RESUMO
The immune landscape of bladder cancer progression is not fully understood, and effective therapies are lacking in advanced bladder cancer. Here, we visualized that bladder cancer cells recruited neutrophils by secreting interleukin-8 (IL-8); in turn, neutrophils played dual functions in bladder cancer, including hepatocyte growth factor (HGF) release and CCL3highPD-L1high super-immunosuppressive subset formation. Mechanistically, c-Fos was identified as the mediator of HGF up-regulating IL-8 transcription in bladder cancer cells, which was central to the positive feedback of neutrophil recruitment. Clinically, compared with serum IL-8, urine IL-8 was a better biomarker for bladder cancer prognosis and clinical benefit of immune checkpoint blockade (ICB). Additionally, targeting neutrophils or hepatocyte growth factor receptor (MET) signaling combined with ICB inhibited bladder cancer progression and boosted the antitumor effect of CD8+ T cells in mice. These findings reveal the mechanism by which tumor-neutrophil cross talk orchestrates the bladder cancer microenvironment and provide combination strategies, which may have broad impacts on patients suffering from malignancies enriched with neutrophils.
Assuntos
Progressão da Doença , Interleucina-8 , Neutrófilos , Microambiente Tumoral , Neoplasias da Bexiga Urinária , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/imunologia , Microambiente Tumoral/imunologia , Humanos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Animais , Camundongos , Interleucina-8/metabolismo , Linhagem Celular Tumoral , Fator de Crescimento de Hepatócito/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Antígeno B7-H1/metabolismo , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Feminino , Masculino , Infiltração de NeutrófilosRESUMO
Cyclic GMP-AMP synthase (cGAS), as a cytosolic DNA sensor, plays a crucial role in antiviral immunity, and its overactivation induces excess inflammation and tissue damage. Macrophage polarization is critically involved in inflammation; however, the role of cGAS in macrophage polarization during inflammation remains unclear. In this study, we demonstrated that cGAS was upregulated in the LPS-induced inflammatory response via the TLR4 pathway, and cGAS signaling was activated by mitochondria DNA in macrophages isolated from C57BL/6J mice. We further demonstrated that cGAS mediated inflammation by acting as a macrophage polarization switch, which promoted peritoneal macrophages and the bone marrow-derived macrophages to the inflammatory phenotype (M1) via the mitochondrial DNA-mTORC1 pathway. In vivo studies verified that deletion of Cgas alleviated sepsis-induced acute lung injury by promoting macrophages to shift from the M1 phenotype to the M2 phenotype. In conclusion, our study demonstrated that cGAS mediated inflammation by regulating macrophage polarization through the mTORC1 pathway, and it further provided a potential therapeutic strategy for inflammatory diseases, especially sepsis-induced acute lung injury.
Assuntos
Lesão Pulmonar Aguda , Macrófagos , Alvo Mecanístico do Complexo 1 de Rapamicina , Nucleotidiltransferases , Sepse , Animais , Camundongos , DNA Mitocondrial/metabolismo , Inflamação , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo , Fenótipo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismoRESUMO
Tripartite motif protein (TRIM) 50 is a new member of the tripartite motif family, and its biological function and the molecular mechanism it is involved in remain largely unknown. The NOD-like receptor family protein (NLRP)3 inflammasome is actively involved in a wide array of biological processes while mechanisms of its regulation remain to be fully clarified. Here, we demonstrate the role of TRIM50 in NLRP3 inflammasome activation. In contrast to the conventional E3 ligase functions of TRIM proteins, TRIM50 mediates direct oligomerization of NLRP3, thereby suppressing its ubiquitination and promoting inflammasome activation. Mechanistically, TRIM50 directly interacts with NLRP3 through its RING domain and induces NLRP3 oligomerization via its coiled-coil domain. Finally, we show that TRIM50 promotes NLRP3 inflammasome-mediated diseases in mice. We thus reveal a novel regulatory mechanism of NLRP3 via TRIM50 and suggest that modulating TRIM50 might represent a therapeutic strategy for NLRP3-dependent pathologies.
