RESUMO
Antigen presentation defects in tumors are prevalent mechanisms of adaptive immune evasion and resistance to cancer immunotherapy, whereas how tumors evade innate immunity is less clear. Using CRISPR screens, we discovered that IGSF8 expressed on tumors suppresses NK cell function by interacting with human KIR3DL2 and mouse Klra9 receptors on NK cells. IGSF8 is normally expressed in neuronal tissues and is not required for cell survival in vitro or in vivo. It is overexpressed and associated with low antigen presentation, low immune infiltration, and worse clinical outcomes in many tumors. An antibody that blocks IGSF8-NK receptor interaction enhances NK cell killing of malignant cells in vitro and upregulates antigen presentation, NK cell-mediated cytotoxicity, and T cell signaling in vivo. In syngeneic tumor models, anti-IGSF8 alone, or in combination with anti-PD1, inhibits tumor growth. Our results indicate that IGSF8 is an innate immune checkpoint that could be exploited as a therapeutic target.
Assuntos
Imunidade Inata , Imunoterapia , Células Matadoras Naturais , Neoplasias , Animais , Feminino , Humanos , Camundongos , Apresentação de Antígeno , Linhagem Celular Tumoral , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Neoplasias/imunologia , Neoplasias/terapiaRESUMO
Virus infection modulates both host immunity and host genomic stability. Poly(ADP-ribose) polymerase 1 (PARP1) is a key nuclear sensor of DNA damage, which maintains genomic integrity, and the successful application of PARP1 inhibitors for clinical anti-cancer therapy has lasted for decades. However, precisely how PARP1 gains access to cytoplasm and regulates antiviral immunity remains unknown. Here, we report that DNA virus induces a reactive nitrogen species (RNS)-dependent DNA damage and activates DNA-dependent protein kinase (DNA-PK). Activated DNA-PK phosphorylates PARP1 on Thr594, thus facilitating the cytoplasmic translocation of PARP1 to inhibit the antiviral immunity both in vitro and in vivo. Mechanistically, cytoplasmic PARP1 interacts with and directly PARylates cyclic GMP-AMP synthase (cGAS) on Asp191 to inhibit its DNA-binding ability. Together, our findings uncover an essential role of PARP1 in linking virus-induced genome instability with inhibition of host immunity, which is of relevance to cancer, autoinflammation, and other diseases.
Assuntos
Antivirais , Nucleotidiltransferases , Antivirais/farmacologia , Citoplasma/genética , Citoplasma/metabolismo , DNA , Dano ao DNA , Instabilidade Genômica , Humanos , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo , Poli(ADP-Ribose) Polimerase-1/metabolismoRESUMO
Mycobacterium tuberculosis is an intracellular pathogen that uses several strategies to interfere with the signalling functions of host immune molecules. Many other bacterial pathogens exploit the host ubiquitination system to promote pathogenesis1,2, but whether this same system modulates the ubiquitination of M. tuberculosis proteins is unknown. Here we report that the host E3 ubiquitin ligase ANAPC2-a core subunit of the anaphase-promoting complex/cyclosome-interacts with the mycobacterial protein Rv0222 and promotes the attachment of lysine-11-linked ubiquitin chains to lysine 76 of Rv0222 in order to suppress the expression of proinflammatory cytokines. Inhibition of ANAPC2 by specific short hairpin RNA abolishes the inhibitory effect of Rv0222 on proinflammatory responses. Moreover, mutation of the ubiquitination site on Rv0222 impairs the inhibition of proinflammatory cytokines by Rv0222 and reduces virulence during infection in mice. Mechanistically, lysine-11-linked ubiquitination of Rv0222 by ANAPC2 facilitates the recruitment of the protein tyrosine phosphatase SHP1 to the adaptor protein TRAF6, preventing the lysine-63-linked ubiquitination and activation of TRAF6. Our findings identify a previously unrecognized mechanism that M. tuberculosis uses to suppress host immunity, and provide insights relevant to the development of effective immunomodulators that target M. tuberculosis.
