RESUMO
Since the discovery of enterovirus A71 (EV-A71) half a century ago, it has been recognized as the cause of large-scale outbreaks of hand-foot-and-mouth disease worldwide, particularly in the Asia-Pacific region, causing great concern for public health and economic burdens. Detailed mechanisms on the modulation of immune responses after EV-A71 infection have not been fully known, and the lack of appropriate models hinders the development of promising vaccines and drugs. In the present study, NOD-scid IL2Rγ-/- (NSG) mice with a human immune system (humanized mice) at the age of 4 weeks were found to be susceptible to a human isolate of EV-A71 infection. After infection, humanized mice displayed limb weakness, which is similar to the clinical features found in some of the EV-A71-infected patients. Histopathological examination indicated the presence of vacuolation, gliosis, or meningomyelitis in brain stem and spinal cord, which were accompanied by high viral loads detected in these organs. The numbers of activated human CD4+ and CD8+ T cells were upregulated after EV-A71 infection, and EV-A71-specific human T cell responses were found. Furthermore, the secretion of several proinflammatory cytokines, such as human gamma interferon (IFN-γ), interleukin-8 (IL-8), and IL-17A, was elevated in the EV-A71-infected humanized mice. Taken together, our results suggested that the humanized mouse model permits insights into the human immune responses and the pathogenesis of EV-A71 infection, which may provide a platform for the evaluation of anti-EV-A71 drug candidates in the future.IMPORTANCE Despite causing self-limited hand-food-and-mouth disease in younger children, EV-A71 is consistently associated with severe forms of neurological complications and pulmonary edema. Nevertheless, only limited vaccines and drugs have been developed over the years, which is possibly due to a lack of models that can more accurately recapitulate human specificity, since human is the only natural host for wild-type EV-A71 infection. Our humanized mouse model not only mimics histological symptoms in patients but also allows us to investigate the function of the human immune system during infection. It was found that human T cell responses were activated, accompanied by an increase in the production of proinflammatory cytokines in EV-A71-infected humanized mice, which might contribute to the exacerbation of disease pathogenesis. Collectively, this model allows us to delineate the modulation of human immune responses during EV-A71 infection and may provide a platform to evaluate anti-EV-A71 drug candidates in the future.
Assuntos
Linfócitos T CD8-Positivos/patologia , Enterovirus Humano A/patogenicidade , Infecções por Enterovirus/patologia , Feto/patologia , Carga Viral/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Células Cultivadas , Enterovirus Humano A/isolamento & purificação , Infecções por Enterovirus/imunologia , Infecções por Enterovirus/virologia , Feto/imunologia , Feto/virologia , Humanos , Mediadores da Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCIDRESUMO
Superparamagnetic iron oxide nanoparticles (SPIONs) have been widely investigated for their biomedical applications in magnetic resonance imaging, targeting therapy, cell labeling, etc. It has been well documented that macrophages produce interleukin (IL)-1ß via several signaling pathways, such as inflammasome activation in response to particles including silica, asbestos and urea crystals with lipopolysaccharide priming. However, the size and dose effects of SPIONs on macrophages and the mechanisms remain unclear. In this study, we explored the cytotoxicity and mechanisms of the synthesized SPIONs with different size distributions of 30, 80 and 120 nm, and compared their potential capability in inducing IL-1ß release in mouse bone marrow-derived macrophages (BMMs). We found that SPIONs induced IL-1ß release in a size- and dose-dependent manner, in which the smallest SPIONs triggered the highest IL-1ß in BMMs. When cellular uptake of SPIONs was inhibited by the actin polymerization inhibitor, cytochalasin D, SPION-induced IL-1ß release was suppressed in BMMs. Preventing lysosome damage with bafilomycin A1 or CA-074-Me also counteracted SPION-induced IL-1ß release. Moreover, SPION-activated IL-1ß release was also attenuated by reactive oxygen species scavengers, diphenylene iodonium or N-acetylcysteine. Our results elucidated the effects of size and dose on the cytotoxicity and mechanisms of IL-1ß release of SPIONs on macrophages, which facilitate the theoretical and experimental application of SPIONs in biotechnology and biomedicine in the future.
