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PANoptosis is a new type of cell death featured with pyroptosis, apoptosis and necroptosis, and is implicated in organ injury and mortality in various inflammatory diseases, such as sepsis and hemophagocytic lymphohistiocytosis (HLH). Reverse electron transport (RET)-mediated mitochondrial reactive oxygen species (mtROS) has been shown to contribute to pyroptosis and necroptosis. In this study we investigated the roles of mtROS and RET in PANoptosis induced by TGF-ß-activated kinase 1 (TAK1) inhibitor 5Z-7-oxozeaenol (Oxo) plus lipopolysaccharide (LPS) as well as the effects of anti-RET reagents on PANoptosis. We showed that pretreatment with anti-RET reagents 1-methoxy PMS (MPMS) or dimethyl fumarate (DMF) dose-dependently inhibited PANoptosis in macrophages BMDMs and J774A.1 cells induced by Oxo/LPS treatment assayed by propidium iodide (PI) staining. The three arms of the PANoptosis signaling pathway, namely pyroptosis, apoptosis and necroptosis signaling, as well as the formation of PANoptosomes were all inhibited by MPMS or DMF. We demonstrated that Oxo/LPS treatment induced RET and mtROS in BMDMs, which were reversed by MPMS or DMF pretreatment. Interestingly, the PANoptosome was co-located with mitochondria, in which the mitochondrial DNA was oxidized. MPMS and DMF fully blocked the mtROS production and the formation of PANoptosome induced by Oxo plus LPS treatment. An HLH mouse model was established by poly(I:C)/LPS challenge. Pretreatment with DMF (50 mg·kg-1·d-1, i.g. for 3 days) or MPMS (10 mg·kg-1·d-1, i.p. for 2 days) (DMF i.g. MPMS i.p.) effectively alleviated HLH lesions accompanied by decreased hallmarks of PANoptosis in the liver and kidney. Collectively, RET and mtDNA play crucial roles in PANoptosis induction and anti-RET reagents represent a novel class of PANoptosis inhibitors by blocking oxidation of mtDNA, highlighting their potential application in treating PANoptosis-related inflammatory diseases. PANoptotic stimulation induces reverse electron transport (RET) and reactive oxygen species (ROS) in mitochondia, while 1-methoxy PMS and dimethyl fumarate can inhibit PANoptosis by suppressing RETmediated oxidation of mitochondrial DNA.
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DNA Mitocondrial , Fumarato de Dimetilo , Animais , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Transporte de Elétrons , Fumarato de Dimetilo/metabolismo , Fumarato de Dimetilo/farmacologia , DNA Mitocondrial/metabolismo , Lipopolissacarídeos/farmacologia , Elétrons , Mitocôndrias , ApoptoseRESUMO
PANoptosis is an emerging form of regulated cell death (RCD) characterized by simultaneous activation of pyroptotic, apoptotic, and necroptotic signaling that not only participates in pathologies of inflammatory diseases but also has a critical role against pathogenic infections. Targeting PANoptosis represents a promising therapeutic strategy for related inflammatory diseases, but identification of inhibitors for PANoptosis remains an unmet demand. Baicalin () is an active flavonoid isolated from Scutellaria baicalensis Georgi (Huangqin), a traditional Chinese medicinal herb used for heat-clearing and detoxifying. Numerous studies suggest that baicalin possesses inhibitory activities on various forms of RCD including apoptosis/secondary necrosis, pyroptosis, and necroptosis, thereby mitigating inflammatory responses. In this study we investigated the effects of baicalin on PANoptosis in macrophage cellular models. Primary macrophages (BMDMs) or J774A.1 macrophage cells were treated with 5Z-7-oxozeaenol (OXO, an inhibitor for TAK1) in combination with TNF-α or LPS. We showed that OXO plus TNF-α or LPS induced robust lytic cell death, which was dose-dependently inhibited by baicalin (50-200 µM). We demonstrated that PANoptosis induction was accompanied by overt mitochondrial injury, mitochondrial DNA (mtDNA) release and Z-DNA formation. Z-DNA was formed from cytosolic oxidized mtDNA. Both oxidized mtDNA and mitochondrial Z-DNA puncta were co-localized with the PANoptosome (including ZBP1, RIPK3, ASC, and caspase-8), a platform for mediating PANoptosis. Intriguingly, baicalin not only prevented mitochondrial injury but also blocked mtDNA release, Z-DNA formation and PANoptosome assembly. Knockdown of ZBP1 markedly decreased PANoptotic cell death. In a mouse model of hemophagocytic lymphohistiocytosis (HLH), administration of baicalin (200 mg/kg, i.g., for 4 times) significantly mitigated lung and liver injury and reduced levels of serum TNF-α and IFN-γ, concomitant with decreased levels of PANoptosis hallmarks in these organs. Baicalin also abrogated the hallmarks of PANoptosis in liver-resident macrophages (Kupffer cells) in HLH mice. Collectively, our results demonstrate that baicalin inhibits PANoptosis in macrophages by blocking mitochondrial Z-DNA formation and ZBP1-PANoptosome assembly, thus conferring protection against inflammatory diseases. PANoptosis is a form of regulated cell death displaying simultaneous activation of pyroptotic, apoptotic, and necroptotic signaling. This study shows that induction of PANoptosis is linked to mitochondrial dysfunction and mitochondrial Z-DNA formation. Baicalin inhibits PANoptosis in macrophages in vitro via blocking mitochondrial dysfunction and the mitochondrial Z-DNA formation and thereby impeding the assembly of ZBP1-associated PANoptosome. In a mouse model of hemophagocytic lymphohistiocytosis (HLH), baicalin inhibits the activation of PANoptotic signaling in liver-resident macrophages (Kupffer cells) in vivo, thus mitigating systemic inflammation and multiple organ injury in mice.
