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Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis (Mtb) infection, with the highest single-cause mortality. Monocarboxylate transporter 4 (Mct4) transports intracellular lactate outside, but its role in regulating host immune response against Mtb infection remains unknown. Mct4 expression was upregulated in Mtb-infected macrophages and in patients with TB. Mct4 silencing/deficiency significantly decreased Mtb survival in macrophages and in lungs and spleens of mice, while Mct4 overexpression facilitated Mtb survival in macrophages. Furthermore, Mct4 promoted intracellular lactate transport, nuclear factor κB (NF-κB) p65 activation, and interleukin-10 (IL-10) production upon Mtb infection. Mechanistically, IL-10 silencing and IL-10-neutralizing antibody blocked Mct4 overexpressing increased Mtb survival. Replenishing lactate and NF-κB p65 inhibitor JSH23 treatment could inhibit Mct4 overexpressing increased NF-κB p65 activation, IL-10 production, and Mtb survival in macrophages. This study demonstrates that Mct4 promotes Mtb survival through restricting intracellular lactate accumulation to promote NF-κB p65-mediated IL-10 production and suggests Mct4-NF-κB p65-IL-10 axis a potential target for TB treatment.
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This work describes the synthesis of C@BiOBr using glucose as the carbon precursor by a repeatable one-step hydrothermal method. Characterization studies indicate that the structure of BiOBr did not change after the carbon layer was encapsulated on the surface. The highest activity is achieved at 1.2-C@BiOBr, with 97% of phenol (50 mg·L-1) degrading within 90 min, and the degradation amount of phenol is determined to be 48.5 mg·g-1 with a speed of 0.54 mg·g-1·min-1. The useful species of phenol degradation are studied and assigned to â¢O2-, 1O2, and h+. The effect of coated carbon layer for photocatalytic degradation of phenol over BiOBr is studied by photoelectrochemical experiments, fluorescence spectra, and density functional theory (DFT) calculations. It is attributed to the good conductivity of carbon, enhanced separation of the photocarriers by carbon coating, and thermodynamically favorable reactive oxygen species (ROS) production on the surface of carbon. This work demonstrates that carbon coating is an effective strategy to improve the photocatalytic activity of BiOBr and reveals the detailed mechanism.
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Tuberculosis (TB) is still an urgent global public health problem. Notably, mucosal-associated invariant T (MAIT) cells play an important role in early anti-TB immune response. Targeted control of them may be an effective method to improve vaccine efficacy and TB treatment. However, the biology and signal regulation mechanisms of MAIT cells in TB patients are still poorly understood. Previous studies have been limited by the lack of reagents to specifically identify MAIT cells. In addition, the use of alternative markers may subsume non-MAIT cell into MAIT cell populations. In this study, the human MR1 tetramer which can specifically identify MAIT cells was used to further explore the effect and mechanism of MAIT cells in anti-TB immune response. Our results showed that the tetramer+ MAIT cells in peripheral blood of TB patients were mainly CD8+ or CD4-CD8- cells, and very few were CD4+ cells. After BCG infecting autologous antigen-presenting cells, MAIT cells in patients produced significantly higher levels of cytokines, lysis and proliferation compared with healthy controls. After suppression of mTORC1 by the mTORC1-specific inhibitor rapamycin, the immune response of MAIT cells in patients was significantly reduced. This study demonstrates that peripheral blood tetramer+ MAIT cells from TB patients have significant anti-TB immune effect, which is regulated by mTORC1. This could provide ideas and potential therapeutic targets for the development of novel anti-TB immunotherapy.
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Vaccination for cancers arising from human papillomavirus (HPV) infection holds immense potential, yet clinical success has been elusive. Herein, we describe vaccination studies involving spherical nucleic acids (SNAs) incorporating a CpG adjuvant and a peptide antigen (E711-19) from the HPV-E7 oncoprotein. Administering the vaccine to humanized mice induced immunity-dependent on the oligonucleotide anchor chemistry (cholesterol vs (C12)9). SNAs containing a (C12)9-anchor enhanced IFN-γ production >200-fold, doubled memory CD8+ T-cell formation, and delivered more than twice the amount of oligonucleotide to lymph nodes in vivo compared to a simple admixture. Importantly, the analogous construct with a weaker cholesterol anchor performed similar to admix. Moreover, (C12)9-SNAs activated 50% more dendritic cells and generated T-cells cytotoxic toward an HPV+ cancer cell line, UM-SCC-104, with near 2-fold greater efficiency. These observations highlight the pivotal role of structural design, and specifically oligonucleotide anchoring strength (which correlates with overall construct stability), in developing efficacious therapeutic vaccines.