Assuntos
Mediadores da Inflamação/metabolismo , Interleucina-1beta/metabolismo , Macrófagos/efeitos dos fármacos , Nanopartículas de Magnetita/toxicidade , Citoesqueleto de Actina/efeitos dos fármacos , Citoesqueleto de Actina/metabolismo , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Feminino , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Tamanho da Partícula , Fagocitose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Via SecretóriaRESUMO
With the rapid pace of industrialization and the increasing intensity of human activities, the global climate change and energy crisis have reached a heightened level of severity. Consequently, achieving an early peak in carbon emissions has become an imperative in addressing this pressing issue. Particularly, coastal provinces, known for their developed economies, high population density, and substantial building energy consumption, have emerged as significant contributors to carbon emissions. Notably, public buildings, serving as critical constituents of the construction industry, possess immense potential for both energy conservation and emissions reduction. In light of this, the present study focuses on Fujian Province, situated along the coast, and constructs a carbon emission estimation model for public buildings based on the Kaya identity. This model takes into account various factors specific to Fujian Province, including population characteristics, economic conditions, tertiary industry development, public building area, and energy consumption. Through scenario analysis, the study projects that the year of peak carbon emissions for public buildings in Fujian Province is estimated to be 2030, 2035, and 2040 under low-carbon, baseline, and high-carbon scenarios respectively. The corresponding peak carbon emission levels are anticipated to reach 23.62 million t, 24.18 million t, and 24.76 million t CO2. Lastly, based on local policies and actual conditions, the study proposes a set of policy measures and feasible approaches tailored to Fujian Province, aiming to achieve an early peak in carbon emissions.
Assuntos
Carbono , China , Carbono/análise , Humanos , Dióxido de Carbono/análise , Mudança Climática , Modelos TeóricosRESUMO
Bursa of Fabricius (BOF) is a unique immune organ of birds. It is the place where lymphocytes develop, differentiate and mature. Young chicken BOF is susceptible to infection and damage, and even atrophy, causing immune suppression, and bringing huge economic losses to chicken production. Therefore, studying the regulatory mechanism of chicken bursa development is of great practical significance for disease prevention and diagnosis. Jinhu silky chicken (JSC) is a local excellent breed in the Fujian Province of China and with strong disease resistance. However, studies on the disease resistance of JSC are scarce. This study aimed to provide a theoretical basis for reproduction and disease control of JSC. Developmental features of the structure and the IL-21-positive cell (IL-21 PC) distribution on the BOF in JSC were measured from 7 to 300 days of age. Bursas of chicken (n = 36) were taken at 7, 35, 70, 150, 240, and 300 days of age for preparation of paraffin sections and stained with hematoxylin-eosin (HE) and immunohistochemistry. The microstructure of JSC's BOF was similar to that of other poultry. The cortical-medullary boundary of the bursa nodule was not obvious at 7 days of age, but it was evident after 35 days of age. Before 70 days of age, IL-21 positive cells (PC) were scattered on the BOF. At 150 days of age, the number of IL-21 PC in the bursa were the highest and the nuclei were clear. The level of IL-21 PC gradually decreased with age. The BOF degenerated and disappeared in 300-day-old JSC. The histological structure of the BOF was similar to that of other poultry. IL-21 PC were widespread in the BOF at different ages, but the numbers were different.
Assuntos
Bolsa de Fabricius , Galinhas , Animais , Bolsa de Fabricius/patologia , Resistência à DoençaRESUMO
Introduction: Temporal lobe epilepsy (TLE) is the most common subtype of epilepsy in adults and is characterized by neuronal loss, gliosis, and sprouting mossy fibers in the hippocampus. But the mechanism underlying neuronal loss has not been fully elucidated. A new programmed cell death, cuproptosis, has recently been discovered; however, its role in TLE is not clear. Methods: We first investigated the copper ion concentration in the hippocampus tissue. Then, using the Sample dataset and E-MTAB-3123 dataset, we analyzed the features of 12 cuproptosis-related genes in TLEs and controls using the bioinformatics tools. Then, the expression of the key cuproptosis genes were confirmed using real-time PCR and immunohistochemical staining (IHC). Finally, the Enrichr database was used to screen the small molecules and drugs targeting key cuproptosis genes in TLE. Results: The Sample dataset displayed four differentially expressed cuproptosis-related genes (DECRGs; LIPT1, GLS, PDHA1, and CDKN2A) while the E-MTAB-3123 dataset revealed seven DECRGs (LIPT1, DLD, FDX1, GLS, PDHB, PDHA1, and DLAT). Remarkably, only LIPT1 was uniformly upregulated in both datasets. Additionally, these DECRGs are implicated in the TCA cycle and pyruvate metabolism-both crucial for cell cuproptosis-as well as various immune cell infiltrations, especially macrophages and T cells, in the TLE hippocampus. Interestingly, DECRGs were linked to most infiltrating immune cells during TLE's acute phase, but this association considerably weakened in the latent phase. In the chronic phase, DECRGs were connected with several T-cell subclasses. Moreover, LIPT1, FDX1, DLD, and PDHB were related to TLE identification. PCR and IHC further confirmed LIPT1 and FDX1's upregulation in TLE compared to controls. Finally, using the Enrichr database, we found that chlorzoxazone and piperlongumine inhibited cell cuproptosis by targeting LIPT1, FDX1, DLD, and PDHB. Conclusion: Our findings suggest that cuproptosis is directly related to TLE. The signature of cuproptosis-related genes presents new clues for exploring the roles of neuronal death in TLE. Furthermore, LIPT1 and FDX1 appear as potential targets of neuronal cuproptosis for controlling TLE's seizures and progression.