Assuntos
Proteínas de Bactérias/imunologia , Proteínas de Bactérias/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , Ubiquitinação , Ciclossomo-Complexo Promotor de Anáfase/química , Animais , Subunidade Apc2 do Ciclossomo-Complexo Promotor de Anáfase/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Células Cultivadas , Citocinas/antagonistas & inibidores , Citocinas/imunologia , Citocinas/metabolismo , Feminino , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Lisina/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Transdução de Sinais , Fator 6 Associado a Receptor de TNF/antagonistas & inibidores , Fator 6 Associado a Receptor de TNF/metabolismo , Fator de Transcrição AP-1/metabolismo , Tuberculose/microbiologia , Virulência/imunologiaRESUMO
Acrylamide (ACR) is a common industrial contaminant with endocrine-disrupting toxicity. Numerous studies have indicated that females and diabetics are more sensitive to environmental contaminants. However, it remains unknown whether female diabetics are susceptible to ACR-induced toxicity and its potential mechanisms. Thus, the female ACR-exposure diabetic Balb/c mice model was established to address these issues. Results showed that ACR could induce liver injury in normal mice and cause more serious inflammatory cell infiltration, hepatocyte volume increase, and fusion in diabetic mice liver. Meanwhile, ACR could lead to exacerbation of diabetic symptoms in diabetic mice by disturbing the glucose and lipid metabolism in the liver, which mainly manifests as the accumulation of liver glycogen and liver lipids, the reduction of the activity/content of glycolytic and metabolizing enzyme as well as pentose phosphatase, upregulation of the gene expression in fatty acid transporter and gluconeogenesis, and downregulation of the gene expression in fatty acid synthesis and metabolism. Moreover, ACR exposure could induce oxidative stress, inflammation, and endoplasmic reticulum stress in the liver by a decrease in hepatic antioxidant enzyme activity and antioxidant content, an increase in inflammatory factor levels, and a change in the related protein expression of endoplasmic reticulum stress (ERS) and apoptosis-related pathways in diabetic mice. Statistical analysis results revealed that ACR-induced liver injury was highly correlated with inflammation and oxidative stress, and ERS and diabetic mice had a higher risk of liver injury than normal mice. Overall results suggested that female diabetic mice easily suffer from ACR-induced toxicity, and the reason was that ACR could induce further damage to the liver by worsening the condition of inflammation, oxidative stress, and ERS in the liver.
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Acrilamida , Diabetes Mellitus Experimental , Estresse do Retículo Endoplasmático , Camundongos Endogâmicos BALB C , Animais , Feminino , Acrilamida/toxicidade , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Camundongos , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Estresse Oxidativo/efeitos dos fármacosRESUMO
Aberrant activation of stimulator of interferon genes (STING) is tightly associated with multiple types of disease, including cancer, infection, and autoimmune diseases. However, the development of STING modulators for the therapy of STING-related diseases is still an unmet clinical need. We employed a high-throughput screening approach based on the interaction of small-molecule chemical compounds with recombinant STING protein to identify functional STING modulators. Intriguingly, the cyclin-dependent protein kinase (CDK) inhibitor Palbociclib was found to directly bind STING and inhibit its activation in both mouse and human cells. Mechanistically, Palbociclib targets Y167 of STING to block its dimerization, its binding with cyclic dinucleotides, and its trafficking. Importantly, Palbociclib alleviates autoimmune disease features induced by dextran sulphate sodium or genetic ablation of three prime repair exonuclease 1 (Trex1) in mice in a STING-dependent manner. Our work identifies Palbociclib as a novel pharmacological inhibitor of STING that abrogates its homodimerization and provides a basis for the fast repurposing of this Food and Drug Administration-approved drug for the therapy of autoinflammatory diseases.