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Vacinas Anticâncer , Proteínas E7 de Papillomavirus , Animais , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/química , Vacinas Anticâncer/administração & dosagem , Camundongos , Proteínas E7 de Papillomavirus/imunologia , Proteínas E7 de Papillomavirus/química , Humanos , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Infecções por Papillomavirus/prevenção & controle , Infecções por Papillomavirus/imunologia , Ácidos Nucleicos/química , Ácidos Nucleicos/imunologia , DNA/química , DNA/imunologiaRESUMO
In this paper, N-doped TiO2 mixed crystals are prepared via direct calcination of TiN for highly selective oxidation of CH4 to HCHO at room temperature. The structures of the prepared TiO2 samples are characterized to be N-doped TiO2 of anatase and rutile mixed crystals. The crystal structures of TiO2 samples are determined by XRD spectra and Raman spectra, while N doping is demonstrated by TEM mapping, ONH inorganic element analysis, and high-resolution XPS results. Significantly, the production rate of HCHO is as high as 23.5 mmol·g-1·h-1 with a selectivity over 90%. Mechanism studies reveal that H2O is the main oxygen source and acts through the formation of ·OH. DFT calculations indicate that the construction of a mixed crystal structure and N-doping modification mainly act by increasing the adsorption capacity of H2O. An efficient photocatalyst was prepared by us to convert CH4 to HCHO with high yield and selectivity, greatly promoting the development of the photocatalytic CH4 conversion study.
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OBJECTIVES AND DESIGN: As an interferon-inducible protein, Viperin has broad-spectrum antiviral effects and regulation of host immune responses. We aim to investigate how Viperin regulates interferon-γ (IFN-γ) production in macrophages to control Mycobacterium tuberculosis (Mtb) infection. METHODS: We use Viperin deficient bone-marrow-derived macrophage (BMDM) to investigate the effects and machines of Viperin on Mtb infection. RESULTS: Viperin inhibited IFN-γ production in macrophages and in the lung of mice to promote Mtb survival. Further insight into the mechanisms of Viperin-mediated regulation of IFN-γ production revealed the role of TANK-binding kinase 1 (TBK1), the TAK1-dependent inhibition of NF-kappa B kinase-epsilon (IKKε), and interferon regulatory factor 3 (IRF3). Inhibition of the TBK1-IKKε-IRF3 axis restored IFN-γ production reduced by Viperin knockout in BMDM and suppressed intracellular Mtb survival. Moreover, Viperin deficiency activated the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway, which promoted IFN-γ production and inhibited Mtb infection in BMDM. Additionally, a combination of the anti-TB drug INH treatment in the absence of Viperin resulted in further IFN-γ production and anti-TB effect. CONCLUSIONS: This study highlights the involvement of TBK1-IKKε-IRF3 axis and JAK-STAT signaling pathways in Viperin-suppressed IFN-γ production in Mtb infected macrophages, and identifies a novel mechanism of Viperin on negatively regulating host immune response to Mtb infection.
