RESUMO
Intracellular pathogens pose a significant threat to animals. In defense, innate immune sensors attempt to detect these pathogens using pattern recognition receptors that either directly detect microbial molecules or indirectly detect their pathogenic activity. These sensors trigger different forms of regulated cell death, including pyroptosis, apoptosis, and necroptosis, which eliminate the infected host cell niche while simultaneously promoting beneficial immune responses. These defenses force intracellular pathogens to evolve strategies to minimize or completely evade the sensors. In this review, we discuss recent advances in our understanding of the cytosolic pattern recognition receptors that drive cell death, including NLRP1, NLRP3, NLRP6, NLRP9, NLRC4, AIM2, IFI16, and ZBP1.
Assuntos
Inflamassomos , Piroptose , Animais , Apoptose , Morte Celular , Humanos , Inflamassomos/metabolismo , NecroptoseRESUMO
Among the caspases that cause regulated cell death, a unique function for caspase-7 has remained elusive. Caspase-3 performs apoptosis, whereas caspase-7 is typically considered an inefficient back-up. Caspase-1 activates gasdermin D pores to lyse the cell; however, caspase-1 also activates caspase-7 for unknown reasons1. Caspases can also trigger cell-type-specific death responses; for example, caspase-1 causes the extrusion of intestinal epithelial cell (IECs) in response to infection with Salmonella enterica subsp. enterica serovar Typhimurium (S. Typhimurium)2,3. Here we show in both organoids and mice that caspase-7-deficient IECs do not complete extrusion. Mechanistically, caspase-7 counteracts gasdermin D pores and preserves cell integrity by cleaving and activating acid sphingomyelinase (ASM), which thereby generates copious amounts of ceramide to enable enhanced membrane repair. This provides time to complete the process of IEC extrusion. In parallel, we also show that caspase-7 and ASM cleavage are required to clear Chromobacterium violaceum and Listeria monocytogenes after perforin-pore-mediated attack by natural killer cells or cytotoxic T lymphocytes, which normally causes apoptosis in infected hepatocytes. Therefore, caspase-7 is not a conventional executioner but instead is a death facilitator that delays pore-driven lysis so that more-specialized processes, such as extrusion or apoptosis, can be completed before cell death. Cells must put their affairs in order before they die.
Assuntos
Caspase 7 , Perforina , Proteínas de Ligação a Fosfato , Proteínas Citotóxicas Formadoras de Poros , Esfingomielina Fosfodiesterase , Animais , Apoptose , Caspase 7/metabolismo , Chromobacterium/imunologia , Células Epiteliais/citologia , Intestinos/citologia , Células Matadoras Naturais/imunologia , Listeria monocytogenes/imunologia , Camundongos , Organoides , Perforina/metabolismo , Proteínas de Ligação a Fosfato/metabolismo , Proteínas Citotóxicas Formadoras de Poros/metabolismo , Esfingomielina Fosfodiesterase/metabolismo , Linfócitos T Citotóxicos/imunologiaRESUMO
Pathogenic microbes invade the human body and trigger a host immune response to defend against the infection. In response, host-adapted pathogens employ numerous virulence strategies to overcome host defense mechanisms. As a result, the interaction between the host and pathogen is a dynamic process that shapes the evolution of the host's immune response. Among the immune responses against intracellular bacteria, pyroptosis, a lytic form of cell death, is a crucial mechanism that eliminates replicative niches for intracellular pathogens and modulates the immune system by releasing danger signals. This review focuses on the role of pyroptosis in combating intracellular bacterial infection. We examine the cell type specific roles of pyroptosis in neutrophils and intestinal epithelial cells. We discuss the regulatory mechanisms of pyroptosis, including its modulation by autophagy and interferon-inducible GTPases. Furthermore, we highlight that while host-adapted pathogens can often subvert pyroptosis, environmental microbes are effectively eliminated by pyroptosis.