Assuntos
Doenças Autoimunes , Neoplasias , Animais , Doenças Autoimunes/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Neoplasias/metabolismo , Piperazinas/farmacologia , Piridinas/farmacologia , Piridinas/uso terapêuticoRESUMO
Chinese seabass (Lateolabrax maculatus) stands out as one of the most sought-after and economically significant species in aquaculture within China. Diseases of L. maculatus occur frequently due to the degradation of the germplasm, the aggravation of environmental pollution of water, and the reproduction of pathogenic microorganisms, inflicting considerable economic losses on the Chinese seabass industry. The Myxovirus resistance (Mx) gene plays pivotal roles in the antiviral immune response ranging from mammals to fish. However, the function of the Mx gene in L. maculatus is still unknown. Firstly, the origin and evolutionary history of Mx proteins was elucidated in this study. Subsequently, an Mx gene from L. maculatus (designed as LmMxA gene) was identified, and its functions in combating antiviral and antibacterial threats were investigated. Remarkably, our findings suggested that while Mx group genes were present in chordates, DYN group genes were present in everything from single-celled animals to humans. Furthermore, our investigation revealed that the LmMxA mRNA level increased in the kidney, spleen and liver subsequent to Vibrio anguillarum and poly(I:C) challenged. Immunofluorescence analysis indicated that LmMxA is predominantly localization in the nucleus and the cytoplasm. Notably, the expression of MAVS, IFN1 and Mx1 increased when LmMxA was overexpression within the EPC cells. Moreover, through assessment via cytopathic effect (CPE), virus titer, and antibacterial activity, it becomes evident that LmMxA exerts a dual role in bolstering both antiviral and antibacterial immune responses. These compelling findings laid the foundation for further exploring the mechanism of LmMxA in response to innate immunity of L. maculatus.
Assuntos
Doenças dos Peixes , Proteínas de Peixes , Imunidade Inata , Proteínas de Resistência a Myxovirus , Filogenia , Animais , Proteínas de Resistência a Myxovirus/genética , Proteínas de Resistência a Myxovirus/metabolismo , Proteínas de Resistência a Myxovirus/imunologia , Doenças dos Peixes/imunologia , Doenças dos Peixes/virologia , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Proteínas de Peixes/química , Imunidade Inata/genética , Regulação da Expressão Gênica/imunologia , Vibrioses/imunologia , Vibrioses/veterinária , Vibrio/fisiologia , Sequência de Aminoácidos , Alinhamento de Sequência/veterinária , Poli I-C/farmacologia , Bass/imunologia , Bass/genética , Perfilação da Expressão Gênica/veterinária , Evolução MolecularRESUMO
Accurate repair of DNA double-stranded breaks by homologous recombination preserves genome integrity and inhibits tumorigenesis. Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor that activates innate immunity by initiating the STING-IRF3-type I IFN signalling cascade1,2. Recognition of ruptured micronuclei by cGAS links genome instability to the innate immune response3,4, but the potential involvement of cGAS in DNA repair remains unknown. Here we demonstrate that cGAS inhibits homologous recombination in mouse and human models. DNA damage induces nuclear translocation of cGAS in a manner that is dependent on importin-α, and the phosphorylation of cGAS at tyrosine 215-mediated by B-lymphoid tyrosine kinase-facilitates the cytosolic retention of cGAS. In the nucleus, cGAS is recruited to double-stranded breaks and interacts with PARP1 via poly(ADP-ribose). The cGAS-PARP1 interaction impedes the formation of the PARP1-Timeless complex, and thereby suppresses homologous recombination. We show that knockdown of cGAS suppresses DNA damage and inhibits tumour growth both in vitro and in vivo. We conclude that nuclear cGAS suppresses homologous-recombination-mediated repair and promotes tumour growth, and that cGAS therefore represents a potential target for cancer prevention and therapy.
Assuntos
Núcleo Celular/metabolismo , Transformação Celular Neoplásica/patologia , Neoplasias/metabolismo , Neoplasias/patologia , Nucleotidiltransferases/metabolismo , Reparo de DNA por Recombinação , Transporte Ativo do Núcleo Celular , Adulto , Animais , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Núcleo Celular/enzimologia , Quebras de DNA de Cadeia Dupla , Dano ao DNA , Feminino , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas de Neoplasias/metabolismo , Neoplasias/genética , Nucleotidiltransferases/deficiência , Fosforilação , Ftalazinas/farmacologia , Piperazinas/farmacologia , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Poli(ADP-Ribose) Polimerase-1/metabolismo , Ligação Proteica/efeitos dos fármacos , Reparo de DNA por Recombinação/genética , Quinases da Família src/metabolismoRESUMO
Environmental endocrine disrupting chemicals (EDCs), are a type of exogenous organic pollutants, are ubiquitous in natural aquatic environments. Currently, in addition to neurological, endocrine, developmental and reproductive toxicity, ecotoxicology studies on immunotoxicity are receiving increasing attention. In this review, the composition of immune system of zebrafish, the common indicators of immunotoxicity, the immunotoxicity of EDCs and their molecular mechanism were summarized. We reviewed the immunotoxicity of EDCs on zebrafish mainly in terms of immune organs, immunocytes, immune molecules and immune functions, meanwhile, the possible molecular mechanisms driving these effects were elucidated in terms of endocrine disruption, dysregulation of signaling pathways, and oxidative damage. Hopefully, this review will provide a reference for further investigation of the immunotoxicity of EDCs.