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Fator Regulador 3 de Interferon , Interferon gama , Macrófagos , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis , Proteínas Serina-Treonina Quinases , Proteínas , Transdução de Sinais , Animais , Interferon gama/metabolismo , Interferon gama/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Mycobacterium tuberculosis/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Fator Regulador 3 de Interferon/metabolismo , Camundongos , Proteínas/genética , Proteínas/metabolismo , Quinase I-kappa B/metabolismo , Janus Quinases/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo CH-CH , Camundongos Knockout , Tuberculose/imunologia , Pulmão/imunologia , Pulmão/microbiologia , Proteína ViperinaRESUMO
Molecular strain can be introduced to influence the outcome of chemical reactions. Once a thermodynamic product is formed, however, reversing the course of a strain-promoted reaction is challenging. Here, a reversible, strain-promoted polymerization in cyclic DNA is reported. The use of nonhybridizing, single-stranded spacers as short as a single nucleotide in length can promote DNA cyclization. Molecular strain is generated by duplexing the spacers, leading to ring opening and subsequent polymerization. Then, removal of the strain-generating duplexers triggers depolymerization and cyclic dimer recovery via enthalpy-driven cyclization and entropy-mediated ring contraction. This reversibility is retained even when a protein is conjugated to the DNA strands, and the architecture of the protein assemblies can be modulated between bivalent and polyvalent states. This work underscores the utility of using DNA not only as a programmable ligand for assembly but also as a route to access restorable bonds, thus providing a molecular basis for DNA-based materials with shape-memory, self-healing, and stimuli-responsive properties.
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DNA , Polimerização , DNA/química , Ciclização , Termodinâmica , Conformação de Ácido NucleicoRESUMO
Gradient matters with hierarchical structures endow the natural world with excellent integrity and diversity. Currently, direct ink writing 3D printing is attracting tremendous interest, and has been used to explore the fabrication of 1D and 2D hierarchical structures by adjusting the diameter, spacing, and angle between filaments. However, it is difficult to generate complex 3D gradient matters owing to the inherent limitations of existing methods in terms of available gradient dimension, gradient resolution, and shape fidelity. Here, we report a filament diameter-adjustable 3D printing strategy that enables conventional extrusion 3D printers to produce 1D, 2D, and 3D gradient matters with tunable heterogeneous structures by continuously varying the volume of deposited ink on the printing trajectory. In detail, we develop diameter-programmable filaments by customizing the printing velocity and height. To achieve high shape fidelity, we specially add supporting layers at needed locations. Finally, we showcase multi-disciplinary applications of our strategy in creating horizontal, radial, and axial gradient structures, letter-embedded structures, metastructures, tissue-mimicking scaffolds, flexible electronics, and time-driven devices. By showing the potential of this strategy, we anticipate that it could be easily extended to a variety of filament-based additive manufacturing technologies and facilitate the development of functionally graded structures.
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In photonic systems, bilayer or multilayer systems exhibit numerous exciting phenomena induced by twisting. Thus, it is highly desired to explore the twisting effect by engineering the light-matter interactions. Optical torque, an important means in optical micromanipulation, can rotate micro-objects in various ways, enabling a wide range of promising applications. In this study, we present an interesting phenomenon called "pure optical twist" (POT), which emerges when a bilayer structure with specific symmetry is illuminated by counter-propagating lights with opposite spin and/or orbital angular momentum. Remarkably, this leads to zero net optical torque but yet possesses an interesting mechanical effect of bilayer system twisting. The crucial determinant of this phenomenon is the rotational symmetries of each layer, which govern the allowed azimuthal channels of the scattered wave. When the rotational symmetries do not allow these channels to overlap, no resultant torque is observed. Our work will encourage further exploration of the twisting effect through engineered light-matter interactions. This opens up the possibility of creating twisted bilayer systems using optical means, and constructing a stable bilayer optical motor that maintains identical rotation frequencies for both layers.
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Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains a global health crisis with substantial morbidity and mortality rates. Type II alveolar epithelial cells (AEC-II) play a critical role in the pulmonary immune response against Mtb infection by secreting effector molecules such as antimicrobial peptides (AMPs). Here, human ß-defensin 1 (hBD1), an important AMP produced by AEC-II, has been demonstrated to exert potent anti-tuberculosis activity. HBD1 overexpression effectively inhibited Mtb proliferation in AEC-II, while mice lacking hBD1 exhibited susceptibility to Mtb and increased lung tissue inflammation. Mechanistically, in A549 cells infected with Mtb, STAT1 negatively regulated hBD1 transcription, while CEBPB was the primary transcription factor upregulating hBD1 expression. Furthermore, we revealed that the ERK1/2 signaling pathway activated by Mtb infection led to CEBPB phosphorylation and nuclear translocation, which subsequently promoted hBD1 expression. Our findings suggest that the ERK1/2-CEBPB-hBD1 regulatory axis can be a potential therapeutic target for anti-tuberculosis therapy aimed at enhancing the immune response of AEC-II cells.