Assuntos
Infecções Bacterianas , Piroptose , Humanos , Morte Celular , Neutrófilos , BactériasRESUMO
Mitochondria, a highly metabolically active organelle, have been shown to play an essential role in regulating innate immune function. Mitochondrial Ca2+ uptake via the mitochondrial Ca2+ uniporter (MCU) is an essential process regulating mitochondrial metabolism by targeting key enzymes involved in the tricarboxylic acid cycle (TCA). Accumulative evidence suggests MCU-dependent mitochondrial Ca2+ signaling may bridge the metabolic reprogramming and regulation of immune cell function. However, the mechanism by which MCU regulates inflammation and its related disease remains elusive. Here we report a critical role of MCU in promoting phagocytosis-dependent activation of NLRP3 (nucleotide-binding domain, leucine-rich repeat containing family, pyrin domain-containing 3) inflammasome by inhibiting phagolysosomal membrane repair. Myeloid deletion of MCU (McuΔmye) resulted in an attenuated phagolysosomal rupture, leading to decreased caspase-1 cleavage and interleukin (IL)-1ß release, in response to silica or alum challenge. In contrast, other inflammasome agonists such as adenosine triphosphate (ATP), nigericin, poly(dA:dT), and flagellin induced normal IL-1ß release in McuΔmye macrophages. Mechanistically, we demonstrated that decreased NLRP3 inflammasome activation in McuΔmye macrophages was caused by improved phagolysosomal membrane repair mediated by ESCRT (endosomal sorting complex required for transport)-III complex. Furthermore, McuΔmye mice showed a pronounced decrease in immune cell recruitment and IL-1ß production in alum-induced peritonitis, a typical IL-1-dependent inflammation model. In sum, our results identify a function of MCU in promoting phagocytosis-dependent NLRP3 inflammatory response via an ESCRT-mediated phagolysosomal membrane repair mechanism.
Assuntos
Canais de Cálcio , Inflamassomos , Proteínas Mitocondriais , Proteína 3 que Contém Domínio de Pirina da Família NLR , Peritonite , Fagocitose , Compostos de Alúmen , Animais , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Caspase 1/metabolismo , Modelos Animais de Doenças , Complexos Endossomais de Distribuição Requeridos para Transporte , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Macrófagos/metabolismo , Camundongos , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Peritonite/induzido quimicamente , Peritonite/metabolismoRESUMO
BACKGROUND: The molecular mechanisms responsible for angiogenesis and abnormal expression of angiogenic factors in gastric cancer, including vascular endothelial growth factor (VEGF), remain unclear. The histone demethylase retinoblastoma binding protein 2 (RBP2) is involved in gastric tumorgenesis by inhibiting the expression of cyclin-dependent kinase inhibitors (CDKIs). METHODS: The expression of RBP2, VEGF, CD31, CD34 and Ki67 was assessed in 30 human gastric cancer samples and normal control samples. We used quantitative RT-PCR, western blot analysis, ELISA, tube-formation assay and colony-formation assay to characterize the change in VEGF expression and associated biological activities induced by RBP2 silencing or overexpression. Luciferase assay and ChIP were used to explore the direct regulation of RBP2 on the promoter activity of VEGF. Nude mice and RBP2-targeted mutant mice were used to detect the role of RBP2 in VEGF expression and angiogenesis in vivo. RESULTS: RBP2 and VEGF were both overexpressed in human gastric cancer tissue, with greater microvessel density (MVD) and cell proliferation as compared with normal tissue. In gastric epithelial cell lines, RBP2 overexpression significantly promoted the expression of VEGF and the growth and angiogenesis of the cells, while RBP2 knockdown had the reverse effect. RBP2 directly bound to the promoter of VEGF to regulate its expression by histone H3K4 demethylation. The subcutis of nude mice transfected with BGC-823 cells with RBP2 knockdown showed reduced VEGF expression and MVD, with reduced carcinogenesis and cell proliferation. In addition, the gastric epithelia of RBP2 mutant mice with increased H3K4 trimethylation showed reduced VEGF expression and MVD. CONCLUSIONS: The promotion of gastric tumorigenesis by RBP2 was significantly associated with transactivation of VEGF expression and elevated angiogenesis. Overexpression of RBP2 and activation of VEGF might play important roles in human gastric cancer development and progression.
