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1.
Neuro Oncol ; 2024 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-39093693

RESUMO

BACKGROUND: Self-renewal of glioma stem cells (GSCs) is responsible for glioblastoma (GBM) therapy-resistant and recurrence. Tumor necrosis factor α (TNFα) and TNF signaling pathway display an antitumor activity in preclinical models and in tumor patients. However, TNFα exhibits no significance for glioma clinical prognosis based on Glioma Genome Atlas database. This study aimed to explore whether TNFα of tumor microenvironment maintains self-renewal of GSCs and promotes worse prognosis in glioma patient. METHODS: Spatial transcriptomics, immunoblotting, sphere formation assay, extreme limiting dilution, and gene expression analysis were used to determine the role of TNFα on GSC's self-renewal. Mass spectrometry, RNA-sequencing detection, bioinformatic analyses, qRT-RNA, immunofluorescence, immunohistochemistry, single cell RNA sequencing, in vitro and in vivo models were used to uncover the mechanism of TNFα-induced GSC self-renewal. RESULTS: Low level of TNFα displays a promoting effect on GSC self-renewal and worse glioma prognosis. Mechanistically, Vasorin (VASN) mediated TNFα-induced self-renewal by potentiating glycolysis. Lactate produced by glycolysis inhibits the TNFα secretion of tumor-associated macrophages (TAMs) and maintains TNFα in a low level. CONCLUSIONS: TNFα-induced GSC self-renewal mediated by VASN provides a possible explanation for the failures of endogenous TNFα effect on GBM. Combination of targeting VASN and TNFα anti-tumor effect may be an effective approach for treating GBM.

2.
BMC Immunol ; 25(1): 56, 2024 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-39169307

RESUMO

BACKGROUND: Leukemia inhibitory factor (LIF) is a multifunctional member of the IL-6 cytokine family that activates downstream signaling pathways by binding to the heterodimer consisting of LIFR and gp130 on the cell surface. Previous research has shown that LIF is highly expressed in various tumor tissues (e.g. pancreatic cancer, breast cancer, prostate cancer, and colorectal cancer) and promotes cancer cell proliferation, migration, invasion, and differentiation. Moreover, the overexpression of LIF correlates with poor clinicopathological characteristics. Therefore, we hypothesized that LIF could be a promising target for the treatment of cancer. In this work, we developed the antagonist antibody 1G11 against LIF and investigated its anti-tumor mechanism and its therapeutic efficacy in mouse models. RESULTS: A series of single-chain variable fragments (scFvs) targeting LIF were screened from a naive human scFv phage library. These scFvs were reconstructed in complete IgG form and produced by the mammalian transient expression system. Among the antibodies, 1G11 exhibited the excellent binding activity to human, cynomolgus monkey and mouse LIF. Functional analysis demonstrated 1G11 could block LIF binding to LIFR and inhibit the intracellular STAT3 phosphorylation signal. Interestingly, 1G11 did not block LIF binding to gp130, another LIF receptor that is involved in forming the receptor complex together with LIFR. In vivo, intraperitoneal administration of 1G11 inhibited tumor growth in CT26 and MC38 models of colorectal cancer. IHC analysis demonstrated that p-STAT3 and Ki67 were decreased in tumor tissue, while c-caspase 3 was increased. Furthermore, 1G11 treatment improves CD3+, CD4 + and CD8 + T cell infiltration in tumor tissue. CONCLUSIONS: We developed antagonist antibodies targeting LIF/LIFR signaling pathway from a naive human scFv phage library. Antagonist anti-LIF antibody exerts antitumor effects by specifically reducing p-STAT3. Further studies revealed that anti-LIF antibody 1G11 increased immune cell infiltration in tumor tissues.


