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Understanding the vascular formation and distribution in metastatic lung tumors is a significant challenge due to autofluorescence, antibody/dye diffusion in dense tumor, and fluorophore stability when exposed to solvent-based clearing agents. Here, an approach is presented that redefines 3D vasculature imaging within metastatic tumor, peritumoral lung tissue, and normal lung. Specifically, a far-red aggregation-induced emission nanoparticle with surface amino groups (termed as TSCN nanoparticle, TSCNNP) is designed for in situ formation of hydrogel (TSCNNP@Gel) inside vasculatures to provide structural support and enhance the fluorescence in solvent-based tissue clearing method. Using this TSCNNP@Gel-reinforced tissue clearing imaging approach, the critical challenges are successfully overcome and comprehensive visualization of the whole pulmonary vasculature up to 2 µm resolution is enabled, including its detailed examination in metastatic tumors. Importantly, features of tumor-associated vasculature in 3D panoramic views are unveiled, providing the potential to determine tumor stages, predict tumor progression, and facilitate the histopathological diagnosis of various tumor types.
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Hidrogéis , Imageamento Tridimensional , Neoplasias Pulmonares , Pulmão , Hidrogéis/química , Animais , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Camundongos , Pulmão/diagnóstico por imagem , Pulmão/irrigação sanguínea , Pulmão/patologia , Humanos , Nanopartículas/química , Linhagem Celular Tumoral , Imagem Óptica/métodos , Corantes Fluorescentes/químicaRESUMO
Despite the extensive development of non-noble metals for the N-alkylation of amines with alcohols, the exploitation of catalysts with high selectivity, activity, and stability still faces challenges. The controllable modification of single-atom sites through asymmetric coordination with a second heteroatom offers new opportunities for enhancing the intrinsic activity of transition metal single-atom catalysts. Here, we prepared the asymmetric N/P hybrid coordination of single-atom Co1-N3P1 by absorbing the Co-P complex on ZIF-8 using a concise impregnation-pyrolysis process. The catalyst exhibits ultrahigh activity and selectivity in the N-alkylation of aniline and benzyl alcohol, achieving a turnover number (TON) value of 3480 and a turnover frequency (TOF) value of 174-h. The TON value is 1 order of magnitude higher than the reported catalysts and even 37-fold higher than that of the homogeneous catalyst CoCl2(PPh3)2. Furthermore, the catalyst maintains its high activity and selectivity even after 6 cycles of usage. Controlling experiments and isotope labeling experiments confirm that in the asymmetric Co1-N3P1 system, the N-alkylation of aniline with benzyl alcohol proceeds via a transfer hydrogenation mechanism involving the monohydride route. Theoretical calculations prove that the superior activity of asymmetric Co1-N3P1 is attributed to the higher d-band energy level of Co sites, which leads to a more stable four-membered ring transition state and a lower reaction energy barrier compared to symmetrical Co1-N4.
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The development of Type I photosensitizers (PSs) is of great importance due to the inherent hypoxic intolerance of photodynamic therapy (PDT) in the hypoxic microenvironment. Compared to Type II PSs, Type I PSs are less reported due to the absence of a general molecular design strategy. Herein, we report that the combination of typical Type II PS and natural substrate carvacrol (CA) can significantly facilitate the Type I pathway to efficiently generate superoxide radical (O2-â¢). Detailed mechanism study suggests that CA is activated into thymoquinone (TQ) by local singlet oxygen generated from the PS upon light irradiation. With TQ as an efficient electron transfer mediator, it promotes the conversion of O2 to O2-⢠by PS via electron transfer-based Type I pathway. Notably, three classical Type II PSs are employed to demonstrate the universality of the proposed approach. The Type I PDT against S. aureus has been demonstrated under hypoxic conditions in vitro. Furthermore, this coupled photodynamic agent exhibits significant bactericidal activity with an antibacterial rate of 99.6% for the bacterial-infection female mice in the in vivo experiments. Here, we show a simple, effective, and universal method to endow traditional Type II PSs with hypoxic tolerance.