Assuntos
Neovascularização Patológica/genética , Proteínas Celulares de Ligação ao Retinol/genética , Fator A de Crescimento do Endotélio Vascular/biossíntese , Adulto , Idoso , Animais , Antígenos CD34/biossíntese , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Antígeno Ki-67/biossíntese , Masculino , Camundongos , Pessoa de Meia-Idade , Neovascularização Patológica/patologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/biossíntese , Proteínas Celulares de Ligação ao Retinol/metabolismo , Neoplasias Gástricas , Fator A de Crescimento do Endotélio Vascular/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Caspases are a family of proteins involved in cell death. Although several caspase members have been well characterized, caspase-2 remains enigmatic. Caspase-2 has been implicated in several phenotypes, but there has been no consensus in the field about its upstream activating signals or its downstream protein targets. In addition, the unique ability of caspase-2 to form a disulfide-bonded dimer has not been studied in depth. Herein, we investigate the disulfide bond in the context of inducible dimerization, showing that disulfide bond formation is dimerization dependent. We also explore and review several stimuli published in the caspase-2 field, test ferroptosis-inducing stimuli, and study in vivo infection models. We hypothesize that the disulfide bond will ultimately prove to be essential for the evolved function of caspase-2. Proving this will require the discovery of cell death phenotypes where caspase-2 is definitively essential.
RESUMO
This study aimed to assess the association of menstrual blood volumes (MBV) and reproductive outcomes in patients after uterine artery embolization (UAE) combined with curettage for caesarean scar pregnancy (CSP). This retrospective observational study enrolled women who underwent UAE plus curettage for CSP at the Interventional Department of Henan Provincial People's Hospital between December 2012 and December 2017. The primary outcome was pregnancy rate and the secondary outcomes were live birth rate (LBR) and interpregnancy interval. This study finally included 37 women (16 women with normal MBV and 21 women with decreased MBV) with pregnancy intention after UAE plus curettage for CSP. The pregnancy rate in women with normal MBV was higher than those with decreased MBV (81.3% vs. 47.6%; P = 0.048). There were no differences between the two groups regarding the interpregnancy interval (18.4 ± 8.7 vs. 22.2 ± 10.0 months, P = 0.233), and LBR (63% vs. 38%, P = 0.191). In conclusion, Women with normal MBV after UAE combined with curettage for CSP management might have a higher pregnancy rate compared with patients with decreased MBV, but there were no differences in LBR between the two groups.
Assuntos
Gravidez Ectópica , Embolização da Artéria Uterina , Gravidez , Humanos , Feminino , Embolização da Artéria Uterina/efeitos adversos , Cicatriz/complicações , Cicatriz/cirurgia , Cesárea/efeitos adversos , Gravidez Ectópica/etiologia , Gravidez Ectópica/cirurgia , Curetagem , Estudos Retrospectivos , Volume Sanguíneo , Resultado do Tratamento , MetotrexatoRESUMO
Pyroptosis and apoptosis are two forms of regulated cell death that can defend against intracellular infection. Although pyroptosis and apoptosis have distinct signaling pathways, when a cell fails to complete pyroptosis, backup pathways will initiate apoptosis. Here, we investigated the utility of apoptosis compared to pyroptosis in defense against an intracellular bacterial infection. We previously engineered Salmonella enterica serovar Typhimurium to persistently express flagellin, and thereby activate NLRC4 during systemic infection in mice. The resulting pyroptosis clears this flagellin-engineered strain. We now show that infection of caspase-1 or gasdermin D deficient macrophages by this flagellin-engineered S. Typhimurium induces apoptosis in vitro. Additionally, we also now engineer S. Typhimurium to translocate the pro-apoptotic BH3 domain of BID, which also triggers apoptosis in macrophages in vitro. In both engineered strains, apoptosis occurred somewhat slower than pyroptosis. During mouse infection, the apoptotic pathway successfully cleared these engineered S. Typhimurium from the intestinal niche, but failed to clear the bacteria in the myeloid niche in the spleen or lymph nodes. In contrast, the pyroptotic pathway was beneficial in defense of both niches. In order to clear an infection, distinct cell types may have specific tasks that they must complete before they die. In some cells, either apoptotic or pyroptotic signaling may initiate the same tasks, whereas in other cell types these modes of cell death may lead to different tasks that may not be identical in defense against infection. We recently suggested that such diverse tasks can be considered as different cellular 'bucket lists' to be accomplished before a cell dies.
