RESUMO
Infections of hepatotropic viruses cause a wide array of liver diseases including acute hepatitis, chronic hepatitis and the consequently developed cirrhosis and hepatocellular carcinoma (HCC). Among the five classical hepatotropic viruses, hepatitis B virus (HBV) and hepatitis C virus (HCV) usually infect human persistently and cause chronic hepatitis, leading to major troubles to humanity. Previous studies have revealed that several types of inflammasomes are involved in the infections of HBV and HCV. Here, we summarize the current knowledge about their roles in hepatitis B and C. NLRP3 inflammasome can be activated and regulated by HBV and HCV. It is found to exert antiviral function or mediates inflammatory response in viral infections depending on different experimental models. Besides NLRP3 inflammasome, IFI16 and AIM2 inflammasomes participate in the pathological process of hepatitis B, and NALP3 inflammasome may sense HCV infection in hepatocytes. The inflammasomes affect the pathological process of viral hepatitis through its downstream secretion of inflammatory cytokines interleukin-1ß (IL-1ß) and IL-18 or induction of pyroptosis resulting from cleaved gasdermin D (GSDMD). However, the roles of inflammasomes in different stages of viral infection remains mainly unclear. More proper experimental models of viral hepatitis should be developed for specific studies in future, so that we can understand more about the complexity of inflammasome regulation and multifunction of inflammasomes and their downstream effectors during HBV and HCV infections.
Assuntos
Hepacivirus , Vírus da Hepatite B , Hepatite B Crônica , Hepatite C Crônica , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Humanos , Inflamassomos/metabolismo , Inflamassomos/imunologia , Hepatite C Crônica/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Hepacivirus/imunologia , Hepatite B Crônica/imunologia , Hepatite B Crônica/metabolismo , Vírus da Hepatite B/imunologia , Proteínas de Ligação a DNA/metabolismo , Interleucina-1beta/metabolismo , Piroptose , Animais , Fosfoproteínas/metabolismo , Proteínas Nucleares/metabolismo , Hepatócitos/virologia , Hepatócitos/imunologia , Interleucina-18/metabolismo , Proteínas de Ligação a Fosfato/metabolismo , GasderminasRESUMO
The NACHT, leucine-rich repeat, and pyrin domains-containing protein 3 (collectively known as NLRP3) inflammasome activation plays a critical role in innate immune and pathogenic microorganism infections. However, excessive activation of NLRP3 inflammasome will lead to cellular inflammation and tissue damage, and naturally it must be precisely controlled in the host. Here, we discovered that solute carrier family 25 member 3 (SLC25A3), a mitochondrial phosphate carrier protein, plays an important role in negatively regulating NLRP3 inflammasome activation. We found that SLC25A3 could interact with NLRP3, overexpression of SLC25A3 and knockdown of SLC25A3 could regulate NLRP3 inflammasome activation, and the interaction of NLRP3 and SLC25A3 is significantly boosted in the mitochondria when the NLRP3 inflammasome is activated. Our detailed investigation demonstrated that the interaction between NLRP3 and SLC25A3 disrupted the interaction of NLRP3-NEK7, promoted ubiquitination of NLRP3, and negatively regulated NLRP3 inflammasome activation. Thus, these findings uncovered a new regulatory mechanism of NLRP3 inflammasome activation, which provides a new perspective for the therapy of NLRP3 inflammasome-associated inflammatory diseases.