Assuntos
Fator Inibidor de Leucemia , Anticorpos de Cadeia Única , Animais , Humanos , Anticorpos de Cadeia Única/imunologia , Anticorpos de Cadeia Única/farmacologia , Camundongos , Fator Inibidor de Leucemia/imunologia , Fator Inibidor de Leucemia/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/imunologia , Receptor gp130 de Citocina/imunologia , Receptor gp130 de Citocina/metabolismo , Receptor gp130 de Citocina/antagonistas & inibidores , Biblioteca de Peptídeos , Transdução de Sinais , Feminino , Macaca fascicularis , Camundongos Endogâmicos BALB C , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Spectrochim Acta A Mol Biomol Spectrosc ; 323: 124923, 2024 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-39096669

RESUMO

In vivo real-time detection of hypochlorous acid (HClO) in biological systems plays a crucial role in diagnosing immune-related diseases. Experimentally, a benzo-bodipy probe based on the photo-induced electron transfer (PeT) sensing mechanism has been developed for live fluorescence imaging. However, there have been no theoretical studies conducted to substantiate the precision of the sensing mechanism. This paper employs density functional theory (DFT) and time-dependent density functional theory (TDDFT) methods to investigate the fluorescence detection mechanism of benzo-bodipy derivatives (BBy-T and BBy-TO), proposing a detection approach based on dark nπ* state quenching. The study reveals that the fluorescence quenching mechanism of BBy-T is primarily regulated by a thiomorpholine moiety, involving a dark nπ* state transition non-radiatively. Furthermore, this paper explains the fluorescence enhancement observed in BBy-TO. Theoretical investigations demonstrate, based on frontier molecular orbitals (FMOs) and hole-electron analysis, that the fluorescence enhancement for BBy-TO is not governed by the previously proposed intramolecular charge transfer (ICT) mechanism in experiments but rather follows a locally excited (LE) ππ* pattern. This work offers new insights for the design of novel fluorescence probes based on bodipy and benzo derivatives, expanding the understanding of their fluorescence properties.

4.
Bioorg Med Chem ; 111: 117844, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-39106652

RESUMO

Monoacylglycerol lipase (MAGL) is a key enzyme responsible for the metabolism of the endocannabinoid 2-arachidonoylglycerol (2-AG), and has attracted great interest due to its involvement in various physiological and pathological processes, such as cancer progression. In the past, a number of covalent irreversible inhibitors have been reported for MAGL, however, experimental evidence highlighted some drawbacks associated with the use of these irreversible agents. Therefore, efforts were mainly focused on the development of reversible MAGL inhibitor in recent years. Here, we designed and synthesized a series of naphthyl amide derivatives (12-39) as another type of reversible MAGL inhibitors, exemplified by ± 34, which displayed good MAGL inhibition with a pIC50 of 7.1, and the potency and selectivity against endogenous MAGL were further demonstrated by competitive ABPP. Moreover, the compound showed appreciable antiproliferative activities against several cancer cells, including H460, HT29, CT-26, Huh7 and HCCLM-3. The investigations culminated in the discovery of the naphthyl amide derivative ± 34, and it may represent as a new scaffold for MAGL inhibitor development, particularly for the reversible ones.


Assuntos
Amidas , Antineoplásicos , Proliferação de Células , Desenho de Fármacos , Inibidores Enzimáticos , Monoacilglicerol Lipases , Monoacilglicerol Lipases/antagonistas & inibidores , Monoacilglicerol Lipases/metabolismo , Humanos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Amidas/química , Amidas/farmacologia , Amidas/síntese química , Relação Estrutura-Atividade , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Estrutura Molecular , Ensaios de Seleção de Medicamentos Antitumorais , Naftalenos/farmacologia , Naftalenos/síntese química , Naftalenos/química , Relação Dose-Resposta a Droga , Simulação de Acoplamento Molecular
5.
Carbohydr Polym ; 343: 122460, 2024 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-39174133

