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INTRODUCTION: The objective of this study was to identify relevant aspects for disability evaluation used in scientific literature for older adults. EVIDENCE ACQUISITION: We employed a systematic review methodology as outlined by the ICF Research Branch. The methodology consists of four steps: 1) identifying studies that focus on disability evaluation among older adults; 2) identifying disability measures used in these studies; 3) linking the concepts contained in these measures to ICF categories; 4) conducting frequency analysis. EVIDENCE SYNTHESIS: A total of 1942 concepts contained in disability measures from 137 studies were extracted. About 97.7% of the concepts could be linked, and 1862 concepts were linked to 52 second-level ICF categories. Of these, 44 categories found in at least 5% of the studies (range 5.1-85.4%) were selected to develop an outcome set that represents the relevant categories, including five categories in the Body Functions component and 39 categories from the Activities and Participation component. CONCLUSIONS: The relevant categories identified in our study reflect the essential areas that measure disability for older adults, providing a scientific basis for developing an ICF Core Set for disability evaluation, in combination with further empirical study and expert survey. Information from the outcome set is also valuable for providing a standardized minimal set for disability measurement, which can be used for data comparison across different studies and the development of an ICF-based disability measurement tool.
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Egg yolk antibodies (IgY) can be prepared in large quantities and economically, and have potential value as polyvalent passive vaccines (against multiple bacteria) in aquaculture. This study prepared live and inactivated Vibrio fluvialis IgY and immunized Carassius auratus prior to infection with V. fluvialis and Aeromonas hydrophila. The results showed that the two IgY antibodies hold effective passive protective rates against V. fluvialis and A. hydrophila in C. auratus. Further, the serum of C. auratus recognized the two bacteria in vitro, with a decrease in the bacteria content of the kidney. The phagocytic activity of C. auratus plasma was enhanced, with a decrease in the expression of inflammatory and antioxidant factors. Pathological sections showed that the kidney, spleen, and intestinal tissue structures were intact, and apoptosis and DNA damage decreased in kidney cells. Moreover, the immunoprotection conferred by the live V. fluvialis IgY was higher than that of the inactivated IgY. Addition, live V. fluvialis immunity induced IgY antibodies against outer membrane proteins of V. fluvialis were more than inactivated V. fluvialis immunity. Furthermore, heterologous immune bacteria will not cause infection, so V. fluvialis can be used to immunize chickens to obtain a large amount of IgY antibody. These findings suggest that the passive immunization effect of live bacterial IgY antibody on fish is significantly better than that of inactivated bacterial antibody, and the live V. fluvialis IgY hold potential value as polyvalent passive vaccines in aquaculture.
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Aeromonas hydrophila , Yema de Huevo , Enfermedades de los Peces , Inmunoglobulinas , Vibriosis , Vibrio , Animales , Inmunoglobulinas/inmunología , Inmunoglobulinas/sangre , Vibriosis/veterinaria , Vibriosis/inmunología , Vibriosis/prevención & control , Vibrio/inmunología , Enfermedades de los Peces/inmunología , Enfermedades de los Peces/prevención & control , Yema de Huevo/inmunología , Aeromonas hydrophila/inmunología , Carpa Dorada/inmunología , Infecciones por Bacterias Gramnegativas/inmunología , Infecciones por Bacterias Gramnegativas/veterinaria , Infecciones por Bacterias Gramnegativas/prevención & control , Anticuerpos Antibacterianos/sangre , Anticuerpos Antibacterianos/inmunología , Inmunización Pasiva/veterinaria , Vacunas Bacterianas/inmunología , Vacunas Bacterianas/administración & dosificaciónRESUMEN
Type I interferon (IFN-I) signalling is intricately involved in the pathogenesis of multiple infectious diseases, autoimmune diseases, and neurological diseases. Acute ischemic stroke provokes overactivation of IFN-I signalling within the injured brain, particularly in microglia. Following cerebral ischemia, damage-associated molecular patterns (DAMPs) released from injured neural cells elicit marked proinflammatory episodes within minutes. Among these, self-nucleic acids, including nuclear DNA and mitochondrial DNA (mtDNA), have been recognized as a critical alarm signal to fan the flames of neuroinflammation, predominantly via inducing IFN-I signalling activation in microglia. The concept of interferon-responsive microglia (IRM), marked by upregulation of a plethora of IFN-stimulated genes, has been emergingly elucidated in ischemic mouse brains, particularly in aged ones. Among the pattern recognition receptors responsible for IFN-I induction, cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) plays integral roles in potentiating microglia-driven neuroinflammation and secondary brain injury after cerebral ischemia. Here, we aim to provide an up-to-date review on the multifaceted roles of IFN-I signalling, the detailed molecular and cellular mechanisms leading to and resulting from aberrant IFN-I signalling activation after cerebral ischemia, and the therapeutic potentials. A thorough exploration of these above points will inform our quest for IFN-based therapies as effective immunomodulatory therapeutics to complement the limited repertoire of thrombolytic agents, thereby facilitating the translation from bench to bedside.