Assuntos
Inflamassomos , Proteínas Mitocondriais , Proteína 3 que Contém Domínio de Pirina da Família NLR , Proteínas de Transporte de Fosfato , Animais , Humanos , Camundongos , Células HEK293 , Inflamassomos/metabolismo , Mitocôndrias/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteínas de Transporte de Fosfato/metabolismo , Proteínas de Transporte de Fosfato/genética , Ubiquitinação , Linhagem Celular , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Técnicas de Silenciamento de GenesRESUMO
How to transfer industrial exhaust gases of nitrogen oxides into high-values product is significantly important and challenging. Herein, we demonstrate an innovative method for artificial synthesis of essential α-amino acids from nitric oxide (NO) by reacting with α-keto acids through electrocatalytic process with atomically dispersed Fe supported on N-doped carbon matrix (AD-Fe/NC) as the catalyst. A yield of valine with 32.1â µmol mgcat -1 is delivered at -0.6â V vs. reversible hydrogen electrode, corresponding a selectivity of 11.3 %. In situ X-ray absorption fine structure and synchrotron radiation infrared spectroscopy analyses show that NO as nitrogen source converted to hydroxylamine that promptly nucleophilic attacked on the electrophilic carbon center of α-keto acid to form oxime and subsequent reductive hydrogenation occurred on the way to amino acid. Over 6 kinds of α-amino acids have been successfully synthesized and gaseous nitrogen source can be also replaced by liquid nitrogen source (NO3 - ). Our findings not only provide a creative method for converting nitrogen oxides into high-valued products, which is of epoch-making significance towards artificial synthesis of amino acids, but also benefit in deploying near-zero-emission technologies for global environmental and economic development.
Assuntos
Aminoácidos Essenciais , Óxido Nítrico , Aminoácidos , Hidrogenação , Carbono , Gases , CetoácidosRESUMO
NLRP3 inflammasome mainly controls interleukin-1ß (IL-1ß) secretion, leading to cell death called pyroptosis constituting a major antiviral host defense and inflammatory diseases upon viral infection. The RAF-MEK1/2-ERK1/2 cascade and downstream c-Jun/Fos and Activator protein-1 (AP1) signaling pathway control the degree of inflammatory response. Influenza A virus (IAV) infection is known to stimulate NLRP3 inflammasome activation and inflammatory responses. Nevertheless, the detailed mechanism by which IAV induces NLRP3 inflammasome activation involved in transcription of pro-IL-1ß mRNA remains elusive. In our study, we found that IAV infection promotes pro-IL-1ß mRNA transcription and activates NLRP3 inflammasome. Detailed studies reveal that type I interferon (IFN-α/IFN-ß) as well as U0126 (a selective inhibitor of MEK-1 and MEK-2) typically inhibit IAV-mediated NLRP3 inflammasome activation via downregulating pro-IL-1ß mRNA. Moreover, knock-down of c-Jun decreases pro-IL-1ß mRNA and inhibits NLRP3 inflammasome activation upon IAV infection. Overall, the findings uncover that AP-1 signaling pathway promotes NLRP3 inflammasome activation upon IAV infection, which provides a new idea for the therapy of NLRP3 inflammasome-associated inflammatory diseases.
Assuntos
Vírus da Influenza A , Influenza Humana , Humanos , Inflamassomos/genética , Vírus da Influenza A/genética , Influenza Humana/genética , Interferon beta/genética , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , RNA Mensageiro , Transdução de Sinais , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismoRESUMO
ASB17, a member of the ankyrin repeat and SOCS box-containing protein (ASB) family, has been supposed to act as an E3 ubiquitin ligase. Actually, little is known about its biological function. In this study, we found that ASB17 knocking-out impaired the expression of the pro-inflammatory cytokines CCL2 and IL-6 in bone marrow-derived dendritic cells (BMDCs) stimulated by lipopolysaccharide (LPS), indicating an inflammation-promoting role of this gene. We reveal that ASB17 promotes LPS-induced nuclear factor kappa B (NF-κB) signal activation through interacting with TNF receptor-associated factor 6 (TRAF6) which is a crucial adaptor protein downstream of toll-like receptors (TLR). ASB17 via its aa177-250 segment interacts with the Zn finger domain of TRAF6. The interaction of ASB17 stabilizes TRAF6 protein through inhibiting K48-linked TRAF6 polyubiquitination. Therefore, we suggest that ASB17 facilitates LPS-induced NF-κB activation by maintaining TRAF6 protein stability. The inflammation enhancer role of ASB17 is recognized here, which provides new understanding of the activation process of inflammation and immune response.