RESUMO

Nanocelluloses (NCs) isolated from lignocellulosic resources usually require harsh chemical pretreatments to remove lignin, which face constraints such as high energy consumption and inefficient resource utilization. An alternative strategy involving the partial retention of lignin can be adopted to endow NCs with better versatility and functionality. The resulting lignin-containing nanocelluloses (LNCs) generally possess better mechanical property, thermal stability, barrier property, antioxidant activity, and surface hydrophobicity than lignin-free NCs, which have attracted extensive interest as a promising green nanomaterial for numerous applications. This review provides a comprehensive overview of the recent advances in the preparation, properties, and food application of LNCs. The effect of residual lignin on the preparation and properties of LNCs is discussed. Furthermore, the key roles of lignin in the properties of LNCs, including particle size, crystalline structure, dispersibility, thermal, mechanical, antibacterial, rheological and adhesion properties, are summarized comprehensively. Furthermore, capitalizing on their dietary fiber and nanostructure properties, the food applications of LNCs in the forms of films, gels and emulsions are also discussed. Finally, the challenges and opportunities regarding the development of LNCs are provided.


Assuntos
Lignina , Nanoestruturas , Lignina/química , Nanoestruturas/química , Celulose/química , Antibacterianos/química , Antibacterianos/farmacologia , Interações Hidrofóbicas e Hidrofílicas , Antioxidantes/química , Antioxidantes/farmacologia , Tamanho da Partícula
6.
Artigo em Inglês | MEDLINE | ID: mdl-39146158

RESUMO

Sound source localization aims to localize objects emitting the sound in visual scenes. Recent works obtaining impressive results typically rely on contrastive learning. However, the common practice of randomly sampling negatives in prior arts can lead to the false negative issue, where the sounds semantically similar to visual instance are sampled as negatives and incorrectly pushed away from the visual anchor/query. As a result, this misalignment of audio and visual features could yield inferior performance. To address this issue, we propose a novel audio-visual learning framework which is instantiated with two individual learning schemes: self-supervised predictive learning (SSPL) and semantic-aware contrastive learning (SACL). SSPL explores image-audio positive pairs alone to discover semantically coherent similarities between audio and visual features, while a predictive coding module for feature alignment is introduced to facilitate the positive-only learning. In this regard SSPL acts as a negative-free method to eliminate false negatives. By contrast, SACL is designed to compact visual features and remove false negatives, providing reliable visual anchor and audio negatives for contrast. Different from SSPL, SACL releases the potential of audio-visual contrastive learning, offering an effective alternative to achieve the same goal. Comprehensive experiments demonstrate the superiority of our approach over the state-of-the-arts. Furthermore, we highlight the versatility of the learned representation by extending the approach to audio-visual event classification and object detection tasks. Code and models are available at: https://github.com/zjsong/SACL.

7.
J Med Chem ; 2024 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-39149790

RESUMO

The protein kinase ataxia telangiectasia mutated (ATM) is a constituent of the phosphatidylinositol 3-kinase-related kinase (PIKK) family, exerting a pivotal influence on diverse cellular processes, notably the signaling of double-strand DNA breaks (DSB) and stress response. The dysregulation of ATM is implicated in the pathogenesis of cancer and other diseases such as neurodegeneration. Hence, ATM is deemed a promising candidate for potential therapeutic interventions across a spectrum of diseases. Presently, while ATM small molecule inhibitors are not commercially available, various selective inhibitors have progressed to the clinical research phase. Specifically, AZD1390, WSD0628, SYH2051, and ZN-B-2262 are under investigation in clinical studies pertaining to glioblastoma multiforme and advanced solid tumors, respectively. In this Perspective, we encapsulate the structure, biological functions, and disease relevance of ATM. Subsequently, we concentrate on the design concepts and structure-activity relationships (SAR) of ATM inhibitors, delineating potential avenues for the development of more efficacious ATM-targeted inhibitors.

