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BACKGROUND: Facioscapulohumeral muscular dystrophy (FSHD) is a high-prevalence autosomal dominant neuromuscular disease characterized by significant clinical and genetic heterogeneity. Genetic diagnosis of FSHD remains a challenge because it cannot be detected by standard sequencing methods and requires a complex diagnosis workflow. METHODS: We developed a comprehensive genetic FSHD detection method based on Oxford Nanopore Technologies (ONT) whole-genome sequencing. Using a case-control design, we applied this procedure to 29 samples and compared the results with those from optical genome mapping (OGM), bisulfite sequencing (BSS), and whole-exome sequencing (WES). RESULTS: Using our ONT-based method, we identified 59 haplotypes (35 4qA and 24 4qB) among the 29 samples (including a mosaic sample), as well as the number of D4Z4 repeat units (RUs). The pathogenetic D4Z4 RU contraction identified by our ONT-based method showed 100% concordance with OGM results. The methylation levels of the most distal D4Z4 RU and the double homeobox 4 gene (DUX4) detected by ONT sequencing are highly consistent with the BSS results and showed excellent diagnostic efficiency. Additionally, our ONT-based method provided an independent methylation profile analysis of two permissive 4qA alleles, reflecting a more accurate scenario than traditional BSS. The ONT-based method detected 17 variations in three FSHD2-related genes from nine samples, showing 100% concordance with WES. CONCLUSIONS: Our ONT-based FSHD detection method is a comprehensive method for identifying pathogenetic D4Z4 RU contractions, methylation level alterations, allele-specific methylation of two 4qA haplotypes, and variations in FSHD2-related genes, which will all greatly improve genetic testing for FSHD.
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Metilação de DNA , Distrofia Muscular Facioescapuloumeral , Sequenciamento Completo do Genoma , Distrofia Muscular Facioescapuloumeral/genética , Distrofia Muscular Facioescapuloumeral/diagnóstico , Humanos , Metilação de DNA/genética , Haplótipos/genética , Masculino , Estudos de Casos e Controles , Proteínas de Homeodomínio/genética , Feminino , Sequenciamento por Nanoporos/métodos , AdultoRESUMO
BACKGROUND: Neuromyelitis Optica Spectrum Disorder (NMOSD) is an autoimmune demyelinating disease characterized by recurrent myelitis and optic neuritis. It is associated with high rates of relapse and disability. The main treatment strategies for acute attacks include intravenous methylprednisolone pulse (IVMP) treatment and rescue treatment with plasma exchange (PLEX). Recently, the blockade of neonatal Fc receptor (FcRn)-IgG interaction has gained momentum as a therapeutic strategy. Efgartigimod, the first approved FcRn inhibitor for treating generalized myasthenia gravis, has shown impressive safety, efficacy, and tolerability, and is being regarded as "PLEX in a bottle". CASE DESCRIPTION: We report a 65-year-old female patient who was diagnosed with anti-AQP4 antibody positive NMOSD. Add-on treatment with efgartigimod to IVMP and intravenous immunoglobulin (IVIG) at the second acute relapse showed favorable results. CONCLUSION: This case suggests that efgartigimod is a potentially effective add-on therapy in acute attacks of AQP4-IgG-positive NMOSD.
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Amyotrophic lateral sclerosis (ALS) is a debilitating and rapidly fatal neurodegenerative disease, which is characterized by the selective loss of the upper and lower motor neurons. The pathogenesis of ALS remains to be elucidated and has been connected to genetic, environmental and immune conditions. Evidence from clinical and experimental studies has suggested that the immune system played an important role in ALS pathophysiology. Autoantibodies are essential components of the immune system. Several autoantibodies directed at antigens associated with ALS pathogenesis have been identified in the serum and/or cerebrospinal fluid of ALS patients. The aim of this review is to summarize the presence and clinical significance of autoantibodies in ALS.
