêutico , ATPases Transportadoras de Cobre , Feminino , Testes Genéticos/métodos , Degeneração Hepatolenticular/tratamento farmacológico , Humanos , Lactente , Masculino , Mutação , Polimorfismo de Nucleotídeo Único , Valor Preditivo dos Testes , Medição de Risco , Resultado do TratamentoRESUMO
Propofol exhibits neuroprotective effects against hypoxic-ischemic brain injury, but the underlying mechanisms are still not clear. Toll-like receptor 4 (TLR4) plays a considerable role in the induction of innate immune and inflammatory responses. The purposes of this study are to investigate the effect of propofol on the oxygen and glucose deprivation (OGD)/reoxygenation (OGD/R) BV2 microglia and to explore the role of TLR4/myeloid differentiation protein 88 (MyD88)/nuclear factor-kappa B (NF-κB) pathway in the neuroprotective effects of propofol. BV2 microglia were placed into an airtight chamber and in glucose-free medium for OGD/reoxygenation. Cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide assay. TLR4 and its downstream signaling molecules, MyD88 and NF-κB expressions were detected by Western blotting. Level of tumor necrosis factor alpha (TNF-α) in culture medium was determined with enzyme-linked immunosorbent assay. BV2 microglia apoptosis was determined by flow cytometry. We found that pretreatment with propofol significantly alleviated the hypoxic injury in BV2 microglia. Propofol inhibited upregulation of TLR4, MyD88, and NF-κB expressions in BV2 microglia exposed to OGD/reoxygenation. Propofol pretreatment also significantly reduced the production of TNF-α and apoptosis in OGD/reoxygenation BV2 microglia. The results indicated that TLR4 and its downstream MyD88-dependent signaling pathway contributed to neuroprotection of propofol to microglia exposed to OGD/reoxygenation.
Assuntos
Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Oxigênio/metabolismo , Propofol/farmacologia , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/genética , Animais , Apoptose/efeitos dos fármacos , Hipóxia Celular , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica , Glucose/deficiência , Camundongos , Microglia/metabolismo , Microglia/patologia , Fator 88 de Diferenciação Mieloide/antagonistas & inibidores , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , NF-kappa B/metabolismo , Oxigênio/farmacologia , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Pituitary adenylate cyclase-activating polypeptide (PACAP) is effective in reducing axonal damage associated with traumatic brain injury (TBI), and has immunomodulatory properties. Toll-like receptor 4 (TLR4) is an important mediator of the innate immune response. It significantly contributes to neuroinflammation induced by brain injury. However, it remains unknown whether exogenous PACAP can modulate TBI through the TLR4/adapter protein myeloid differentiation factor 88 (MyD88)/nuclear factor-κB (NF-κB) signaling pathway. In this study, we investigated the potential neuroprotective mechanisms of PACAP pretreatment in a weight-drop model of TBI. PACAP38 was microinjected intracerebroventricularly before TBI. Brain samples were extracted from the pericontusional area in the cortex and hippocampus. We found that TBI induced significant upregulation of TLR4, with peak expression occurring 24 h post-trauma, and that pretreatment with PACAP significantly improved motor and cognitive dysfunction, attenuated neuronal apoptosis, and decreased brain edema. Pretreatment with PACAP inhibited upregulation of TLR4 and its downstream signaling molecules MyD88, p-IκB, and NF-κB, and suppressed increases in the levels of the downstream inflammatory agents interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α), in the brain tissue around the injured cortex and in the hippocampus. Administration of PACAP both in vitro and in vivo attenuated the ability of the TLR4 agonist lipopolysaccharide (LPS) to increase TLR4 protein levels. Therefore, PACAP exerts a neuroprotective effect in this rat model of TBI, by inhibiting a secondary inflammatory response mediated by the TLR4/MyD88/NF-κB signaling pathway in microglia and neurons, thereby reducing neuronal death and improving the outcome following TBI.
Assuntos
Lesões Encefálicas/tratamento farmacológico , Fator 88 de Diferenciação Mieloide/fisiologia , NF-kappa B/fisiologia , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/administração & dosagem , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/farmacologia , Transdução de Sinais/fisiologia , Receptor 4 Toll-Like/fisiologia , Animais , Axônios/efeitos dos fármacos , Axônios/metabolismo , Axônios/patologia , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Modelos Animais de Doenças , Masculino , Fármacos Neuroprotetores/administração & dosagem , Neurotransmissores/administração & dosagem , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacosRESUMO
OBJECT: The neuroprotective effects of pituitary adenylate cyclise-activating polypeptide (PACAP) have been well documented in vivo and in vitro. However, the mechanisms by which PACAP protected microglia from ischemic/hypoxic injury via inhibition of microglia activation remain unclear. Toll-like receptor 4 (TLR4) plays a considerable role in the induction of innate immune and inflammatory responses. The purpose of this study is to investigate the effect of PACAP on the oxygen and glucose deprivation (OGD)/reoxygenation BV2 microglia and to explore the role of TLR4/myeloid differentiation protein 88 (MyD88)/nuclear factor-kappa B (NF-kappaB) pathway in the neuroprotective effects of PACAP. METHODS: We conducted OGD/reoxygenation by placing BV2 microglia into an airtight chamber and in glucose-free medium. BV2 microglia cell viability was determined by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide] assay. Western blot was utilized to detect TLR4, MyD88 expression, inhibitory protein of NF-kappaB (IkappaB) phosphorylation/degradation, NF-kappaB activation. Level of tumor necrosis factor-alpha (TNF-alpha) in culture medium was measured with enzyme-linked immunosorbent assay (ELISA). Apoptosis was determined by flow cytometry. RESULTS: We found that pretreatment with PACAP to BV2 cells immediately before OGD/reoxygenation significantly alleviated microglia hypoxic injury. PACAP inhibited upregulation of TLR4, MyD88 and NF-kappaB in BV2 microglial cells exposed to OGD/reoxygenation. PACAP administration also significantly reduced the production of proinflammatory cytokines and apoptosis in BV2 microglia exposed to OGD/reoxygenation. DISCUSSION: Pretreatment with PACAP inhibited activation of the TLR4/MyD88/NF-kappaB signaling pathway and decreased inflammatory cytokine levels, as well as apoptosis in microglia, thereby attenuating microglia hypoxic injury. Our results suggested that TLR4-mediated MyD88-dependent signaling pathway contributed to neuroprotection of PACAP to microglia against OGD/reoxygenation.