8.
J Anim Sci ; 2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-39051732

RESUMO

Zearalenone (ZEN) is a non-steroidal estrogenic mycotoxin produced by Fusarium strains that is harmful to the intestinal health of animals and is widely present in contaminated crops. The objective of this study was to investigate the potential therapeutic target of ZEN-induced jejunal damage in weaned gilts. Sixteen weaned gilts either received a basal diet or a basal diet supplemented with 3.0 mg/kg ZEN in a 32-day experiment. The results showed that ZEN at the concentration of 3.0 mg/kg diet activated the inflammatory response and caused oxidative stress of gilts (P < 0.05). ZEN exposure resulted in the up-regulation (P < 0.05) of the Exchange protein directly activated by the cAMP 1/Ras-related protein1/c-Jun N-terminal kinase (Epac1/Rap1/JNK signaling pathway in the jejunum of gilts in vivo and in the intestinal porcine epithelial cells in vitro. The cell viability, EdU-positive cells, and the mRNA expression of B-cell lymphoma-2 (Bcl-2) were decreased, whereas the reactive oxygen species production and the mRNA expressions of Bcl-2-associated X (Bax) and Cysteine-aspartic acid protease 3 (Caspase3) were increased (P < 0.05) by ZEN. However, ZEN increased the mRNA expression of Bcl-2 and decreased the mRNA expressions of Bax and caspase3 (P < 0.05) after the Epac1 was blocked. These results collectively indicated that 3.0 mg ZEN /kg diet induced jejunal damage via the Epac1/Rap1/JNK signaling pathway.

9.
Nat Protoc ; 2024 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-39026122

RESUMO

The evolution and mutation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are urgent concerns as they pose the risk of vaccine failure and increased viral transmission. However, affordable and scalable tools allowing rapid identification of SARS-CoV-2 variants are not readily available, which impedes diagnosis and epidemiological surveillance. Here we present a colorimetric nucleic acid assay named MARVE (multiplexed, preamplification-free, single-nucleotide-resolved viral evolution) that is convenient to perform and yields single-nucleotide resolution. The assay integrates nucleic acid strand displacement reactions with enzymatic amplification to colorimetrically sense viral RNA using a metal ion-incorporated DNA probe (TEprobe). We provide detailed guidelines to design TEprobes for discriminating single-nucleotide variations in viral RNAs, and to fabricate a test paper for the detection of SARS-CoV-2 variants of concern. Compared with other nucleic acid assays, our assay is preamplification-free, single-nucleotide-resolvable and results are visible via a color change. Besides, it is smartphone readable, multiplexed, quick and cheap ($0.30 per test). The protocol takes ~2 h to complete, from the design and preparation of the DNA probes and test papers (~1 h) to the detection of SARS-CoV-2 or its variants (30-45 min). The design of the TEprobes requires basic knowledge of molecular biology and familiarity with NUPACK or the Python programming language. The fabrication of the origami papers requires access to a wax printer using the CAD and PDF files provided or requires users to be familiar with AutoCAD to design new origami papers. The protocol is also applicable for designing assays to detect other pathogens and their variants.

10.
Artigo em Inglês | MEDLINE | ID: mdl-39046858

RESUMO

Source-free domain adaptation has developed rapidly in recent years, where the well-trained source model is adapted to the target domain instead of the source data, offering the potential for privacy concerns and intellectual property protection. However, a number of feature alignment techniques in prior domain adaptation methods are not feasible in this challenging problem setting. Thereby, we resort to probing inherent domain-invariant feature learning and propose a curriculum-style self-training approach for source-free domain adaptive semantic segmentation. In particular, we introduce a curriculum-style entropy minimization method to explore the implicit knowledge from the source model, which fits the trained source model to the target data using certain information from easy-to-hard predictions. We then train the segmentation network by the proposed complementary curriculum-style self-training, which utilizes the negative and positive pseudo labels following the curriculum-learning manner. Although negative pseudo-labels with high uncertainty cannot be identified with the correct labels, they can definitely indicate absent classes. Moreover, we employ an information propagation scheme to further reduce the intra-domain discrepancy within the target domain, which could act as a standard post-processing method for the domain adaptation field. Furthermore, we extend the proposed method to a more challenging black-box source model scenario where only the source model's predictions are available. Extensive experiments validate that our method yields state-of-the-art performance on source-free semantic segmentation tasks for both synthetic-to-real and adverse conditions datasets. The code and corresponding trained models are released at https://github.com/yxiwang/ATP.

