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1.
Nanoscale ; 2024 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-39292163

RESUMO

Emergent ferromagnetism in ß-Ga2O3 with an ultra-wide bandwidth and high electrical breakdown strength offers exciting opportunities for fabricating robust spintronic devices. One pertinent obstacle in the material has been the low saturation magnetization, which precludes its practical application in magnetic devices. In this work, large-scale Fe-doped ß-Ga2O3 diluted magnetic semiconductor (DMS) films are synthesized using a polymer-assisted deposition method, and the effect of Fe doping on their structural and magnetic properties is investigated. Remarkably, the optimal sample exhibits a high saturation magnetization (70 emu cm-3 at 300 K), much larger than those in previously reported stable oxide DMS films, as well as a low coercivity (12 Oe at 300 K). Further analysis shows that our samples manifest a typical bound magnetic polaron (BMP) model and the high saturation magnetization originates from the strong ferromagnetic coupling between the BMPs which is enhanced by Ga vacancies. The Fe-doped ß-Ga2O3 thin films with high saturation magnetization and low coercivity may provide a promising platform for related semiconductor spintronics.

2.
J Nanobiotechnology ; 22(1): 522, 2024 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-39215337

RESUMO

Titanium alloys represent the prevailing material employed in orthopedic implants, which are present in millions of patients worldwide. The prolonged presence of these implants in the human body has raised concerns about possible health effects. This study presents a comprehensive analysis of titanium implants and surrounding tissue samples obtained from patients who underwent revision surgery for therapeutic reasons. The surface of the implants exhibited nano-scale corrosion defects, and nanoparticles were deposited in adjacent samples. In addition, muscle in close proximity to the implant showed clear evidence of fibrotic proliferation, with titanium content in the muscle tissue increasing the closer it was to the implant. Transcriptomics analysis revealed SNAI2 upregulation and activation of PI3K/AKT signaling. In vivo rodent and zebrafish models validated that titanium implant or nanoparticles exposure provoked collagen deposition and disorganized muscle structure. Snai2 knockdown significantly reduced implant-associated fibrosis in both rodent and zebrafish models. Cellular experiments demonstrated that titanium dioxide nanoparticles (TiO2 NPs) induced fibrotic gene expression at sub-cytotoxic doses, whereas Snai2 knockdown significantly reduced TiO2 NPs-induced fibrotic gene expression. The in vivo and in vitro experiments collectively demonstrated that Snai2 plays a pivotal role in mediating titanium-induced fibrosis. Overall, these findings indicate a significant release of titanium nanoparticles from the implants into the surrounding tissues, resulting in muscular fibrosis, partially through Snai2-dependent signaling.


Assuntos
Fibrose , Fatores de Transcrição da Família Snail , Titânio , Peixe-Zebra , Titânio/química , Animais , Fatores de Transcrição da Família Snail/metabolismo , Fatores de Transcrição da Família Snail/genética , Humanos , Próteses e Implantes , Masculino , Transdução de Sinais/efeitos dos fármacos , Nanopartículas Metálicas/química , Músculo Esquelético/metabolismo , Músculo Esquelético/efeitos dos fármacos , Ratos , Camundongos
3.
Sci Total Environ ; 951: 175711, 2024 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-39181255

RESUMO

The widespread utilization of plastic and cobalt alloy products in industries and medicine has led to the increased presence of their degradation byproducts, microplastics (MPs), and cobalt nanoparticles (Co NPs), in the environment and organisms. While these particles can circulate throughout the body via the circulatory system, their specific adverse effects and mechanisms on the vascular system remain unclear. Employing scanning electron microscope (SEM) analysis and other methodologies, we demonstrate the potential adsorption and aggregation phenomena between MPs and Co NPs. In vitro experiments illustrate that ingestion of either MPs or Co NPs compromises vascular endothelial cell function and induces the generation of reactive oxygen species (ROS). Notably, this effect is markedly attenuated when a combination of MPs and Co NPs is administered compared to MPs alone. Additionally, zebrafish experiments validate our in vitro findings. Mechanistic studies have demonstrated that both MPs and Co NPs induce aberrant Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling. Intriguingly, a weaker activation level is observed when these agents are administered in combination compared to when they are administered individually. Our study provides novel insights into the interaction between MPs and Co NPs and their detrimental effects on vascular endothelial cells.