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Confronting the rising tide of ischemic stroke and its associated mortality and morbidity with ageing, prevention and acute management of ischemic stroke is of paramount importance. Mounting observational studies have established a non-linear association of vitamin D status with cardiovascular diseases, including ischemic stroke. Paradoxically, current clinical trials fail to demonstrate the cardiovascular benefits of vitamin D supplementation. We aim to update recent clinical and experimental findings on the role of vitamin D in the disease course of ischemic stroke, from its onset, progression, recovery, to recurrence, and the established and alternative possible pathophysiological mechanisms. This review justifies the necessities to address stroke etiological subtypes and focus on vitamin D-deficient subjects for investigating the potential of vitamin D supplementation as a preventive and therapeutic approach for ischemic stroke. Well-powered clinical trials are warranted to determine the efficacy, safety, timing, target individuals, optimal dosages, and target 25OHD concentrations of vitamin D supplementation in the prevention and treatment of ischemic stroke.
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Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Deficiencia de Vitamina D , Humanos , Vitamina D/uso terapéutico , Deficiencia de Vitamina D/complicaciones , Deficiencia de Vitamina D/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/complicaciones , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular/etiología , VitaminasRESUMEN
In the field of drug development and repositioning, the prediction of drug-disease associations is a critical task. A recently proposed method for predicting drug-disease associations based on graph convolution relies heavily on the features of adjacent nodes within the homogeneous network for characterizing information. However, this method lacks node attribute information from heterogeneous networks, which could hardly provide valuable insights for predicting drug-disease associations. In this study, a novel drug-disease association prediction model called DAHNGC is proposed, which is based on a graph convolutional neural network. This model includes two feature extraction methods that are specifically designed to extract the attribute characteristics of drugs and diseases from both homogeneous and heterogeneous networks. First, the DropEdge technique is added to the graph convolutional neural network to alleviate the oversmoothing problem and obtain the characteristics of the same nodes of drugs or diseases in the homogeneous network. Then, an automatic feature extraction method in the heterogeneous network is designed to obtain the features of drugs or diseases at different nodes. Finally, the obtained features are put into the fully connected network for nonlinear transformation, and the potential drug-disease pairs are obtained by bilinear decoding. Experimental results demonstrate that the DAHNGC model exhibits good predictive performance for drug-disease associations.
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Desarrollo de Medicamentos , Redes Neurales de la ComputaciónRESUMEN
Vitamin D deficiency is associated with worse clinical outcomes after ischemic stroke; nevertheless, the pathophysiological mechanisms remain largely unexplored. In this study, we characterized the molecular mechanisms of how vitamin D signaling modulated stroke progression in male mouse ischemia-reperfusion stroke models. We found that vitamin D receptor (VDR) exhibited a predominant upregulation in peri-infarct microglia/macrophages following cerebral ischemia. Conditional Vdr inactivation in microglia/macrophages markedly augmented infarct volumes and neurological deficits. VDR-deficient microglia/macrophages exhibited a more primed proinflammatory phenotype with substantial secretion of TNF-α and IFN-γ. These inflammatory cytokines further enhanced CXCL10 release from endothelial cells and blood-brain barrier disruption, and ultimately infiltration of peripheral T lymphocytes. Notably, blocking TNF-α and IFN-γ significantly ameliorated stroke phenotypes in Vdr conditional knockout mice. Collectively, VDR signaling in microglia/macrophages plays a crucial role in restraining ischemia-elicited neuroinflammation and stroke progression. Our findings delineate a novel mechanism underlying the association between vitamin D deficiency and poor stroke outcomes, and underline the significance of maintaining a functional vitamin D signaling in the management of acute ischemic stroke.
