Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 134
Filtrar
1.
Bioorg Chem ; 116: 105366, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34560561

RESUMO

In recent years, tumor immunotherapy, especially the combination of PD1/PD-L1 inhibitors and chemotherapy, has developed rapidly. However, the systemic side effects induced by chemotherapy remain a crucial problem that needs to be addressed. Antibody drug conjugates (ADCs) are exceptional target-specific prodrugs that greatly improve the therapeutic window of chemotherapy drugs. Therefore, designing PD-L1-targeting ADCs is an interesting research project. In this study, we confirmed for the first time that the commercial anti-PD-L1 antibody Atezolizumab has better endocytosis efficiencies than Avelumab, and was more suitable for ADC design. Then, the most popular cytotoxic payload MMAE was conjugated to Atezolizumab via a classical dipeptide (valine-alanine) linker to generate a bifunctional PD-L1 ADC (ADC 3). An in vitro cytotoxicity test indicated the potent tumor cell inhibitory activity of ADC 3, with EC50 values of 9.75 nM to 11.94 nM. In addition, a co-culture of PBMCs in vitro proved that ADC 3 retained the immune activation effect of the Atezolizumab antibody. Moreover, ADC 3 exhibited a higher tumor inhibition rate and tumor regression rate in humanized immune system mice. To the best of our knowledge, this is the most active PD-L1-ADC reported thus far, which may promote the development of immunotherapy and novel ADCs.

2.
Cell Rep ; 36(9): 109639, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34469723

RESUMO

Normal neurodevelopment relies on intricate signaling pathways that balance neural stem cell (NSC) self-renewal, maturation, and survival. Disruptions lead to neurodevelopmental disorders, including microcephaly. Here, we implicate the inhibition of NSC senescence as a mechanism underlying neurogenesis and corticogenesis. We report that the receptor for activated C kinase (Rack1), a family member of WD40-repeat (WDR) proteins, is highly enriched in NSCs. Deletion of Rack1 in developing cortical progenitors leads to a microcephaly phenotype. Strikingly, the absence of Rack1 decreases neurogenesis and promotes a cellular senescence phenotype in NSCs. Mechanistically, the senescence-related p21 signaling pathway is dramatically activated in Rack1 null NSCs, and removal of p21 significantly rescues the Rack1-knockout phenotype in vivo. Finally, Rack1 directly interacts with Smad3 to suppress the activation of transforming growth factor (TGF)-ß/Smad signaling pathway, which plays a critical role in p21-mediated senescence. Our data implicate Rack1-driven inhibition of p21-induced NSC senescence as a critical mechanism behind normal cortical development.

3.
Oncol Lett ; 22(5): 749, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34539853

RESUMO

The receptor tyrosine kinase, anexelekto (Axl) is involved in tumor cell growth, migration and invasion, and has been associated with chemotherapy resistance, which makes it an attractive target for cancer therapy. In total, six Axl-targeted monoclonal antibodies (mAbs) and two antibody-drug conjugates have been reported in the last 10 years, which have been shown to have bioactivity in inhibiting tumor cell proliferation and migration. The Axl external cell domain (Axl-ECD), consisting of 426 amino acids, has always been used as an antigen in the screening process for all six of these Axl-targeted mAbs. However, the Axl functional domain, which interacts with its natural ligand, growth arrest-specific protein 6 (Gas6), is only a small part of the Axl-ECD. Antibodies targeting the Axl functional domain may efficiently block Gas6-Axl binding and attenuate its downstream signals and activities. To the best of our knowledge, no mAbs targeting the Axl functional domain have been reported. In the present study, a major Axl functional domain interacting with Gas6 was determined using bioinformatics and structural biology methods. In MDA-MB-231 breast cancer cell assays, anti-Axl mAbs targeting this relatively specific Axl functional domain almost completely neutralized the stimulation of Gas6 in both Axl phosphorylation and cell migration assays, and showed similar activity to the positive control drug R428 (a small molecular tyrosine kinase inhibitor of Axl currently in phase II clinical trials) in the cell migration assay. Given the important role of Axl in tumor development and chemotherapy resistance, Axl-targeted mAbs could be used to inhibit tumor cells directly, as well as reduce the development of chemotherapy resistance by blocking Axl activity. The application of Axl-targeted mAbs combined with chemotherapy provides a promising treatment strategy for patients with tumors, particularly those with triple-negative breast cancer, for whom no targeted therapy is currently available.