Assuntos
Cobalto , Nanopartículas Metálicas , Microplásticos , Fator 2 Relacionado a NF-E2 , Peixe-Zebra , Fator 2 Relacionado a NF-E2/metabolismo , Cobalto/toxicidade , Animais , Nanopartículas Metálicas/toxicidade , Microplásticos/toxicidade , Transdução de Sinais/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Poluentes Químicos da Água/toxicidade
4.
Adv Mater ; 36(40): e2405943, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39155588

RESUMO

Osteoarthritis (OA) is a degenerative bone and joint disease characterized by decreased cartilage lubrication, leading to continuous wear and ultimately irreversible damage. This situation is particularly challenging for early-stage OA, as current bio-lubricants lack precise targeting for small inflammatory lesions. In this work, an antibody-mediated targeting hydrogel microspheres (HMS) is developed to precisely lubricate the local injury site of cartilage and prevent the progression of early OA. Anti-Collagen type I (Anti-Col1) is an antibody that targets cartilage injury sites in early OA stages. It is anchored on a HMS matrix made of Gelatin methacrylate (GelMA) and poly (sulfobetaine methacrylate) (PSBMA) to create targeted HMS (T-G/S HMS). The T-G/S HMS's high hydrophilicity, along with the dynamic interaction between its surficial Anti-Col1 and the Col1 on cartilage injury site, ensures its precise and effective lubrication of early OA lesions. Consequently, injecting T-G/S HMS into rats with early OA significantly slows disease progression and reduces symptoms. In conclusion, the developed injectable targeted lubricating HMS and the precisely targeted lubrication strategy represent a promising, convenient technique for treating OA, particularly for slowing the early-stage OA progression.


Assuntos
Cartilagem Articular , Hidrogéis , Microesferas , Osteoartrite , Animais , Hidrogéis/química , Ratos , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/patologia , Cartilagem Articular/metabolismo , Osteoartrite/tratamento farmacológico , Osteoartrite/patologia , Lubrificação , Colágeno Tipo I/metabolismo , Metacrilatos/química , Ratos Sprague-Dawley
5.
Phytochemistry ; 226: 114219, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38997098

RESUMO

Eight previously undescribed sesquiterpene lactones (1-8), together with six known ones (9-14) were isolated from the aerial parts of Tithonia diversifolia (Hemsl.) A. Gray. The absolute configurations of these compounds were elucidated using HRMS, NMR spectroscopy, optical rotation measurements, X-ray crystallography, and ECD. Among them, sesquiterpene lactones 2-4 share a unique carbon skeleton with a rare C-3/C-4 ring-opened structure. Compounds 1 and 8 showed moderate inhibitory effects toward CT26 murine colon carcinoma cells by promoting lipid ROS production, highlighting their potential as ferroptosis inducers.


Assuntos
Antineoplásicos Fitogênicos , Asteraceae , Ferroptose , Lactonas , Sesquiterpenos , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Sesquiterpenos/isolamento & purificação , Lactonas/química , Lactonas/farmacologia , Lactonas/isolamento & purificação , Ferroptose/efeitos dos fármacos , Animais , Camundongos , Asteraceae/química , Estrutura Molecular , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Ensaios de Seleção de Medicamentos Antitumorais , Relação Estrutura-Atividade , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Proliferação de Células/efeitos dos fármacos , Componentes Aéreos da Planta/química , Espécies Reativas de Oxigênio/metabolismo
6.
Nanomaterials (Basel) ; 14(13)2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38998744

RESUMO

Since single-layer graphene [...].