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Mycobacterium tuberculosis , Tuberculose , beta-Defensinas , Animais , Humanos , Camundongos , Células Epiteliais Alveolares , beta-Defensinas/genética , beta-Defensinas/farmacologia , Proteína beta Intensificadora de Ligação a CCAAT/genética , Células Epiteliais , Sistema de Sinalização das MAP Quinases , Tuberculose/metabolismoRESUMO
Due to the inherent radiation tolerance, patients who suffered from glioma frequently encounter tumor recurrence and malignant progression within the radiation target area, ultimately succumbing to treatment ineffectiveness. The precise mechanism underlying radiation tolerance remains elusive due to the dearth of in vitro models and the limitations associated with animal models. Therefore, a bioprinted glioma model is engineered, characterized the phenotypic traits in vitro, and the radiation tolerance compared to 2D ones when subjected to X-ray radiation is assessed. By comparing the differential gene expression profiles between the 2D and 3D glioma model, identify functional genes, and analyze distinctions in gene expression patterns. Results showed that 3D glioma models exhibited substantial alterations in the expression of genes associated with the stromal microenvironment, notably a significant increase in the radiation tolerance gene ITGA2 (integrin subunit A2). In 3D glioma models, the knockdown of ITGA2 via shRNA resulted in reduced radiation tolerance in glioma cells and concomitant inhibition of the p-AKT pathway. Overall, 3D bioprinted glioma model faithfully recapitulates the in vivo tumor microenvironment (TME) and exhibits enhanced resistance to radiation, mediated through the ITGA2/p-AKT pathway. This model represents a superior in vitro platform for investigating glioma radiotherapy tolerance.
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Glioma , Proteínas Proto-Oncogênicas c-akt , Animais , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Glioma/genética , Glioma/radioterapia , Glioma/metabolismo , Transdução de Sinais , Microambiente TumoralRESUMO
Tuberculosis has the highest mortality rate worldwide for a chronic infectious disease caused by a single pathogen. RNA-binding proteins (RBPs) are involved in autophagy - a key defense mechanism against Mycobacterium tuberculosis (M. tuberculosis) infection - by modulating RNA stability and forming intricate regulatory networks. However, the functions of host RBPs during M. tuberculosis infection remain relatively unexplored. Zinc finger NFX1-type containing 1 (ZNFX1), a conserved RBP critically involved in immune deficiency diseases and mycobacterial infections, is significantly upregulated in M. tuberculosis-infected macrophages. Here, we aimed to explore the immunoregulatory functions of ZNFX1 during M. tuberculosis infection. We observed that Znfx1 knockout markedly compromised the multifaceted immune responses mediated by macrophages. This compromise resulted in reduced phagocytosis, suppressed macrophage activation, increased M. tuberculosis burden, progressive lung tissue injury, and chronic inflammation in M. tuberculosis-infected mice. Mechanistic investigations revealed that the absence of ZNFX1 inhibited autophagy, consequently mediating immune suppression. ZNFX1 critically maintained AMPK-regulated autophagic flux by stabilizing protein kinase AMP-activated catalytic subunit alpha 2 mRNA, which encodes a key catalytic α subunit of AMPK, through its zinc finger region. This process contributed to M. tuberculosis growth suppression. These findings reveal a function of ZNFX1 in establishing anti-M. tuberculosis immune responses, enhancing our understanding of the roles of RBPs in tuberculosis immunity and providing a promising approach to bolster antituberculosis immunotherapy.