4.
Front Microbiol ; 12: 692279, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335518

RESUMO

Staphylococcus aureus is a major pathogenic bacterium that causes a variety of clinical infections. The emergence of multi-drug resistant mechanisms requires novel strategies to mitigate S. aureus infection. Alpha-hemolysin (Hla) is a key virulence factor that is believed to play a significant role in the pathogenesis of S. aureus infections. In this study, we screened a naïve human Fab library for identification of monoclonal antibodies targeting Hla by phage display technology. We found that the monoclonal antibody YG1 blocked the Hla-mediated lysis of rabbit red blood cells and inhibited Hla binding to A549 cells in a concentration-dependent manner. YG1 also provided protection against acute peritoneal infection, bacteremia, and pneumonia in murine models. We further characterized its epitope using different Hla variants and found that the amino acids N209 and F210 of Hla were functionally and structurally important for YG1 binding. Overall, these results indicated that targeting Hla with YG1 could serve as a promising protective strategy against S. aureus infection.

5.
Mol Pharmacol ; 100(3): 193-202, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34315811

RESUMO

Phagocytic resistance plays a key role in tumor-mediated immune escape, so phagocytosis immune checkpoints are a potential target for cancer immunotherapy. CD47 is one of the important phagocytosis immune checkpoints; thus, blocking the interaction between CD47 and signal regulatory protein α (SIRPα) may provide new options for cancer treatment. Using computer-aided targeted epitope mammalian cell-displayed antibody library, we screened and obtained an engineered SIRPα variant fragment crystallizable fusion protein, FD164, with higher CD47-binding activity than wild-type SIRPα Compared with wild-type SIRPα, FD164 has approximately 3-fold higher affinity for binding to CD47, which further enhanced its phagocytic effect in vitro and tumor suppressor activity in vivo. FD164 maintains the similar antitumor activity of the clinical research drug Hu5F9 in the mouse xenograft model. Furthermore, FD164 combined with rituximab can significantly improve the effect of single-agent therapy. On the other hand, compared with Hu5F9, FD164 does not cause hemagglutination, and its ability to bind to red blood cells or white blood cells is weaker at the same concentration. Finally, it was confirmed by computer structure prediction and alanine scanning experiments that the N45, E47, 52TEVYVK58, K60, 115EVTELTRE122, and E124 residues of CD47 are important for SIRPα or FD164 recognition. Briefly, we obtained a high-affinity SIRPα variant FD164 with balanced safety and effectiveness. SIGNIFICANCE STATEMENT: Up to now, few clinically marketed drugs targeting CD47 have been determined to be effective and safe. FD164, a potential signal regulatory protein α variant fragment crystallizable protein with balanced safety and effectiveness, could provide a reference for the development of antitumor drugs.


Assuntos
Antígenos de Diferenciação/genética , Antígenos de Diferenciação/imunologia , Antígeno CD47/imunologia , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Animais , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Antígenos de Diferenciação/efeitos adversos , Antígenos de Diferenciação/química , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Burkitt/tratamento farmacológico , Linfoma de Burkitt/imunologia , Linfoma de Burkitt/patologia , Antígeno CD47/química , Células CHO , Linhagem Celular , Cricetulus , Desenho de Fármacos , Epitopos/química , Epitopos/genética , Epitopos/imunologia , Hemaglutinação/efeitos dos fármacos , Imunoterapia , Camundongos SCID , Modelos Moleculares , Fagocitose/efeitos dos fármacos , Fagocitose/imunologia , Receptores Imunológicos/química , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Rituximab/uso terapêutico , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Angew Chem Int Ed Engl ; 60(38): 20906-20914, 2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34255409

RESUMO

A universal strategy is developed to construct a cascade Z-Scheme system, in which an effective energy platform is the core to direct charge transfer and separation, blocking the unexpected type-II charge transfer pathway. The dimension-matched (001)TiO2 -g-C3 N4 /BiVO4 nanosheet heterojunction (T-CN/BVNS) is the first such model. The optimized cascade Z-Scheme exhibits ≈19-fold photoactivity improvement for CO2 reduction to CO in the absence of cocatalysts and costly sacrificial agents under visible-light irradiation, compared with BVNS, which is also superior to other reported Z-Scheme systems even with noble metals as mediators. The experimental results and DFT calculations based on van der Waals structural models on the ultrafast timescale reveal that the introduced T as the platform prolongs the lifetimes of spatially separated electrons and holes and does not compromise their reduction and oxidation potentials.