7.
Anal Methods ; 16(24): 3895-3906, 2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38828983

RESUMO

The pollutant o-aminophenol (o-AP) presents considerable risk to environmental safety, and its detection is therefore critical. Although various optical and electrochemical methods have been proposed for the detection of o-AP, there are a limited number of detection methods based on photoelectrochemical (PEC) sensors. In this study, a sensitive visible-light-driven PEC sensor was developed for o-AP detection in water. A conjugated microporous polymer (CMP)-coated graphene heterostructure (CMP-rGO) was synthesized and used to develop a PEC sensor. Under optimal conditions, the proposed sensor exhibited a high sensitivity of 0.03 µM with a wide linear range of 0.0034-37.6 µM. The PEC sensor also displayed acceptable repeatability and reproducibility, good long-term stability, and excellent recovery (98-102%). In addition, the binding patterns of CMP to o-AP and o-AP analog molecules were analyzed by molecular docking. Therefore, this study provides a new and feasible PEC sensor-based detection scheme for o-AP detection.

8.
Nanoscale ; 16(26): 12670-12679, 2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-38888799

RESUMO

BiOCl has attracted much attention due to its robust layered structure, excellent photocatalytic activity and nontoxicity. However, its practical application is hindered by its narrowband UV photoresponse and rapid recombination of photocarriers. Herein, zero-dimensional Bi-anchoring carbon quantum dot (Bi-CD)/two-dimensional BiOCl heterojunction (Bi-CD/BiOCl) photocatalysts are designed and synthesized by a facile hydrothermal method. Under 190-1100 nm broadband light irradiation, the optimized Bi-CD/BiOCl sample exhibits a superb rhodamine B (RhB) degradation rate of nearly 100%, which is 2.3 (1.7) times that of pristine BiOCl (CD/BiOCl). Additionally, the optimized sample exhibits an RhB degradation rate of up to 88.1% even under direct outdoor light and robust durability in water solution. Experimental results combined with DFT calculations reveal that the superior photocatalytic activity arises from the synergetic effects of broader light absorption due to the incorporation of CD, extra hot electron excitation by the localized surface plasmon resonance (LSPR) effect of metallic Bi, and enhanced electron transfer across the heterojunction interface as well as the existence of more oxygen vacancy traps in BiOCl. This work gives insights into the structure and photocatalytic properties of Bi-CD/BiOCl and provides a new strategy for the design and fabrication of robust high-performance photocatalysts under wide spectrum light irradiation.

9.
Antioxidants (Basel) ; 13(4)2024 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-38671878

RESUMO

Iron overload-associated osteoporosis presents a significant challenge to bone health. This study examines the effects of arecoline (ACL), an alkaloid found in areca nut, on bone metabolism under iron overload conditions induced by ferric ammonium citrate (FAC) treatment. The results indicate that ACL mitigates the FAC-induced inhibition of osteogenesis in zebrafish larvae, as demonstrated by increased skeletal mineralization and upregulation of osteogenic genes. ACL attenuates FAC-mediated suppression of osteoblast differentiation and mineralization in MC3T3-E1 cells. RNA sequencing analysis suggests that the protective effects of ACL are related to the regulation of ferroptosis. We demonstrate that ACL inhibits ferroptosis, including oxidative stress, lipid peroxidation, mitochondrial damage, and cell death under FAC exposure. In this study, we have identified heme oxygenase-1 (HO-1) as a critical mediator of ACL inhibiting ferroptosis and promoting osteogenesis, which was validated by HO-1 knockdown and knockout experiments. The study links ACL to HO-1 activation and ferroptosis regulation in the context of bone metabolism. These findings provide new insights into the mechanisms underlying the modulation of osteogenesis by ACL. Targeting the HO-1/ferroptosis axis is a promising therapeutic approach for treating iron overload-induced bone diseases.

10.
Front Plant Sci ; 15: 1344972, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38425798

RESUMO

Over the past several decades, a decreasing trend in solar radiation has been observed during the wheat growing season. The effects of shade stress on grain yield formation have been extensively studied. However, little information on shade stress's effects on protein formation warrants further investigation. Two wheat cultivars were grown under three treatments, no shade as the control group (CK), shading from the joint to the anthesis stage (S1), and shading from the joint to the mature stage (S2), to investigate the effects of shade stress on the free amino acids of the caryopsis and endosperm and protein accumulation during grain filling. The dry mass of caryopsis and endosperm was significantly decreased under shade stress, whereas Glu, Ser, Ala, and Asp and protein relative content increased during grain filling. The observed increases in total protein in S1 and S2 were attributed to the increases in the SDS-isoluble and SDS-soluble protein extracts, respectively. S1 improved polymer protein formation, but S2 delayed the conversion of albumins and globulins into monomeric and polymeric proteins. Moreover, shade stress increased the proportion of SDS-unextractable polymeric protein, which represented an increase in the degree of protein polymerization. The polymerization of protein interrelations between protein components and accumulation in caryopsis and endosperm provided novel insights into wheat quality formation under shade stress.