RESUMO
Pyroptosis and apoptosis are two forms of regulated cell death that can defend against intracellular infection. When a cell fails to complete pyroptosis, backup pathways will initiate apoptosis. Here, we investigated the utility of apoptosis compared to pyroptosis in defense against an intracellular bacterial infection. We previously engineered Salmonella enterica serovar Typhimurium to persistently express flagellin, and thereby activate NLRC4 during systemic infection in mice. The resulting pyroptosis clears this flagellin-engineered strain. We now show that infection of caspase-1 or gasdermin D deficient macrophages by this flagellin-engineered S. Typhimurium induces apoptosis in vitro. Additionally, we engineered S. Typhimurium to translocate the pro-apoptotic BH3 domain of BID, which also triggers apoptosis in macrophages in vitro. During mouse infection, the apoptotic pathway successfully cleared these engineered S. Typhimurium from the intestinal niche but failed to clear the bacteria from the myeloid niche in the spleen or lymph nodes. In contrast, the pyroptotic pathway was beneficial in defense of both niches. To clear an infection, cells may have specific tasks that they must complete before they die; different modes of cell death could initiate these 'bucket lists' in either convergent or divergent ways.
Although alive and healthy cells are essential for survival, in certain circumstances such as when a cell becomes infected it is beneficial for cells to deliberately die through a process known as regulated cell death. There are several types of regulated cell death, each with distinct pathways and mechanisms. However, if the initial pathway is blocked, cells can use an alternative one, suggesting that they can compensate for one other. Two forms of regulated cell death named pyroptosis and apoptosis can be used by infected cells to limit the spread of pathogens. However, it was not clear if these two forms or additional 'back-up' apoptosis pathways which are induced when pyroptosis fails are equally efficient at clearing infections and how they might vary in different cell types. To address this, Abele et al. investigated cell death in live mice infected with the bacterium Salmonella. Different organs in which the bacterium infects distinct cell types were examined. Experiments showed that pyroptosis could eliminate bacteria from both intestinal cells as well as immune cells found throughout the body, called macrophages. In contrast, apoptosis was only able to clear infection from intestinal cells. The findings can be explained by prior studies showing both apoptosis and pyroptosis lead to the same outcome in intestinal cells dead cells are expelled from the body through a process called extrusion to maintain the barrier function of the intestine. However, in macrophages, the different pathways lead to different outcomes, indicating they are not entirely interchangeable. Overall, the findings of Abele et al. underscore the complexity of cellular responses to infection and the nuanced roles of different cell death pathways. This provides further evidence that cells might have specific tasks they need to complete before death in order to effectively clear an infection. These tasks may differ depending on cell type and the form of regulated cell death, and may not be equally efficient at clearing an infection.
