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1.
Oncogene ; 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38858591

RESUMO

Circulating tumor cells (CTCs) play a critical role as initiators in tumor metastasis, which unlocks an irreversible process of cancer progression. Regarding the fluid environment of intravascular CTCs, a comprehensive understanding of the impact of hemodynamic shear stress on CTCs is of profound significance but remains vague. Here, we report a microfluidic circulatory system that can emulate the CTC microenvironment to research the responses of typical liver cancer cells to varying levels of fluid shear stress (FSS). We observe that HepG2 cells surviving FSS exhibit a marked overexpression of TLR4 and TPPP3, which are shown to be associated with the colony formation, migration, and anti-apoptosis abilities of HepG2. Furthermore, overexpression of these two genes in another liver cancer cell line with normally low TLR4 and TPPP3 expression, SK-Hep-1 cells, by lentivirus-mediated transfection also confirms the critical role of TLR4 and TPPP3 in improving colony formation, migration, and survival capability under a fluid environment. Interestingly, in vivo experiments show SK-Hep-1 cells, overexpressed with these genes, have enhanced metastatic potential to the liver and lungs in mouse models via tail vein injection. Mechanistically, TLR4 and TPPP3 upregulated by FSS may increase FSS-mediated cell survival and metastasis through the p53-Bax signaling pathway. Moreover, elevated levels of these genes correlate with poorer overall survival in liver cancer patients, suggesting that our findings could offer new therapeutic strategies for early cancer diagnosis and targeted treatment development.

2.
Opt Express ; 32(12): 21977-21987, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38859538

RESUMO

Quantum teleportation is a building block in quantum computation and quantum communication. The continuous-variable polarization squeezed state is a key resource in quantum networks, offering advantages for long-distance distribution and direct interfacing of quantum nodes. Although polarization squeezed state has been generated and distributed between remote users, it is a long-standing goal to implement controlled quantum teleportation of the polarization squeezed state with multiple remote users. Here, we propose a feasible scheme to teleport a polarization squeezed state among multiple remote users under control. The polarization state is transferred between different remote quantum networks, and the controlled quantum teleportation of the polarization state can be implemented in one quantum network involving multiple remote users. The results show that such a controlled quantum teleportation can be realized with 36 users through about 6-km free-space or fiber quantum channels, where the fidelity of 0.352 is achieved beyond the classical limit of 0.349 with an input squeezing variance of 0.25. This scheme provides a direct reference for the experimental implementation of remote and controlled quantum teleportation of polarization states, thus enabling more teleportation-based quantum network protocols.

3.
Angew Chem Int Ed Engl ; : e202408989, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38837505

RESUMO

The extensive industrial applications of fuel oil, a critical strategic resource, are accompanied by significant environmental and health concerns due to the presence of sulfur-containing compounds in its composition, which result in hazardous combustion waste. Extensive research has been conducted to develop technologies for low-vulcanization fuel production to address this issue. Consequently, the investigation of catalysts for environmentally friendly and safe photocatalytic desulfurization becomes imperative. To that end, we have designed efficient MIL-101(Fe)/CQDs@g-C3N4 (MIL101/CDs-C3N4) Z-scheme heterojunction photocatalysts with high carrier separation and mobility through a thermal polymerization-hydrothermal strategy. The high concentration of photogenerated carriers facilitates the activation of oxygen and H2O2, leading to increased production of ROS (·O2-, ·OH, h+), thereby enhancing the photocatalytic desulfurization (PODS). Additionally, DFT calculations were utilized to determine the electron migration pathways of the catalysts and adsorption energies of DBT (dibenzothiophene). Moreover, Gibbs free energy calculations indicated that MIL101/CDs-C3N4 exhibited the lowest activation energy for oxygen and H2O2. The mechanism of photocatalytic desulfurization was proposed through a combination of theoretical calculations and experimental studies. This study provides guidance for the development of MOF-based Z-scheme systems and their practical application in desulfurization processes.