Assuntos
Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Proteínas com Motivo Tripartido , Animais , Camundongos , Inflamassomos/metabolismo , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas com Motivo Tripartido/genética , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , UbiquitinaçãoRESUMO
Macrophages are represented in all tissues by phenotypically distinct resident populations that show great functional diversity. Macrophages generally play a protumoral role, and they are attractive targets for cancer therapy. In this study, we found that CD169+ macrophages depletion inhibited the growth of established Lewis lung carcinoma tumors in mice. Benefits must be weighed against potential adverse effects in cancer therapy. Here, we investigated the adverse effects of CD169+ macrophages depletion on bone and bone marrow in mice bearing Lewis lung carcinoma tumors. Our studies showed that depletion of CD169+ macrophages in LLC tumor-bearing mice disrupted bone homeostasis, including bone weight loss and bone mineral density decrease. Further studies revealed that bone marrow erythropoiesis was severely impaired after depletion of CD169+ macrophages in LLC tumor-bearing mice. Our findings suggest that depletion of macrophages for cancer therapy may be associated with potential adverse effects that need to be recognized, prevented, and optimally managed.
Assuntos
Medula Óssea/imunologia , Osso e Ossos/imunologia , Carcinoma Pulmonar de Lewis/imunologia , Eritropoese/imunologia , Homeostase/imunologia , Macrófagos/imunologia , Animais , Densidade Óssea/efeitos dos fármacos , Densidade Óssea/imunologia , Medula Óssea/metabolismo , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/genética , Linhagem Celular Tumoral , Células Cultivadas , Toxina Diftérica/administração & dosagem , Toxina Diftérica/farmacologia , Eritropoese/genética , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/genética , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/imunologia , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/metabolismo , Homeostase/efeitos dos fármacos , Homeostase/genética , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismoRESUMO
Silver complexes are active constituents of the metal-based compounds; several studies suggest that silver complexes possess antimicrobial and anticancer properties. We have recently reported that Ag-SP-DNC, a novel silver and singly protonated dehydronorcantharidin complex, triggers oxidative stress-mediated apoptosis of lung cancer cells. In this study, we investigated the anticancer effects of Ag-SP-DNC in CT-26 murine colon carcinoma model. Ag-SP-DNC induced apoptosis of CT-26 cells, together with inhibition of cell proliferation; treatment of CT-26 tumor-bearing mice with Ag-SP-DNC delayed tumor growth. We also explored the mechanism of action of Ag-SP-DNC and found that Ag-SP-DNC treatment of CT-26 cells was associated with high levels of intracellular reactive oxygen species. The further experiments revealed that Ag-SP-DNC-treated cells underwent loss of mitochondrial membrane potential concomitant with intracellular calcium overload and caspase-3 activation. Taken together, our study demonstrates the potent anticancer effects of Ag-SP-DNC to colorectal cancer.
Assuntos
Antineoplásicos/farmacologia , Neoplasias do Colo/tratamento farmacológico , Complexos de Coordenação/farmacologia , Modelos Animais de Doenças , Compostos Organometálicos/farmacologia , Prótons , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Camundongos , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-AtividadeRESUMO
Three new geranylated flavanones, named as paucatalinone A (1), B (2), and isopaucatalinone B (3), were isolated from the fruits of Paulownia catalpifolia Gong Tong (Scrophulariaceae). Their structures were well determined by means of IR, MS, 1D and 2D NMR, and CD techniques. Paucatalinone A (1) is the first sample as a dimeric geranylated flavanone derivative isolated from natural products. Paucatalinone A (1) displayed good antiproliferative effects on human lung cancer cells A549 and resulted in a clear increase of the percentage of cells in G1 phase and a decrease in the percentage of cells in S and G2/M phases in comparison with control cells.
Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Scrophulariaceae/química , Antineoplásicos Fitogênicos/isolamento & purificação , Linhagem Celular Tumoral/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Flavanonas/química , Flavanonas/isolamento & purificação , Flavanonas/farmacologia , Frutas/química , Fase G1/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/patologia , Espectroscopia de Ressonância Magnética , Estrutura MolecularRESUMO
Cyclic GMP-AMP synthase (cGAS) is a key innate immune sensor that recognizes cytosolic DNA to induce immune responses against invading pathogens. The role of cGAS is conventionally recognized as a nucleotidyltransferase to catalyze the synthesis of cGAMP upon recognition of cytosolic DNA, which leads to the activation of STING and production of type I/III interferon to fight against the pathogen. However, given that hepatocytes are lack of functional STING expression, it is intriguing to define the role of cGAS in hepatocellular carcinoma (HCC), the liver parenchymal cells derived malignancy. In this study, we revealed that cGAS was significantly downregulated in clinical HCC tissues, and its dysregulation contributed to the progression of HCC. We further identified cGAS as an immune tyrosine inhibitory motif (ITIM) containing protein, and demonstrated that cGAS inhibited the progression of HCC and increased the response of HCC to sorafenib treatment by suppressing PI3K/AKT/mTORC1 pathway in cellular and animal models. Mechanistically, cGAS recruits SH2-containing tyrosine phosphatase 1 (SHP1) via ITIM, and dephosphorylates p85 in phosphatidylinositol 3-kinase (PI3K), which leads to the suppression of AKT-mTORC1 pathway. Thus, cGAS is identified as a novel tumor suppressor in HCC via its function independent of its conventional role as cGAMP synthase, which indicates a novel therapeutic strategy for advanced HCC by modulating cGAS signaling.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Nucleotidiltransferases , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/metabolismo , Nucleotidiltransferases/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Humanos , Animais , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Linhagem Celular Tumoral , Masculino , Transdução de Sinais , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Camundongos Nus , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Nucleotídeos Cíclicos/metabolismoRESUMO
Ras-related C3 botulinum toxin substrate 1 (RAC1) overexpressiosn and hyperactivation are correlated with aggressive growth and other malignant characteristics in a wide variety of cancers including hepatocellular carcinoma (HCC). However, the regulatory mechanism of RAC1 expression and activation in HCC is not fully understood. Here, we demonstrated that E3 ubiquitin ligase MG53 (also known as tripartite motif 72, TRIM72) acted as a direct inhibitor of RAC1, and it catalyzed the ubiquitination of RAC1 and further inhibited RAC1 activity in HCC cells. Mechanistically, MG53 directly bound with RAC1 through its coiled-coil domain and suppressed RAC1 activity by catalyzing the Lys48 (K48)-linked polyubiquitination of RAC1 at Lys5 residue in HCC cells. We further demonstrated that MG53 significantly suppressed the malignant behaviors of HCC cells and enhanced the chemosensitivity of HCC cells to sorafenib treatment by inhibiting RAC1-MAPK signaling axis. In summary, we identified MG53 as a novel RAC1 inhibitor and tumor suppressor in HCC, and it suppressed HCC progression by inducing K48-linked polyubiquitination of RAC1 and further inhibiting the RAC1-MAPK signaling. Altogether, our investigation provided a new therapeutic strategy for RAC1 overactivated tumors by modulating MG53.
RESUMO
Hepatocellular carcinoma (HCC), a heterogeneous cancer with high mortality, is resistant to single targeted therapy; thus, combination therapy based on synthetic lethality is a promising therapeutic strategy for HCC. Poly (adenosine diphosphate [ADP]-ribose) polymerase 1 (PARP1) is the most recognized target for synthetic lethality; however, the therapeutic effect of PARP1 inhibition on HCC is disappointing. Therefore, exploring new synthetic lethal partners for the efficient manipulation of HCC is urgently required. In this study, we identified Src and PARP1 as novel synthetic lethal partners, and the combination therapy produced significant anti-tumor effects without causing obvious side effects. Mechanistically, Src interacted with PARP1 and phosphorylated PARP1 at the Y992 residue, which further mediated resistance to PARP1 inhibition. Overall, this study revealed that Src-mediated PARP1 phosphorylation induced HCC resistance to PARP1 inhibitors and indicated a therapeutic window of the Y992 phosphorylation of PARP1 for HCC patients. Moreover, synthetic lethal therapy by co-targeting PARP1 and Src have the potential to broaden the strategies for HCC and might benefit HCC patients with high Src activation and resistance to PARP1 inhibitors alone.
Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Quinases da Família src/antagonistas & inibidores , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Dasatinibe/administração & dosagem , Dasatinibe/farmacologia , Dimetil Sulfóxido/administração & dosagem , Dimetil Sulfóxido/farmacologia , Modelos Animais de Doenças , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos NOD , Fosforilação , Ftalazinas/administração & dosagem , Ftalazinas/farmacologia , Piperazinas/administração & dosagem , Piperazinas/farmacologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra , Quinases da Família src/metabolismoRESUMO
Previously the synthesis of novel somatostatin mimetic from 1-deoxynojirimycin (DNJ) led to identification of a compound with affinity for human somatostatin receptor subtypes 4 and 5 (hSSTR4 and hSSTR5). Here we examined the properties of this peptidomimetic in a human umbilical vein endothelial cell (HUVEC) based assays. The peptidomimetic prevented capillary tube formation based on HUVECs. It also inhibited HUVEC proliferation by inducing G1 phase cell cycle arrest and apoptosis. Stress fiber assembly and cell migration in HUVECs was markedly suppressed by the somatostatin receptor ligand.
Assuntos
1-Desoxinojirimicina/farmacologia , Materiais Biomiméticos/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Somatostatina/farmacologia , 1-Desoxinojirimicina/química , Materiais Biomiméticos/química , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Fase G1/efeitos dos fármacos , Humanos , Somatostatina/química , Veias Umbilicais/citologiaRESUMO
Luteolin, 3',4',5,7-tetrahydroxyflavone, has been shown to possess antioxidant, anti-inflammation and anti-cancer properties. However, its role in lung cancer remains poorly understood. Here we examined the anti-tumorigenic role of luteolin in a commonly used lung cancer cell line. Luteolin inhibited the growth of A549 cells by inducing G1 phase cell cycle arrest and apoptosis. Furthermore, stress fiber assembly and cell migration in A549 cells was markedly suppressed by luteolin.
Assuntos
Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Luteolina/fisiologia , Animais , Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Apoptose , Ciclo Celular , Linhagem Celular Tumoral , Movimento Celular , Relação Dose-Resposta a Droga , Humanos , Luteolina/metabolismo , Potenciais da Membrana , Camundongos , Membranas Mitocondriais/metabolismoRESUMO
OBJECTIVE: To study the chemical constituents of Salsola collina. METHODS: The compounds were isolated by column chromatography, and their structures were identified by physical and chemical properties and spectral data. RESULTS: Seven compounds were isolated and identified as n-lignoceric acid (1), n-dotriacontanic acid (2), beta-sitosterol (3), 5, 2'-dihydroxy-6, 7-methylenedioxy-isoflavone (4), vanillic acid (5), (-)syringaresinol 4,4'-bis-O-beta-D-glucopyranoside (6), salicylic acid (7). CONCLUSION: The compounds of 1, 2, 4, 5 and 6 are isolated from the plant for the first time.