11.
Int J Clin Health Psychol ; 24(3): 100484, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39055856

RESUMO

Background: Detecting and responding to target objects in the visual environment is a key factor in goal-directed behavior. Exposure to chronic stress often results in alterations of prefrontal cortex (PFC) function, which may impact PFC-dependent selective attention process. This study aimed to investigate the effect of chronic academic stress on attentional control process. Method: Both the stress group and the control group performed an arrow-based version of the Eriksen Flanker task. Event-related potentials (ERP) were recorded while the participants performed the task. Results: The behavioural results exhibited decreased Flanker RT effect for the stress group compared to the control group, suggesting a reduced interference under stress. The ERP results showed that stress group showed decreased frontal N2 but increased early P3 and late P3/LPC activities compared to the control group. These results suggest reduced conflict monitoring but increased conflict resolution process under stress. Conclusions: The chronic academic stress improves attentional control by reducing the conflict monitoring and enhancing conflict resolution processes.

12.
ACS Sens ; 9(7): 3466-3488, 2024 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-38991227

RESUMO

Organ-on-a-Chip (OOC) technology, which emulates the physiological environment and functionality of human organs on a microfluidic chip, is undergoing significant technological advancements. Despite its rapid evolution, this technology is also facing notable challenges, such as the lack of vascularization, the development of multiorgan-on-a-chip systems, and the replication of the human body on a single chip. The progress of microfluidic technology has played a crucial role in steering OOC toward mimicking the human microenvironment, including vascularization, microenvironment replication, and the development of multiorgan microphysiological systems. Additionally, advancements in detection, analysis, and organoid imaging technologies have enhanced the functionality and efficiency of Organs-on-Chips (OOCs). In particular, the integration of artificial intelligence has revolutionized organoid imaging, significantly enhancing high-throughput drug screening. Consequently, this review covers the research progress of OOC toward Human-on-a-chip, the integration of sensors in OOCs, and the latest applications of organoid imaging technologies in the biomedical field.


Assuntos
Dispositivos Lab-On-A-Chip , Organoides , Humanos , Técnicas Analíticas Microfluídicas/instrumentação , Técnicas Analíticas Microfluídicas/métodos , Sistemas Microfisiológicos
13.
Cell Rep ; 43(7): 114458, 2024 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-38996070

RESUMO

Regulatory T (Treg) cells play a critical regulatory role in the immune system by suppressing excessive immune responses and maintaining immune balance. The effective migration of Treg cells is crucial for controlling the development and progression of inflammatory diseases. However, the mechanisms responsible for directing Treg cells into the inflammatory tissue remain incompletely elucidated. In this study, we identified BAF60b, a subunit of switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complexes, as a positive regulator of Treg cell migration that inhibits the progression of inflammation in experimental autoimmune encephalomyelitis (EAE) and colitis animal models. Mechanistically, transcriptome and genome-wide chromatin-landscaped analyses demonstrated that BAF60b interacts with the transcription factor RUNX1 to promote the expression of CCR9 on Treg cells, which in turn affects their ability to migrate to inflammatory tissues. Our work provides insights into the essential role of BAF60b in regulating Treg cell migration and its impact on inflammatory diseases.