4.
Adv Sci (Weinh) ; : e2401069, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38874129

RESUMO

In recent decades, research on Extracellular Vesicles (EVs) has gained prominence in the life sciences due to their critical roles in both health and disease states, offering promising applications in disease diagnosis, drug delivery, and therapy. However, their inherent heterogeneity and complex origins pose significant challenges to their preparation, analysis, and subsequent clinical application. This review is structured to provide an overview of the biogenesis, composition, and various sources of EVs, thereby laying the groundwork for a detailed discussion of contemporary techniques for their preparation and analysis. Particular focus is given to state-of-the-art technologies that employ both microfluidic and non-microfluidic platforms for EV processing. Furthermore, this discourse extends into innovative approaches that incorporate artificial intelligence and cutting-edge electrochemical sensors, with a particular emphasis on single EV analysis. This review proposes current challenges and outlines prospective avenues for future research. The objective is to motivate researchers to innovate and expand methods for the preparation and analysis of EVs, fully unlocking their biomedical potential.

5.
Anal Chem ; 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38869321

RESUMO

Herein, we, for the first time, synthesize silver nanoparticles (Ag NPs) within the nanochannels of amino group-functionalized vertically ordered mesoporous silica films (NH2-VMSF) and investigate their coreaction accelerator role in the luminol-dissolved oxygen (O2) electrochemical stripping chemiluminescence (ESCL) system. The synthesized Ag NPs are capable of electrocatalytic reduction of O2 to superoxide radicals, and meanwhile, sliver ions (Ag+) electrochemically stripped from Ag NPs can promote the amount of luminol anion radicals, generating the boosted ECL intensity of the luminol-dissolved O2 system. This proposed Ag NPs@NH2-VMSF on the indium tin oxide electrode was applied to construct the ESCL aptasensor for quantitative determination of prostate-specific antigen (PSA), yielding a low detection limit [0.19 pg/mL (S/N = 3)] and a broad linear dynamic range (1 pg/mL to 100 ng/mL). Furthermore, good analytical performance of PSA in serum with satisfactory recoveries and low relative standard deviation values is achieved by our developed ESCL aptasensor, rendering it a convenient and sensitive method for PSA determination in clinical applications and further broadening the strategy of ESCL techniques.

7.
Sci Rep ; 14(1): 13461, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38862664

RESUMO

Nowadays, what captures consumers' primary attention is how to purchase electric vehicles with long range and desirable price. Lightweight construction stands as one of the most effective approaches for prolonging range and lowering costs. As a consequence, it is particularly imperative to undertake lightweight design optimization for the battery bracket of new energy vehicles by applying 3D printing technology. To actualize this goal, Rhino software was initially employed for 3D modeling to design the battery bracket system for a pure electric vehicle in China. Subsequently, topology optimization design of the battery bracket was carried out by adopting Altair Inspire software. Last but not least, manufacturing and assembly inspection were completed using a 3D printer. The results show that the maximum displacement of the battery lower tray bracket after topology optimization is 3.20 mm, which is slightly higher than before, but still relatively small. The maximum Mises equivalent stress rose to 240.7 MPa post-optimization, but brought about a uniform stress distribution at the bottom of the bracket. In comparison, the minimum factor of safety met design requirements at 1. The mass was lessened to 0.348 kg, representing a 49.2% decrease in comparison with pre-optimization levels. The 3D-printed bracket was fabricated by employing a 3D printer, thereby achieving the aforementioned mass abatement. The battery pack parts exhibited a bright surface with low roughness and no discernible warping or deformation defects. As revealed by the assembly results, the components of the battery pack bracket are tightly coordinated with each other, with no evident assembly conflicts, revealing that the dimensional accuracy and fit of the completed parts meet production requirements. These findings lay solid groundwork for the mass production of high-performance battery pack brackets.