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Esclerose Lateral Amiotrófica , Autoanticorpos , Esclerose Lateral Amiotrófica/imunologia , Esclerose Lateral Amiotrófica/sangue , Humanos , Autoanticorpos/imunologia , Autoanticorpos/sangue , Relevância ClínicaRESUMO
Myasthenic crisis (MC) is a life-threatening state with respiratory failure in patients with myasthenia gravis (MG). The fast-acting immunomodulatory therapies for treating MC included plasma exchange (PE) and intravenous immunoglobulin (IVIG). However, the efficacy and the impact on antibody changes remained unknown. We prospectively followed 40 anti-acetylcholine receptors (AChR) antibody-positive MC patients who received either PE (n = 12) or IVIG (n = 28) at crisis. PE was associated with a reduced ICU stay length (p = 0.018) and an early response by the average changes in MGFA-QMG (p = 0.003), MMT (p = 0.020), and ADL (p = 0.011) at one-week off-ventilation. However, the clinical efficacy was equally comparable in both groups after 1 month. Post-treatment hemoglobin drop was significant in both groups, while IVIG was associated with a significant reduction in anti-AChR antibody titers (p < 0.001). This analysis provides real-world evidence in supporting the use of PE as a fast-acting therapy for shortening the ICU stay in AChR-associated MC.
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Imunoglobulinas Intravenosas , Miastenia Gravis , Autoanticorpos , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Troca Plasmática , Estudos Prospectivos , Receptores ColinérgicosRESUMO
IL-37 is a newly identified immune-suppressive factor; however, the function, cellular sources, and mechanism of IL-37 in humoral immunity and Myasthenia gravis (MG) are still unclear. In this study, we found IL-37 were substantially downregulated in the serum and PBMCs of MG patients compared with healthy controls. The lower IL-37 was associated with severer disease (quantitative MG score) and higher follicular Th (Tfh)/Tfh17 and B cell numbers. Flow cytometry analysis revealed that IL-37 was mainly produced by CD4+ T cells without overlapping with Th1, Th17, and Tfh subsets in MG patients. Regulatory IL-37+ T cell rarely expressed Foxp3 and CD25 but produced numerous IL-4. Tfh and B cell expressed high levels of SIGIRR, the receptor of IL-37, in MG patients. Mechanically, IL-37 directly bond to SIGIRR, repressed the proliferation, cytokine production of Tfh and B cells, and the secretion of autoantibody via inhibition of STAT3 signaling in Tfh and B cells.
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Autoimunidade/imunologia , Linfócitos B/imunologia , Interleucina-1/imunologia , Miastenia Gravis/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Células Th17/imunologia , Adulto , Autoanticorpos/imunologia , Células Cultivadas , Feminino , Humanos , Imunidade Humoral/imunologia , Masculino , Pessoa de Meia-IdadeRESUMO
Fluid-attenuated inversion recovery vascular hyperintensity (FVH) is frequently observed in patients with acute ischemic stroke (AIS). FVH is associated with functional outcome at 3 months in AIS patients receiving endovascular thrombectomy. In the present study, we assessed whether FVH predicted early neurological deterioration (END) and hemorrhagic transformation (HT) within 72 h in AIS patients receiving endovascular thrombectomy. We retrospectively analyzed 104 patients with acute internal-carotid-artery or proximal middle-cerebral-artery occlusion within 16 h after symptom onset. Before thrombectomy, all patients underwent brain magnetic resonance imaging. END was defined as an increase of 4 points or more from baseline National Institutes of Health Stroke Scale (NIHSS) during 72 h following onset. HT was assessed by brain computed tomography. Statistical analyses were performed to predict END and HT. The proportion of high FVH score, high American Society of Intervention and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) grade in non-END group was higher than that in END group (p < 0.001, p < 0.001, respectively). FVH score was positively correlated with ASITN/SIR grade (r = 0.461, p < 0.001). FVH score was a predictor factor for END (adjusted OR, 13.552; 95% CI, 2.408-76.260; p = 0.003), while FVH score was not a predictor factor for HT. Furthermore, NIHSS at admission (adjusted OR, 1.112; 95% CI, 1.006-1.228; p = 0.038) and high-density lipoprotein cholesterol (adjusted OR, 18.865; 95% CI, 2.998-118.683; p = 0.002) were predictor factors for HT. To assess FVH score before thrombectomy might be useful for predicting END in AIS patients receiving endovascular thrombectomy.