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Disruptores Endócrinos , Animais , Disruptores Endócrinos/toxicidade , Peixe-Zebra , Sistema Imunitário , Reprodução , EcotoxicologiaRESUMO
Tetrabromobisphenol A bis(2-hydroxyethyl) ether (TBBPA-DHEE) is the major TBBPA derivative. It has been detected in different environmental samples. Previous studies show that TBBPA-DHEE caused neurotoxicity in rats. In this study, juvenile zebrafish were exposed to various concentrations of TBBPA-DHEE to ascertain the potential neurotoxicity of TBBPA-DHEE, the chemical, and its possible molecular mechanism of action. Behavioral analysis revealed that TBBPA-DHEE could significantly increase the swimming distance and speed in the 1.5 mg/L group compared to the control. In contrast, the swimming distance and speed were significantly reduced in the 0.05 and 0.3 mg/L groups, affecting learning, memory, and neurodevelopment. Similarly, TBBPA-DHEE exposure caused a concentration-dependent significant increase in the levels of excitatory neurotransmitters, namely, dopamine, norepinephrine, and epinephrine, which could be attributed to the change observed in zebrafish behavior. This demonstrates the neurotoxicity of TBBPA-DHEE on juvenile zebrafish. The concentration-dependent increase in the IBR value revealed by the IBR index reveals the noticeable neurotoxic effect of TBBPA-DHEE. Transcriptomic analysis shows that TBBPA-DHEE exposure activated the PPAR signaling pathways, resulting in a disturbance of fatty acid (FA) metabolism and changes in the transcript levels of genes involved in these pathways, which could lead to lipotoxicity and hepatotoxicity. Our findings demonstrate a distinct endocrine-disrupting response to TBBPA-DHEE exposure, possibly contributing to abnormal behavioral alterations. This study provides novel insights into underlying the mechanisms and effects of TBBPA-DHEE on aquatic organisms, which may be helpful forenvironmental/human health risk assessments of the emerging pollutant.
Assuntos
Retardadores de Chama , Peixe-Zebra , Humanos , Ratos , Animais , Peixe-Zebra/metabolismo , Éteres/análise , Éteres/metabolismo , Análise de Sequência de RNA , Retardadores de Chama/toxicidade , Retardadores de Chama/análise , Retardadores de Chama/metabolismoRESUMO
Decabrominated diphenyl ether (BDE-209) is a typical persistent organic pollutant that can cross the placental barrier, increasing the exposure risk for offspring. Norepinephrine (NE) from nerve terminals and acetylcholine (Ach) can bind to specific receptors on immune cells, inhibit the immune function of the body then cause immunotoxicity. However, whether maternal exposure to BDE-209 could lead to immunotoxicity in the offspring by acting on the sympathetic and parasympathetic nervous systems remains unclear. In view of this, the pregnancy and lactation rat BDE-209 exposure model was established and the results demonstrated that pregnancy and lactation BDE-209 exposure could induce immunotoxicity to female offspring via affecting immunopathology (hematological and biochemical parameters, organ indices, and spleen histopathological), decreasing humoral immunity (serum hemolysin, immunoglobulins, and cytokine productions), damaging cellular immunity (splenic lymphocytes and spleen cytokine productions), and restraining nonspecific immunity. Moreover, a dramatically significant correlation was observed between spleen nerve indices and immunity indices. Additionally, the mechanism revealed that maternal BDE-209 exposure caused offspring immunotoxicity through (1) activating MHC/PKCθ/NF-κB pathway; (2) promoting sympathetic nervous pathway, by upregulating the expression of ß2AR protein, which in turn elevating cAMP, following activate PKA and phosphorylate CREB, ultimately leading to immunotoxicity;(3) activating parasympathetic nerve pathway by reducing the binding with Ach and α7nAchR, upregulating the expression of JAK2 and phosphorylating STAT3, induced immunotoxicity of female offspring.