Assuntos
Movimento Celular , Inflamação , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Animais , Camundongos , Inflamação/patologia , Inflamação/metabolismo , Montagem e Desmontagem da Cromatina , Proteínas Cromossômicas não Histona/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/genética , Humanos , Fatores de Transcrição/metabolismo , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Colite/metabolismo , Colite/patologia , Colite/imunologia , Colite/genética
14.
J Phys Chem A ; 128(27): 5285-5297, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38950340

RESUMO

The role of Dy-S coordination in a single-molecule magnet (SMM) is investigated via an ab initio study in a group of mononuclear structures. The SMM performance of this group is well interpreted via a concise criterion consisting of long quantum tunneling of magnetization (QTM) time τQTM and high effective barrier for magnetic reversal Ueff. The best SMMs in the selected group, i.e., 1Dy (CCDC refcode: PUKFAF) and 2Dy (CCDC refcode: NIKSEJ), are just those holding the longest τQTM and the highest Ueff simultaneously. Further analysis based on the crystal field model and ab initio magneto-structural exploration indicates that the influence of Dy-S coordination on the SMM performance of 1Dy is weaker than that of axial Dy-O coordination. Thus, Dy-S coordination is more likely to play an auxiliary role rather than a dominant one. However, if placed at the suitable equatorial position, Dy-S coordination could provide important support for good SMM performance. Consequently, starting from 1Dy, we built two new structures where Dy-S coordination only exists at the equatorial position and two axial positions are occupied by strong Dy-O/Dy-F coordination. Compared to 1Dy and 2Dy, these new ones are predicted to have significantly longer τQTM and higher Ueff, as well as a nearly doubled blocking temperature TB. Thus, they are probable candidates of SMM having clearly improved performance.

15.
Eur J Med Chem ; 276: 116649, 2024 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-38972078

RESUMO

Guided by the X-ray cocrystal structure of the lead compound 4a, we developed a series of thieno[3,2-d]pyrimidine and heterocyclic fused pyrimidines demonstrating potent antiproliferative activity against four tumor cell lines. Two analogs, 13 and 25d, exhibited IC50 values around 1 nM and overcame P-glycoprotein (P-gp)-mediated multidrug resistance (MDR). At low concentrations, 13 and 25d inhibited both the colony formation of SKOV3 cells in vitro and tubulin polymerization. Furthermore, mechanistic studies showed that 13 and 25d induced G2/M phase arrest and apoptosis in SKOV3 cells, as well as dose-dependent inhibition of tumor cell migration and invasion at low concentrations. Most notably, the X-ray cocrystal structures of compounds 4a, 25a, and the optimal molecule 13 in complex with tubulin were elucidated. This study identifies thieno[3,2-d]pyrimidine and heterocyclic fused pyrimidines as representatives of colchicine-binding site inhibitors (CBSIs) with potent antiproliferative activity.


Assuntos
Antineoplásicos , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Pirimidinas , Moduladores de Tubulina , Tubulina (Proteína) , Humanos , Pirimidinas/farmacologia , Pirimidinas/química , Pirimidinas/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Tubulina (Proteína)/metabolismo , Relação Estrutura-Atividade , Moduladores de Tubulina/farmacologia , Moduladores de Tubulina/química , Moduladores de Tubulina/síntese química , Estrutura Molecular , Apoptose/efeitos dos fármacos , Relação Dose-Resposta a Droga , Linhagem Celular Tumoral , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/síntese química , Descoberta de Drogas , Modelos Moleculares
16.
J Drug Target ; : 1-10, 2024 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-39072640

RESUMO

Antibody-drug conjugates (ADCs) have emerged as a novel class of targeted cancer therapies and been successfully applied in the treatment of breast cancer (BC). Discoidin domain receptor 1 (DDR1) is a single transmembrane receptor tyrosine kinase and has been identified as a possible target for cancer. In this study, we explored the potential of an anti-DDR1 ADC, named T4H11-DM4, for the treatment of DDR1-positive BC. We demonstrated that high protein expression and RNA expression of DDR1 in BC tissues. In vitro, T4H11-DM4 was potently cytotoxic to DDR1-expressing BC cells, with IC50 in the nanomolar range. In mice BC xenograft models, T4H11-DM4 dramatically eliminated BC tumours, without observable toxicity. Taken together, our findings demonstrated that DDR1 can serve as a promising therapeutic target for BC.