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Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/cirurgia , Humanos , Infarto da Artéria Cerebral Média/terapia , AVC Isquêmico/diagnóstico por imagem , AVC Isquêmico/cirurgia , Estudos Retrospectivos , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/cirurgia , Trombectomia/métodos , Resultado do TratamentoRESUMO
BACKGROUND: Invasive and non-invasive mechanical ventilation (MV) have been combined as sequential MV in the treatment of respiratory failure. However, the effectiveness remains unclear. Here, we performed a randomized controlled study to assess the efficacy and safety of sequential MV in the treatment of tuberculosis with respiratory failure. METHODS: Forty-four tuberculosis patients diagnosed with respiratory failure were randomly divided into sequential MV group (n = 24) and conventional MV group (n = 20). Initially, the patients in both groups received invasive positive pressure ventilation. When the patients' conditions were relieved, the ventilation modality in sequential MV group was switched to oronasal face mask continuous positive airway pressure until weaning. RESULTS: After treatment, the patients in sequential MV group had similar respiratory rate, heart rate, oxygenation index, alveolo-arterial oxygen partial pressure difference (A-aDO2), blood pH, PaCO2 to those in conventional MV group (all P value > 0.05). There was no significant difference in ventilation time and ICU stay between the two groups (P > 0.05), but sequential MV group significantly reduced the time of invasive ventilation (mean difference (MD): - 36.2 h, 95% confidence interval (CI) - 53.6, - 18.8 h, P < 0.001). Sequential MV group also reduced the incidence of ventilator-associated pneumonia (VAP; relative risk (RR): 0.44, 95% CI 0.24, 0.83, P = 0.006) and atelectasis (RR:0.49, 95% CI 0.24,1.00, P = 0.040). CONCLUSIONS: Sequential MV was effective in treating tuberculosis with respiratory failure. It showed advantages in reducing invasive ventilation time and ventilator-associated adverse events. REGISTRATION NUMBER FOR CLINICAL TRIAL: Chinese Clinical Trial Registry ChiCTR2000032311, April 21st, 2020.
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Pneumonia Associada à Ventilação Mecânica/etiologia , Respiração Artificial/métodos , Insuficiência Respiratória/terapia , Tuberculose/complicações , Adulto , Idoso , Feminino , Humanos , Masculino , Máscaras/efeitos adversos , Pessoa de Meia-Idade , Estudos Prospectivos , Respiração Artificial/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: The Tibetan highland fish, Gymnocypris przewalskii, migrates from Lake Qinghai to its spawning grounds every summer. This seasonal reproduction is critically regulated by intrinsic and extrinsic signals. However, the molecular mechanisms that process environmental oscillations to initiate the seasonal mating are largely unknown. RESULTS: A transcriptomic analysis was conducted on the brain and gonad of male and female G. przewalskii in reproductive and nonreproductive seasons. We obtained 2034, 760, 1158 and 17,856 differentially expressed genes between the reproductively active and dormant female brain, male brain, ovary and testis. Among these genes, DIO2 was upregulated in the reproductively active brain and gonad of both males and females. Neuroactive ligand-receptor genes were activated in male and female brain. Functional enrichment analysis suggested that retinol metabolism was uniquely stimulated in reproductively active males. Genes involved in GnRH signaling and sex hormone synthesis exhibited higher expression levels in brain and gonad during the reproductive season. A co-expression network classified all the genes into 9 modules. The network pinpointed CDC42 as the hub gene that connected the pathways in responsible for modulating reproduction in G. przewalskii. Meanwhile, the sex pheromone receptor gene prostaglandin receptor was identified to link to multiple endocrine receptors, such as GnRHR2 in the network. CONCLUSIONS: The current study profiled transcriptomic variations between reproductively active and dormant fish, highlighting the potential regulatory mechanisms of seasonal reproduction in G. przewalskii. Our data suggested that the seasonal regulation of reproduction in G. przewalskii was controlled by the external stimulation of photoperiodic variations. The activated transcription of neuroendocrine and sex hormone synthesis genes contributed to seasonal reproduction regulation in G. przewalskii, which was presumably influenced by the increased day-length during the breeding season.