11.
Food Chem ; 444: 138667, 2024 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-38335686

RESUMO

Iron-copper nanozymes (Fe-Cu NZs) with good peroxidase activity were prepared through hydrothermal method by using copper nitrate as copper source, iron acetate as iron source and 2, 5-dihydroxyterephthalic acid as organic ligand. Upon oxidation of the colourless TMB to light blue products by Fe-Cu NZs, the addition of Norfloxacin (NOR) resulted in a colour change to dark blue. The absorbance of the system correlated linearly with NOR concentration in the range of 3.3 µM to 66 µM, and the detection limit (LOD) was 0.386 µM. A rapid colourimetric assay for the determination of NOR in food matrices was developed, with a detection time of only one minute. Additionally, the assay facilitated the simultaneous catalytic degradation of NOR via Fe-Cu NZs. The primary degradation mechanism of NOR was identified as the transformation of the quinolone ring and the cleavage of the C9 = C10 double bond, which was substantiated by high-performance liquid chromatography (HPLC).


Assuntos
Norfloxacino , Quinolonas , Ferro/química , Cobre/química , Antioxidantes , Colorimetria/métodos , Peróxido de Hidrogênio
12.
Anal Methods ; 16(7): 1012-1020, 2024 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-38304962

RESUMO

Isoniazid is a first-line drug used to treat tuberculosis. However, its excessive use can lead to serious adverse effects. Thus, strict monitoring of the isoniazid levels in medications and human systems is required. In this study, a new polymer (AlPc-TB POP) containing a metal phthalocyanine and Tröger's base was synthesized and explored as an electrocatalyst for the oxidation of isoniazid. The results indicated that the polymer is an excellent electron-transfer medium for isoniazid oxidation. The AlPc-TB POP-based sensor quantified isoniazid in the linear range of 0.1-130 µM, with a detection limit of 0.0185 µM. The response of the developed sensor to isoniazid was reproducible and stable. Furthermore, this method can accurately determine isoniazid levels by ignoring the influence of common interfering species in tablets and biological samples. This study contributes to the development of nitrogen-rich porous organic polymers and offers a novel strategy for addressing challenges in disease therapeutic efficacy and public safety monitoring.


Assuntos
Indóis , Isoindóis , Isoniazida , Compostos Organometálicos , Polímeros , Humanos , Alumínio , Antituberculosos/uso terapêutico
13.
Nanomaterials (Basel) ; 14(3)2024 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-38334583

RESUMO

Recently, it has been reported that the skyrmion Hall effect can be suppressed in an elliptical skyrmion-based device. Given that defects are unavoidable in materials, it is necessary and important to investigate the dynamics of an elliptical skyrmion in a defective racetrack device. In this work, the current-driven dynamics of an elliptical skyrmion in a defective racetrack device are systematically studied using micromagnetic simulations. The system energy analysis reveals that the magnetic parameters of the circular defect play critical roles in determining the type (repulsive or attractive) and the magnitude of the force on the elliptical skyrmion. The simulated trajectories show that the primary motion modes of the elliptical skyrmion in the defective racetrack can be divided into four types, which are dependent on the values of the Dzyaloshinskii-Moriya interaction (DMI) constant Dd, the perpendicular magnetic anisotropy constant Kd, the magnitude of the driving current density J, and the size d of the defect. Further investigation of the motion-mode phases of the skyrmion reveals the synthetic effects of Dd, Kd, J, and d. Finally, the minimum depinning current density J, which linearly depends on the parameters of Dd and Kd, is obtained for a skyrmion completely pinned in the defect. Our findings give insights into the dynamics of an elliptical skyrmion in the presence of a defect with different magnetic parameters in a racetrack device and may be useful for performance enhancement of skyrmion-based racetrack memory devices.