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Benzoquinonas , Fotoquimioterapia , Fármacos Fotossensibilizantes , Staphylococcus aureus , Benzoquinonas/química , Benzoquinonas/farmacologia , Benzoquinonas/metabolismo , Fármacos Fotossensibilizantes/farmacologia , Animais , Camundongos , Feminino , Fotoquimioterapia/métodos , Transporte de Elétrons/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Cimenos/farmacologia , Cimenos/química , Antibacterianos/farmacologia , Oxigênio Singlete/metabolismo , Superóxidos/metabolismo , Infecções Estafilocócicas/tratamento farmacológico , Humanos , Luz , Camundongos Endogâmicos BALB CRESUMO
Chemoresistance is the main obstacle in the clinical treatment of osteosarcoma (OS). In this study, we investigated the role of EF-hand domain-containing protein 1 (EFHD1) in OS chemotherapy resistance. We found that the expression of EFHD1 was highly correlated with the clinical outcome after chemotherapy. We overexpressed EFHD1 in 143B cells and found that it increased their resistance to cell death after drug treatment. Conversely, knockdown of EFHD1 in 143BR cells (a cisplatin-less-sensitive OS cell line derived from 143B cells) increased their sensitivity to treatment. Mechanistically, EFHD1 bound to adenine nucleotide translocase-3 (ANT3) and inhibited its conformational change, thereby inhibiting the opening of the mitochondrial membrane permeability transition pore (mPTP). This effect could maintain mitochondrial function, thereby favoring OS cell survival. The ANT3 conformational inhibitor carboxyatractyloside (CATR), which can promote mPTP opening, enhanced the chemosensitivity of EFHD1-overexpressing cells when combined with cisplatin. The ANT3 conformational inhibitor bongkrekic acid (BKA), which can inhibit mPTP opening, restored the resistance of EFHD1 knockdown cells. In conclusion, our results suggest that EFHD1-ANT3-mPTP might be a promising target for OS therapy in the future.
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Proliferação de Células , Cisplatino , Resistencia a Medicamentos Antineoplásicos , Proteínas de Transporte da Membrana Mitocondrial , Poro de Transição de Permeabilidade Mitocondrial , Osteossarcoma , Humanos , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Osteossarcoma/tratamento farmacológico , Osteossarcoma/genética , Poro de Transição de Permeabilidade Mitocondrial/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/genética , Linhagem Celular Tumoral , Cisplatino/farmacologia , Neoplasias Ósseas/patologia , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genética , Translocador 3 do Nucleotídeo Adenina/metabolismo , Translocador 3 do Nucleotídeo Adenina/genética , Antineoplásicos/farmacologia , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Animais , Camundongos , Ligação ProteicaRESUMO
Chronic wounds pose a significant global public health challenge due to their suboptimal treatment efficacy caused by bacterial infections and microcirculatory disturbances. Inspired by the biofunctionality of natural skin, an artificial skin (HV@BC@TBG) is bioengineered with bacterial cellulose (BC) sandwiched between photosensitizers (PS) and functionalized living cells. Glucose-modified PS (TBG) and vascular endothelial growth factor (VEGF)-functionalized living cells (HV) are successively modified on each side of BC through biological metabolism and bio-orthogonal reaction. As the outermost layer, the TBG layer can generate reactive oxygen species (ROS) upon light illumination to efficiently combat bacterial infections. The HV layer is the inner layer near the diabetic wound, which servs as a living factory to continuously secrete VEGF to accelerate wound repair by promoting fibroblast proliferation and angiogenesis. The sandwiched structural artificial skin HV@BC@TBG is nontoxic, biocompatible, and demonstrated its ability to significantly accelerate the healing process of infected diabetic wounds, rendering it a promising next-generation medical therapy for chronic wound management.