Assuntos
Éteres Difenil Halogenados , Exposição Materna , Efeitos Tardios da Exposição Pré-Natal , Animais , Feminino , Gravidez , Éteres Difenil Halogenados/toxicidade , Exposição Materna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/imunologia , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Ratos , Baço/efeitos dos fármacos , Baço/imunologia , Sistema Nervoso Autônomo/efeitos dos fármacos , Ratos Sprague-Dawley , Poluentes Ambientais/toxicidade , Masculino , Citocinas/metabolismoRESUMO
PURPOSE: This study aimed to improve the safety and accuracy of radiotherapy by establishing tolerance (TL) and action (AL) limits for the gamma index in patient-specific quality assurance (PSQA) for intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT) using SunCHECK software, as per AAPM TG-218 report recommendations. METHODS: The study included 125 patients divided into six groups by treatment regions (H&N, thoracic and pelvic) and techniques (VMAT, IMRT). SunCHECK was used to calculate the gamma passing rate (%GP) and dose error (%DE) for each patient, for the planning target volume and organs at risk (OARs). The TL and AL were then determined for each group according to TG-218 recommendations. We conducted a comprehensive analysis to compare %DE among different groups and examined the relationship between %GP and %DE. RESULTS: The TL and AL of all groups were more stringent than the common standard as defined by the TG218 report. The TL and AL values of the groups differed significantly, and the values for the thoracic groups were lower for both VMAT and IMRT. The %DE of the parameters D95%, D90%, and Dmean in the planning target volume, and Dmean and Dmax in OARs were significantly different. The dose deviation of VMAT was larger than IMRT, especially in the thoracic group. A %GP and %DE correlation analysis showed a strong correlation for the planning target volume, but a weak correlation for the OARs. Additionally, a significant correlation existed between %GP of SunCHECK and Delta4. CONCLUSION: The study established TL and AL values tailored to various anatomical regions and treatment techniques at our institution. Establishing PSQA workflows for VMAT and IMRT offers valuable clinical insights and guidance. We also suggest developing a standard combining clinically relevant metrics with %GP to evaluate PSQA results comprehensively.
Assuntos
Órgãos em Risco , Garantia da Qualidade dos Cuidados de Saúde , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador , Radioterapia de Intensidade Modulada , Humanos , Radioterapia de Intensidade Modulada/métodos , Radioterapia de Intensidade Modulada/normas , Planejamento da Radioterapia Assistida por Computador/métodos , Planejamento da Radioterapia Assistida por Computador/normas , Garantia da Qualidade dos Cuidados de Saúde/normas , Órgãos em Risco/efeitos da radiação , Software , Raios gama , Neoplasias/radioterapia , Guias de Prática Clínica como Assunto/normasRESUMO
PURPOSE: Exercise-based cardiac rehabilitation (EBCR) improves functional capacity in heart failure (HF). However, data on the effect of EBCR in patients with advanced HF and left ventricular assist devices (LVADs) are limited. This meta-analysis aimed to evaluate the impact of EBCR on the functional ability of LVAD patients by comparing the corresponding outcome indicators between the EBCR and ST groups. METHODS: PubMed, Embase, Clinical Trials, and Cochrane Library databases were searched for studies assessing and comparing the effects of EBCR and standard therapy (ST) in patients following LVAD implantation. Using pre-defined criteria, appropriate studies were identified and selected. Data from selected studies were extracted in a standardized fashion, and a meta-analysis was performed using a fixed-effects model. The protocol was registered on INPLASY (202340073). RESULTS: In total, 12 trials involving 477 patients were identified. The mean age of the participants was 52.9 years, and 78.6% were male. The initiation of EBCR varied from LVAD implantation during the index hospitalization to 11 months post-LVAD implantation. The median rehabilitation period ranged from 2 weeks to 18 months. EBCR was associated with improved peak oxygen uptake (VO2) in all trials. Quantitative analysis was performed in six randomized studies involving 214 patients (EBCR: n = 130, ST: n = 84). EBCR was associated with a significantly high peak VO2 (weighted mean difference [WMD] = 1.64 mL/kg/min; 95% confidence interval [CI], 0.20-3.08; p = .03). Similarly, 6-min walk distance (6MWD) showed significantly greater improvement in the EBCR group than in the ST group (WMD = 34.54 m; 95% CI, 12.47-56.42; p = .002) in 266 patients (EBCR, n = 140; ST, n = 126). Heterogeneity was low among the included trials. None of the included studies reported serious adverse events related to EBCR, indicating the safety of EBCR after LVAD implantation. CONCLUSION: This study demonstrated that EBCR following LVAD implantation is associated with greater improvement in functional capacity compared with ST as reflected by the improved peak VO2 and 6MWD values. Considering the small number of patients in this analysis, further research on the clinical impact of EBCR in LVAD patients is warranted.