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Cyprinidae/genética , Evolução Molecular , Filogenia , Transcriptoma/genética , Animais , Cyprinidae/classificação , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/genética , Lagos , Masculino , Reprodução/genética , Estações do Ano , TibetRESUMO
BACKGROUND: Numerous studies suggested that PM2.5 exposure was associated with increased risk of Alzheimer's disease (AD). But the precise mechanisms by which PM2.5 contributed to AD pathogenesis have not been clarified. METHODS: In the presence or absence of neurons, oligomeric amyloid beta (oAß)-primed microglia were stimulated with PM2.5. Firstly, we determined the effects of PM2.5 exposure on neuronal injury and inflammation in neurons-microglia co-cultures. Then, we examined whether NLRP3 inflammasome activation was involved in PM2.5-induced inflammation. After that, we investigated whether PM2.5 exposure increased ROS level in oAß-stimulated microglia. At last, we examined whether ROS and NLRP3 inflammasome activation was required for PM2.5-induced neuronal injury in neurons-microglia co-cultures. RESULTS: In the present study, we showed that PM2.5 exposure aggravated oAß-induced neuronal injury and inflammation in neurons-microglia co-cultures via increasing IL-1ß production. Further, PM2.5-induced IL-1ß production in oAß-stimulated microglia was possibly dependent on NLRP3 inflammasome activation. Meanwhile, PM2.5 exposure increased ROS level in oAß-stimulated microglia. ROS was required for PM2.5-induced IL-1ß production and NLRP3 inflammasome activation in oAß-stimulated microglia. More importantly, ROS and NLRP3 inflammasome activation was required for PM2.5-induced neuronal injury in neurons-microglia co-cultures. CONCLUSIONS: For the first time, these results suggested that the effects of PM2.5 under AD context were possibly mediated by NLRP3 inflammasome activation, which was triggered by ROS. Taken together, these findings have deepened our understanding on the role of PM2.5 in AD pathogenesis.
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Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/toxicidade , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neurônios/metabolismo , Material Particulado/toxicidade , Fragmentos de Peptídeos/toxicidade , Animais , Células Cultivadas , Técnicas de Cocultura , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Tamanho da Partícula , GravidezRESUMO
BACKGROUND: Recently, several studies have demonstrated that the NLRP3 inflammasome participates in detecting cellular damage and mediating inflammatory responses to aseptic tissue injury following cerebral ischemia. More importantly, blocking or inhibiting NLRP3 inflammasome at multiple levels, such as its expression, assembly and activity, may offer substantial promise to salvage neurological deterioration during ischemic stroke. However, the specific mechanisms about the contribution of NLRP3 to neurovascular damage remain to be established. MATERIALS AND METHODS: In this paper, we will review the molecular structure, expression and assembly of NLRP3 inflammasome, and illustrate its possible roles and effects in ischemic stroke. Moreover, we will speculate its activity and mechanism in stroke pathogenesis, and present the recent advances and challenges in potential therapies targeting NLRP3 inflammsome. RESULTS AND CONCLUSION: Mounting evidence has demonstrated that NLRP3 inflammasome plays a prominent role in the pathogenesis and progression of ischemic stroke, which indicates the higher possibility to target NLRP3 inflammasome in future stroke therapy. However, many aspects of the biology of NLRP3 inflammasome to stroke are still not well defined or even completely unknown. As the mechanistic insight of the NLRP3 inflammasomes increases, opportunities to develop new therapeutic strategies for patients with ischemic stroke are expected to enhance proportionately.
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Isquemia Encefálica/imunologia , Inflamassomos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Acidente Vascular Cerebral/imunologia , Animais , Encéfalo/imunologia , Encéfalo/metabolismo , Isquemia Encefálica/metabolismo , Humanos , Inflamassomos/química , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/química , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Conformação Proteica , Acidente Vascular Cerebral/metabolismoRESUMO
OBJECTIVE: The aim of this study was to validate the reliability of the Chinese version of Addenbrooke's Cognitive Examination III (ACE-III) for detecting dementia. Furthermore, the present study compares the diagnostic accuracy of ACE-III with that of mini-mental state examination (MMSE). METHODS: One hundred seventy-seven patients with dementia and 180 healthy controls were included in the study. RESULTS: The reliability of ACE-III was very good (α-coefficient = 0.888). There was a significant negative correlation between Clinical Dementia Rating Scale score and total ACE-III score. Further, there was a positive correlation between MMSE score and total ACE-III score. Age exerted a significant effect on total ACE-III score, memory score, and language score. In the present study, the cutoff score of 83 showed a sensitivity of 91.1% and a specificity of 83.1%. CONCLUSIONS: The present findings support that the Chinese version of ACE-III is a reliable assessment tool for dementia. Copyright © 2017 John Wiley & Sons, Ltd.