Assuntos
Ácidos Graxos/isolamento & purificação , Isoflavonas/isolamento & purificação , Plantas Medicinais/química , Salsola/química , Ácido Vanílico/isolamento & purificação , Anti-Hipertensivos/química , Anti-Hipertensivos/isolamento & purificação , Cromatografia em Camada Fina , Dissacarídeos/química , Dissacarídeos/isolamento & purificação , Ácidos Graxos/química , Isoflavonas/química , Estrutura Molecular , Naftalenos/química , Naftalenos/isolamento & purificação , Componentes Aéreos da Planta/química , Sitosteroides/química , Sitosteroides/isolamento & purificação , Ácido Vanílico/químicaRESUMO
The prevalence of colorectal cancer (CRC) continues to increase. Treatment of CRC remains a significant clinical challenge, and effective therapies for advanced CRC are desperately needed. Increasing attention and ongoing research efforts have focused on krill oil that may provide health benefits to the human body. Here we report that krill oil exerts in vitro anticancer activity through a direct inhibition on proliferation, colony formation, migration, and invasion of mouse colon cancer cells. Krill oil inhibited the proliferation and colony formation of CT-26 colon cancer cells by causing G0/G1 cell cycle arrest and apoptosis. Cell cycle arrest was attributable to reduction of cyclin D1 levels in krill oil-treated cells. Further studies revealed that krill oil induced mitochondrial-dependent apoptosis of CT-26 cells, including loss of mitochondrial membrane potential, increased cytosolic calcium levels, activation of caspase-3, and downregulation of anti-apoptotic proteins MCL-1 and BCL-XL. Krill oil suppressed migration of CT-26 cells by disrupting the microfilaments and microtubules. Extracellular signal-regulated protein kinase (ERK) plays crucial roles in regulating proliferation and migration of cancer cells. We found that krill oil attenuated the activation of ERK signaling pathway to exert the effects on cell cycle, apoptosis, and migration of colon cancer cells. We speculate that polyunsaturated fatty acids of krill oil may dampen ERK activation by decreasing the phospholipid saturation of cell membrane. Although findings from in vitro studies may not necessarily translate in vivo, our study provides insights into the possibility that krill oil or its components could have therapeutic potential in colon cancer.
Assuntos
Antineoplásicos/farmacologia , Neoplasias do Colo/tratamento farmacológico , Euphausiacea/química , Óleos de Peixe/farmacologia , Animais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Ensaios de Seleção de Medicamentos Antitumorais , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Células Tumorais CultivadasRESUMO
The anemia of inflammation is related in part to abnormal erythropoiesis in bone marrow. G-CSF regulates granulopoiesis and is increased during systemic inflammation. Here, we have showed that high levels of G-CSF are associated with repression of bone marrow erythropoiesis and expansion of splenic erythropoiesis in Escherichia coli-infected mice and lipopolysaccharide-treated mice. Under lipopolysaccharide-induced systemic inflammatory conditions in mice, G-CSF neutralization with antibody alleviated the blockage of bone marrow erythropoiesis, prevented the enhancement of splenic erythropoiesis, ameliorated splenomegaly, and reduced the brittleness of spleen. We further demonstrated that after lipopolysaccharide treatment, TLR4-knockout mice display low levels of G-CSF, healthy bone marrow erythropoiesis, almost no stress erythropoiesis in the spleen, and normal size and toughness of spleen. In addition, we found HIF-mediated erythropoietin production is essential for splenic erythropoiesis in the setting of G-CSF-induced suppression of bone marrow erythropoiesis. Our findings identify G-CSF as a critical mediator of inflammation-associated erythropoiesis dysfunction in bone marrow and offer insight into the mechanism of G-CSF-induced splenic erythropoiesis. We provide experimentally significant dimension to the biology of G-CSF.
Assuntos
Medula Óssea/metabolismo , Eritropoese/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Baço/metabolismo , Síndrome de Resposta Inflamatória Sistêmica/metabolismo , Animais , Medula Óssea/efeitos dos fármacos , Eritropoese/genética , Eritropoetina/biossíntese , Escherichia coli , Infecções por Escherichia coli/metabolismo , Infecções por Escherichia coli/microbiologia , Injeções Subcutâneas , Lipopolissacarídeos/efeitos adversos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais/genética , Baço/efeitos dos fármacos , Síndrome de Resposta Inflamatória Sistêmica/induzido quimicamente , Receptor 4 Toll-Like/deficiência , Receptor 4 Toll-Like/genéticaRESUMO
During the progression of coronavirus disease 2019 (COVID-19), immune response and inflammation reactions are dynamic events that develop rapidly and are associated with the severity of disease. Here, we aimed to develop a predictive model based on the immune and inflammatory response to discriminate patients with severe COVID-19. COVID-19 patients were enrolled, and their demographic and immune inflammatory reaction indicators were collected and analyzed. Logistic regression analysis was performed to identify the independent predictors, which were further used to construct a predictive model. The predictive performance of the model was evaluated by receiver operating characteristic curve, and optimal diagnostic threshold was calculated; these were further validated by 5-fold cross-validation and external validation. We screened three key indicators, including neutrophils, eosinophils, and IgA, for predicting severe COVID-19 and obtained a combined neutrophil, eosinophil, and IgA ratio (NEAR) model (NEU [109/liter] - 150×EOS [109/liter] + 3×IgA [g/liter]). NEAR achieved an area under the curve (AUC) of 0.961, and when a threshold of 9 was applied, the sensitivity and specificity of the predicting model were 100% and 88.89%, respectively. Thus, NEAR is an effective index for predicting the severity of COVID-19 and can be used as a powerful tool for clinicians to make better clinical decisions. IMPORTANCE The immune inflammatory response changes rapidly with the progression of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and is responsible for clearance of the virus and further recovery from the infection. However, the intensified immune and inflammatory response in the development of the disease may lead to more serious and fatal consequences, which indicates that immune indicators have the potential to predict serious cases. Here, we identified both eosinophils and serum IgA as prognostic markers of COVID-19, which sheds light on new research directions and is worthy of further research in the scientific research field as well as clinical application. In this study, the combination of NEU count, EOS count, and IgA level was included in a new predictive model of the severity of COVID-19, which can be used as a powerful tool for better clinical decision-making.