7.
Front Cell Infect Microbiol ; 11: 658141, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33854984

RESUMO

IFN-γ is produced upon stimulation with S. aureus and may play a detrimental role during infection. However, whether hemolysins play a role in the mechanism of IFN-γ production has not been fully characterized. In this study, we demonstrated that Hlb, one of the major hemolysins of S. aureus, upregulated IFN-γ production by CD56bright NK cells from human peripheral blood mononuclear cells (PBMCs). Further investigation showed that Hlb increased calcium influx and induced phosphorylation of ERK1/2. Either blocking calcium or specifically inhibiting phosphorylation of ERK1/2 decreased the production of IFN-γ induced by Hlb. Moreover, we found that this process was dependent on the sphingomyelinase activity of Hlb. Our findings revealed a novel mechanism of IFN-γ production in NK cells induced by Hlb, which may be involved in the pathogenesis of S. aureus.


Assuntos
Leucócitos Mononucleares , Staphylococcus aureus , Antígeno CD56 , Proteínas Hemolisinas , Humanos , Interferon gama , Células Matadoras Naturais , Esfingomielina Fosfodiesterase
8.
Front Immunol ; 12: 654649, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33868297

RESUMO

Extracellular traps released by neutrophils (NETs) are essential for the clearance of Pseudomonas aeruginosa. Alkaline protease (AprA) secreted by P. aeruginosa negatively correlates with clinical improvement. Moreover, anti-AprA in patients with cystic fibrosis (CF) can help identify patients with aggressive forms of chronic infection. However, the mechanism underlying the clinical outcomes remains unclear. We demonstrated that aprA deficiency in P. aeruginosa decreased the bacterial burden and reduced lung infection. AprA degraded NET components in vitro and in vivo but did not affect NET formation. Importantly, antibodies induced by AprA acted as an agonist and directly enhanced the degrading activities of AprA. Moreover, antisera from patients with P. aeruginosa infection exhibited antibody-dependent enhancement (ADE) similar to that of the antibodies we prepared. Our further investigations showed that the interaction between AprA and the specific antibodies might make the enzyme active sites better exposed, and subsequently enhance the recognition of substrates and accelerate the degradation. Our findings revealed that AprA secreted by P. aeruginosa may aggravate infection by destroying formed NETs, an effect that was further enhanced by its antibodies.


Assuntos
Anticorpos Antibacterianos/imunologia , Antígenos de Bactérias/imunologia , Proteínas de Bactérias/imunologia , Endopeptidases/imunologia , Armadilhas Extracelulares/imunologia , Infecções por Pseudomonas/imunologia , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/imunologia , Animais , Citotoxicidade Celular Dependente de Anticorpos , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Modelos Animais de Doenças , Endopeptidases/genética , Endopeptidases/metabolismo , Armadilhas Extracelulares/enzimologia , Feminino , Interações Hospedeiro-Patógeno/imunologia , Humanos , Camundongos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Pneumonia Bacteriana/imunologia , Pneumonia Bacteriana/metabolismo , Pneumonia Bacteriana/microbiologia , Pneumonia Bacteriana/patologia , Infecções por Pseudomonas/metabolismo , Pseudomonas aeruginosa/enzimologia , Pseudomonas aeruginosa/patogenicidade
9.
Front Immunol ; 12: 656090, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33841441

RESUMO

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with multiple autoantibody production and often affects the kidneys, known as lupus nephritis. However, the mechanism underlying lupus nephritis development is unclear. Biofilms that protect bacteria from stress are ubiquitous in almost every environment. Here, we identified that a conserved peptide (HU1) derived from DNABII proteins, one of major bacterial biofilm components, was specifically recognized by sera from about 47% patients with SLE. Moreover, the serum anti-HU1 levels showed a significant positive correlation with lupus nephritis occurrence. Presence of antibodies against HU1 in pristane-induced mice aggravated lupus nephritis, although these antibodies also attenuated bacterial biofilm formation. We further identified that antibodies against HU1 cross-recognized protein disulfide isomerase (P4HB) located on the renal cell surface and inhibited the activities of this enzyme. Our findings reveal a novel mechanism underlying the development of lupus nephritis triggered by bacterial biofilms.