14.
Toxics ; 12(2)2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38393225

RESUMO

Cobalt alloys have numerous applications, especially as critical components in orthopedic biomedical implants. However, recent investigations have revealed potential hazards associated with the release of nanoparticles from cobalt-based implants during implantation. This can lead to their accumulation and migration within the body, resulting in adverse reactions such as organ toxicity. Despite being a primary interface for cobalt nanoparticle (CoNP) exposure, skeletal muscle lacks comprehensive long-term impact studies. This study evaluated whether selenium nanoparticles (SeNPs) could mitigate CoNP toxicity in muscle cells and zebrafish models. CoNPs dose-dependently reduced C2C12 viability while elevating reactive oxygen species (ROS) and apoptosis. However, low-dose SeNPs attenuated these adverse effects. CoNPs downregulated myogenic genes and α-smooth muscle actin (α-SMA) expression in C2C12 cells; this effect was attenuated by SeNP cotreatment. Zebrafish studies confirmed CoNP toxicity, as it decreased locomotor performance while inducing muscle injury, ROS generation, malformations, and mortality. However, SeNPs alleviated these detrimental effects. Overall, SeNPs mitigated CoNP-mediated cytotoxicity in muscle cells and tissue through antioxidative and antiapoptotic mechanisms. This suggests that SeNP-coated implants could be developed to eliminate cobalt nanoparticle toxicity and enhance the safety of metallic implants.

15.
Nanoscale ; 16(9): 4866-4871, 2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38315558

RESUMO

Owing to its stable graphene-like honeycomb structure, suitable band gap, and nontoxicity, SnC monolayer (ML) has attracted increasing attention in photocatalytic applications. One pertinent obstacle inherent to SnC ML-based photocatalysts has been the high energy barrier in hydrogen evolution reaction (HER) that always requires external energy input and/or strongly acidic conditions. Herein, we propose a two-dimensional (2D) SnC/ZrS2 van der Waals heterostructure (vdWHS) for highly efficient photocatalytic water splitting using first-principles calculations. The results show that the pristine vdWHS is an S-scheme heterostructure that works in acidic conditions for water splitting owing to the high energy barrier in HER. Notably, detailed further investigations show that doping Si in the SnC ML of the vdWHS can solve this high barrier problem, leading to a high-performance low-cost photocatalyst. Our work offers a convenient strategy to solve the notorious high barrier problem in HER that often troubles the SnC ML and other 2D materials such as transition metal dichalcogenide MLs for the design and fabrication of highly efficient photocatalysts.

16.
Int J Ophthalmol ; 17(1): 188-200, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38239939

RESUMO

AIM: To summarize the application of deep learning in detecting ophthalmic disease with ultrawide-field fundus images and analyze the advantages, limitations, and possible solutions common to all tasks. METHODS: We searched three academic databases, including PubMed, Web of Science, and Ovid, with the date of August 2022. We matched and screened according to the target keywords and publication year and retrieved a total of 4358 research papers according to the keywords, of which 23 studies were retrieved on applying deep learning in diagnosing ophthalmic disease with ultrawide-field images. RESULTS: Deep learning in ultrawide-field images can detect various ophthalmic diseases and achieve great performance, including diabetic retinopathy, glaucoma, age-related macular degeneration, retinal vein occlusions, retinal detachment, and other peripheral retinal diseases. Compared to fundus images, the ultrawide-field fundus scanning laser ophthalmoscopy enables the capture of the ocular fundus up to 200° in a single exposure, which can observe more areas of the retina. CONCLUSION: The combination of ultrawide-field fundus images and artificial intelligence will achieve great performance in diagnosing multiple ophthalmic diseases in the future.

17.
Nanotechnology ; 35(17)2024 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-38241719

RESUMO

Fe-doped SiGe bulk alloys are fabricated using non-equilibrium spark plasma sintering (SPS) and their structure and ferromagnetic and magneto-transport properties are investigated. X-ray diffraction and high-resolution transmission electron microscope measurements show that the obtained alloys are composed of SiGe polycrystals. Magnetization measurements reveal that the Fe-doped SiGe alloys exhibit ferromagnetism up to 259 K, and their Curie temperature increases with Fe doping concentration up to 8%. Moreover, transport measurements of the Fe-doped SiGe alloys show typical metal-insulator transition characteristics of doped semiconductors as well as anomalous Hall effect and intriguing positive-to-negative magnetoresistance, indicating that the obtained alloys are diluted magnetic semiconductors (DMSs). Our results provide insight into the SPS-prepared Fe-doped SiGe bulk alloys and may be useful for the design, fabrication, and application of group-IV DMSs.