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Macrophages represent the first lines of innate defense against pathogenic infections and are poised to undergo multiple forms of regulated cell death (RCD) upon infections or toxic stimuli, leading to multiple organ injury. Triptolide, an active compound isolated from Tripterygium wilfordii Hook F., possesses various pharmacological activities including anti-tumor and anti-inflammatory effects, but its applications have been hampered by toxic adverse effects. It remains unknown whether and how triptolide induces different forms of RCD in macrophages. In this study, we showed that triptolide exhibited significant cytotoxicity on cultured macrophages in vitro, which was associated with multiple forms of lytic cell death that could not be fully suppressed by any one specific inhibitor for a single form of RCD. Consistently, triptolide induced the simultaneous activation of pyroptotic, apoptotic and necroptotic hallmarks, which was accompanied by the co-localization of ASC specks respectively with RIPK3 or caspase-8 as well as their interaction with each other, indicating the formation of PANoptosome and thus the induction of PANoptosis. Triptolide-induced PANoptosis was associated with mitochondrial dysfunction and ROS production. PANoptosis was also induced by triptolide in mouse peritoneal macrophages in vivo. Furthermore, triptolide caused kidney and liver injury, which was associated with systemic inflammatory responses and the activation of hallmarks for PANoptosis in vivo. Collectively, our data reveal that triptolide induces PANoptosis in macrophages in vitro and exhibits nephrotoxicity and hepatotoxicity associated with induction of PANoptosis in vivo, suggesting a new avenue to alleviate triptolide's toxicity by harnessing PANoptosis.
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Diterpenos , Fenantrenos , Camundongos , Animais , Apoptose , Macrófagos/metabolismo , Diterpenos/efeitos adversos , Diterpenos/metabolismo , Fenantrenos/toxicidade , Fenantrenos/metabolismo , Compostos de Epóxi/toxicidade , Compostos de Epóxi/metabolismoRESUMO
Necroptosis has been implicated in various inflammatory diseases including tumor-necrosis factor-α (TNF-α)-induced systemic inflammatory response syndrome (SIRS). Dimethyl fumarate (DMF), a first-line drug for treating relapsing-remitting multiple sclerosis (RRMS), has been shown to be effective against various inflammatory diseases. However, it is still unclear whether DMF can inhibit necroptosis and confer protection against SIRS. In this study, we found that DMF significantly inhibited necroptotic cell death in macrophages induced by different necroptotic stimulations. Both the autophosphorylation of receptor-interacting serine/threonine kinase 1 (RIPK1) and RIPK3 and the downstream phosphorylation and oligomerization of MLKL were robustly suppressed by DMF. Accompanying the suppression of necroptotic signaling, DMF blocked the mitochondrial reverse electron transport (RET) induced by necroptotic stimulation, which was associated with its electrophilic property. Several well-known anti-RET reagents also markedly inhibited the activation of the RIPK1-RIPK3-MLKL axis accompanied by decreased necrotic cell death, indicating a critical role of RET in necroptotic signaling. DMF and other anti-RET reagents suppressed the ubiquitination of RIPK1 and RIPK3, and they attenuated the formation of necrosome. Moreover, oral administration of DMF significantly alleviated the severity of TNF-α-induced SIRS in mice. Consistent with this, DMF mitigated TNF-α-induced cecal, uterine, and lung damage accompanied by diminished RIPK3-MLKL signaling. Collectively, DMF represents a new necroptosis inhibitor that suppresses the RIPK1-RIPK3-MLKL axis through blocking mitochondrial RET. Our study highlights DMF's potential therapeutic applications for treating SIRS-associated diseases.