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Transtornos Cognitivos/diagnóstico , Demência/diagnóstico , Testes Neuropsicológicos/normas , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Transtornos Cognitivos/psicologia , Demência/psicologia , Feminino , Humanos , Idioma , Masculino , Pessoa de Meia-Idade , Curva ROC , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
As the most common type of neurodegenerative disease, Alzheimer's disease (AD) is characterized by the accumulation of amyloid-ß peptide (Aß) within the brain. Triggering receptor expressed on myeloid cells (TREM) 1 is an immune receptor expressed by mononuclear phagocytes including monocytes and microglia, coupling with TYRO protein tyrosine kinase binding protein to regulate immune reactions. Emerging evidence indicates that rs6910730G, an intronic variant of TREM1, is associated with an increased Aß neuropathology in the brains of elderly subjects, but the underlying mechanisms remain unclear. Here, using two independent cohorts of healthy individuals, we provided evidence that rs6910730G reduced the ability of human monocytes for Aß phagocytosis, and this reduction was likely attributed to a decreased monocytic TREM1 expression. By knockdown and overexpression of Trem1 in mouse primary microglia, we showed that TREM1 facilitated microglial phagocytosis of Aß. In support of this finding, knockdown of Trem1 in the brains of APP/PSEN1 mice increased Aß1-42 levels and total amyloid burden, whereas selective overexpression of Trem1 on microglia or activation of Trem1 signaling by an agonistic antibody ameliorated Aß neuropathology and rescued AD-related spatial cognitive impairments. Altogether, these findings uncover the role of TREM1 in microglial Aß clearance, and establish TREM1 as a potential therapeutic target for AD.
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Peptídeos beta-Amiloides/farmacologia , Encéfalo/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Glicoproteínas de Membrana/metabolismo , Fragmentos de Peptídeos/farmacologia , Fagocitose/efeitos dos fármacos , Receptores Imunológicos/metabolismo , Idoso , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Animais , Animais Recém-Nascidos , Anticorpos/farmacologia , Encéfalo/citologia , Células Cultivadas , Regulação da Expressão Gênica/genética , Humanos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Camundongos Transgênicos , Microglia/metabolismo , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Presenilina-1/genética , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Receptor Gatilho 1 Expresso em Células MieloidesRESUMO
BACKGROUND AND AIM: The severity of cerebral microbleeds (CMBs) affected the prognosis of patients with acute cerebrovascular disease. Considering the impact of CMBs on clinical decision, it is necessary to assess the risk factors of CMBs. We aimed to evaluate the independent risk factors of CMBs in patients with acute ischemic stroke of large-artery atherosclerosis. MATERIALS AND METHODS: 112 patients were enrolled in the study. The baseline information, the results of laboratory examination and cranial MRI were collected. The independent risk factors of CMBs in patients with acute ischemic stroke due to large-artery atherosclerosis were evaluated. RESULTS: CMBs were found in 56 (50%) patients. Older age and higher homocysteine (Hcy) level were associated with an elevated chance of occurrence of CMBs. Further, there was a positive correlation between CMBs grade and serum Hcy level. CONCLUSIONS: Serum Hcy level is strongly associated with the presence of CMBs in patients with acute ischemic stroke due to large-artery atherosclerosis. Serum Hcy level may be a potential therapeutic target for alleviating adverse clinical outcomes of CMBs.