Assuntos
Apoptose , Flagelina , Animais , Camundongos , Morte Celular , Caspase 1/metabolismo , Salmonella typhimurium/genética , Salmonella typhimurium/metabolismo , Piroptose , Inflamassomos/metabolismoRESUMO
The innate immune response is the first-line host defense against pathogens. Cytosolic nucleic acids, including both DNA and RNA, represent a special type of danger signal to initiate an innate immune response. Activation of cytosolic nucleic acid sensors is tightly controlled in order to achieve the high sensitivity needed to combat infection while simultaneously preventing false activation that leads to pathologic inflammatory diseases. In this review, we focus on post-translational modifications of key cytosolic nucleic acid sensors that can reversibly or irreversibly control these sensor functions. We will describe phosphorylation, ubiquitination, SUMOylation, neddylation, acetylation, methylation, succinylation, glutamylation, amidation, palmitoylation, and oxidation modifications events (including modified residues, modifying enzymes, and modification function). Together, these post-translational regulatory modifications on key cytosolic DNA/RNA sensing pathway members reveal a complicated yet elegantly controlled multilayer regulator network to govern innate immune activation.
Assuntos
Ácidos Nucleicos , DNA/metabolismo , Processamento de Proteína Pós-Traducional , RNA/metabolismo , Transdução de SinaisRESUMO
Herpes simplex virus type 1 (HSV-1) infection can manifest locally as mucocutaneous lesions or keratitis and can also spread to the central nervous system to cause encephalitis. HSV-1 establishes a lifelong latent infection and neither cure nor vaccine is currently available. The innate immune response is the first line of defense against infection. Caspases and gasdermins are important components of innate immunity. Caspases are a family of cysteine proteases, most of which mediate regulated cell death. Gasdermins are a family of pore-forming proteins that trigger lytic cell death. To determine whether caspases or gasdermins contribute to innate immune defenses against HSV-1, we screened mice deficient in specific cell death genes. Our results indicate a modest role for caspase-6 in defense against HSV-1. Further, Asc-/-Casp1/11-/- mice also had a modest increased susceptibility to HSV-1 infection. Caspase-7, -8, and -14 did not have a notable role in controlling HSV-1 infection. We generated Gsdma1-Gsdma2-Gsdma3 triple knockout mice, which also had normal susceptibility to HSV-1. We confirmed that the previously published importance of RIPK3 during systemic HSV-1 infection also holds true during skin infection. Overall, our data highlight that as a successful pathogen, HSV-1 has multiple ways to evade host innate immune responses.
Assuntos
Herpes Simples , Herpesvirus Humano 1 , Animais , Caspase 6 , Caspase 7 , Caspases/genética , Herpesvirus Humano 1/fisiologia , Imunidade Inata , Camundongos , Camundongos Knockout , Proteínas Citotóxicas Formadoras de Poros , ProteínasRESUMO
In neutrophils, caspase-11 cleaves gasdermin D (GSDMD), causing pyroptosis to clear cytosol-invasive bacteria. In contrast, caspase-1 also cleaves GSDMD but seems to not cause pyroptosis. Here, we show that this pyroptosis-resistant caspase-1 activation is specifically programmed by the site of translocation of the detected microbial virulence factors. We find that pyrin and NLRC4 agonists do not trigger pyroptosis in neutrophils when they access the cytosol from endosomal compartment. In contrast, when the same ligands penetrate through the plasma membrane, they cause pyroptosis. Consistently, pyrin detects extracellular Yersinia pseudotuberculosis ΔyopM in neutrophils, driving caspase-1-GSDMD pyroptosis. This pyroptotic response drives PAD4-dependent H3 citrullination and results in extrusion of neutrophil extracellular traps (NETs). Our data indicate that caspase-1, GSDMD, or PAD4 deficiency renders mice more susceptible to Y. pseudotuberculosis ΔyopM infection. Therefore, neutrophils induce pyroptosis in response to caspase-1-activating inflammasomes triggered by extracellular bacterial pathogens, but after they phagocytose pathogens, they are programmed to forego pyroptosis.