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Celulose , Fármacos Fotossensibilizantes , Pele Artificial , Fator A de Crescimento do Endotélio Vascular , Cicatrização , Cicatrização/efeitos dos fármacos , Celulose/química , Celulose/farmacologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Animais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Humanos , Espécies Reativas de Oxigênio/metabolismo , Camundongos , Fibroblastos/efeitos dos fármacos , Fibroblastos/citologia , Proliferação de Células/efeitos dos fármacos , Glucose/químicaRESUMO
The poor performance of recycled concrete aggregate (RCA) leads to greater creep in recycled aggregate concrete (RAC) compared to natural aggregate concrete (NAC). To enhance the quality of RCA, this paper utilizes a 2% concentration of a nano-SiO2 (NS) solution for pre-soaking RCA. This study aims to replace natural aggregate (NA) with NS-modified recycled aggregate (SRCA) and investigate the creep and shrinkage properties of NS-modified recycled aggregate concrete (SRAC) at various SRCA replacement rates. Subsequently, the creep and shrinkage strains of NAC, SRAC, and RAC are simulated using the finite element method. Finally, a comparative analysis is conducted with the predicted creep and shrinkage strains from CEB-FIP, ACI, B3, and GL2000 models. The experimental results indicate that the creep and shrinkage deformation of SRAC increases with the SRCA replacement rate. Compared to NAC, the creep and shrinkage deformation of SRAC at replacement rates of 30%, 50%, 70%, and 100% increased by 2%, 7%, 13%, and 30%, respectively. However, when 100% of the natural aggregate is replaced with SRCA, the creep and shrinkage deformation decreases by 7% compared to RAC. Moreover, the CEB-FIP and ACI models can predict the creep and shrinkage deformation of concrete reasonably well.
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Recycled aggregate concrete (RAC) possesses different mechanical properties than ordinary concrete because of inherent faults in recycled aggregates (RAs), such as the old interfacial transition zone (ITZ). However, the application of nano-SiO2 presents an effective methodology to enhance the quality of RA. In this study, nano-SiO2-modified recycled aggregate (SRA) was used to replace natural aggregate (NA), and the stress-strain relationships and cyclic behavior of nano-SiO2-modified recycled aggregate concrete (SRAC) with different SRA replacement rates were investigated. After evaluating the skeleton curve of SRAC specimens, the existing constitutive models were compared. Additionally, the study also proposed a stress-strain model designed to predict the mechanical behavior of concrete in relation to the SRA replacement rate. The results show that compared with RAC, the axial compressive strength of SRAC specimens showed increases of 40.27%, 29.21%, 26.55%, 16.37%, and 8.41% at specific SRA replacement rates of 0%, 30%, 50%, 70%, and 100%, respectively. Moreover, the study found that the Guo model's calculated results can accurately predict the skeleton curves of SRAC specimens.
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[This corrects the article DOI: 10.1016/j.isci.2021.102791.].
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ZFP36L1, which is a negative regulator of gene transcripts, has been proven to regulate the progression of several carcinomas. However, its role in sarcoma remains unknown. Here, by using data analyses and in vivo experiments, we found that ZFP36L1 inhibited the lung metastasis of osteosarcoma (OS). Knockdown of ZFP36L1 promoted OS cell migration by activating TGF-ß signaling and increasing SDC4 expression. Intriguingly, we observed a positive feedback loop between SDC4 and TGF-ß signaling. SDC4 protected TGFBR3 from matrix metalloproteinase (MMP)-mediated cleavage and therefore relieved the inhibition of TGF-ß signaling by soluble TGFBR3, while TGF-ß signaling positively regulated SDC4 transcription. We also proved that ZFP36L1 regulated SDC4 mRNA decay through adenylate-uridylate (AU)-rich elements (AREs) in its 3'UTR. Furthermore, treatment with SB431542 (a TGF-ß receptor kinase inhibitor) and MK2 inhibitor III (a MAPKAPK2 inhibitor that increases the ability of ZFP36L1 to degrade mRNA) dramatically inhibited OS lung metastasis, suggesting a promising therapeutic approach for the treatment of OS lung metastasis.
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Neoplasias Ósseas , Neoplasias Pulmonares , Osteossarcoma , Humanos , Retroalimentação , Fator de Crescimento Transformador beta/metabolismo , Osteossarcoma/genética , Osteossarcoma/metabolismo , Neoplasias Ósseas/genética , Neoplasias Pulmonares/genética , Linhagem Celular Tumoral , Fator 1 de Resposta a Butirato , Sindecana-4/metabolismoRESUMO
Selective and targeted removal of individual species or strains of bacteria from complex communities can be desirable over traditional and broadly acting antibiotics in several conditions. However, strategies that can detect and ablate bacteria with high specificity are emerging in recent years. Herein, a platform is reported that uses bacteria as a template to synthesize polymers containing guanidinium groups for self-selective depletion of specific pathogenic bacteria without disturbing microbial communities. Different from conventional antibiotics, repeated treatment of bacteria with the templated polymers does not evolve drug resistance mutants after 20 days of serial passaging. Especially, high in vivo therapeutic effectiveness of the templated polymers is achieved in E. coli- and P. aeruginosa-induced microbial peritonitis. The templated polymers have shown high selectivity in in vivo antimicrobial activity, which has excellent potential as systemic antimicrobials against bacterial infections.