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Isquemia Encefálica/etiologia , Hemorragia Cerebral/etiologia , Homocisteína/sangue , Hiper-Homocisteinemia/complicações , Arteriosclerose Intracraniana/complicações , Acidente Vascular Cerebral/etiologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Isquemia Encefálica/sangue , Isquemia Encefálica/diagnóstico por imagem , Hemorragia Cerebral/sangue , Hemorragia Cerebral/diagnóstico por imagem , China , Feminino , Humanos , Hiper-Homocisteinemia/sangue , Hiper-Homocisteinemia/diagnóstico , Arteriosclerose Intracraniana/sangue , Arteriosclerose Intracraniana/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Índice de Gravidade de Doença , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/diagnóstico por imagem , Regulação para CimaRESUMO
Toll-like receptors (TLR) are key components of innate immunity that play significant roles in immune defense against pathogens invasion. Recent frequent outbreaks of the "white spot disease" caused by parasitic infection in farmed Tibetan fishes had resulted in great economic losses. However, to our knowledge, the roles of TLRs in mediating immune response to parasitic infection in Tibetan fishes remain to be determined. Here, we performed data-mining on a widely-farmed Tibetan fish (Gymnocypris przewalskii or Gp) transcriptome to determine the genetic variation and expression pattern of TLRs. We totally obtained 14 GpTLRs and identified 5 with a complete coding sequence. Phylogenetic analysis verified their identities and supported the classification of TLRs into six families as in other vertebrates. The TLR family motifs, such as leucine rich repeat (LRR) and Toll/interleukin (IL)-1 receptor (TIR) domain, are conserved in GpTLR1-5. Selective pressure test demonstrated that all known GpTLRs are under purifying selection, except GpTLR4 underwent positive selection. Further, site model analysis suggested that 11 positively selected sites are found in LRR domain of GpTLR4. Three positively selected sites are located on outside surface of TLR4 3D structure, indicating that function of GpTLR4 may be affected. Tissue specific expression analysis showed all GpTLRs are present in gill, head-kidney and spleen but the relative abundance varied among tissues. In response to parasite Ichthyophthirius multifiliis infection, 5 GpTLR (GpTLR1, -2, -4, -9 and -20) expressions were induced. Intriguingly, GpTLR4 was significantly up-regulated in gills, while GpTLR19 and GpTLR21 unexpectedly showed no any change. In summary, these results revealed the first genomic resources of TLR family and several parasitic infection responsive TLRs in Tibetan fish. These findings provide key information for future studies aiming to understand the molecular mechanisms underlying the immune response to pathogen invasion in Tibetan fishes.
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Carpas/genética , Carpas/imunologia , Infecções por Cilióforos , Doenças dos Peixes , Hymenostomatida , Receptores Toll-Like/genética , Receptores Toll-Like/imunologia , Animais , Sequência de Bases , Carpas/parasitologia , Infecções por Cilióforos/genética , Infecções por Cilióforos/imunologia , Infecções por Cilióforos/veterinária , Evolução Molecular , Doenças dos Peixes/genética , Doenças dos Peixes/imunologia , Variação Genética , Brânquias/imunologia , Rim Cefálico/imunologia , Dados de Sequência Molecular , Filogenia , Baço/imunologia , Tibet , TranscriptomaRESUMO
AIMS: Epigallocatechin-3-gallate (EGCG), a major catechin found in green tea, displays a variety of pharmacological properties and recently received attention as a prospective dietary intervention in cardiovascular diseases (CVD). This study was conducted to test the hypothesis that EGCG was able to inhibit tumor necrosis factor-α (TNF-α)-induced production of monocyte chemoattractant protein-1 (MCP-1) in human umbilical vein endothelial cells (HUVECs) and investigated the underlying molecular mechanisms. METHODS: The inhibitory effect of EGCG on TNF-α-induced expression of MCP-1 was measured using ELISA and RT-qPCR. The effect of EGCG on TNF-α-induced nuclear factor-kappa B (NF-κB) activation was investigated by western blot and luciferase assays. Monocyte adhesion assay was detected by microscope. RESULTS: EGCG significantly suppressed the TNF-α-induced protein and mRNA expression of MCP-1. Investigation of the mechanism suggested that EGCG suppressed the TNF-α-mediated NF-κB activation. In addition, the 67-kD laminin receptor (67LR) was involved in EGCG-mediated suppression of MCP-1 generation. Furthermore, EGCG potently inhibited monocyte adhesion to activated HUVECs. CONCLUSION: EGCG suppresses TNF-α-induced MCP-1 expression in HUVECs. This effect was mediated by 67LR and was via the inhibition of NF-κB activation. Our results demonstrated that EGCG might be a possible medicine for CVD prevention and treatment.