Assuntos
Inflamassomos , Toxinas Biológicas , Camundongos , Animais , Inflamassomos/metabolismo , Proteínas de Ligação a Fosfato/metabolismo , Neutrófilos/metabolismo , Pirina/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Caspase 1/metabolismo , Caspases/metabolismo , Bactérias/metabolismoRESUMO
Hepatocellular carcinoma (HCC) is generally known as one of the most common cancers in the world. Nowadays, interventional therapies such as transcatheter arterial chemoembolization (TACE) have emerged as an efficient therapy for HCC patients. Accumulating evidence has unveiled that long non-coding RNAs (lncRNAs) are crucial regulators in HCC progression. Nonetheless, the biological function of lncRNA zinc finger and SCAN domain containing 16 antisense RNA 1 (ZSCAN16-AS1) in HCC has not been systematically clarified. RT-qPCR was used to test ZSCAN16-AS1 expression in HCC cells. The biological functions of RP11-757 G1.5 on HCC cell proliferation, migration, invasion and apoptosis were investigated by colony formation, EdU, CCK-8 and transwell assays, as well as flow cytometry analysis. RNA immunoprecipitation (RIP), RNA pull-down and luciferase reporter assays were utilized to explore the specific mechanism of ZSCAN16-AS1. ZSCAN16-AS1 was significantly up-regulated in HCC cells. ZSCAN16-AS1 silence inhibited HCC cell proliferation, migration and invasion, while it accelerated HCC cell apoptosis. ZSCAN16-AS1 worked as a competing endogenous RNA (ceRNA) to regulate sperm associated antigen 9 (SPAG9) expression through sponging miR-181 c-5p. Moreover, SPAG9 could activate the c-Jun-N-terminal kinase (JNK) pathway. Taken together, our study elucidated that ZSCAN16-AS1 expedited HCC progression via modulating the miR-181 c-5p/SPAG9 axis to activate the JNK pathway, which might be a highly potential HCC therapy and treatment target.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Carcinogênese/metabolismo , Carcinoma Hepatocelular/metabolismo , Progressão da Doença , Neoplasias Hepáticas/metabolismo , Sistema de Sinalização das MAP Quinases/genética , MicroRNAs/metabolismo , RNA Antissenso , RNA Longo não Codificante/metabolismo , Proteínas Repressoras/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Apoptose/genética , Carcinogênese/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , RNA Longo não Codificante/genética , Proteínas Repressoras/genética , Transfecção , Carga Tumoral/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: There has been very limited investigation regarding the comparison of adverse events (AEs) among radiofrequency ablation (RFA), conventional transarterial chemoembolization (cTACE), and drug-eluting bead TACE (DEB-TACE) in treating HCC patients; therefore, the present study aimed to resolve this issue. METHODS: Two-hundred and forty-six HCC patients (with a total of 267 procedures [treatment times]) treated with RFA (73 patients with 79 procedures), cTACE (86 patients with 94 procedures), or DEB-TACE (87 patients with 94 procedures) were included. Demographic and clinical data were collected. The information on AEs was also retrieved and analyzed. RESULTS: Total AEs incidence was notably different among the RFA group, cTACE group, and DEB-TACE group and was the highest in cTACE group (86.2%), then in DEB-TACE group (76.6%), and the lowest in RFA group (63.3%). Regarding specific AEs incidence, the incidences of fever, fatigue, and nausea were distinctive among the three groups, while no distinctiveness was found in incidence of other AEs. Furthermore, multivariate logistic regression revealed that cTACE (versus RFA) was independently correlated with increased risk of total AEs, fatigue, and nausea/vomiting; however, the interventional therapies were not independently correlated with the risk of pain, fever or constipation. Other independent predictive factors for total AEs risk were male gender, bronchial asthma, and disease duration. CONCLUSION: cTACE resulted in the highest AEs incidence compared with RFA and DEB-TACE in treating HCC patients.