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Lesiones Encefálicas , Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Deficiencia de Vitamina D , Ratones , Masculino , Animales , Microglía , Accidente Cerebrovascular Isquémico/complicaciones , Enfermedades Neuroinflamatorias , Factor de Necrosis Tumoral alfa , Vitamina D , Células Endoteliales , Macrófagos , Accidente Cerebrovascular/complicaciones , Isquemia Encefálica/complicaciones , Isquemia Encefálica/genética , Lesiones Encefálicas/complicaciones , Modelos Animales de Enfermedad , Ratones Noqueados , Infarto , Deficiencia de Vitamina D/complicaciones , Infarto de la Arteria Cerebral Media/complicacionesRESUMEN
BACKGROUND: Combined central and peripheral demyelination (CCPD) is a disease of inflammatory demyelination that affects central and peripheral nerves simultaneously or temporally separated. OBJECTIVES: This study evaluated the clinical characteristics and the existence of antinodal/paranodal antibodies in patients with CCPD. METHODS: We reviewed the clinical manifestations, laboratory tests, electrophysiological examinations, neuroimaging findings, treatment, and prognosis of 31 patients with CCPD. Using a live cell-based assay, we tested antinodal/paranodal antibodies. RESULTS: The most common symptoms were motor weakness (83.3%), hyporeflexia (63.3%), and sphincter disturbance (58.1%). In total, 16.6% of patients had impaired vision symptoms, whereas 33.3% of patients had abnormal visual-evoked potentials (VEPs). A total of 21.1% (4/19) of patients were positive for anti-AQP4 (aquaporin 4) antibodies, 20.0% (2/10) of patients were positive for anti-NF155 (neurofascin-155) antibodies, and 10.0% (1/10) of patients were positive for anti-MAG (myelin-associated glycoprotein) antibodies. The effective rates of intravenous corticosteroids, intravenous immunoglobulins, and rituximab were 72.2%, 37.5%, and 100%, respectively. At the illness peak, 75% of patients with CCPD had an mRS (modified Rankin Scale) score of 4 or greater. In remission, 37.5% had an mRS score of 4 or greater. CONCLUSION: The clinical manifestations of patients with CCPD are highly heterogeneous. We recommend testing antinodal/paranodal antibodies for patients with CCPD.
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Autoanticuerpos , Enfermedades Desmielinizantes , Enfermedades Desmielinizantes/tratamiento farmacológico , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Pronóstico , RituximabRESUMEN
The social and public health burdens of ischemic stroke have been increasing worldwide. In addition to focal brain damage, acute ischemic stroke (AIS) provokes systemic abnormalities across peripheral organs. AIS profoundly alters the autonomic nervous system, hypothalamic-pituitary-adrenal axis, and immune system, which further yield deleterious organ-specific consequences. Poststroke systemic pathological alterations in turn considerably contribute to the progression of ischemic brain injury, which accounts for the substantial impact of systemic complications on stroke outcomes. This review provides a comprehensive and updated pathophysiological model elucidating the systemic effects of AIS. To address their clinical significance and inform stroke management, we also outline the resulting systemic complications at particular stages of AIS and highlight the mechanisms. Future therapeutic strategies should attempt to integrate the treatment of primary brain lesions with interventions for secondary systemic complications, and should be tailored to patient individualized characteristics to optimize stroke outcomes.
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Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Encéfalo , Humanos , Sistema Hipotálamo-Hipofisario , Sistema Hipófiso-SuprarrenalRESUMEN
Multiple sclerosis (MS) is an autoimmune disorder influenced by genetic and environmental factors. Many studies have provided insights into genetic factors' contribution to MS via large-scale genome-wide association study (GWAS) datasets. However, genetic variants identified to date do not adequately explain genetic risks for MS. This study hypothesized that novel MS risk genes could be identified by analyzing the MS-GWAS dataset using gene-based tests. We analyzed a GWAS dataset consisting of 9,772 MS cases and 17,376 healthy controls of European descent. We performed gene-based tests of 464,357 autosomal single nucleotide polymorphisms (SNPs) using two methods (PLINK and VEGAS2) and identified 28 shared genes satisfied p-value < 4.56 × 10-6. In further gene expression analysis, ten of the 28 genes were significantly differentially expressed in the MS case-control gene expression omnibus (GEO) database. GALC and HLA-DOB showed the most prominent differences in gene expression (two- and three-fold, respectively) between MS patients and healthy controls. In conclusion, our results reveal more information about MS hereditary characteristics and provide a basis for further studies.