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Catequina/análogos & derivados , Quimiocina CCL2/biossíntese , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Chá/química , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Catequina/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Quimiocina CCL2/genética , Relação Dose-Resposta a Droga , Humanos , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
Accumulation of amyloid-ß peptides (Aß) within brain is a major pathogenic hallmark of Alzheimer's disease (AD). Emerging evidence suggests that autophagy, an important intracellular catabolic process, is involved in Aß clearance. Here, we investigated whether temsirolimus, a newly developed compound approved by Food and Drug Administration and European Medicines Agency for renal cell carcinoma treatment, would promote autophagic clearance of Aß and thus provide protective effects in cellular and animal models of AD. HEK293 cells expressing the Swedish mutant of APP695 (HEK293-APP695) were treated with vehicle or 100nM temsirolimus for 24h in the presence or absence of 3-methyladenine (5mM) or Atg5-siRNA, and intracellular Aß levels as well as autophagy biomarkers were measured. Meanwhile, APP/PS1 mice received intraperitoneal injection of temsirolimus (20mg/kg) every 2 days for 60 days, and brain Aß burden, autophagy biomarkers, cellular apoptosis in hippocampus, and spatial cognitive functions were assessed. Our results showed that temsirolimus enhanced Aß clearance in HEK293-APP695 cells and in brain of APP/PS1 mice in an autophagy-dependent manner. Meanwhile, temsirolimus attenuated cellular apoptosis in hippocampus of APP/PS1 mice, which was accompanied by an improvement in spatial learning and memory abilities. In conclusion, our study provides the first evidence that temsirolimus promotes autophagic Aß clearance and exerts protective effects in cellular and animal models of AD, suggesting that temsirolimus administration may represent a new therapeutic strategy for AD treatment. Meanwhile, these findings emphasize the notion that many therapeutic agents possess pleiotropic actions aside from their main applications.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Antineoplásicos/farmacologia , Encéfalo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Sirolimo/análogos & derivados , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/genética , Animais , Antineoplásicos/uso terapêutico , Autofagia/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Células HEK293 , Humanos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos Transgênicos , Fármacos Neuroprotetores/uso terapêutico , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/metabolismoRESUMO
OBJECTIVE: To explore the characteristics of cognitive impairment and correlation analysis in patients with chronic renal failure (CRF). METHODS: The Addenbrooke's cognitive examination revised (ACE-R) scale was used to evaluate the cognitive function for 101 cases of chronic renal failure patients (group CRF) receiving outpatient and inpatient treatments and selected 30 individuals with normal renal function as normal controls (group NC) for cross-sectional analysis. T test, receiver operating characteristic (ROC) curve and other statistical methods were adopted for comparing differences. RESULTS: (1) Compared with group NC (83.4 ± 6.5), group CRF (71.9 ± 17.6) showed significantly statistical difference on Addenbrooke's cognitive examination revised (ACE-R) scale scores (P < 0.01); (2)compared with normal controls, the patients with CRF had significantly statistical difference on the scores of visual spatial ability (11.5 ± 3.2, 14.0 ± 3.0 respectively), language fluency (7.0 ± 2.6, 8.7 ± 1.9) (P < 0.01) and memory (18.1 ± 7.0, 21.5 ± 3.6 respectively) (P < 0.05); (3) the cognitive function of patients with CRF were significantly positive correlated with glomerular filtration rate (GFR) (r = 0.614, P < 0.01) and negatively correlated with the duration of illness (r = -0.492, P < 0.01); (4) From ROC curve and the area under curve (AUC), ACE-R scale (AUC = 0.680) showed a higher sensitivity than mini-mental state examination scale (AUC = 0.576) in assessing cognitive function in patients with CRF (P < 0.01). CONCLUSION: (1) Under similar basic conditions of age, level of education and background, CRF patients showed significant damage overall cognitive function, cognitive impairment in visual spatial ability, executive function, long-term memory and logical judgment ability was particularly impaired. Immediate and delayed memory, attention, orientation and language ability also manifested different degrees of decline; (2) the severity of cognitive impairment in patients with CFR was closely related with the level of GFR; (3) the ACE-R scale showed a higher sensitivity than mini-mental state examination scale in assessing cognitive function in patients with CRF.