Assuntos
Autoanticorpos/imunologia , Bactérias/imunologia , Biofilmes , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/imunologia , Nefrite Lúpica/etiologia , Nefrite Lúpica/patologia , Sequência de Aminoácidos , Animais , Antígenos de Bactérias/química , Antígenos de Bactérias/imunologia , Autoanticorpos/sangue , Autoantígenos/imunologia , Biomarcadores , Modelos Animais de Doenças , Progressão da Doença , Suscetibilidade a Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Imunofluorescência , Humanos , Lúpus Eritematoso Sistêmico/patologia , Nefrite Lúpica/sangue , Camundongos , Camundongos Transgênicos , Peptídeos/química , Peptídeos/imunologia , Terpenos/efeitos adversos
10.
Biochem Biophys Res Commun ; 549: 120-127, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33667709

RESUMO

Staphylococcal enterotoxin B (SEB), one of the exotoxins produced by Staphylococcus aureus, is the key toxin that causes poisoning reactions and toxic shock syndrome. In the current research work, a novel human antibody named LXY8 was screened from a human phage display antibody library, and LXY8 blocked the interaction between SEB and the T cell receptor (TCR). The binding activity between LXY8 and SEB was 0.525 nM. Furthermore, LXY8 could effectively inhibit the SEB-induced activation of peripheral blood mononuclear cells and release of cytokines. In the BALB/c mouse model, LXY8 effectively neutralized SEB toxicity in vivo. Finally, based on computer-guided molecular modeling, we designed a series of SEB mutation sites; these sites facilitated the determination of the key residues (i.e.176EFNN179) of SEB recognized by LXY8. The research revealed that the 176EFNN179 residues of SEB are important for specific antibody-antigen recognition. The results may be helpful for the development of antibody-based therapy for SEB-induced toxic shock syndrome.


Assuntos
Anticorpos Antibacterianos/análise , Anticorpos Monoclonais/análise , Anticorpos Neutralizantes/análise , Enterotoxinas/imunologia , Epitopos/imunologia , Animais , Células CHO , Proliferação de Células , Técnicas de Visualização da Superfície Celular , Cricetulus , Citocinas/metabolismo , Enterotoxinas/antagonistas & inibidores , Mapeamento de Epitopos , Feminino , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Camundongos Endogâmicos BALB C , Ligação Proteica , Receptores de Antígenos de Linfócitos T/metabolismo
11.
PLoS Comput Biol ; 17(3): e1008769, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33735194

RESUMO

Extensive amounts of multi-omics data and multiple cancer subtyping methods have been developed rapidly, and generate discrepant clustering results, which poses challenges for cancer molecular subtype research. Thus, the development of methods for the identification of cancer consensus molecular subtypes is essential. The lack of intuitive and easy-to-use analytical tools has posed a barrier. Here, we report on the development of the COnsensus Molecular SUbtype of Cancer (COMSUC) web server. With COMSUC, users can explore consensus molecular subtypes of more than 30 cancers based on eight clustering methods, five types of omics data from public reference datasets or users' private data, and three consensus clustering methods. The web server provides interactive and modifiable visualization, and publishable output of analysis results. Researchers can also exchange consensus subtype results with collaborators via project IDs. COMSUC is now publicly and freely available with no login requirement at http://comsuc.bioinforai.tech/ (IP address: http://59.110.25.27/). For a video summary of this web server, see S1 Video and S1 File.