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Human trajectories can be tracked by the internal processing of a camera as an edge device. This work aims to match peoples' trajectories obtained from cameras to sensor data such as acceleration and angular velocity, obtained from wearable devices. Since human trajectory and sensor data differ in modality, the matching method is not straightforward. Furthermore, complete trajectory information is unavailable; it is difficult to determine which fragments belong to whom. To solve this problem, we newly proposed the SyncScore model to find the similarity between a unit period trajectory and the corresponding sensor data. We also propose a Likelihood Fusion algorithm that systematically updates the similarity data and integrates it over time while keeping other trajectories in mind. We confirmed that the proposed method can match human trajectories and sensor data with an accuracy, a sensitivity, and an F1 of 0.725. Our models achieved decent results on the UEA dataset.
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Algoritmos , Dispositivos Eletrônicos Vestíveis , Humanos , Análise de DadosRESUMO
Pyrethroids are synthetic organic insecticides. Deltamethrin, as one of the pyrethroids, has high insecticidal activity against pests and parasites and is less toxic to mammals, and is widely used in cities and urban areas worldwide. After entering the natural environment, deltamethrin circulates between solid, liquid and gas phases and enters organisms through the food chain, posing significant health risks. Increasing evidence has shown that deltamethrin has varying degrees of toxicity to a variety of organisms. This review summarized worldwide studies of deltamethrin residues in different media and found that deltamethrin is widely detected in a range of environments (including soil, water, sediment, and air) and organisms. In addition, the metabolism of deltamethrin, including metabolites and enzymes, was discussed. This review shed the mechanism of toxicity of deltamethrin and its metabolites, including neurotoxicity, immunotoxicity, endocrine disruption toxicity, reproductive toxicity, hepatorenal toxicity. This review is aim to provide reference for the ecological security and human health risk assessment of deltamethrin.
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Inseticidas , Nitrilas , Piretrinas , Piretrinas/toxicidade , Nitrilas/toxicidade , Inseticidas/toxicidade , Humanos , Animais , Resíduos de Praguicidas/toxicidade , Resíduos de Praguicidas/análise , Medição de Risco , Poluentes Ambientais/toxicidadeRESUMO
Mycobacterial arabinogalactan (AG) is an essential cell wall component of mycobacteria and a frequent structural and bio-synthetical target for anti-tuberculosis (TB) drug development. Here, we report that mycobacterial AG is recognized by galectin-9 and exacerbates mycobacterial infection. Administration of AG-specific aptamers inhibits cellular infiltration caused by Mycobacterium tuberculosis (Mtb) or Mycobacterium bovis BCG, and moderately increases survival of Mtb-infected mice or Mycobacterium marinum-infected zebrafish. AG interacts with carbohydrate recognition domain (CRD) 2 of galectin-9 with high affinity, and galectin-9 associates with transforming growth factor ß-activated kinase 1 (TAK1) via CRD2 to trigger subsequent activation of extracellular signal-regulated kinase (ERK) as well as induction of the expression of matrix metalloproteinases (MMPs). Moreover, deletion of galectin-9 or inhibition of MMPs blocks AG-induced pathological impairments in the lung, and the AG-galectin-9 axis aggravates the process of Mtb infection in mice. These results demonstrate that AG is an important virulence factor of mycobacteria and galectin-9 is a novel receptor for Mtb and other mycobacteria, paving the way for the development of novel effective TB immune modulators.