Assuntos
Transtornos Cognitivos , Falência Renal Crônica , Testes Neuropsicológicos , Área Sob a Curva , Atenção , Estudos Transversais , Humanos , Memória , Curva ROCRESUMO
Efgartigimod was the first-in-class neonatal Fc receptor antagonist approved for the treatment of acetylcholine receptor antibody positive (AChR+), Myasthenia Gravis Foundation of America (MGFA) Class II-IV generalized myasthenia gravis (gMG) patients. As a novel therapy, the clinical experiences are still lacking, especially for the use of efgartigimod in manifest and impending myasthenic crisis (IMC). We reported three AChR+, gMG patients, two with myasthenic crisis (MC) and one with IMC, treated with efgartigimod. MGFA class, MG-Activity of Daily Living score (MG-ADL), Quantitative MG score (QMG), and Muscle Research Council sum score (MRC), concentration of anti-AChR antibody, IgG, globulin, and albumin, subsets of T and B lymphocyte were evaluated or measured before, during and after efgartigimod treatment. All patients showed fast and robust response to efgartigimod with marked improvement in MGFA, MG-ADL, QMG, and MRC scores. Patient 1 did not respond effectively to IVIg but was successfully rescued by add-on efgartigimod. She extubated at 7 days after the first infusion and got rid of NIV after 14-days treatment. Patient 2 and patient 3 directly used efgartigimod when symptoms were not ameliorated by adjusting of oral drugs. Patient 2 wean from BiPAP at seven days after the first infusion. Patient 3 in IMC status, overcame the severe dysphagia at three days after the first infusion. Clinical symptoms continued to improve 1-2 weeks after discharge. Concentration of anti-AChR antibody, IgG and globulin were remarkably reduced by efgartigimod treatment. Our study supported that efgartigimod could act as a fast-acting rescue therapy for patients with MC or IMC. Larger studies from multicenter are required to provide further evidence.
RESUMO
OBJECTIVE: Efgartigimod, a neonatal Fc receptor antagonist, facilitates antibody degradation including pathogenic IgGs. The ADAPT study demonstrated the tolerability and efficacy of efgartigimod in the treatment of generalized myasthenia gravis (gMG). However, very limited evidence is available for the Chinese population, and it remains inconclusive about which kind of patients are selected to preferentially receive efgartigimod in real-world settings. METHODS: This multicenter cohort study included gMG patients treated at 14 neuromuscular reference centers in China. The Myasthenia Gravis Activities of Daily Living (MG-ADL) score, immunosuppressants, and the incidence of treatment-emergent adverse events (TEAEs) were prospectively collected. RESULTS: Of the 1640 gMG admitted between September and December 2023, 61 (3.7%) received efgartigimod for at least one treatment cycle. Among them, 56 cases (92%) were anti-AChR antibody-positive, 4 were anti-MuSK antibody-positive, and 1 was seronegative. Thymoma-associated myasthenia gravis accounted for most cases (44%, 27 out of 61). The principal causes of efgartigimod initiation included MG acute exacerbation (MGAE) (48%, 29 out of 61) and myasthenic crisis (MC) (15%, 9 out of 61). Clinically meaningful improvement was rapidly achieved in 97% (58 out of 61) of patients at 1.3 ± 0.7 weeks. By week 12, the MG-ADL score reduced to 3.8 ± 4.1 (baseline:10.5 ± 5.2) for all participants, while it reduced to 4.0 ± 4.7 for MGAE and 3.8 ± 4.2 for MC, respectively. All but one TMG patient required no additional rescue therapies after efgartigimod initiation. 11.5% (7 out of 61) reported ≥1 TEAEs. INTERPRETATION: This multicenter cohort study demonstrated the efficacy of efgartigimod in rapid control of gMG. Patients with MGAE or MC would benefit from efgartigimod treatment.