17.
Environ Int ; 190: 108870, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38972114

RESUMO

OBJECTIVE: Dementia is an important disease burden among the elderly, and its occurrence may be profoundly affected by environmental factors. Evidence of the relationship between air pollution and dementia is emerging, but the extent to which this can be offset by lifestyle factors remains ambiguous. METHODS: This study comprised 155,828 elder adults aged 60 years and above in the UK Biobank who were dementia-free at baseline. Cox proportional hazard models were conducted to examine the associations of annual average levels of air pollutants in 2010, including nitrogen dioxide (NO2), nitrogen oxides (NOX), particulate matter (PM2.5, PM10, and PMcoarse) and lifestyle factors recorded at baseline [physical activity (PA), sleep patterns, or smoking status] with incident risk of dementia, and their interactions on both multiplicative and additive scales. RESULTS: During a 12-year period of follow-up, 4,389 incidents of all-cause dementia were identified. For each standarddeviationincrease in ambient NO2, NOX or PM2.5, all-cause dementia risk increases by 1.07-fold [hazard ratio (HR) and 95 % confidence interval (CI) = 1.07 (1.04, 1.10)], 1.05-fold (95 % CI: 1.02, 1.08) and 1.07-fold (95 % CI: 1.04, 1.10), whereas low levels of PA, poor sleep patterns, and smoking are associated with an elevated risk of dementia [HR (95 % CI) = 1.17 (1.09, 1.26), 1.13 (1.00, 1.27), and 1.14 (1.07, 1.21), respectively]. Furthermore, these air pollutants show joint effects with low PA, poor sleep patterns, and smoking on the onset of dementia. The moderate to high levels of PA could significantly or marginally significantly modify the associations between NO2, NOX or PM2.5 (P-int = 0.067, 0.036, and 0.067, respectively) and Alzheimer's disease (AD), but no significant modification effects are found for sleep patterns or smoking status. CONCLUSION: The increased exposures of NO2, NOX, or PM2.5 are associated with elevated risk of dementia among elderly UK Biobank population. These air pollutants take joint effects with low PA, poor sleep patterns, and smoking on the development of dementia. In addition, moderate to high levels of PA could attenuate the incident risk of AD caused by air pollution. Further prospective researches among other cohort populations are warranted to validate these findings.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , Demência , Exposição Ambiental , Estilo de Vida , Material Particulado , Humanos , Demência/epidemiologia , Demência/induzido quimicamente , Idoso , Poluição do Ar/estatística & dados numéricos , Masculino , Feminino , Reino Unido/epidemiologia , Exposição Ambiental/estatística & dados numéricos , Poluentes Atmosféricos/análise , Estudos Prospectivos , Material Particulado/análise , Pessoa de Meia-Idade , Dióxido de Nitrogênio/análise , Bancos de Espécimes Biológicos , Idoso de 80 Anos ou mais , Incidência , Fatores de Risco , Óxidos de Nitrogênio/análise , Modelos de Riscos Proporcionais , Biobanco do Reino Unido
18.
Int J Biol Macromol ; 277(Pt 1): 134015, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39038566

RESUMO

Nanocellulose has been favored as one of the most promising sustainable nanomaterials, due to its competitive advantages and superior performances such as hydrophilicity, renewability, biodegradability, biocompatibility, tunable surface features, excellent mechanical strength, and high specific surface area. Based on the above properties of nanocellulose and the advantages of hydrogels such as high water absorption, adsorption, porosity and structural adjustability, nanocellulose based hydrogels integrating the benefits of both have attracted extensive attention as promising materials in various fields. In this review, the main fabrication strategies of nanocellulose based hydrogels are initially discussed in terms of different crosslinking methods. Then, the typical properties of nanocellulose based hydrogels are comprehensively summarized, including porous structure, swelling ability, adsorption, mechanical, self-healing, smart response performances. Especially, relying on these properties, the general application of nanocellulose based hydrogels in food field is also discussed, mainly including food packaging, food detection, nutrient embedding delivery, 3D food printing, and enzyme immobilization. Finally, the safety of nanocellulose based hydrogel is summarized, and the current challenges and future perspectives of nanocellulose based hydrogels are put forward.