Assuntos
Teste para COVID-19/métodos , COVID-19/diagnóstico , COVID-19/imunologia , Regras de Decisão Clínica , Índice de Gravidade de Doença , Adulto , Idoso , Biomarcadores/sangue , COVID-19/sangue , Tomada de Decisão Clínica/métodos , Progressão da Doença , Eosinófilos/metabolismo , Feminino , Humanos , Imunoglobulina A/sangue , Inflamação/sangue , Inflamação/diagnóstico , Inflamação/virologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Valor Preditivo dos Testes , Prognóstico , Sensibilidade e EspecificidadeRESUMO
Cyclic GMP-AMP synthase (cGAS) functions as an essential DNA sensor, which senses the cytoplasmic double-stranded DNA and activates the antiviral response. However, the posttranslational modification of cGAS remains to be fully understood and whether it has arginine methylation modification remains unknown. Here, we identified protein arginine methyltransferase 5 (PRMT5) as a direct binding partner of cGAS, and it catalyzed the arginine symmetrical dimethylation of cGAS at the Arg124 residue. Further investigation demonstrated that methylation of cGAS by PRMT5 attenuated cGAS-mediated antiviral immune response by blocking the DNA binding ability of cGAS. Oral administration of PRMT5 inhibitors significantly protected mice from HSV-1 infection and prolonged the survival time of these infected mice. Therefore, our findings revealed an essential regulatory effect of PRMT5 on cGAS-mediated antiviral immune response and provided a promising potential antiviral strategy by modulating PRMT5.
Assuntos
Herpes Simples , Proteína-Arginina N-Metiltransferases/metabolismo , Animais , Antivirais/farmacologia , Arginina/metabolismo , Herpes Simples/genética , Imunidade , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo , Proteína-Arginina N-Metiltransferases/genéticaRESUMO
Hydroxysafflor Yellow A has been demonstrated to attenuate pressure overloaded hypertrophy in rats and inhibit platelet aggregation. Herein we found that Hydroxysafflor Yellow A prevented cerebral ischemia-reperfusion injury by inhibition of thrombin generation. In addition, treatment with Hydroxysafflor Yellow A significantly inhibited NF-kappaB p65 nuclear translation and p65 binding activity, both mRNA and protein levels of ICAM-1 and the infiltration of neutrophils. Mean while, Hydroxysafflor Yellow A had the capacity to improve neurological deficit scores, increase the number of the surviving hippocampal CA1 pyramidal cells and decrease the plasma angiotensin II level. These results illustrated that anti-cerebral ischemic mechanism of Hydroxysafflor Yellow A may be due to its suppression of thrombin generation and inhibition of thrombin-induced inflammatory responses by reducing angiotensin II content.