RESUMO
Emergence of dysmorphic neurons is the primary pathology in focal cortical dysplasia (FCD) associated pediatric intractable epilepsy; however, the etiologies related to the development and function of dysmorphic neurons are not fully understood. Our previous studies revealed that the expression of vascular endothelial growth factor-C (VEGF-C) and corresponding receptors VEGFR-2, VEGFR-3 was increased in the epileptic lesions of patients with tuberous sclerosis complex or mesial temporal lobe epilepsy. Here, we showed that the expression of VEGF-C, VEGFR-2, and VEGFR-3 was increased at both mRNA and protein levels in patients with cortical lesions of type I, IIa, and IIb FCD. The immunoreactivity of VEGF-C, VEGFR-2 and VEGFR-3 was located in the micro-columnar neurons in FCD type I lesions, dysplastic neurons (DNs) in FCD type IIa lesions, balloon cells (BCs) and astrocytes in FCD type IIb lesions. Additionally, the amplitude of evoked-EPSCs (eEPSC) mediated by NMDA receptor, the ratio of NMDA receptor- and AMPA receptor-mediated eEPSC were increased in the dysmorphic neurons of FCD rats established by prenatal X-ray radiation. Furthermore, NMDA receptor mediated current in dysmorphic neurons was further potentiated by exogenous administration of VEGF-C, however, could be antagonized by ki8751, the blocker of VEGFR-2. These results suggest that VEGF-C system participate in the pathogenesis of cortical lesions in patients with FCD in association with modulating NMDA receptor-mediated currents.
Assuntos
Malformações do Desenvolvimento Cortical , Fator C de Crescimento do Endotélio Vascular , Animais , Epilepsia , Humanos , Malformações do Desenvolvimento Cortical/patologia , Malformações do Desenvolvimento Cortical do Grupo I , Ratos , Receptores de N-Metil-D-Aspartato , Fator C de Crescimento do Endotélio Vascular/genética , Fator C de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
Objective: Central nervous system infections (CNSIs), especially viral encephalitis and meningitis, are well-recognized causes of medically refractory epilepsy. Although surgery is an effective and durable intervention against these infections, the seizure control outcomes described in previous surgical series have been variable. Accordingly, it is not clear which variables are most valuable in predicting seizure control following surgery for CNSI. The aim of this meta-analysis was to identify the predictors of favorable surgical outcomes in CNSI-related epilepsy. Methods: The PubMed, EMBASE, Cochrane Library, WANGFANG, VIP, CBM, and CNKI databases were searched for studies according to the inclusion criteria. Prognostic factors, surgical outcomes, and patient characteristics were extracted. Heterogeneity was detected by the I2 and Q statistics. Results: Seventeen studies were included in our meta-analysis. Eight predictors of favorable outcomes (Engel Class I/II) were determined, including abnormal MRI findings, meningitis, temporal location only, regional ictal pattern, unilateral ictal pattern, older age at epilepsy, longer silent period, and longer time from infection, as follows: OR = 3.34 (95% CI 1.44-7.74), OR = 0.31 (95% CI 0.13-0.70), OR = 0.34 (95% CI 0.16-0.74), OR = 5.65 (95% CI 1.75-18.30), and OR = 9.53 (95% CI 2.36-38.48), respectively, and MD = 2.15 (95% CI 0.20-4.11), MD = 2.40 (95% CI 0.09-4.70), and MD = 8.49 (95% CI 1.50-15.48), respectively. A subgroup analysis found the following associations: regional and unilateral ictal patterns in viral encephalitis, a younger age at infection in parasitic encephalopathy, an older age at surgery, a longer time from onset, and a longer time from infection in unexplained meningitis. A sensitivity analysis restricted to studies that included each variable yielded robust results. Little evidence of publication bias was observed. Conclusions: This meta-analysis suggests that abnormal MRI findings, meningitis, temporal location only, regional and unilateral ictal patterns, older age at epilepsy, longer silent period, and longer time from infection are predictive factors in patients with favorable surgical outcomes in CNSI-related epilepsy. In addition, different infective agents influenced the results in regional and unilateral ictal patterns in ictal electroencephalography, as well as the relationship between age at infection and surgery and the time from epilepsy onset and infection.