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Escherichia coli , Polímeros , Polímeros/uso terapêutico , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , BactériasRESUMO
The development of new antimicrobial agents to treat infections caused by Gram-negative bacteria is of paramount importance due to increased antibiotic resistance worldwide. Herein, we show that a water-soluble porphyrin-cored hyperbranched conjugated polyelectrolyte (PorHP) exhibits high photodynamic bactericidal activity against the Gram-negative bacteria tested, including a multidrug-resistant (MDR) pathogen, while demonstrating low cytotoxicity toward mammalian cells. Comprehensive analyses reveal that the antimicrobial activity of PorHP proceeds via a multimodal mechanism by effective bacterial capsule shedding, strong bacterial outer membrane binding, and singlet oxygen generation. Through this multimodal antimicrobial mechanism, PorHP displays significant performance for Gram-negative bacteria with >99.9% photodynamic killing efficacy. Overall, PorHP shows great potential as an antimicrobial agent in fighting the growing threat of Gram-negative bacteria.
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Anti-Infecciosos , Bactérias Gram-Negativas , Animais , Polieletrólitos/farmacologia , Anti-Infecciosos/farmacologia , Oxigênio Singlete , Antibacterianos/química , Testes de Sensibilidade Microbiana , Mamíferos/metabolismoRESUMO
The function of signal regulatory protein alpha (SIRPA) has been well studied in macrophages and dendritic cells, but relatively less in tumors. Notably, SIRPA is upregulated in osteosarcoma tissues, particularly in metastatic tissues, and is associated with unfavorable clinical outcomes. Knockdown of SIRPA impaired OS cell migration by decreasing specificity protein 1 (SP1) stability and arginine uptake. Importantly, SIRPA phosphorylated SP1 at threonine 278 (Thr278) through extracellular signal-regulated kinase (ERK) activation to protect SP1 from proteasomal degradation. In addition, SP1 increased solute carrier family 7 member 3 (SLC7A3) expression by binding to the SLC7A3 promoter and increased the capability of arginine uptake, thereby facilitating OS cell migration. More interestingly, arginine promoted the stability of SP1 in an ERK-independent manner and thus formed the "SP1 stabilization circle". Combined treatment with the anti-SIRPA antibody and arginase, which blocked the circle, impaired tumor metastasis in mice bearing xenografts formed from SIRPA-overexpressing cells. In summary, our study demonstrates that the upregulation of SIRPA promotes OS metastasis via the "SP1 stabilization circle" and SLC7A3-mediated arginine uptake, which might serve as a target for OS treatment.
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Entrepreneurship is a tool for driving economic and social progress. Especially in Hong Kong, the government has recently taken steps to encourage young people to engage in entrepreneurship. However, Hong Kong youths' entrepreneurial intentions are still low. The objective of this study is to empirically explore the impacts of personality traits on start-up preparation among Hong Kong youths through the constructs of the theory of planned behavior (TPB). Through a multi-channel survey, we finally collected 230 valid respondents aged 18 to 40. In addition, this study used SmartPLS software to conduct confirmatory factor analysis for the measurement model as well as path analysis for the structural model. This study's results suggested that creativity, risk-taking propensity, need for achievement, and internal locus of control influence TPB models' components and indirectly influence start-up preparation through TPB models' components. Also, attitude and perceived behavioral control influence intention, and intention influences preparation. Furthermore, prior entrepreneurial experience and entrepreneurship education positively influence preparation. In conclusion, this study revealed the mediating effects of TPB components between four personality traits and start-up preparation. Finally, this study had theoretical implications by providing the influence of six personality traits on youths' entrepreneurial intention and preparation through the TPB model and the human capital theory. This study also had practical implications by providing suggestions for the government and higher education institutions.