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BACKGROUND: Neuroinflammation and immune responses occurring minutes to hours after stroke are associated with brain injury after acute ischemic stroke (AIS). PPARγ coactivator-1α (PGC-1α), as a master coregulator of gene expression in mitochondrial biogenesis, was found to be transiently upregulated in microglia after AIS. However, the role of microglial PGC-1α in poststroke immune modulation remains unknown. METHODS: PGC-1α expression in microglia from human and mouse brain samples following ischemic stroke was first determined. Subsequently, we employed transgenic mice with microglia-specific overexpression of PGC-1α for middle cerebral artery occlusion (MCAO). The morphology and gene expression profile of microglia with PGC-1α overexpression were evaluated. Downstream inflammatory cytokine production and NLRP3 activation were also determined. ChIP-Seq analysis was performed to detect PGC-1α-binding sites in microglia. Autophagic and mitophagic activity was further monitored by immunofluorescence staining. Unc-51-like autophagy activating kinase 1 (ULK1) expression was evaluated under the PGC-1α interaction with ERRα. Finally, pharmacological inhibition and genomic knockdown of ULK1 were performed to estimate the role of ULK1 in mediating mitophagic activity after ischemic stroke. RESULTS: PGC-1α expression was shortly increased after ischemic stroke, not only in human brain samples but also in mouse brain samples. Microglia-specific PGC-1α overexpressing mice exhibited significantly decreased neurologic deficits after ischemic injury, with reduced NLRP3 activation and proinflammatory cytokine production. ChIP-Seq analysis and KEGG pathway analysis revealed that mitophagy was significantly enhanced. PGC-1α significantly promoted autophagic flux and induced autolysosome formation. More specifically, the autophagic clearance of mitochondria was enhanced by PGC-1α regulation, indicating the important role of mitophagy. Pharmacological inhibition or knockdown of ULK1 expression impaired autophagic/mitophagic activity, thus abolishing the neuroprotective effects of PGC-1α. CONCLUSIONS: Mechanistically, in AIS, PGC-1α promotes autophagy and mitophagy through ULK1 and reduces NLRP3 activation. Our findings indicate that microglial PGC-1α may be a promising therapeutic target for AIS.
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Lesiones Encefálicas/patología , Isquemia Encefálica/metabolismo , Encéfalo/patología , Inflamación/patología , Microglía/metabolismo , Fármacos Neuroprotectores/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Anciano de 80 o más Años , Animales , Autofagia , Homólogo de la Proteína 1 Relacionada con la Autofagia/antagonistas & inhibidores , Homólogo de la Proteína 1 Relacionada con la Autofagia/metabolismo , Secuencia de Bases , Lesiones Encefálicas/complicaciones , Lesiones Encefálicas/genética , Isquemia Encefálica/complicaciones , Isquemia Encefálica/genética , Isquemia Encefálica/patología , Línea Celular , Femenino , Perfilación de la Expresión Génica , Genoma , Humanos , Inflamación/complicaciones , Inflamación/genética , Integrasas/metabolismo , Masculino , Ratones Endogámicos C57BL , Microglía/patología , Microglía/ultraestructura , Mitofagia , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Factores de Tiempo , Transcripción GenéticaRESUMEN
OBJECTIVE: To explore the level and influencing factors of frontline nurses' post-traumatic growth (PTG) during COVID-19 epidemic. METHODS: A cross-sectional survey was conducted in February 2020 in three hospitals in China. The Post-traumatic Growth Inventory (PTGI) was used to investigate the PTG of frontline nurses. Data on related factors, including demographic characteristics and subjective variables, were collected. The Event-Related Rumination Inventory was used to assess rumination. Pearson's or Spearman's correlation was calculated for bivariate analysis. Independent sample t-tests or one-way analysis of variance and multiple linear regression analysis were used to examine the related factors. RESULTS: A total of 179 frontline nurses were recruited, and 167 were included in the analyses. The mean PTG score was 70.53±17.26. The bivariate analyses showed that deliberate rumination was modestly positively correlated with PTG (r=0.557, p<0.01), while intrusive rumination had a modest negative correlation with PTG (r=-0.413, p<0.01). Multiple linear regression demonstrated that working years, self-confidence in frontline work, awareness of risk, psychological intervention or training during the epidemic and deliberate rumination were the main influencing factors of PTG among frontline nurses and accounted for 42.5% of the variance (F=31.626, p<0.001). CONCLUSIONS: The PTG of frontline nurses was at a medium to high level and was influenced by working years, self-confidence in frontline work, awareness of risk, psychological intervention or training and deliberate rumination. It is necessary to strengthen psychological guidance and training for frontline nurses and promote their deliberate rumination on epidemic events to improve their PTG.