18.
Phytochemistry ; 219: 113962, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38185394

RESUMO

Thirteen previously undescribed iridoids (1-13), together with five known iridoids (14-18) were isolated from the roots and rhizomes of Valeriana jatamansi Jones. Their structures with absolute configurations were elucidated by analysis of MS, NMR, optical rotation and their experimental and calculated electronic circular dichroism spectra. All of the isolated compounds were tested for their protective effects against α-hemolysin-induced cell death in A549 cells. Compounds 14, 16 and 17 showed moderate protective effects, and compounds 15 and 18 showed weak protective effects.


Assuntos
Nardostachys , Valeriana , Rizoma , Valeriana/química , Proteínas Hemolisinas/análise , Estrutura Molecular , Iridoides/farmacologia , Iridoides/química , Raízes de Plantas/química
19.
Fitoterapia ; 174: 105840, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38296167

RESUMO

The phytochemical investigation of the aerial parts of Isodon japonica var. glaucocalyx afforded four undescribed (glaucocalyxin O-R, 1-4) and six known ent-kauranoids (5-10). Their structures were established using NMR and MS measurements. Compounds 1 and 2 are dimeric ent-kaurane-type diterpenoids. Moreover, the plausible biogenetic pathways for compounds 1 and 2 were proposed as Michael addition between two monomers. Eight compounds were assayed for their anti-inflammatory activity by evaluating NO production in LPS-induced RAW 267.4 cells, and compounds 7, 8 and 9 exhibited relatively remarkable anti-inflammatory activities at 10 µM.


Assuntos
Antineoplásicos Fitogênicos , Diterpenos do Tipo Caurano , Diterpenos , Isodon , Isodon/química , Estrutura Molecular , Diterpenos do Tipo Caurano/farmacologia , Diterpenos do Tipo Caurano/química , Diterpenos/química , Anti-Inflamatórios/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais
20.
Cancer Lett ; 583: 216635, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38237887

RESUMO

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer (BC) with a high mortality rate, and few effective therapeutic strategies are available. CCL5/CCR5 is an appealing immunotherapeutic target for TNBC. However, its signaling mechanism is poorly understood and its direct antagonists have not been reported. Here, we developed a high-throughput screening (HTS) assay for discovering its antagonists. Verteporfin was identified as a more selective and potent antagonist than the known CCR5 antagonist maraviroc. Without photodynamic therapy, verteporfin demonstrated significant inhibition on TNBC tumor growth through immune regulation, remarkable suppression of lung metastasis by cell-intrinsic mechanism, and a significant extension of overall survival in vivo. Mechanistically, CCR5 was found to be essential for expression of the key hippo effector YAP1. It promoted YAP1 transcription via HIF-1α and exerted further control over the migration of CD8+ T, NK, and MDSC immune cells through chemokines CXCL16 and CXCL8 which were identified from RNA-seq. Moreover, the CCR5-YAP1 axis played a vital role in promoting metastasis by modulating ß-catenin and core epithelial-mesenchymal transition transcription factors ZEB1 and ZEB2. It is noteworthy that the regulatory relationship between CCR5 and YAP1 was observed across various BC subtypes, TNBC patients, and showed potential relevance in fifteen additional cancer types. Overall, this study introduced an easy-to-use HTS assay that streamlines the discovery of CCL5/CCR5 axis antagonists. Verteporfin was identified as a specific molecular probe of this axis with great potentials as a therapeutic agent for treating sixteen malignant diseases characterized by heightened CCR5 and YAP1 levels.


Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/patologia , Verteporfina/farmacologia , Quimiocina CCL5 , Transdução de Sinais , Maraviroc/farmacologia , Linhagem Celular Tumoral , Movimento Celular , Receptores CCR5/metabolismo
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