8.
Cell Commun Signal ; 22(1): 318, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38858740

RESUMO

OBJECTIVES: Interleukin 33 (IL-33) is a crucial inflammatory factor that functions as an alarm signal in endometriosis (EMs). Epithelial-mesenchymal transition (EMT), a process related to inflammatory signals, intracellular reactive oxygen species (ROS) production, and lipid peroxidation, have been proposed as potential mechanisms that contribute to the development and progression of EMs. IL-33 is highly upregulated in the ectopic milieu. Moreover, ectopic endometrial cells constitutively express interleukin-33 receptor ST2 (IL-33R). However, the role of IL-33/ST2 in the EMT of EMs remains largely unknown. In this study, we aimed to mechanistically determine the role of IL-33/ST2 in EMs-associated fibrosis. MATERIALS AND METHODS: We established a non-lethal oxidative stress model to explore the conditions that trigger IL-33 induction. We performed α-smooth muscle actin (α-SMA) protein detection, cell counting kit-8 (CCK-8) assays, and scratch assays to analyze the impact of IL-33 on primary endometrial stromal cells (ESCs) proliferation and invasion. Clinical samples from patients with or without EMs were subjected to immunohistochemical (IHC) and and immunofluorescence(IF) staining to assess the clinical relevance of IL-33 receptor ST2 and EMT-related proteins. Furthermore, we used the ectopic human endometrial epithelial cell line 12Z and normal human epithelial cell line EEC to evaluate the effects of IL-33 on Wnt/ß-catenin signaling. The effect of IL-33 on EMT-associated fibrosis was validated in vivo by intraperitoneal injections of IL-33 and antiST2. RESULTS: We observed that ectopic milieu, characterized by ROS, TGF-ß1, and high level of estrogen, triggers the secretion of IL-33 from ectopic ESCs. Ectopic endometrial lesions exhibited higher level of fibrotic characteristics and ST2 expression than that in the normal endometrium. Exogenous recombinant human (rhIL-33) enhanced ESC migration and survival. Similarly, 12Z cells displayed a higher degree of EMT characteristics with elevated expression of CCN4 and Fra-1, downstream target genes of the WNT/ß-catenin pathway, than that observed in EECs. Conversely, blocking IL-33 with neutralizing antibodies, knocking down ST2 or ß-catenin with siRNA, and ß-catenin dephosphorylation abolished its effects on EMT promotion. In vivo validation demonstrated that IL-33 significantly promotes EMs-related fibrosis through the activation of Wnt/ß-catenin signaling. CONCLUSION: Our data strongly support the vital role of the IL-33/ST2 pathway in EMs-associated fibrosis and emphasize the importance of the EMT in the pathophysiology of fibrosis. Targeting the IL-33/ST2/Wnt/ß-catenin axis may hold promise as a feasible therapeutic approach for controlling fibrosis in EMs.


Assuntos
Endometriose , Transição Epitelial-Mesenquimal , Proteína 1 Semelhante a Receptor de Interleucina-1 , Interleucina-33 , beta Catenina , Feminino , Endometriose/metabolismo , Endometriose/patologia , Endometriose/genética , Interleucina-33/metabolismo , Interleucina-33/genética , Transição Epitelial-Mesenquimal/genética , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , beta Catenina/metabolismo , Animais , Fosforilação , Camundongos , Endométrio/patologia , Endométrio/metabolismo , Adulto , Proliferação de Células , Movimento Celular , Transdução de Sinais
9.
Clin Interv Aging ; 19: 779-793, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38751855

RESUMO

Purpose: Long-term care facilities are increasingly challenged with meeting the diverse healthcare needs of the elderly population, particularly concerning medication management. Understanding medication information literacy and behavior among this demographic is imperative. Therefore, this qualitative study aims to explore medication information literacy and develop distinct medication profiles among elderly long-term care residents. Material and Methods: In this study, we conducted in-depth semi-structured interviews with 32 participants aged 65 or older residing in a long-term care facility. The interviews were designed to explore participants' understanding of medication information, medication management practices, and experiences with healthcare providers. Thematic analysis was employed to analyze the interview data, allowing for the identification of common patterns and themes related to medication-taking behavior among the elderly residents. Results: The thematic analysis revealed four distinct medication behavior profiles among the elderly long-term care residents: (1) Proactive Health Self-Managers, (2) Medication Information Adherents, (3) Experience-Based Medication Users, and (4) Nonadherent Medication Users. These findings provide valuable insights into the diverse approaches to medication management within long-term care facilities and underscore the importance of tailored interventions to support the specific needs of each profile. Conclusion: This study highlights the necessity for tailored medication education and support to optimize medication management for the elderly. With the aging population expansion, addressing the unique medication challenges within long-term care facilities becomes increasingly critical. This research contributes to ongoing endeavors to enhance healthcare services for the elderly, striving for safer and more effective medication-taking behavior.