Assuntos
Mycobacterium tuberculosis , Peixe-Zebra , Animais , Galactanos , Galectinas/genética , CamundongosRESUMO
OBJECTIVE: Although the application of del Nido cardioplegia solution (DNC) in adult cardiac surgery is accumulating, the feasibility and safety of this myocardial protection strategy in adults remains controversial. We aimed to update our previous meta-analysis to determine the myocardial protective effect of DNC versus conventional cardioplegia (CC) in adult cardiac surgery. METHODS: A comprehensive literature search was performed using PubMed, EMBASE, the Cochrane Library, and International Clinical Trials Registry Platform databases through November 2020. RESULTS: Thirty-seven observational studies and four randomized controlled trials (RCTs) including 21,779 patients were identified. The DNC group was associated with decreased postoperative cardiac enzymes [troponin T (cTnT) and creatine kinase-MB (CK-MB)] [standardized mean differences (SMD): -0.59, 95% confidence interval (CI): -0.99 to -0.19, p = 0.004], cardiopulmonary bypass (CPB) time (MD: -9.31, 95% CI: -13.10 to -5.51, p < 0.00001), aortic cross-clamp (ACC) time (MD: -7.20, 95% CI: -10.31 to -4.09, p < 0.00001), and cardioplegia volume (SMD: -1.95, 95% CI: -2.46 to -1.44, p < 0.00001). Intraoperative defibrillation requirement was less in the DNC group [relative risk (RR): 0.50, 95% CI: 0.33 to 0.75, p = 0.0007]. The pooled analysis revealed no significant difference in operative mortality among the patients assigned to DNC and those undergoing CC. CONCLUSION: In adult cardiac surgery, compared to CC, myocardial protection used with DNC yield similar or better short-term clinical outcomes. More high-quality trials and RCTs reflecting long-term follow-up morbidity and mortality are required in the future to confirm these findings.
Assuntos
Procedimentos Cirúrgicos Cardíacos , Soluções Cardioplégicas , Adulto , Humanos , Soluções Cardioplégicas/uso terapêutico , Parada Cardíaca Induzida , Miocárdio , Período Pós-Operatório , Estudos Retrospectivos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
OBJECTIVE: Although the application of venovenous extracorporeal membrane oxygenation (VV-ECMO) in coronavirus disease 2019 (COVID-19) patients with acute respiratory distress syndrome (ARDS) is accumulating, the feasibility and safety of this therapy remain controversial. We aimed to evaluate the effect of VV-ECMO in the treatment of these patients. METHODS: A comprehensive literature search was performed using PubMed, Embase, the Cochrane Library, and International Clinical Trials Registry Platform databases through November 2021. According to the inclusion and exclusion criteria, the included studies were screened, and meta-analysis was performed by R software (version 4.0.2). RESULTS: Forty-two studies including 2037 COVID-19 patients supported with VV-ECMO due to ARDS were identified. The pooled analysis revealed that 30-, 60-, and 90-day mortality among patients were respectively 46% (95% CI 37%-57%, I2 = 66%), 46% (95% CI 30%-70%, I2 = 93%), and 49% (95% CI 43%-58%, I2 = 52%), and the pooled incidence rate of in-hospital mortality, major bleeding, hemorrhagic stroke, thrombosis, pulmonary embolism, deep venous thrombosis, and renal replacement therapy were respectively 35%, 39%, 11%, 40%, 15%, 21%, and 44%. CONCLUSION: Although COVID-19 patients may have a higher risk of bleeding, hemorrhagic stroke, and acute kidney injury during ECMO therapy, the survival rate was more than half of the cases. Our data may support the application of VV-ECMO in COVID-19 patients.