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Proteínas Quinases , Fator de Necrose Tumoral alfa , Camundongos , Animais , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases/metabolismo , Fumarato de Dimetilo , Necroptose , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Síndrome de Resposta Inflamatória Sistêmica , Fosforilação Oxidativa , ApoptoseRESUMO
Activation of NLR family pyrin domain-containing 3 (NLRP3) inflammasome plays important role in defending against infections, but its aberrant activation is causally linked to many inflammatory diseases, thus being a therapeutic target for these diseases. Theaflavin, one major ingredient of black tea, exhibits potent anti-inflammatory and anti-oxidative activities. In this study, we investigated the therapeutic effects of theaflavin against NLRP3 inflammasome activation in macrophages in vitro and in animal models of related diseases. We showed that theaflavin (50, 100, 200 µM) dose-dependently inhibited NLRP3 inflammasome activation in LPS-primed macrophages stimulated with ATP, nigericin or monosodium urate crystals (MSU), evidenced by reduced release of caspase-1p10 and mature interleukin-1ß (IL-1ß). Theaflavin treatment also inhibited pyroptosis as shown by decreased generation of N-terminal fragment of gasdermin D (GSDMD-NT) and propidium iodide incorporation. Consistent with these, theaflavin treatment suppressed ASC speck formation and oligomerization in macrophages stimulated with ATP or nigericin, suggesting reduced inflammasome assembly. We revealed that theaflavin-induced inhibition on NLRP3 inflammasome assembly and pyroptosis resulted from ameliorated mitochondrial dysfunction and reduced mitochondrial ROS production, thereby suppressing interaction between NLRP3 and NEK7 downstream of ROS. Moreover, we showed that oral administration of theaflavin significantly attenuated MSU-induced mouse peritonitis and improved the survival of mice with bacterial sepsis. Consistently, theaflavin administration significantly reduced serum levels of inflammatory cytokines including IL-1ß and attenuated liver inflammation and renal injury of mice with sepsis, concomitant with reduced generation of caspase-1p10 and GSDMD-NT in the liver and kidney. Together, we demonstrate that theaflavin suppresses NLRP3 inflammasome activation and pyroptosis by protecting mitochondrial function, thus mitigating acute gouty peritonitis and bacterial sepsis in mice, highlighting a potential application in treating NLRP3 inflammasome-related diseases.
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Gota , Peritonite , Sepse , Camundongos , Animais , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Espécies Reativas de Oxigênio , Nigericina/uso terapêutico , Peritonite/tratamento farmacológico , Antioxidantes/uso terapêutico , Sepse/complicações , Sepse/tratamento farmacológico , Caspases , Trifosfato de Adenosina , Interleucina-1beta/metabolismoRESUMO
The acquisition and processing of skylight polarization information forms the cornerstone in modern navigation systems that are developed by imitating certain biological mechanisms. The accuracy of skylight polarization mode information plays a major part in improving the accuracy of polarized light navigation. This paper mainly focuses on developing a methodology that can avoid the error caused by the inaccurate rotation of the polarizer and manual readings from non-electrical equipment, when the time-sequence polarization measurement system is used to obtain the skylight polarization mode information. We propose an adaptive algorithm that can obtain the pictures of angle of polarization and degree of polarization with sets of random rotation angles with no need for precise readings for the rotation angle of the polarizer. By allocating initial random values to rotation angles, a simple iterative estimation method like the Gaussian-Newton method can be used to converge calculated angle of polarization and degree of polarization values to their respective real values. The experiment results show that the proposed method can be used to estimate polarization information with high accuracy and universality under various experiment settings including both sunny and cloudy weathers. Meanwhile, the time efficiency of the proposed method is comparable to traditional methods.