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Adaptación Psicológica , COVID-19 , Enfermeras y Enfermeros/psicología , Estrés Laboral , Crecimiento Psicológico Postraumático , Trauma Psicológico , Adulto , Concienciación , China , Estudios Transversales , Epidemias , Femenino , Humanos , Masculino , Análisis de Regresión , SARS-CoV-2 , Autoimagen , PensamientoRESUMEN
OBJECTIVE: To expound the roles of mTOR and NF-kB signaling pathway in intermittent hypoxia (IH)-induced damage of hippocampal neurons. METHODS: For rat experiments, mTOR inhibitor (Rapamycin, Rapa) and NF-κB signaling inhibitor (ammonium pyrrolidine dithiocarbamate, PDTC) were applied to inhibit mTOR and NF-κB signaling, respectively. For neuron experiments, hippocampal neurons from rat were successfully cultured. Different concentrations of Rapa and PDTC were added to the cultured hippocampal neurons. Rat or primary hippocampal neurons were exposed to normoxic or IH conditions after administration of Rapa and PDTC. The effects of Rapa and PDTC administration on learning and memory ability of rats and hippocampal injury after IH exposure were assayed by Morris water maze and H&E staining. Electron microscope was utilized to examine primary hippocampal neuron ultrastructure changes after IH exposure and Rapa or PDTC administration. The expressions of NF-κB-p65, IκBα, IKKß, BDNF, TNF-α, IL-1ß, PSD-95 and SYN in hippocampal neurons were examined. RESULTS: Compared with normal control rats or neurons, IH-treated group had elevated expression levels of NF-kB, TNF-α and IL-1ß and suppressed expression level of BDNF, PSD-95 and SYN. These results were reversed upon pre-treatment with Rapa and PDTC. Furthermore, IκBα and IKKß expressions were down-regulated in IH group. No notable difference was manifested in PDTC pre-treatment group, while a prominent increase was shown after Rapa pre-administration. CONCLUSION: The administration of PDTC and Rapa could prevent IH-induced hippocampal neuron impairment, indicating that inhibition of the mTOR and NF-κB pathway may likely act as a therapeutic target for obstructive sleep apnea.
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Antioxidantes/farmacología , Hipocampo/metabolismo , Hipoxia/metabolismo , FN-kappa B/metabolismo , Neuronas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Pirrolidinas/farmacología , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Tiocarbamatos/farmacología , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Hipocampo/efectos de los fármacos , Hipoxia/tratamiento farmacológico , Masculino , FN-kappa B/antagonistas & inhibidores , Neuronas/efectos de los fármacos , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Apnea Obstructiva del Sueño/tratamiento farmacológico , Apnea Obstructiva del Sueño/metabolismo , Serina-Treonina Quinasas TOR/antagonistas & inhibidoresRESUMEN
Background: Intracerebral hemorrhage (ICH) is a fatal subtype of stroke that lacks effective therapy. Blood-brain barrier (BBB) damage is a hallmark of ICH-induced brain injury that leads to edema formation, leukocytes infiltration, influx of blood components into the perihematomal (PHE) region, and eventually brain injury. Astrocytes are essential for the formation and maintenance of the BBB by providing secreted molecules that contribute to the association between these cells. Sonic hedgehog (SHH) derived from astrocytes promotes the maturity and integrity of the BBB by upregulating tight junctions (TJs) in brain capillary endothelial cells (ECs). However, the effect of SHH on BBB in ICH has not been investigated. Methods: Cyclopamine (CYC) is a potent, selective inhibitor that specifically blocks the SHH signaling pathway. Here, we used pharmacological inhibitions (CYC and its derivatives) to determine a critical role of the SHH signaling pathway in promoting BBB integrity after ICH by mechanisms of regulating the TJ proteins in vivo and in vitro. Results: The expression of astrocytic SHH was upregulated in mouse brains after ICH. Compared with the vehicle-treated group, inhibition of the SHH signaling pathway with CYC and its derivatives treatments aggravated neurological function deficits, brain edema, hematoma volume, and BBB impairment by downregulating TJs in ECs through the SHH-Gli-1 axis in vivo and in vitro. Conclusions: SHH signaling pathway at the level of the BBB provides a barrier-promoting effect, suggesting that the SHH signaling pathway may function as a potential therapeutic target for restoring BBB function in ICH.