Assuntos
Biologia Computacional/métodos , Internet , Neoplasias , Software , Algoritmos , Análise por Conglomerados , Consenso , Humanos , Neoplasias/classificação , Neoplasias/genética
12.
Exp Ther Med ; 21(2): 136, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33456503

RESUMO

e23sFv is a HER2-targeted single-chain variable fragment (scFV) that was characterized as the targeting portion of a HER2-targeted tumour proapoptotic molecule in our previous study. In vitro antibody affinity maturation is a method to enhance antibody affinity either by complementarity-determining region (CDR) mutagenesis or by framework region (FR) engraftment. In the present study, the affinity of e23sFv was enhanced using two strategies. In one approach, site-directed mutations were introduced into the FRs of e23sFv (designated EMEY), and in the other approach e23sFv FRs were substituted with FRs from the most homologous screened antibodies (designated EX1 and EX2). Notably, EX1 derived from the FR engraftment strategy demonstrated a 4-fold higher affinity for HER2 compared with e23sFv and was internalized into HER2-overexpressing cells; however, EMEY and EX2 exhibited reduced affinity for HER2 and decreased internalization potential compared with EX1. The 3D structure of EX1 and the HER2-EX1 complex was acquired using molecular homology modelling and docking and the HER2 epitopes of EX1 and the molecular interaction energy of the EX1-HER2 complex were predicted. In the present study, it was demonstrated that scFv affinity improvement based on sequence alignment was feasible and effective. Moreover, the FR grafting strategy was indicated to be more effective and simple compared with site-directed mutagenesis to improve e23sFv affinity. In conclusion, it was indicated that the affinity-improved candidate EX1 may present a great potential for the diagnosis and treatment of HER2-overexpressing tumours.

13.
Signal Transduct Target Ther ; 5(1): 82, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32467564

RESUMO

Although targeted therapy has been extensively investigated for breast cancers, a molecular target with broad application is currently unavailable due to the high heterogeneity of these cancers. Mammaglobin-A (Mam-A), which is overexpressed in most breast carcinomas, has been proposed as a promising target. However, the lack of specific targeting moieties due to uncertain binding epitopes hampers further translational study. Here, seven potential epitopes of Mam-A were disclosed, and a unique epitope was then identified in most types of breast cancers, despite the genotypic heterogeneity. With phage display technology, the epitope was determined to be N-terminal amino acids 42-51 of Mam-A (N42-51). Then, the N42-51 epitope-specific monoclonal antibody, mAb785, was conjugated to poly lactic-co-glycolic acid (PLGA) nanoparticles loaded with therapeutic agents, thereby enhancing the drug uptake and therapeutic efficacy in different genotypes of breast cancers. The computer simulation of the N42-51 epitope and the mAb785 structures, as well as their interactions, further revealed the specific targeting mechanism of the mAb785-conjugated nanoparticles to breast cancers.


Assuntos
Anticorpos Monoclonais/farmacologia , Antineoplásicos Imunológicos/farmacologia , Neoplasias da Mama/terapia , Mamoglobina A/farmacologia , Anticorpos Monoclonais/imunologia , Antineoplásicos Imunológicos/imunologia , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Epitopos/genética , Epitopos/imunologia , Feminino , Humanos , Mamoglobina A/genética , Mamoglobina A/imunologia , Nanopartículas/química , Proteínas de Neoplasias/genética , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia
14.
Chem Commun (Camb) ; 56(36): 4926-4929, 2020 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-32239036

RESUMO

Ultrathin zinc phthalocyanine/graphene/BiVO4 heterojunctions have been successfully synthesized for efficient wide visible-light catalytic conversion of CO2 to CO with 14-time photoactivity improvement compared to the bare BiVO4 nanosheet, attributed to the strengthened Z-scheme charge transfer and separation by increasing the optimized amount of highly dispersed ZnPc via the pre-modified graphene-modulated assembly.