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OBJECTIVE: To explore the mechanism of a false-negative result from karyotyping of chorionic villi cells for a trisomy 13 fetus featuring multiple malformations. METHODS: For a fetus with multiple malformations by ultrasonography and a 46,XY karyotype by chorionic villi analysis, amniocytes were further analyzed with quantitative fluorescence PCR (QF-PCR), G-banded karyotyping and chromosomal microarray analysis (CMA). Meanwhile, non-invasive prenatal testing (NIPT) was conducted on peripheral blood sample from the pregnant woman to determine the chromosomal composition of cytotrophoblast. After induction of labor, common aneuploidies in placenta and fetal tissue were also analyzed by QF-PCR. RESULTS: QF-PCR, chromosomal karyotyping and CMA analysis of the amniocytes all suggested complete trisomy 13 (47,XY,+13) in the fetus. NIPT also suggested existence of fetal trisomy 13. QF-PCR analysis of the placenta and fetal tissues revealed that cells derived from the maternal surface and right side of fetal surface harbored mosaic trisomy 13, while those derived from other sites of fetal surface of the placenta, umbilical cord, amniotic membrane and fetal muscle tissue harbored trisomy 13. CONCLUSION: Karyotyping of long-term cultured chorionic villus sample may give rise to false negative results due to placental mosaicism. To ensure accurate prenatal diagnosis, discordance between karyotyping of chorionic villi cells, fetal ultrasound and NIPT result should be verified by amniocentesis or cordocentesis and application of multiple cytogenetic and molecular techniques.
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Amostra da Vilosidade Coriônica , Cariotipagem , Diagnóstico Pré-Natal , Síndrome da Trissomia do Cromossomo 13/genética , Amniocentese , Feminino , Feto , Humanos , Cariótipo , Mosaicismo , Gravidez , Síndrome da Trissomia do Cromossomo 13/diagnósticoRESUMO
OBJECTIVE: To detect mutations of SLC25A13 gene in 20 families affected with citrin deficiency and provide prenatal diagnosis for them. METHODS: The 20 probands and their parents were subjected to high-frequency mutation screening combined with Sanger sequencing. After confirming the genotype of each pedigree, genetic counseling and prenatal diagnosis were performed for their subsequent pregnancies. RESULTS: Biallelic pathogenic mutations of the SLC25A13 gene were identified in all probands. These included three deletions (c.851del4, c.1092_1095delT, and c.495delA), two splice-site mutations (IVS6+5G to A and IVS11+1G to A), two nonsense mutations (c.775C to T (p.Q259X) and c.72T to A (p.Y24X)), one duplication mutation (c.1638_1660dup), one insertion (IVSl6ins3kb), and one missense mutation (c.1775A to C (p.Q592P)). Among 24 fetuses undergoing prenatal diagnosis, 8 had normal genotypes, 11 were mutation carriers, while 5 harbored biallelic mutations. Those with wild type alleles or heterozygous SLC25A13 mutations were delivered. Two fetuses harboring homozygous c.851del4 mutations were also delivered. Three fetuses harboring biallelic mutations were terminated. CONCLUSION: Analysis of SLC25A13 gene mutations in families affected by citrin deficiency can provide evidence for molecular diagnosis and facilitate genetic counseling and prenatal diagnosis for the subsequent pregnancy, which can effectively reduce the risk of birth of further affected children.
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Citrulinemia/genética , Proteínas de Transporte da Membrana Mitocondrial/genética , Diagnóstico Pré-Natal , Análise Mutacional de DNA , Feminino , Feto , Humanos , Mutação , GravidezRESUMO
OBJECTIVE: To explore the genotype-phenotype correlation of a child with chromosome 18q deletion syndrome. METHODS: G-banded karyotyping, single nucleotide polymorphism array (SNP array) and fluorescence in situ hybridization (FISH) were performed on the child with abnormal phenotypes. Genotype-phenotype correlation was explored following accurate mapping of the breakpoints on chromosome 18q. SNP array was also performed on the genome DNA derived from peripheral venous blood samples from both parents. RESULTS: Chromosomal analysis revealed that the child has a karyotype of 46, XY, del(18) (q23). SNP array analysis detected a 9.855 Mb deletion (chr18: 68 158 880-78 014 123) at 18q22.2q23. Mapping of the breakpoints suggested that the deletion has overlapped with that of distal chromosome 18q deletion syndrome and encompassed several critical regions for this syndrome. SNP array performed on parental samples suggested that the 18q22.2q23 deletion was de novo in origin. FISH analysis of peripheral blood sample from the child confirmed the presence of 18qter deletion. CONCLUSION: The phenotype of this child may be attributed to the deletion of distal 18q22.2q23, which has encompassed several critical regions for the 18q deletion syndrome.