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BACKGROUND: Though increasing epidemiological studies have evaluated the correlation between serum calcium contents and Parkinson's disease (PD), the results are inconsistent. At present, whether there is a causal association between serum calcium content and PD remains undetermined. OBJECTIVE AND METHODS: This study was designed to explore the relationship between increased serum calcium contents and PD risk. In this present study, a Mendelian randomization trial was carried out using a large-scale serum calcium genome-wide association study (GWAS) dataset (N = 61,079, Europeans) and a large-scale PD GWAS dataset (N = 8,477, Europeans including 4,238 PD patients and 4,239 controls). Here, a total of four Mendelian randomization methods comprising weighted median, inverse-variance weighted meta-analysis (IVW), MR-Egger, and MR-PRESSO were used. RESULTS: Our data concluded that genetically higher serum calcium contents were not significantly related to PD. CONCLUSION: In conclusion, we provided genetic evidence that there was no direct causal relationship between serum calcium contents and PD. Hence, calcium supplementation may not result in reduced PD risk.
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The rs6647 variant G allele in SERPINA1 gene was reported to be associated with the risk of large artery atherosclerotic stroke (LAS), however, the mechanism remains unclear. Here, we performed a functional annotation of the rs6647 variant by using the software HaploReg version 4.1 (HaploReg v4.1). Next, the expression quantitative trait loci (eQTLs) analysis of multiple datasets was conducted for determining the association between the rs6647 and SERPINA1 expression in various tissues. Then, a case-control gene expression analysis was done using two independent ischemic stroke (IS) gene expression datasets. Finally, SERPINA1 expression in whole blood samples from 8 LAS patients and 14 healthy persons were compared. The functional annotation suggested that the rs6647 regulates gene expression in multiple human tissues especially in brain and blood. The eQTLs analysis revealed a significant association of the rs6647 G allele with increased expression of SERPINA1 gene only in whole blood. Compared with the controls, there was an increased expression of SERPINA1 gene in whole blood in both IS patients and LAS patients. SERPINA1 gene expression in whole blood bridges the rs6647 variant G allele with increased LAS risk, providing new insights into the mechanisms underlying role of the rs6647 in determining LAS risk.
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Aterosclerosis/genética , Expresión Génica/genética , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple/genética , Accidente Cerebrovascular/genética , alfa 1-Antitripsina/genética , Adulto , Alelos , Estudios de Casos y Controles , Femenino , Perfilación de la Expresión Génica/métodos , Genotipo , Humanos , Masculino , Sitios de Carácter Cuantitativo/genéticaRESUMEN
Rationale: Mitochondrial dysfunction and oxidative stress occur in vascular dementia (VaD), but the specific molecular mechanism regulating these events remains unclear. Peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α) is a master regulator for mitochondrial function. This study aims to investigate whether PGC-1α is involved in the pathophysiology of VaD. Methods: We firstly generated PGC-1αf/f Eno2-Cre mice to induce neuron-specific overexpression of PGC-1α by crossbreeding PGC-1αf/f mice with Eno2-cre mice. Then, the mice were subjected to bilateral common carotid artery stenosis to induce chronic cerebral hypoperfusion. Neurological function and hippocampal PGC-1α expression was evaluated. Next, RNA-Seq analysis and Seahorse assay were performed on the hippocampal neurons. In addition, mitochondrial antioxidants, uncoupling proteins, ROS production and the activation of glial cells were also measured. Results: Our results showed that hippocampal PGC-1α expression is down-regulated in the mouse VaD model induced by chronic cerebral hypoperfusion. In contrast, neuronal PGC-1α overexpression significantly ameliorated cognitive deficits. RNA-Seq analysis indicated that PGC-1α improved energy metabolism of neurons under hypoxic condition, and Seahorse assay confirmed that PGC-1α increases the metabolic activity of neurons. Further study demonstrated that PGC-1α boosted the expressions of mitochondrial antioxidants and uncoupling proteins (UCPs), including SOD2, Prx3, GPx1, UCP2, UCP4 and UCP5, which in turn reduced reactive oxygen species (ROS) production. Moreover, the activation of microglia and astrocytes was also found to decrease in the hippocampus. All of these changes greatly contributed to protect hippocampal neurons against ischemic insults. Conclusions: PGC-1α could suppress the excessive ROS and neuroinflammation in the hippocampus, opening up a potential therapeutic target for cognitive impairment.