Assuntos
Assistência de Longa Duração , Adesão à Medicação , Pesquisa Qualitativa , Humanos , Idoso , Masculino , Feminino , Idoso de 80 Anos ou mais , Letramento em Saúde , Entrevistas como Assunto , Casas de Saúde , Competência em Informação , Conhecimentos, Atitudes e Prática em Saúde
10.
J Hazard Mater ; 474: 134692, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38810575

RESUMO

Long-term changes in dry deposition fluxes (DDF) and health risks for toxic elements (TE) in total suspended particles (TSP) in the Bohai Rim region are important for assessing control effects of pollution sources. Thus, we investigated the trends in DDF and concentrations for TSP and TE and health risks of TE in eight cities in the region from 2011-2020. TSP concentration and DDF showed general downward trends. Compared to the before Clear Air Action Plan (BCAAP, 2011-2012) period, concentration and DDF of TE over the Clear Air Action Plan (CAAP, 2013-2017) period substantially decreased, with the highest decrease rates in Zn, Cd, and Cr. During the study period, non-carcinogenic (HI) and total carcinogenic (TCR) risks for children and adults were 0.09 and 0.04, and 1.54 × 10-5 and 2.65 × 10-5, respectively, with Cr6+ and As being dominant contributors. Compared to the BCAAP period, HI and TCR over the CAAP period decreased by 36.8 % and 32.4 %, respectively. However, their risks increased over the Blue Sky Protection Campaign (BSPC, 2018-2020) period. Potential source contribution function suggested substantial changes in potential risk areas over different control periods, with the BSPC primarily being on land and the Yellow Sea.

12.
Chemistry ; : e202303861, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38751155

RESUMO

The Guerbet reaction is important for the synthesis of longer-chain monoalcohols like isobutanol through catalytic transfer hydrogenation from short-chain methanol and ethanol. However, the mechanism becomes complicated, especially considering the variations in the different metal-ligand cooperation (MLC) catalysts used. In order to further understand the Guerbet reaction, DFT studies were performed to figure out the detailed mechanism initiated by the unique Mn-PCP MLC Catalyst. Our results suggest that even with the assistance of the carbanion site of the PCP ligand, the direct substitution mechanism is less favored than the condensation-reduction mechanism. The key step of the reaction is the final reduction of the carbonyl, in which the 1,4-reduction of the unsaturated aldehyde is prior to the 3,4-reduction or 1,2-reduction due to the stronger interaction between the catalyst and the substrate. It is found that the production of isobutanol is preferred over n-butanol because of the lower total free energy barrier and lower relative free energy of the product. Finally, by changing the electronic effect of the carbanion site of the catalyst, we found that the relation between the electronic effect and the highest free energy span was not monotonous and a point with optimal electronic effect exists numerically.

13.
FASEB J ; 38(10): e23651, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38752537

RESUMO

Singleton-Merten syndrome (SMS) is a rare immunogenetic disorder affecting multiple systems, characterized by dental dysplasia, aortic calcification, glaucoma, skeletal abnormalities, and psoriasis. Glaucoma, a key feature of both classical and atypical SMS, remains poorly understood in terms of its molecular mechanism caused by DDX58 mutation. This study presented a novel DDX58 variant (c.1649A>C [p.Asp550Ala]) in a family with childhood glaucoma. Functional analysis showed that DDX58 variant caused an increase in IFN-stimulated gene expression and high IFN-ß-based type-I IFN. As the trabecular meshwork (TM) is responsible for controlling intraocular pressure (IOP), we examine the effect of IFN-ß on TM cells. Our study is the first to demonstrate that IFN-ß significantly reduced TM cell viability and function by activating autophagy. In addition, anterior chamber injection of IFN-ß remarkably increased IOP level in mice, which can be attenuated by treatments with autophagy inhibitor chloroquine. To uncover the specific mechanism underlying IFN-ß-induced autophagy in TM cells, we performed microarray analysis in IFN-ß-treated and DDX58 p.Asp550Ala TM cells. It showed that RSAD2 is necessary for IFN-ß-induced autophagy. Knockdown of RSAD2 by siRNA significantly decreased autophagy flux induced by IFN-ß. Our findings suggest that DDX58 mutation leads to the overproduction of IFN-ß, which elevates IOP by modulating autophagy through RSAD2 in TM cells.