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Transtornos Cromossômicos/genética , Polimorfismo de Nucleotídeo Único/genética , Deleção Cromossômica , Cromossomos Humanos Par 18/genética , Estudos de Associação Genética/métodos , Genótipo , Humanos , Lactente , FenótipoRESUMO
Cucurbitacin E (CucE), a triterpenoid isolated from Cucurbitaceae plants, has been shown to possess an anti-inï¬ammatory or immunosuppressive activity in vitro and in vivo, yet the underlying mechanism has been incompletely understood. The aim of the present study was to explore its effect on cytokine expression and the underlying mechanism in human Jurkat T cells as a cellular model. The results showed that CucE significantly inhibited the production of interleukin-2, tumor necrosis factor-α, and interferon-γ in culture medium of cells treated with phorbol 12,13-dibutyrate (PDB) plus ionomycin (Ion). Furthermore, the mRNA levels of these cytokines in activated Jurkat T cells were also decreased upon CucE treatment, suggesting a potential modulatory effect on the critical signaling pathways for cytokine expression, including nuclear factor-κB (NF-κB) or mitogen-activated protein kinases (MAPKs). In support of its effect on the NF-κB signaling pathway, CucE decreased the phosphorylation levels of inhibitor of κB (IκB) and NF-κB/p65 in PDB + Ion-stimulated cells. Further supporting this, the nuclear translocation of NF-κB/p65 was significantly suppressed in response to PDB plus Ion stimulation in the presence of CucE. The phosphorylation of p38MAPK, c-Jun N-terminal kinase (JNK), and Erk1/2, however, was not decreased or slightly increased at some time points by CucE treatment. Collectively, these data suggest that CucE may exhibit immunosuppressive effect by attenuating critical cytokine expression through down-regulating the NF-κB signaling pathway.
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Citocinas/metabolismo , Regulação para Baixo , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Triterpenos/farmacologia , Humanos , Células Jurkat , Sistema de Sinalização das MAP QuinasesRESUMO
Background: Lung adenocarcinoma (LUAD) represents a prevalent subtype of non-small cell lung cancer with a complex molecular landscape. Dysregulated cellular energetics, notably the interplay between hypoxia and glycolysis, has emerged as a hallmark feature of LUAD tumorigenesis and progression. In this study, we aimed to identify hypoxia and glycolysis related gene signatures and construct a prognostic model to enhance the clinical management of LUAD. Methods: A gene signature associated with hypoxia and glycolysis was established within the The Cancer Genome Atlas (TCGA) cohort and subsequently validated in the GSE31210 cohort. Additionally, a nomogram was formulated to aid in predictive modeling. Subsequently, an evaluation of the tumor microenvironment and immune checkpoints expression levels was conducted to discern disparities between low risk and high risk groups. Lastly, an exploration for drugs with potential effectiveness was carried out. Results: Our analyses revealed a distinct hypoxia and glycolysis related gene signature consisting of 6 genes significantly associated with LUAD patient survival. Integration of these genes into the prognostic model demonstrated superior predictive accuracy for patient outcomes. Furthermore, we developed a user-friendly nomogram that effectively translates the model's prognostic information into a practical tool for clinical decision-making. Conclusion: This study elucidates the critical role of hypoxia and glycolysis related genes in LUAD and offers a novel prognostic model with promising clinical utility. This model has the potential to refine risk stratification and guide personalized therapeutic interventions, ultimately improving the prognosis of LUAD patients.
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PANoptosis is manifested with simultaneous activation of biomarkers for both pyroptotic, apoptotic and necroptotic signaling via the molecular platform PANoptosome and it is involved in pathologies of various inflammatory diseases including hemophagocytic lymphohistiocytosis (HLH). Scutellarin is a flavonoid isolated from herbal Erigeron breviscapus (Vant.) Hand.-Mazz. and has been shown to possess multiple pharmacological effects, but it is unknown whether scutellarin has any effects on PANoptosis and related inflammatory diseases. In this study, we found that scutellarin inhibited cell death in bone marrow-derived macrophages (BMDMs) and J774A.1 cells treated with TGF-ß-activated kinase 1 (TAK1) inhibitor 5Z-7-oxozeaenol (OXO) plus lipopolysaccharide (LPS), which has been commonly used to induce PANoptosis. Western blotting showed that scutellarin dose-dependently inhibited the activation biomarkers for pyroptotic (Caspase-1p10 and GSDMD-NT), apoptotic (cleaved Casp3/8/9 and GSDME-NT), and necroptotic (phosphorylated MLKL) signaling. The inhibitory effect of scutellarin was unaffected by NLRP3 or Caspase-1 deletion. Interestingly, scutellarin blocked the assembly of PANoptosome that encompasses ASC, RIPK3, Caspase-8 and ZBP1, suggesting its action on upstream signaling. Consistent with this, scutellarin inhibited mitochondrial damage and mitochondrial reactive oxygen species (mtROS) generation in cells treated with OXO+LPS. Further, mito-TEMPO that can scavenge mtROS significantly inhibited OXO+LPS-induced PANoptotic cell death. In line with the in vitro results, scutellarin markedly alleviated systemic inflammation, multiple organ injury, and activation of PANoptotic biomarkers in mice with HLH. Collectively, our data suggest that scutellarin can inhibit PANoptosis by suppressing mitochondrial damage and mtROS generation and thereby mitigating multiple organ injury in mice with inflammatory disorders.