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Disfunción Cognitiva/metabolismo , Demencia Vascular/metabolismo , Hipocampo/metabolismo , Mitocondrias/metabolismo , Neuronas/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/fisiología , Animales , Línea Celular , Modelos Animales de Enfermedad , Hipocampo/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/patología , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Fibroblast growth factor 23 (FGF23), which is involved in the regulation of vitamin D, is an emerging independent risk factor for cardiovascular diseases. Previous studies have demonstrated a positive association between FGF23 and stroke. In this study, we aimed to assess the association of FGF23 with ischemic stroke and its subtypes by applying a Mendelian randomization (MR) framework. Five genetic variants obtained from a genome-wide association study involving 16,624 European subjects were used as valid instruments of circulating FGF23 levels. MR was applied to infer the causality of FGF23 levels and the risk of ischemic stroke using data from the MEGASTROKE consortium. Subsequently, several MR analyses, including inverse-variance weighted meta-analysis, MR-Egger, weighted median estimate (WME), MR Pleiotropy Residual Sum and Outlier were performed. The heterogeneity test analysis, including Cochran's Q, I 2 test and leave-one-out analysis were also applied. Furthermore, potential horizontal/vertical pleiotropy was assessed. Lastly, the power of MR analysis was tested. Three validated variants were found to be associated with circulating FGF23 levels and were used for further investigation. We found that high expression level of FGF23 was not associated with any ischemic stroke. However, a causal association between genetically predicted FGF23 levels and the risk of large-artery atherosclerotic stroke (LAS) was significant, with an odds ratio of 1.74 (95% confidence interval = 1.08-2.81) per standard deviation increase in circulating FGF23 levels. Our findings provide support for the causal association between FGF23 and LAS, and therefore, offer potential therapeutic targets for LAS. The specific roles of FGF23 in LAS and associated molecules require further investigation.
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Etanercept biosimilar recombinant human tumour necrosis factor-α receptor II: IgG Fc fusion protein (rhTNFR-Fc, trade name Yisaipu) has shown good efficacy in the treatment of moderate-to-severe plaque psoriasis. To compare the efficacy and safety of rhTNFR-Fc plus methotrexate (MTX) and rhTNFR-Fc plus placebo in Chinese patients with moderate-to-severe plaque psoriasis. In this multicentre, randomized, placebo-controlled trial, patients with moderate-to-severe plaque psoriasis were enrolled and randomly assigned in a 1:1 ratio to receive rhTNFR-Fc plus MTX or rhTNFR-Fc plus placebo. The primary endpoint was the proportion of patients achieving Psoriasis Area and Severity Index improvement of at least 75% (PASI 75) from baseline at week 24. Adverse events (AEs) were recorded to evaluate safety. Efficacy analysis was performed using the intent-to-treat principle. A total of 466 patients were enrolled and randomly received rhTNFR-Fc plus MTX (combination group, n = 233) or rhTNFR-Fc plus placebo (monotherapy group, n = 233). PASI 75 at week 24 was significantly higher in the combination group than in the monotherapy group (81.86% vs. 65.50%, p < 0.001). Similar results were observed in other PASI improvement scores at week 12 [PASI 75, 62.39% vs. 44.54% (p < 0.001); PASI 50, 87.17% vs. 75.55% (p = 0.001); and PASI 90, 34.07% vs. 18.78% (p < 0.001)] and week 24 [PASI 50, 92.48% vs. 85.59% (p = 0.019); and PASI 90, 64.16% vs. 42.36% (p < 0.001)]. Significantly more patients had a static Physicians' Global Assessment of clear or almost clear in the combination group than in the monotherapy group at week 12 (26.46% vs. 12.50%, p < 0.001) and week 24 (62.38% vs. 40.83%, p < 0.001). The most common AEs in the two groups were upper respiratory tract infection and abnormal liver function. The combination therapy of rhTNFR-Fc plus MTX was an effective therapy for moderate-to-severe plaque psoriasis with an acceptable safety and tolerability profile, indicating that it was feasible and well tolerated for patients.