Assuntos
Peptídeos e Proteínas de Sinalização Intracelular , Lipopolissacarídeos , Fator 6 Associado a Receptor de TNF , Animais , Humanos , Camundongos , Inflamação/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Lipopolissacarídeos/metabolismo , NF-kappa B/metabolismo , Fator 6 Associado a Receptor de TNF/metabolismo , UbiquitinaçãoRESUMO
Accurately regulating the selectivity of the oxygen reduction reaction (ORR) is crucial to renewable energy storage and utilization, but challenging. A flexible alteration of ORR pathways on atomically dispersed Zn sites towards high selectivity ORR can be achieved by tailoring the coordination environment of the catalytic centers. The atomically dispersed Zn catalysts with unique O- and C-coordination structure (ZnO3 C) or N-coordination structure (ZnN4 ) can be prepared by varying the functional groups of corresponding MOF precursors. The coordination environment of as-prepared atomically dispersed Zn catalysts was confirmed by X-ray absorption fine structure (XAFs). Notably, the ZnN4 catalyst processes a 4â e- ORR pathway to generate H2 O. However, controllably tailoring the coordination environment of atomically dispersed Zn sites, ZnO3 C catalyst processes a 2â e- ORR pathway to generate H2 O2 with a near zero overpotential and high selectivity in 0.1â M KOH. Calculations reveal that decreased electron density around Zn in ZnO3 C lowers the d-band center of Zn, thus changing the intermediate adsorption and contributing to the high selectivity towards 2â e- ORR.
RESUMO
Excessive inflammatory responses induced upon SARS-CoV-2 infection are associated with severe symptoms of COVID-19. Inflammasomes activated in response to SARS-CoV-2 infection are also associated with COVID-19 severity. Here, we show a distinct mechanism by which SARS-CoV-2 N protein promotes NLRP3 inflammasome activation to induce hyperinflammation. N protein facilitates maturation of proinflammatory cytokines and induces proinflammatory responses in cultured cells and mice. Mechanistically, N protein interacts directly with NLRP3 protein, promotes the binding of NLRP3 with ASC, and facilitates NLRP3 inflammasome assembly. More importantly, N protein aggravates lung injury, accelerates death in sepsis and acute inflammation mouse models, and promotes IL-1ß and IL-6 activation in mice. Notably, N-induced lung injury and cytokine production are blocked by MCC950 (a specific inhibitor of NLRP3) and Ac-YVAD-cmk (an inhibitor of caspase-1). Therefore, this study reveals a distinct mechanism by which SARS-CoV-2 N protein promotes NLRP3 inflammasome activation and induces excessive inflammatory responses.
Assuntos
COVID-19/metabolismo , Proteínas do Nucleocapsídeo de Coronavírus/metabolismo , Inflamassomos/metabolismo , Inflamação/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , SARS-CoV-2/metabolismo , Animais , COVID-19/virologia , Células Cultivadas , Citocinas/metabolismo , Células HEK293 , Humanos , Inflamassomos/genética , Lesão Pulmonar/genética , Lesão Pulmonar/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Fosfoproteínas/metabolismo , Ligação Proteica , SARS-CoV-2/fisiologia , Células THP-1RESUMO
Developing high-performance electrocatalysts toward hydrogen evolution reaction is important for clean and sustainable hydrogen energy, yet still challenging. Herein, we report a single-atom strategy to construct excellent metal-organic frameworks (MOFs) hydrogen evolution reaction electrocatalyst (NiRu0.13-BDC) by introducing atomically dispersed Ru. Significantly, the obtained NiRu0.13-BDC exhibits outstanding hydrogen evolution activity in all pH, especially with a low overpotential of 36 mV at a current density of 10 mA cm-2 in 1 M phosphate buffered saline solution, which is comparable to commercial Pt/C. X-ray absorption fine structures and the density functional theory calculations reveal that introducing Ru single-atom can modulate electronic structure of metal center in the MOF, leading to the optimization of binding strength for H2O and H*, and the enhancement of HER performance. This work establishes single-atom strategy as an efficient approach to modulate electronic structure of MOFs for catalyst design.