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Apigenina , Glucuronatos , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Mitocôndrias , Espécies Reativas de Oxigênio , Apigenina/farmacologia , Apigenina/uso terapêutico , Glucuronatos/farmacologia , Glucuronatos/uso terapêutico , Animais , Espécies Reativas de Oxigênio/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Camundongos , Linhagem Celular , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/imunologia , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Necroptose/efeitos dos fármacos , Masculino , MAP Quinase Quinase Quinases/metabolismo , Inflamação/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Zearalenona/administração & dosagem , Lactonas , ResorcinóisRESUMO
Computer-generated holograms are crucial for a wide range of applications such as 3D displays, information encryption, data storage, and opto-electronic computing. Orbital angular momentum (OAM), as a new degree of freedom with infinite orthogonal states, has been employed to expand the hologram bandwidth. However, in order to reduce strong multiplexing crosstalk, OAM holography suffers from a fundamental sampling criterion that the image sampling distance should be no less than the diameter of largest addressable OAM mode, which severely hinders the increase in resolution and capacity. Here we establish a comprehensive model on multiplexing crosstalk in OAM holography, propose a pseudo incoherent approach that is almost crosstalk-free, and demonstrate an analogous coherent solution by temporal multiplexing, which dramatically eliminates the crosstalk and largely relaxes the constraint upon sampling condition of OAM holography, exhibiting a remarkable resolution enhancement by several times, far beyond the conventional resolution limit of OAM holography, as well as a large scaling of OAM multiplexing capacity at fixed resolution. Our method enables OAM-multiplexed holographic reconstruction with high quality, high resolution, and high capacity, offering an efficient and practical route towards the future high-performance holographic systems.
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Necroptosis is a necrotic form of regulated cell death, which is primarily mediated by the receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like (MLKL) pathway in a caspase-independent manner. Necroptosis has been found to occur in virtually all tissues and diseases evaluated, including pancreatitis. Celastrol, a pentacyclic triterpene extracted from the roots of Tripterygium wilfordii (thunder god vine), possesses potent anti-inflammatory and anti-oxidative activities. Yet, it is unclear whether celastrol has any effects on necroptosis and necroptotic-related diseases. Here we showed that celastrol significantly suppressed necroptosis induced by lipopolysaccharide (LPS) plus pan-caspase inhibitor (IDN-6556) or by tumor-necrosis factor-α in combination with LCL-161 (Smac mimetic) and IDN-6556 (TSI). In these in vitro cellular models, celastrol inhibited the phosphorylation of RIPK1, RIPK3, and MLKL and the formation of necrosome during necroptotic induction, suggesting its possible action on upstream signaling of the necroptotic pathway. Consistent with the known role of mitochondrial dysfunction in necroptosis, we found that celastrol significantly rescued TSI-induced loss of mitochondrial membrane potential. TSI-induced intracellular and mitochondrial reactive oxygen species (mtROS), which are involved in the autophosphorylation of RIPK1 and recruitment of RIPK3, were significantly attenuated by celastrol. Moreover, in a mouse model of acute pancreatitis that is associated with necroptosis, celastrol administration significantly reduced the severity of caerulein-induced acute pancreatitis accompanied by decreased phosphorylation of MLKL in pancreatic tissues. Collectively, celastrol can attenuate the activation of RIPK1/RIPK3/MLKL signaling likely by attenuating mtROS production, thereby inhibiting necroptosis and conferring protection against caerulein-induced pancreatitis in mice.
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Pancreatite , Camundongos , Animais , Pancreatite/induzido quimicamente , Pancreatite/tratamento farmacológico , Proteínas Quinases/metabolismo , Necroptose , Ceruletídeo , Doença Aguda , Triterpenos Pentacíclicos , Caspases/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , ApoptoseRESUMO
Spatial mode (de)multiplexing of orbital angular momentum (OAM) beams is a promising solution to address future bandwidth issues, but the rapidly increasing divergence with the mode order severely limits the practically addressable number of OAM modes. Here we present a set of multi-vortex geometric beams (MVGBs) as high-dimensional information carriers for free-space optical communication, by virtue of three independent degrees of freedom (DoFs) including central OAM, sub-beam OAM, and coherent-state phase. The novel modal basis set has high divergence degeneracy, and highly consistent propagation behaviors among all spatial modes, capable of increasing the addressable spatial channels by two orders of magnitude than OAM basis as predicted. We experimentally realize the tri-DoF MVGB mode (de)multiplexing and data transmission by the conjugated modulation method, demonstrating lower error rates caused by center offset and coherent background noise, compared with OAM basis. Our work provides a potentially useful basis for the next generation of large-scale dense data communication.