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Mycobacterium tuberculosis , Tuberculose , Animais , Camundongos , Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia/genética , Macrófagos/metabolismoRESUMO
Background: Despite consensus that vaccines play an important role in combatting the global spread of infectious diseases, vaccine inequity is still a prevalent issue due to a deep-seated mentality of self-priority. We aimed to evaluate the existence and possible outcomes of a more equitable global vaccine distribution and explore a concrete incentive mechanism that promotes vaccine equity. Methods: We designed a metapopulation epidemiological model that simultaneously considers global vaccine distribution and human mobility, which we then calibrated by the number of infections and real-world vaccination records during the coronavirus disease 2019 (COVID-19) pandemic from March 2020 to July 2021. We explored the possibility of the enlightened self-interest incentive mechanism, which comprises improving one's own epidemic outcomes by sharing vaccines with other countries, by evaluating the number of infections and deaths under various vaccine sharing strategies using the proposed model. To understand how these strategies affect the national interests, we distinguished imported from local cases for further cost-benefit analyses that rationalise the enlightened self-interest incentive mechanism behind vaccine sharing. Results: The proposed model accurately reproduces the real-world cumulative infections for both global and regional epidemics (R2>0.990), which can support the following evaluations of different vaccine sharing strategies: High-income countries can reduce 16.7 (95% confidence interval (CI) = 8.4-24.9, P < 0.001) million infection cases and 82.0 (95% CI = 76.6-87.4, P < 0.001) thousand deaths on average by more actively sharing vaccines in an enlightened self-interest manner, where the reduced internationally imported cases outweigh the threat from increased local infections. Such vaccine sharing strategies can also reduce 4.3 (95% CI = 1.2-7.5, P < 0.01) million infections and 7.0 (95% CI = 5.7-8.3, P < 0.001) thousand deaths in middle- and low-income countries, effectively benefiting the whole global population. Lastly, the more equitable vaccine distribution could help largely reduce the global mobility reduction needed for pandemic control. Conclusions: The incentive mechanism of enlightened self-interest we explored here could motivate vaccine equity by realigning the national interest to more equitable vaccine distributions. The positive results could promote multilateral collaborations in global vaccine redistribution and reconcile conflicted national interests, which could in turn benefit the global population.
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COVID-19 , Vacinas , Humanos , Vacinação , COVID-19/epidemiologia , COVID-19/prevenção & controle , Análise Custo-Benefício , Pandemias/prevenção & controleRESUMO
Purpose: Chronic postsurgical pain (CPSP) is a common complication after thoracic surgery and associated with long-term adverse outcomes. This study aims to develop two prediction models for CPSP after video-assisted thoracic surgery (VATS). Methods and Analysis: This single-center prospective cohort study will include a total of 500 adult patients undergoing VATS lung resection (n = 350 for development and n = 150 for external validation). Patients will be enrolled continuously at The First Affiliated Hospital of Soochow University in Suzhou, China. The cohort for external validation will be recruited in another time period. The outcome is CPSP, which is defined as pain with the numerical rating scale score of 1 or higher 3 months after VATS. Univariate and multivariable logistic regression analyses will be performed to develop two CPSP prediction models based on patients' data of postoperative day 1 and day 14, respectively. For internal validation, we will use the bootstrapping validation technique. For external validation, the discrimination capability of the models will be assessed using the area under the receiver operating characteristic curve, and the calibration will be evaluated using the calibration curve and Hosmer-Lemeshow goodness-of-fit statistic. The results will be presented in model formulas and nomograms. Conclusion: Based on the development and validation of the prediction models, our results contribute to early prediction and treatment of CPSP after VATS. Trial Registration: Chinese Clinical Trial Register (ChiCTR2200066122).
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S100A10, a member of the S100 protein family, is upregulated in multiple human malignancies and plays a key role in regulating tumor progression. This study aimed to reveal the underlying mechanism by which S100A10 in regulates the proliferation, migration, and invasion of glioma. The expression and clinical information data of S100A10 were downloaded from public databases (TCGA, CGGA, and GEPIA2). S100A10 expression levels in glioma tumor tissues and adjacent nontumor tissues were compared by immunohistochemistry (IHC). The functional roles of S100A10 in glioma were assessed by cell counting kit-8 (CCK-8) cell proliferation assay, wound healing assay, transwell assay, and flow cytometry. miRDB and double luciferase assay were used to predict and identify potential S100A10 mRNA-complementary miRNAs, and the roles of miR-21-5p in glioma cell were examined by targeted knockdown or overexpression miR-21-5p in glioma cell lines. We found that S100A10 was overexpressed in glioma tissues and predicted a worse prognosis. S100A10 knockdown significantly inhibited glioma cell proliferation, invasion, and migration. Furthermore, we demonstrated that miR-21-5p inhibits glioma proliferation, migration, and invasion by targeting S100A10. This study showed S100A10 was a new prognostic predictor among glioma patients and provided new insights into the pathogenesis of gliomas, suggesting that miR-21-5p /S100A10 axis may serve as a valuable therapeutic target for glioma.