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Mitochondria are believed to have originated ~2.5 billion years ago. As well as energy generation in cells, mitochondria have a role in defence against bacterial pathogens. Despite profound changes in mitochondrial morphology and functions following bacterial challenge, whether intracellular bacteria can hijack mitochondria to promote their survival remains elusive. We report that Listeria monocytogenes-an intracellular bacterial pathogen-suppresses LC3-associated phagocytosis (LAP) by modulation of mitochondrial Ca2+ (mtCa2+) signalling in order to survive inside cells. Invasion of macrophages by L. monocytogenes induced mtCa2+ uptake through the mtCa2+ uniporter (MCU), which in turn increased acetyl-coenzyme A (acetyl-CoA) production by pyruvate dehydrogenase. Acetylation of the LAP effector Rubicon with acetyl-CoA decreased LAP formation. Genetic ablation of MCU attenuated intracellular bacterial growth due to increased LAP formation. Our data show that modulation of mtCa2+ signalling can increase bacterial survival inside cells, and highlight the importance of mitochondrial metabolism in host-microbial interactions.
Assuntos
Sinalização do Cálcio , Listeria monocytogenes/fisiologia , Proteínas Associadas aos Microtúbulos/antagonistas & inibidores , Mitocôndrias/metabolismo , Fagocitose , Acetilcoenzima A/metabolismo , Acetilação , Animais , Proteínas Relacionadas à Autofagia/metabolismo , Cálcio/metabolismo , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Listeria monocytogenes/crescimento & desenvolvimento , Listeria monocytogenes/metabolismo , Macrófagos/metabolismo , Macrófagos/microbiologia , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismo , Mutação , NADPH Oxidases/metabolismoRESUMO
Staphylococcus aureus is a major human pathogen that causes an array of infections ranging from minor skin infections to more serious infections, including osteomyelitis, endocarditis, necrotizing pneumonia and sepsis1. These more serious infections usually arise from an initial bloodstream infection and are frequently recalcitrant to antibiotic treatment1. Phagocytosis by macrophages and neutrophils is the primary mechanism through which S. aureus infection is controlled by the immune system2. Macrophages have been shown to be a major reservoir of S. aureus in vivo3, but the role of macrophages in the induction of antibiotic tolerance has not been explored. Here, we show that macrophages not only fail to efficiently kill phagocytosed S. aureus, but also induce tolerance to multiple antibiotics. Reactive oxygen species generated by respiratory burst attack iron-sulfur cluster-containing proteins, including TCA-cycle enzymes, result in decreased respiration, lower ATP and increased antibiotic tolerance. We further show that respiratory burst induces antibiotic tolerance in the spleen during a murine systemic infection. These results suggest that a major component of the innate immune response is antagonistic to the bactericidal activities of antibiotics.
Assuntos
Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/metabolismo , Animais , Linhagem Celular , Ciclo do Ácido Cítrico , Modelos Animais de Doenças , Farmacorresistência Bacteriana/imunologia , Feminino , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Imunidade Inata , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NADPH Oxidases/deficiência , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Neutrófilos/imunologia , Fagocitose , Espécies Reativas de Oxigênio/metabolismo , Explosão Respiratória , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/genética , Staphylococcus aureus/imunologiaRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Nowadays, the synthesis and characterization of gold nanoparticles (AuNPs) from plant based extracts and effects of their anticancer have concerned an important interest. Marsdenia tenacissima (MT), a conventional Chinese herbal medicine, has long been used for thousands of years to treat tracheitis, asthma, rheumatism, etc. In this present study, we optimize the reaction of parameters to manage the nanoparticle size, which was categorized by high-resolution transmission electron microscopy (HR-TEM). A different characterization method, for example, UV-visible spectroscopy (UV-vis), fourier-transform infrared spectroscopy (FT-IR) and X-ray diffraction (XRD) were performed to consider the synthesized AuNPs getting from the MT leaf extract. The MT-AuNPs were analyzed for their cytotoxicity property against HepG2 cells by MTT analysis. The apoptosis was evaluated by using reactive oxygen species (ROS), migration assay, mitochondrial membrane potential (MMP) and apoptotic protein expression. Interestingly, the findings of our study observed the cytotoxicity effect of synthesized MT-AuNPs at a concentration of 59.62 ± 4.37 µg after 24 hrs treatment. Apoptosis was induced by the MT-AuNPs with enhanced ROS, changed MMP and inhibit the migration assay. Finally, the apoptosis was confirmed by the considerable up-regulation of Bax, caspase-9 and caspase-3, while the anti-apoptotic protein expressions of Bcl-2 and Bcl-XL were down-regulated. Although, in this studies, we evaluated the characterization, synthesis and anticancer action of gold nanoparticles from MT (MT-AuNPS) helpful for liver cancer therapeutics.