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Background: Necroptosis, an innovative type of programmed cell death, involves the formation of necrosomes and eventually mediates necrosis. Multiple lines of evidence suggest that necroptosis plays a major role in the development of human cancer. However, the role of necroptosis in lung adenocarcinoma (LUAD) remains unclear. In this study, we aimed to construct an NRL-related prognostic model and comprehensively analyze the role of NRL in LUAD. Methods: A necroptosis-related lncRNA (NRL) signature was constructed in the training cohort and verified in the validation and all cohorts based on The Cancer Genome Atlas database. In addition, a nomogram was developed. The tumor microenvironment (TME), checkpoint, human leukocyte antigen, and m6A methylation levels were compared between low-risk and high-risk groups. Then, we identified five truly prognostic lncRNAs (AC107021.2, AC027117.1, FAM30A, FAM83A-AS1, and MED4-AS1) and constructed a ceRNA network, and four hub genes of downstream genes were identified and analyzed using immune, pan-cancer, and survival analyses. Results: The NRL signature could accurately predict the prognosis of patients with LUAD, and patients with low risk scores were identified with an obvious "hot" immune infiltration level, which was strongly associated with better prognosis. Based on the ceRNA network, we postulated that NRLs regulated the TME of patients with LUAD via cyclin-dependent kinase (CDK) family proteins. Conclusion: We constructed an NRL signature and a ceRNA network in LUAD and found that NRLs may modulate the immune microenvironment of LUAD via CDK family proteins.
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Discovery of anti-inflammatory drugs that can suppress T lymphocyte activation and proliferation by inhibiting TCR/CD3 and IL-2/IL-2R signaling is still needed in clinic, though rapamycin and other related reagents have made great success. Taraxasterol (TAS) is an active ingredient of dandelion, an anti-inflammatory medicinal herb with low in vivo toxicity that has long been used in China. Yet the action mechanism of TAS on lymphocytes remains elusive. The anti-inflammatory effects of TAS were evaluated in C57BL/6 mouse primary lymphocytes stimulated with concanavalin A (Con A) in vitro and in mouse model of Con A-induced acute hepatitis in vivo. Our results showed that TAS significantly suppressed Con A-induced acute hepatitis in a mouse model, reducing the hepatic necrosis areas, the release of aminotransferases, and the production of IL-2 and other inflammatory cytokines. Supporting this, in vitro study also showed that TAS reduced the production of IL-2 and the expression of IL-2 receptor subunit α (CD25) upon the stimulation of Con A, which was likely mediated by suppressing NF-κB activation. The downstream pathways of IL-2/IL-2R signaling, including the activation of PI3K/PDK1/mTOR, STAT3 and STAT5, were also suppressed by TAS. Consistently, Con A-induced T cell proliferation was also inhibited by TAS in vitro. Our data indicate that TAS can suppress both T lymphocyte activation and cell proliferation by down-regulating IL-2 expression and its signaling pathway thereby ameliorating Con A-induced acute hepatitis, highlighting TAS as a potential drug candidate for treating inflammatory diseases including autoimmune hepatitis.
Assuntos
Anti-Inflamatórios/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Interleucina-2/imunologia , Esteróis/uso terapêutico , Linfócitos T/efeitos dos fármacos , Triterpenos/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Proliferação de Células/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Concanavalina A , Citocinas/sangue , Feminino , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/patologia , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Esteróis/farmacologia , Linfócitos T/imunologia , Triterpenos/farmacologiaRESUMO
Background: Pyroptosis is a new type of programmed cell death, accompanied by an intense inflammatory response. Previous studies have shown that pyroptosis can modify long-chain non-coding RNA (lncRNA), thereby affecting the occurrence and progression of tumors. However, the underlying role of pyroptosis-related lncRNA in lung adenocarcinoma (LUAD) remains to be elucidated. Therefore, the purpose of our study was to evaluate the prognostic value of pyrolysis-related lncRNA in patients with LUAD. Methods: A total of 454 LUAD samples were downloaded from The Cancer Genome Atlas (TCGA) database. Pearson's correlation coefficient was used to identify the pyroptosis-related lncRNAs. Unsupervised consensus clustering was used to identify the various LUAD molecular subtypes. A least absolute shrinkage and selection operator (LASSO) analysis was conducted to construct a prognostic signature. Results: An 11-lncRNA prognostic signature out of 19 identified pyroptosis-related prognostic lncRNAs was constructed. The patients with LUAD were divided into low-risk and high-risk groups. Patients in the high-risk group had higher score values and mortality. The immune score, stromal score, and estimate score were lower in the high-risk group. The risk score was an independent predictor for OS in multivariate Cox regression analyses (HR > 1, p < 0.01). BTLA, PD-1, PD-L1, CTLA, and CD47 were lower expressed in the high-risk group. Conclusions: Our study identified an 11-pyroptosis-related lncRNA signature. These findings could further clarify the role of pyroptosis in LUAD and guide the prognosis and individualized treatment of patients.