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Innate immune signaling in macrophages during viral infection is regulated by ISGylation, the covalent attachment of the ubiquitin-like protein interferon-stimulated gene 15 (ISG15) to protein targets. Here, we explored the role of ISGylation in the macrophage response to infection with Mycobacterium tuberculosis. In human and mouse macrophages, the E3 ubiquitin ligases HERC5 and mHERC6, respectively, mediated the ISGylation of the phosphatase PTEN, which promoted its degradation. The decreased abundance of PTEN led to an increase in the activity of the PI3K-AKT signaling pathway, which stimulated the synthesis of proinflammatory cytokines. Bacterial growth was increased in culture and in vivo when human or mouse macrophages were deficient in the major E3 ISG15 ligase. The findings expand the role of ISGylation in macrophages to antibacterial immunity and suggest that HERC5 signaling may be a candidate target for adjunct host-directed therapy in patients with tuberculosis.
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Fosfatidilinositol 3-Quinases , Ubiquitina-Proteína Ligases , Animais , Humanos , Camundongos , Antibacterianos , Citocinas/metabolismo , Interferons , Peptídeos e Proteínas de Sinalização Intracelular/genética , PTEN Fosfo-Hidrolase/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinas/metabolismoRESUMO
BACKGROUND: Epithelial-to-mesenchymal transition (EMT) and cancer stem-like cells (CSLCs) play crucial role in tumor metastasis and drug-resistance. Disheveled3 (DVL3) is involved in malignant behaviors of cancer. However, the role and potential mechanism of DVL3 remain elusive in EMT and CSLCs of colorectal cancer (CRC). METHODS: UALCAN and PrognoScan databases were employed to evaluate DVL3 expression in CRC tissues and its correlation with CRC prognosis, respectively. Transwell, sphere formation and CCK8 assay were used to assess metastasis, stemness and drug sensitivity of CRC cells, respectively. Western blotting and dual luciferase assay were performed to analyze the protein expression and Wnt/ß-catenin activation, respectively. Lentiviral transfection was used to construct the stable cell lines. Animal studies were performed to analyze the effect of silencing DVL3 on tumorigenicity and metastasis of CRC cells in vivo. RESULTS: DVL3 was overexpressed in CRC tissues and several CRC cell lines. DVL3 expression was also higher in CRC tissues with lymph node metastasis than tumor tissues without metastasis, and correlated with poor prognosis of CRC patients. DVL3 positively regulated the abilities of migration, invasion and EMT-like molecular changes in CRC cells. Moreover, DVL3 promoted CSLCs properties and multidrug resistance. We further identified that Wnt/ß-catenin was crucial for DVL3-mediated EMT, stemness and SOX2 expression, while silencing SOX2 inhibited DVL3-mediated EMT and stemness. Furthermore, c-Myc, a direct target gene of Wnt/ß-catenin, was required for SOX2 expression and strengthened EMT and stemness via SOX2 in CRC cells. Finally, knockdown of DVL3 suppressed tumorigenicity and lung metastasis of CRC cells in nude mice. CONCLUSION: DVL3 promoted EMT and CSLCs properties of CRC via Wnt/ß-catenin/c-Myc/SOX2 axis, providing a new strategy for successful CRC treatment.