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COVID-19 , Oxigenação por Membrana Extracorpórea , Acidente Vascular Cerebral Hemorrágico , Síndrome do Desconforto Respiratório , Humanos , COVID-19/terapia , COVID-19/complicações , Oxigenação por Membrana Extracorpórea/efeitos adversos , Acidente Vascular Cerebral Hemorrágico/complicações , Hemorragia/etiologia , Síndrome do Desconforto Respiratório/etiologia , Estudos RetrospectivosRESUMO
Lanthanide-based nanocrystals possess three unique physical properties that make them attractive for facilitating photoreactions, namely photon upconversion luminescence, Lewis acid catalytic activity and photothermal properties. When co-doped with a suitable sensitizer and activator lanthanide ions, rare-earth fluoride nanocrystals upconvert near-infrared light to higher energy photons that can be used to excite photosensitizers that absorb ultraviolet and visible light in photocatalytic and photopolymerization reactions. Surface lanthanide ions on nanocrystals also have the propensity to behave as Lewis acid (LA) catalytic sites. In addition, NIR-light excited lanthanides such as Nd3+ undergo cross-relaxation interaction with neighbouring ground-state ions followed by non-radiative decay to generate heat (i.e., photothermal) which enhances the rate of chemical reactions. In this perspective, we provide a survey of the recent progress in the use of lanthanide-based nanocrystals as upconverting nanolamps, LA catalysts and photothermal nanoheaters in driving synthetic and polymerization reactions, and the challenges that need to be further addressed in order for this vibrant research area to develop and grow.
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INTRODUCTION: Ventricular septal rupture (VSR) following acute myocardial infarction (AMI) is a rare but serious complication often causing cardiogenic shock (CS). The timing of surgery is a difficult problem for surgeons because of high mortality and surgical complexity. We present a case of successful use of extracorporeal membrane oxygenation (ECMO) for maintaining haemodynamic stability preoperative and delaying surgical repair of VSR patient in severe CS. CASE REPORT: A 57-year-old man with AMI complicated by severe CS due to an massive VSR. Emergency surgery was considered a too high mortality risk. The patient was implanted with a percutaneous veno-arterial ECMO (VA-ECMO) system as a bridge to surgery for stabilizing general condition. On the 31th day after ECMO implantation, the ventricular septal defect was successfully repaired and weaning from the ECMO. DISCUSSION: This case study illustrates that it may be considered to use long term ECMO preoperative to delayed surgery which leads to higher survival in cases of massive VSR patient after AMI in hemodynamically compromised patients. Still the optimal duration of mechanical circulatory support and the optimal timing for surgery need more research to define. CONCLUSION: This case indicates the feasibility of preoperative using of a long term VA-ECMO as a bridge to surgical repair of VSR patient after AMI in severe CS. The optimal duration of mechanical circulatory support and the optimal timing for surgery still require further investigation.
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INTRODUCTION: Although venovenous extracorporeal membrane oxygenation (VV ECMO) is a reasonable salvage treatment for acute respiratory distress syndrome (ARDS), it requires sedating the patient. Sevoflurane and propofol have pulmonary protective and immunomodulatory properties. This study aimed to compare the effectiveness of sevoflurane and propofol on rats with induced ARDS undergoing VV ECMO. METHODS: Fifteen sprague-dawley (SD) rats were randomly divided into three groups: Con group, sevoflurane (Sevo) group and propofol (Pro) group. Arterial blood gas tests were performed at time pointsT0 (baseline), T1 (the time to ARDS), and T2 (weaning from ECMO). Oxygenation index (PaO2/FiO2) was calculated, and lung edema assessed by determining the lung wet:dry ratio. The protein concentration in bronchial alveolar lavage fluid (BALF) was determined by using bicinchoninic acid assay. Haematoxylin and eosin staining was used to evaluate the lung pathological scores in each group. IL-1ß and TNF-α were also measured in the BALF, serum and lung. RESULTS: Oxygenation index showed improvement in the Sevo group versus Pro group. The wet:dry ratio was reduced in the Sevo group compared with propofol-treated rats. Lung pathological scores were substantially lower in the Sevo group versus the Pro group. Protein concentrations in the BALF and levels of IL-1ß and TNF-α in the Sevo group were substantially lower versus Pro group. CONCLUSION: This study demonstrates that compared with propofol, sevoflurane was more efficacious in improving oxygenation and decreasing inflammatory response in rat models with ARDS subject to VV ECMO treatment.