16.
Mucosal Immunol ; 12(5): 1164-1173, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31278373

RESUMO

Alternative splicing (AS) of mRNA is known to be involved in regulation of immune cell differentiation and activation. Elongation factor Tu GTP binding domain containing 2 (Eftud2) is an AS factor to potentially modulate innate immune response in macrophages. In this study, we investigate its involvement in the pathogenesis of colitis-associated cancer (CAC). Using an established mouse model of CAC, we show that Eftud2 is constantly overexpressed in the colonic tissues as well as infiltrating macrophages. Myeloid-specific knockout of Eftud2 remarkably suppresses chronic intestinal inflammation and tumorigenesis, which is associated with decreased production of inflammatory cytokines and tumorigenic factors. Repression of colonic inflammation and colorectal tumor development in Eftud2-deficient mice is due to the impaired activation of NF-κB signaling in LPS-challenged macrophages. Furthermore, the alteration of Eftud2-mediated AS involving the components of TLR4-NF-κB cascades underlies the impairment of NF-κB activation. Overall, these findings provide new insights into the tight link between inflammation and cancer and modulation of AS in innate immune signals may be a potentially therapeutic avenue for CAC treatment.


Assuntos
Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/metabolismo , Colite/complicações , Colite/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Ribonucleoproteína Nuclear Pequena U5/metabolismo , Animais , Biomarcadores , Transformação Celular Neoplásica/genética , Colite/patologia , Neoplasias do Colo/etiologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Modelos Animais de Doenças , Suscetibilidade a Doenças , Deleção de Genes , Imunidade Inata , Camundongos , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Ribonucleoproteína Nuclear Pequena U5/genética , Transdução de Sinais , Spliceossomos/metabolismo , Receptor 4 Toll-Like/metabolismo
17.
Angew Chem Int Ed Engl ; 58(32): 10873-10878, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31199043

RESUMO

Cascade charge transfer was realized by a H-bond linked zinc phthalocyanine/BiVO4 nanosheet (ZnPc/BVNS) composite, which subsequently works as an efficient wide-visible-light-driven photocatalyst for converting CO2 into CO and CH4 , as shown by product analysis and 13 C isotopic measurement. The optimized ZnPc/BVNS nanocomposite exhibits a ca. 16-fold enhancement in the quantum efficiency compared with the reported BiVO4 nanoparticles at the excitation of 520 nm with an assistance of 660 nm photons. Experimental and theoretical results show the exceptional activities are attributed to the rapid charge separation by a cascade Z-scheme charge transfer mechanism formed by the dimension-matched ultrathin (ca. 8 nm) heterojunction nanostructure. The central Zn2+ in ZnPc could accept the excited electrons from the ligand and then provide a catalytic function for CO2 reduction. This Z-scheme is also feasible for other MPc, such as FePc and CoPc, together with BVNS.

18.
Oncol Lett ; 17(6): 5784-5792, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31186805

RESUMO

AXL receptor tyrosine kinase ligand (AXL), a tyrosine kinase receptor that is commonly overexpressed in numerous types of cancer, significantly promotes drug resistance and metastasis in tumor cells. Inhibition of the AXL/growth arrest-specific 6 (Gas6) signaling pathway is emerging as a potential anticancer therapeutic strategy. In the present study, on the basis of the three-dimensional complex structure of AXL/Gas6, the critical residues (E56, E59 and T77) in AXL binding to Gas6 were determined using computer graphics analysis and the distance geometry method. Subsequently, four-variant AXL-ECD-Fc-M1 (G32S, D87G, V92A and G127R) and AXL-ECD-Fc-M2 (G32A, D87A, V92A and G127A) were predicted as high-affinity mutants; AXL-ECD-Fc-M3 (E56R and T77R) and AXL-ECD-Fc-M4 (E59R and T77R) were predicted as low-affinity mutants. The results of the present study revealed that the half-maximal effect concentrations of AXL-ECD-Fc-M1 and AXL-ECD-Fc-M2 were ~0.141 and 0.375 µg/ml, respectively, whereas that of the wild-type protein (AXL-ECD-Fc-WT) was 0.514 µg/ml. Furthermore, adding the high-affinity mutants into culture medium to capture free Gas6 significantly inhibited AXL/Gas6 binding and thus blocked the downstream signaling pathway. In addition, the high-affinity mutants effectively suppressed the migration and metastasis of SKOV3 and A549 cells. Conversely, compared with AXL-ECD-Fc-WT, the low-affinity AXL mutants AXL-ECD-Fc-M3 and AXL-ECD-Fc-M4 lost all inhibitory activities. These findings highlight AXL as a potential therapeutic target and demonstrated that the key residues E56, E59 and T77 may be crucial sites for abolishing the activity of the AXL/Gas6 pathway in cancer therapy.