Assuntos
Isquemia Encefálica/metabolismo , Chalcona/análogos & derivados , Inflamação/prevenção & controle , Quinonas/farmacologia , Traumatismo por Reperfusão , Trombina/antagonistas & inibidores , Animais , Isquemia Encefálica/patologia , Chalcona/farmacologia , Masculino , Ratos , Ratos Wistar , Trombina/biossínteseRESUMO
Previously N-(8-(3-ethynylphenoxy)octyl-1-deoxynojirimycin 1 has been shown to display properties associated with inhibition of angiogenesis. Here we examined the anti-tumourigenic role of 1 in a lung cancer cell line. This agent altered cell surface oligosaccharide expression and inhibited the growth of A549 cells by inducing G1 phase cell cycle arrest and apoptosis. Furthermore, stress fibre assembly and cell migration in A549 cells was markedly suppressed by 1.
Assuntos
1-Desoxinojirimicina/análogos & derivados , Antineoplásicos/química , Neoplasias Pulmonares/tratamento farmacológico , 1-Desoxinojirimicina/química , 1-Desoxinojirimicina/uso terapêutico , Antineoplásicos/uso terapêutico , Apoptose , Linhagem Celular Tumoral , Movimento Celular , Fase G1 , Humanos , Neoplasias Pulmonares/metabolismo , Oligossacarídeos/metabolismo , Fibras de Estresse/metabolismoRESUMO
Proteoglycans (PGs) are composed of a core protein and one or more chains of glycosaminoglycans (GAGs). The highly heterogeneous GAG chains play an irreplaceable role in the functions of PGs. However, the lack of an approach to control the exact structure of GAG chains conjugated to PGs tremendously hinders functional studies of PGs. Herein, by using glypican-3 as a model, we establish an aldehyde tag-based approach to assemble PGs with specific GAG chains on the surface of living cells. We show that the engineered glypican-3 can regulate Wnt and Hedgehog signaling like the wild type. Furthermore, we also present a method for studying the interaction of PGs with their target glycoproteins by combining the assembly of PGs carrying specific GAG chains with metabolic glycan labeling, and most importantly, we obtain evidence of GPC3 directly interacting with Frizzled. In conclusion, this study provides a very useful platform for structural and functional studies of PGs with specific GAG chains.
Assuntos
Glicosaminoglicanos , Glipicanas/metabolismo , Proteoglicanas , Animais , Metabolismo dos Carboidratos , Linhagem Celular , Glicômica/métodos , Glicosaminoglicanos/química , Glicosaminoglicanos/metabolismo , Células HEK293 , Humanos , Camundongos , Proteoglicanas/química , Proteoglicanas/metabolismo , Transdução de SinaisRESUMO
Macrophages are recognized as one of the major cell types in tumor microenvironment, and macrophage infiltration has been predominantly associated with poor prognosis among patients with breast cancer. Using the murine models of triple-negative breast cancer in CD169-DTR mice, we found that CD169+ macrophages support tumor growth and metastasis. CD169+ macrophage depletion resulted in increased accumulation of CD8+ T cells within tumor, and produced significant expansion of CD8+ T cells in circulation and spleen. In addition, we observed that CD169+ macrophage depletion alleviated tumor-induced splenomegaly in mice, but had no improvement in bone loss and repression of bone marrow erythropoiesis in tumor-bearing mice. Cancer cells and tumor associated macrophages exploit the upregulation of the immunosuppressive protein PD-L1 to subvert T cell-mediated immune surveillance. Within the tumor microenvironment, our understanding of the regulation of PD-L1 protein expression is limited. We showed that there was a 5-fold higher relative expression of PD-L1 on macrophages as compared with 4T1 tumor cells; coculture of macrophages with 4T1 cells augmented PD-L1 levels on macrophages, but did not upregulate the expression of PD-L1 on 4T1 cells. JAK2/STAT3 signaling pathway was activated in macrophages after coculture, and we further identified the JAK2 as a critical regulator of PD-L1 expression in macrophages during coculture with 4T1 cells. Collectively, our data reveal that breast cancer cells and CD169+ macrophages exhibit bidirectional interactions that play a critical role in tumor progression, and inhibition of JAK2 signaling pathway in CD169+ macrophages may be potential strategy to block tumor microenvironment-derived immune escape.