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Etanercept/uso terapéutico , Fragmentos Fc de Inmunoglobulinas/genética , Inmunoglobulina G/genética , Metotrexato/uso terapéutico , Psoriasis/tratamiento farmacológico , Receptores Tipo II del Factor de Necrosis Tumoral/genética , Proteínas Recombinantes de Fusión/genética , Adulto , Biosimilares Farmacéuticos , China , Método Doble Ciego , Quimioterapia Combinada , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Placebos , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
Ischemic stroke (IS) and Parkinson's disease (PD) are two neurological diseases that often strike individuals of advanced age. Although thought of as a disease of old age, PD can occur in younger patients. In many of these cases, genetic mutations underlie the disease. As with PD, stroke can also have a genetic component. Although many of the risk factors for IS are considered to be modifiable, a significant portion is not, suggesting that some of stroke risk factors may have a genetic origin. Large-scale genome-wide association studies (GWAS) have identified several IS and PD gene variants recently. Converging epidemiologic and pathological evidence suggests that IS and PD may be linked. However, it is still unclear whether these two conditions share a common mechanism. Here, we sought to determine the genetic mechanism underlying the possible association between IS and PD. We conducted a multi-step systemic analysis comprising (1) identification of IS and PD variants validated by known GWAS, (2) two separate gene-based tests using Versatile Gene-based Association Study 2 (VEGAS2) and PLINK, (3) a transcriptome-wide association study (TWAS), and (4) analyses of gene expression using an online tool in Gene Expression Omnibus. Our investigation revealed that IS and PD have in common five shared genes: GPX7, LBH, ZCCHC10, DENND2A, and NUDT14, which pass gene-based tests. Functionally, these genes are expressed differentially in IS and PD patients compared to neurologically healthy control subjects. This genetic overlap may provide clues on how IS and PD are linked mechanistically. This new genetic insight into these two diseases may be very valuable for narrowing the focus of future studies on the genetic basis of IS and PD and for developing novel therapies.
RESUMEN
AIMS: Although converging evidence from experimental and epidemiological studies indicates Alzheimer's disease (AD) and ischemic stroke (IS) are related, the genetic basis underlying their links is less well characterized. Traditional SNP-based genome-wide association studies (GWAS) have failed to uncover shared susceptibility variants of AD and IS. Therefore, this study was designed to investigate whether pleiotropic genes existed between AD and IS to account for their phenotypic association, although this was not reported in previous studies. METHODS: Taking advantage of large-scale GWAS summary statistics of AD (17,008 AD cases and 37,154 controls) and IS (10,307 IS cases and 19,326 controls), we performed gene-based analysis implemented in VEGAS2 and Fisher's meta-analysis of the set of overlapped genes of nominal significance in both diseases. Subsequently, gene expression analysis in AD- or IS-associated expression datasets was conducted to explore the transcriptional alterations of pleiotropic genes identified. RESULTS: 16 AD-IS pleiotropic genes surpassed the cutoff for Bonferroni-corrected significance. Notably, MS4A4A and TREM2, two established AD-susceptibility genes showed remarkable alterations in the spleens and brains afflicted by IS, respectively. Among the prioritized genes identified by virtue of literature-based knowledge, most are immune-relevant genes (EPHA1, MS4A4A, UBE2L3 and TREM2), implicating crucial roles of the immune system in the pathogenesis of AD and IS. CONCLUSIONS: The observation that AD and IS had shared disease-associated genes offered mechanistic insights into their common pathogenesis, predominantly involving the immune system. More importantly, our findings have important implications for future research directions, which are encouraged to verify the involvement of these candidates in AD and IS and interpret the exact molecular mechanisms of action.