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Neoplasias Colorretais , Proteínas Desgrenhadas , Transição Epitelial-Mesenquimal , Via de Sinalização Wnt , beta Catenina , Animais , Camundongos , beta Catenina/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Camundongos Nus , Humanos , Proteínas Desgrenhadas/genética , Células-Tronco NeoplásicasRESUMO
OBJECTIVE: Tuberculosis is the leading killer among the chronic single-source infectious diseases. Mycobacterium tuberculosis can induce necrotic-dominant multiple modes of cell death in macrophages, which accelerates bacterium dissemination and expands tissue injury in host lungs. Mining drugs to counteract Mycobacterium tuberculosis-induced cell death would be beneficial to tuberculosis patients. METHODS: In this study, the protective drug was screened out from the FDA-approved drug library in Mycobacterium tuberculosis-infected macrophages with CCK-8 assay. The death mode regulated by the drug was identified using transcriptomic sequencing, cytomorphological observation, and in the experimental mouse Mycobacterium tuberculosis-infection model. The functional mechanism was explored using western blot, co-immunoprecipitation, and DARTS assay. The intracellular bacterial survival was detected using colony forming unit assays. RESULTS: Cisatracurium besylate was identified to be highly protective for the viability of macrophages during Mycobacterium tuberculosis infection via inhibiting necroptosis. Cisatracurium besylate prevented RIPK3 to be associated with the executive molecule MLKL for forming the necroptotic complex, resulting in the inhibition of MLKL phosphorylation and pore formation on cell membrane. However, Cisatracurium besylate did not interfere with the association between RIPK3 with its upstream kinase RIPK1 or ZBP1 but regulated RIPK3 autophosphorylation. Moreover, Cisatracurium besylate significantly inhibited the expansion of intracellular Mycobacterium tuberculosis both in vitro and in vivo, which also displayed a strong auxiliary bacteriostatic effect to support the therapeutic efficacy of isoniazid and rifampicin, the first-line anti-tubercular drugs. CONCLUSION: Cisatracurium besylate performs anti-Mycobacterium tuberculosis and anti-necroptotic roles, which potentiates its application to be an adjuvant drug for antituberculosis therapy to assist the battle against drug-resistant tuberculosis.
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Mycobacterium tuberculosis , Tuberculose , Camundongos , Animais , Apoptose , Mycobacterium tuberculosis/metabolismo , Isoniazida/farmacologia , Isoniazida/uso terapêutico , Necroptose , Proteínas Quinases/metabolismo , Tuberculose/tratamento farmacológico , Tuberculose/metabolismo , Antibacterianos/farmacologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Macrófagos/metabolismoRESUMO
Optical fields and forces can be greatly enhanced for a microparticle when the whispering gallery modes (WGMs) are excited. In this paper, by solving the scattering problem using the generalized Mie theory, the morphology-dependent resonances (MDRs) and resonant optical forces derived from the coherent coupling of WGMs are investigated in multiple-sphere systems. When the spheres approach each other, the bonding and antibonding modes of MDRs emerge and correspond to the attractive and repulsive forces, respectively. More importantly, the antibonding mode is good at propagating light forward, while the optical fields decay rapidly for the bonding mode. Moreover, the bonding and antibonding modes of MDRs in the PT-symmetric system can persist only when the imaginary part of the refractive index is small enough. Interestingly, it is also shown that for a PT-symmetric structure, only a minor imaginary part of the refractive index is required to generate a significant pulling force at MDRs, making the whole structure move against the light propagation direction. Our work deepens the understanding of the collective resonance behavior of multiple spheres and paves the way for potential applications in particle transportation, non-Hermitian systems, integrated optical devices, etc.
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3,4-Enhanced polymerization of isoprene catalyzed by late transition metal with high activity remains one of the great challenges in synthetic rubber chemistry. Herein, a library of [N, N, X] tridentate iminopyridine iron chloride pre-catalysts (Fe 1-4) with the side arm were synthesized and confirmed by the element analysis and HRMS. All the iron compounds served as highly efficient pre-catalysts for 3,4-enhanced (up to 62%) isoprene polymerization when 500 equivalent MAOs were utilized as co-catalysts, delivering the corresponding high-performance polyisoprenes. Furthermore, optimization via single factor and response surface method, it was observed that the highest activity was obtained by complex Fe 2 with 4.0889 × 107 g·mol(Fe)-1·h-1 under the following conditions: Al/Fe = 683; IP/Fe = 7095; t = 0.52 min.