RESUMO
Activation of the NACHT, leucine-rich repeat, and pyrin domains-containing protein 3 (collectively known as NLRP3) inflammasome plays a key role in host immune response, which is the first line of defense against cellular stresses and pathogen infections. However, excessive inflammasome activation damages host cells, and therefore it must be precisely controlled. Here, we discover that Cullin1 (CUL1), a key component of the Skp1-Cullin1-F-box E3 ligase, plays a critical role in controlling the NLRP3 inflammasome. CUL1 represses inflammasome assembly in cultured cells, suppresses NLRP3 function in human monocytic cell line macrophages, and attenuates inflammatory responses in mouse model. Detailed studies demonstrate that CUL1 interacts with NLRP3 and promotes NLRP3 ubiquitination, but not protein degradation, to repress the NLRP3 inflammasome activation. Moreover, upon inflammatory stimuli, including ATP and nigericin treatments, CUL1 disassociates from NLRP3 to release the repression of the NLRP3 inflammasome. Thus, this study reveals a distinct and unique mechanism underlying the control of systematic activation of the NLRP3 inflammasome.-Wan, P., Zhang, Q., Liu, W., Jia, Y., Ai, S., Wang, T., Wang, W., Pan, P., Yang, G., Xiang, Q., Huang, S., Yang, Q., Zhang, W., Liu, F., Tan, Q., Zhang, W., Wu, K., Liu, Y., Wu, J. Cullin1 binds and promotes NLRP3 ubiquitination to repress systematic inflammasome activation.
Assuntos
Proteínas Culina/metabolismo , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ubiquitinação/fisiologia , Trifosfato de Adenosina/metabolismo , Animais , Linhagem Celular , Feminino , Células HEK293 , Humanos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/metabolismo , Nigericina/metabolismo , Proteólise , Células THP-1 , Ubiquitina-Proteína Ligases/metabolismoRESUMO
A flame retardant, ammonium salt of 1-hydroxyethylidene-1,1-diphosphonic acid (AHEDPA), was synthesized by a facile one-step methodology and was proven to have achieved remarkable improved flame retardancy of cotton with exceptional durability because AHEDPA with functional groups PO-(NH4+)2 could react with OH of cellulose to form new POC bonds characterized by Fourier transform infrared (FT-IR) spectra, which further verify that AHEDPA was chemically bound to cotton instead of as additive or mixing into polymer. Combustion behaviors of the control and treated cotton were assessed by cone calorimetry, vertical flammability and limiting oxygen index (LOI) tests. The cone calorimetry results display that the peak heat release rate (PHRR) and total heat release (THR) of cotton fabric treated by 30% AHEDPA were reduced up to 95% and 68%, respectively, compared with those of control cotton. No after-flame and after-glow phenomena for treated cotton were observed in vertical flammable test. LOI test evinces that the cotton fabric treated with 30-40 % AHEDPA could be used as a durable flame retardant fabric with a LOI value of 26.2-29.5% after 50 laundering cycles. Thermogravimetric (TG) data both in nitrogen and in air atmosphere reveal that the AHEDPA treated cotton notably increased the char yield by catalyzing dehydration of cellulose, thus protecting the underlying matrix from heat and fuel. The efficient and durable flame retardant for the AHEDPA by the one-step synthesis method has great development prospects in industrial.
RESUMO
A new halogen-free and formaldehyde-free ammonium salt of melamine hexa(methylphosphonic acid) (AMHMPA) was facilely synthesized as flame retardant (FR) material under water-solvent and low temperature condition to counter inflammable cotton fabric fire hazard. The reactive PO(NH4)2 and PO(OH)2 groups from AMHMPA reacted with cotton reactive OH groups to form POC bonds. A layer of AMHMPA was coated onto the treated-cotton surface, and a carbon skeleton was formed after combustion. The char residue percentages of the treated-cotton fabrics and untreated fabric were 38.5 and 3.6% at 600⯰C, respectively. The phosphorus contents for the control, treated-cotton and burned-cotton were 0, 37.499 and 24.896%, respectively. The LOIs of cotton treated with 30-90â¯g/L AMHMPA reached 32.0-43.0%. After 50 laundering cycles (LCs), the LOIs still maintained 26.0-33.4%. AMHMPA-treated cotton had no cytotoxicity towards the environment and humans. These results demonstrated that AMHMPA-treated cotton exhibited eco-friendly, outstanding durability and excellent flame retardancy. TG-IR and cone calorimeter results confirmed AMHMPA condensation phase flame retardant mechanism.