19.
Scand J Immunol ; 90(2): e12777, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31075180

RESUMO

TAM family members (TYRO3, AXL and MERTK) play essential roles in the resolution of inflammation and in infectious diseases and cancer. AXL, a tyrosine kinase receptor, is commonly overexpressed in several solid tumours and numerous hematopoietic malignancies including acute myeloid leukaemia, acute lymphocytic leukaemia, chronic myeloid leukaemia, chronic lymphocytic leukaemia and multiple myeloma. AXL significantly promotes tumour cell migration, invasion and metastasis, as well as angiogenesis. AXL also plays an important role in inflammation and macrophage ontogeny. Recent studies have revealed that AXL contributes to leukaemic phenotypes through activation of oncogenic signalling pathways that lead to increased cell migration and proliferation. To evaluate the mechanisms underlying the role of AXL signalling in tumour metastasis, we screened a phage display library to generate a novel human monoclonal antibody, named DAXL-88, that recognizes both human and murine AXL. The concentrations of DAXL-88 required for 50% maximal binding to human and murine AXL were 0.118 and 0.164 µg/mL, respectively. Furthermore, DAXL-88 bound to human AXL with high affinity (KD  ~ 370 pM). DAXL-88 blocked the interaction between AXL and its ligand, growth arrest-specific gene 6 (GAS6), with a half maximal inhibitory concentration of 2.16 µg/mL. Moreover, DAXL-88 inhibited AXL/GAS6-dependent cell signalling, which is implicated in cell migration and invasion. In conclusion, the novel anti-AXL DAXL-88 high-affinity antibody blocks the interaction between AXL and GAS6 and inhibits tumour cell migration and invasion induced by GAS6. Thus, DAXL-88 offers promise for the development of targeted therapeutic strategies in solid tumours, leukaemias and other lymphoid neoplasms.


Assuntos
Anticorpos Monoclonais/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neoplasias Ovarianas/patologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Células A549 , Anticorpos Monoclonais/imunologia , Linhagem Celular Tumoral , Movimento Celular , Feminino , Humanos , Simulação de Acoplamento Molecular , Invasividade Neoplásica/patologia , Invasividade Neoplásica/prevenção & controle , Metástase Neoplásica/prevenção & controle , Ligação Proteica , Proteínas Proto-Oncogênicas/imunologia , Receptores Proteína Tirosina Quinases/imunologia , Transdução de Sinais
20.
J Cell Sci ; 132(10)2019 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-31028177

RESUMO

Necroptosis is a regulated form of necrotic cell death that is mediated by receptor-interacting serine/threonine-protein kinase 1 (RIPK1), RIPK3 and mixed-lineage kinase domain-like protein (MLKL), which mediates necroptotic signal transduction induced by tumor necrosis factor (TNF). Although many target proteins for necroptosis have been identified, no report had indicated that FK506-binding protein 12 (FKBP12, also known as FKBP1A), an endogenous protein that regulates protein folding and conformation alteration, is involved in mediating necroptosis. In this study, we found that FKBP12 acts as a novel target protein in mediating necroptosis and the related systemic inflammatory response syndrome triggered by TNF. The mechanistic study discovered that FKBP12 is essential for initiating necrosome formation and RIPK1-RIPK3-MLKL signaling pathway activation in response to TNF receptor 1 ligation. In addition, FKBP12 is indispensable for RIPK1 and RIPK3 expression and subsequent spontaneous phosphorylation, which are essential processes for initial necrosome formation and necroptotic signal transduction; therefore, FKBP12 may target RIPK1 and RIPK3 to mediate necroptosis in vitro and in vivo Collectively, our data demonstrate that FKBP12 could be a potential therapeutic target for the clinical treatment of necroptosis-associated diseases.


Assuntos
Proteínas Quinases/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Proteína 1A de Ligação a Tacrolimo/metabolismo , Animais , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Necroptose/fisiologia , Fosforilação , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Transdução de Sinais , Síndrome de Resposta Inflamatória Sistêmica/metabolismo , Síndrome de Resposta Inflamatória Sistêmica/patologia , Serina-Treonina Quinases TOR/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...