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Antineoplásicos/química , Antineoplásicos/farmacologia , Ouro/química , Ouro/farmacologia , Neoplasias Hepáticas/patologia , Marsdenia/química , Nanopartículas Metálicas/química , Antineoplásicos/síntese química , Técnicas de Química Sintética , Células Hep G2 , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Nanotecnologia , Extratos Vegetais/químicaRESUMO
Increased glucose metabolism in immune cells not only serves as a hallmark feature of acute inflammation but also profoundly affects disease outcome following bacterial infection and tissue damage. However, the role of individual glucose metabolic pathways during viral infection remains largely unknown. Here we demonstrate an essential function of the hexosamine biosynthesis pathway (HBP)-associated O-linked ß-N-acetylglucosamine (O-GlcNAc) signaling in promoting antiviral innate immunity. Challenge of macrophages with vesicular stomatitis viruses (VSVs) enhances HBP activity and downstream protein O-GlcNAcylation. Human and murine cells deficient of O-GlcNAc transferase, a key enzyme for protein O-GlcNAcylation, show defective antiviral immune responses upon VSV challenge. Mechanistically, O-GlcNAc transferase-mediated O-GlcNAcylation of the signaling adaptor MAVS on serine 366 is required for K63-linked ubiquitination of MAVS and subsequent downstream retinoic-acid inducible gene-like receptor -antiviral signaling activation. Thus, our study identifies a molecular mechanism by which HBP-mediated O-GlcNAcylation regulates MAVS function and highlights the importance of glucose metabolism in antiviral innate immunity.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Imunidade Inata/imunologia , N-Acetilglucosaminiltransferases/metabolismo , Infecções por Rhabdoviridae/imunologia , Vírus da Estomatite Vesicular Indiana/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Chlorocebus aethiops , Glucose/metabolismo , Células HEK293 , Células HT29 , Hexosaminas/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , N-Acetilglucosaminiltransferases/genética , Infecções por Rhabdoviridae/virologia , Células THP-1 , Células VeroRESUMO
This study aims to investigate the menstrual recovery outcome of scar pregnancy patients who received uterine artery embolization combined with curettage, and its influencing factors.The data of 119 patients with scar pregnancy, who received uterine artery embolization combined with curettage between December 2012 and December 2016 in Henan Provincival People's Hospital, were collected. The menstruation recovery of these patients was followed up, and factors that have influence on menstrual blood volume were analyzed using SPSS V.17.0.Follow-up data were available in 101/119 (84.9%) women. The median follow-up time was 22.7 months (range: 1.6-50.6 months); 58 (57.4%) patients had reduced menstrual blood volume, and 2 patients (2%) had amenorrhea. The proportion of patients with reduced menstrual blood volume, who were embolized with polyvinyl alcohol (PVA), PVA combined with gelatin sponge, and gelatin sponge between < and ≥33 years old was 41.7% versus 66.7%, 40% versus 57.1% and 60.6% versus 68.0%. The average age of patients with reduced menstrual blood volume (34.3 years) was greater than patients with normal menstrual blood volume (31.4 years), but the difference was not statistically significant (Pâ=â.07).Reduced menstrual blood volume can occur in scar pregnancy patients who received uterine artery embolization combined with curettage. The influence of the embolic agent PVA on menstrual blood volume depends on age, but the difference was not statistically significant.