Assuntos
Celulose , Hidrogéis , Hidrogéis/química , Celulose/química , Nanoestruturas/química , Embalagem de Alimentos , Porosidade , Materiais Biocompatíveis/química , Adsorção
19.
Polymers (Basel) ; 16(14)2024 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-39065329

RESUMO

High-strength concrete (HSC) has a high compressive strength, high density, excellent durability, and seepage resistance, but its deformation ability is weak. Adding fibers can improve the physical and mechanical properties of HSC. Additionally, the HSC structure may face the threat of fire. In the process of fire extinguishing, the damage mechanism of high-temperature-resistant concrete is complicated due to the different contact conditions with water at different locations. Hence, it is essential to conduct pertinent research on the behavior of fiber-reinforced HSC with different cooling methods after high-temperature action. In this paper, polyvinyl alcohol fiber (PVA fiber) was selected to be added into the HSC to carry out high-temperature experimental research, so as to explore the apparent changes, failure pattern, and mass loss rate of the fiber-reinforced HSC using different cooling methods and analyze the influence of its residual compressive strength and flexural strength. The test results suggest that, with the increase in heating temperature, the color of the specimen's surface transitions from dark blue-gray to white, and the quantity of surface cracks on the specimen gradually rises. The mechanical strength gradually decreases as the heating temperature increases. At a consistent heating temperature, the mechanical strength initially rises, and then falls with an increase in fiber content. The maximum compressive strength and flexural strength were achieved at PVA fiber contents of 0.2% and 0.3%, respectively. For different temperatures and fiber contents, the mechanical strength after natural cooling is generally higher than that after immersion cooling. In addition, X-ray polycrystalline diffractometry (XRD) and scanning electron microscopy (SEM) tests were conducted to analyze the compositional alterations and microstructure of the fiber-reinforced HSC following high-temperature exposure, accompanied by an explanation of the factors influencing the alterations in the physical and mechanical properties. Therefore, the findings of this study can serve as a valuable reference for the utilization of HSC in engineering structures and contribute to the advancement of HSC technology.

20.
Data Brief ; 55: 110576, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39006349

RESUMO

HnRNPK, a prominent member of the heterogeneous nuclear ribonucleoprotein (hnRNP) family, is widely expressed in mammalian tissues and plays a crucial role in animal development. Despite its well-established functions, limited information is available regarding its role in skeletal muscle development and regeneration. To elucidate the functional role of hnRNPK in skeletal muscle, we utilized Pax7CreER; HnrnpkLoxP/LoxP (Hnrnpk pKO) mice as a model, isolated primary mouse skeletal muscle satellite cells (MuSCs), and induced hnRNPK knockout using 4-OTH. Transcriptome sequencing was performed on four distinct groups: Hnrnpk pKO MuSCs undergoing proliferation for 24 h (ethanol 24 h) and 48 h (ethanol 48 h) after treatment with ethanol as the control, as well as Hnrnpk pKO MuSCs undergoing proliferation for 24 h (4-OHT 24 h) and 48 h (4-OHT 48 h) after treatment with 4-OHT as the hnRNPK-induced knockout group. The RNA sequencing data was generated using the Illumina HiSeq 2000/2500 sequencing platform. The raw data files have been archived in the Sequence Read Archive at the China National Center for Bioinformation (CNCB) under the accession number CRA015864. This data article is related to the research paper "Deletion of heterogeneous nuclear ribonucleoprotein K in satellite cells leads to inhibited skeletal muscle regeneration in mice, Genes & Diseases 11: 101,062, DOI: 10.1016/j.gendis.2023.06.031".

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