RESUMO
Colonic patches, the counterparts of Peyer's patches in the small intestine, are dynamically regulated lymphoid tissues in the colon that have an important role in defensing against microbial infections. Berberine is an isoquinoline alkaloid extracted from medicinal herbs including Rhizoma coptidis and has long been used for the treatment of infectious gastroenteritis, but its impact on the colonic lymphoid tissues (such as colonic patches) is unknown. In this study, we aimed to investigate whether berberine had any influences on the colonic patches in mice with bacterial infection. The results showed that oral berberine administration in bacterial infected mice substantially enhanced the hypertrophy of colonic patches, which usually possessed the features of two large B-cell follicles with a separate T-cell area. Moreover, the colonic patches displayed follicular dendritic cell networks within the B-cell follicles, indicative of mature colonic patches containing germinal centers. Concomitant with enlarged colonic patches, the cultured colon of infected mice treated with berberine secreted significantly higher levels of interleukin-1ß (IL-1ß), IL-6, TNF-α, and CCL-2, while NLRP3 inhibitor MMC950 or knockout of NLRP3 gene abrogated berberine-induced hypertrophy of colonic patches, suggesting the involvement of the NLRP3 signaling pathway in this process. Functionally, oral administration of berberine ameliorated liver inflammation and improved formed feces in the colon. Altogether, these results indicated that berberine was able to augment the hypertrophy of colonic patches in mice with bacterial infection probably through enhancing local inflammatory responses in the colon.
Assuntos
Infecções Bacterianas/patologia , Berberina/uso terapêutico , Colo/efeitos dos fármacos , Tecido Linfoide/efeitos dos fármacos , Doenças Peritoneais/patologia , Animais , Linfócitos B/efeitos dos fármacos , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/metabolismo , Colo/crescimento & desenvolvimento , Colo/patologia , Citocinas/metabolismo , Células Dendríticas/efeitos dos fármacos , Feminino , Gastroenterite/tratamento farmacológico , Tecido Linfoide/crescimento & desenvolvimento , Tecido Linfoide/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Doenças Peritoneais/tratamento farmacológico , Doenças Peritoneais/metabolismo , Linfócitos T/efeitos dos fármacosRESUMO
The flavonoid baicalin has been reported to possess potent anti-inflammatory activities by suppressing inflammatory signaling pathways. However, whether baicalin can suppress the activation of NOD-like receptor (NLR) family, pyrin containing domain 3 (NLRP3) inflammasome in macrophages is largely unknown. Here, we showed that baicalin treatment dose-dependently inhibited adenosine triphosphate (ATP) or nigericin-induced NLRP3 inflammasome activation, as revealed by the decreased release of mature interleukin (IL)-1ß, active caspase-1p10, and high-mobility group box-1 protein from lipopolysaccharide (LPS)-primed bone marrow-derived macrophages. The formation of ASC specks, a critical marker of NLRP3 inflammasome assembly, was robustly inhibited by baicalin in the macrophages upon ATP or nigericin stimulation. All these inhibitory effects of baicalin could be partly reversed by MDL12330A or H89, both of which are inhibitors of the protein kinase A (PKA) signaling pathway. Consistent with this, baicalin strongly enhanced PKA-mediated phosphorylation of NLRP3, which has been suggested to prevent ASC recruitment into the inflammasome. Of note, the PKA inhibitor H89 could block baicalin-induced NLRP3 phosphorylation on PKA-specific sites, further supporting PKA's role in this process. In addition, we showed that when administered pre and post exposure to Escherichia coli infection baicalin treatment significantly improved mouse survival in bacterial sepsis. Baicalin administration also significantly reduced IL-1ß levels in the sera of bacterial infected mice. Altogether, our results revealed that baicalin inhibited NLRP3 inflammasome activation at least partly through augmenting PKA signaling, highlighting its therapeutic potential for the treatment of NLRP3-related inflammatory diseases.