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Aqueous organic redox flow batteries (AORFBs) are a promising technology for large-scale electricity energy storage to realize efficient utilization of intermittent renewable energy. In particular, organic molecules are a class of metal-free compounds that consist of earth-abundant elements with good synthetic tunability, electrochemical reversibility and reaction rates. However, the short cycle lifetime and low capacity of AORFBs act as stumbling blocks for their practical deployment. To circumvent these issues, here, we report molecular engineered dihydroxyanthraquinone (DHAQ)-based alkaline electrolytes. Via computational studies and operando measurements, we initially demonstrate the presence of a hydrogen bond-mediated degradation mechanism of DHAQ molecules during electrochemical reactions. Afterwards, we apply a molecular engineering strategy based on redox-active polymers to develop capacity-boosting composite electrolytes. Indeed, by coupling a 1,5-DHAQ/poly(anthraquinonyl sulfide)/carbon black anolyte and a [Fe(CN)6]3-/4- alkaline catholyte, we report an AORFB capable of delivering a stable cell discharge capacity of about 573 mAh at 20 mA/cm2 after 1100 h of cycling and an average cell discharge voltage of about 0.89 V at the same current density.
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BACKGROUND: The zinc transporters Zrt- and Irt-related protein (ZIP/SLC39) are overexpressed in human tumors and correlate with poor prognosis; however, their contributions to carcinogenesis and chemoresistance in osteosarcoma (OS) remain unclear. METHODS: We collected 64 OS patient tissues with (n = 12) or without (n = 52) chemotherapy. The expression levels of ZIP10 were measured by immunohistochemistry and applied to prognostic analysis. ZIP10 was knocked down or overexpressed in OS cell lines to explore its effect on proliferation and chemoresistance. RNA sequencing, quantitative real-time PCR, and western blotting analysis were performed to explore ZIP10-regulated downstream target genes. A xenograft mouse model was established to evaluate the mechanisms by which ZIP10 modulates chemoresistance in OS cells. RESULTS: The expression of ZIP10 was significantly induced by chemotherapy and highly associated with the clinical outcomes of OS. Knockdown of ZIP10 suppressed OS cell proliferation and chemoresistance. In addition, ZIP10 promoted Zn content-induced cAMP-response element binding protein (CREB) phosphorylation and activation, which are required for integrin α10 (ITGA10) transcription and ITGA10-mediated PI3K/AKT pathway activation. Importantly, ITGA10 stimulated PI3K/AKT signaling but not the classical FAK or SRC pathway. Moreover, overexpression of ZIP10 promoted ITGA10 expression and conferred chemoresistance. Treatment with the CREB inhibitor 666-15 or the PI3K/AKT inhibitor GSK690693 impaired tumor chemoresistance in ZIP10-overexpressing cells. Finally, a xenograft mouse model established by subcutaneous injection of 143B cells confirmed that ZIP10 mediates chemotherapy resistance in OS cells via the ZIP10-ITGA10-PI3K/AKT axis. CONCLUSIONS: We demonstrate that ZIP10 drives OS proliferation and chemoresistance through ITGA10-mediated activation of the PI3K/AKT pathway, which might serve as a target for OS treatment.
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Proteínas de Transporte de Cátions/genética , Cadeias alfa de Integrinas/metabolismo , Osteossarcoma/genética , Osteossarcoma/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Animais , Proteínas de Transporte de Cátions/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Técnicas de Silenciamento de Genes , Xenoenxertos , Humanos , Camundongos , Modelos Biológicos , Osteossarcoma/patologia , FosforilaçãoRESUMO
Although angiogenesis-osteogenesis coupling is important in ankylosing spondylitis (AS), therapeutic agents targeting the vasculature remain elusive. Here, we identified activating transcription factor 6 (ATF6) as an important regulator of angiogenesis in the pathogenesis of AS. First, we found that ATF6 and fibroblast growth factor 2 (FGF2) levels were higher in SKG mice and in cartilage of pateints with AS1. The proangiogenic activity of human chondrocytes was enhanced by the activation of the ATF6-FGF2 axis following 7 days of stimulation with inflammatory factors, e.g., tumor necrosis factor alpha (TNF-α), interferon-γ (IFN-γ) or interleukin-17 (IL-17). Mechanistically, ATF6 interacted with the FGF2 promotor and promoted its transcription. Treatment with the ATF6 inhibitor Ceapin-A7 inhibited angiogenesis in vitro and angiogenesis-osteogenesis coupling in vivo. ATF6 may aggravate angiogenesis-osteogenesis coupling during AS by mediating FGF2 transcription in chondrocytes, implying that ATF6 represents a promising therapeutic target for AS.