Assuntos
Autofagia , Interferon beta , Pressão Intraocular , Malha Trabecular , Autofagia/efeitos dos fármacos , Malha Trabecular/metabolismo , Malha Trabecular/efeitos dos fármacos , Humanos , Animais , Camundongos , Pressão Intraocular/fisiologia , Interferon beta/metabolismo , Masculino , Feminino , Glaucoma/patologia , Glaucoma/metabolismo , Glaucoma/genética , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/patologia , Perda Auditiva Neurossensorial/metabolismo , Proteína DEAD-box 58/metabolismo , Proteína DEAD-box 58/genética , Camundongos Endogâmicos C57BL , Mutação , Atrofia Óptica/genética , Atrofia Óptica/metabolismo , Atrofia Óptica/patologia , Linhagem , Odontodisplasia , Calcificação Vascular , Hipoplasia do Esmalte Dentário , Metacarpo/anormalidades , Osteoporose , Doenças Musculares , Doenças da Aorta , Receptores Imunológicos
14.
Bioorg Chem ; 148: 107433, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38754311

RESUMO

Second-generation AR antagonists, such as enzalutamide, are the primary therapeutic agents for advanced prostate cancer. However, the development of both primary and secondary drug resistance leads to treatment failures and patient mortality. Bifunctional agents that simultaneously antagonize and degrade AR block the AR signaling pathway more completely and exhibit excellent antiproliferative activity against wild-type and drug-resistant prostate cancer cells. Here, we reported the discovery and optimization of a series of biphenyl derivatives as androgen receptor antagonists and degraders. These biphenyl derivatives exhibited potent antiproliferative activity against LNCaP and 22Rv1 cells. Our discoveries enrich the diversity of small molecule AR degraders and offer insights for the development of novel AR degraders for the treatment of enzalutamide-resistant prostate cancer.


Assuntos
Antagonistas de Receptores de Andrógenos , Antineoplásicos , Benzamidas , Compostos de Bifenilo , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Nitrilas , Feniltioidantoína , Neoplasias da Próstata , Receptores Androgênicos , Humanos , Masculino , Benzamidas/farmacologia , Benzamidas/química , Benzamidas/síntese química , Nitrilas/química , Nitrilas/farmacologia , Feniltioidantoína/farmacologia , Feniltioidantoína/análogos & derivados , Feniltioidantoína/química , Compostos de Bifenilo/farmacologia , Compostos de Bifenilo/antagonistas & inibidores , Receptores Androgênicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Estrutura Molecular , Antagonistas de Receptores de Andrógenos/farmacologia , Antagonistas de Receptores de Andrógenos/química , Antagonistas de Receptores de Andrógenos/síntese química , Antagonistas de Receptores de Andrógenos/uso terapêutico , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Relação Dose-Resposta a Droga , Linhagem Celular Tumoral
15.
Life Sci ; 349: 122718, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38754815

RESUMO

Chronic obstructive pulmonary disease (COPD) is projected to become the third leading cause of death globally by 2030. Despite the limited treatment options available for advanced COPD, which are mostly restricted to costly lung transplants, physical ablation therapy offers promising alternatives. This technique focuses on ablating lesioned airway epithelium, reducing secretions and obstructions, and promoting normal epithelial regeneration, demonstrating significant therapeutic potential. Physical ablation therapy primarily involves thermal steam ablation, cryoablation, targeted lung denervation, and high-voltage pulsed electric field ablation. These methods help transform the hypersecretory phenotype, alleviate airway inflammation, and decrease the volume of emphysematous lung segments by targeting goblet cells and damaged lung areas. Compared to traditional treatments, endoscopic physical ablation offers fewer injuries, quicker recovery, and enhanced safety. However, its application in COPD remains limited due to inconsistent clinical outcomes, a lack of well-understood mechanisms, and the absence of standardized guidelines. This review begins by exploring the development of these ablation techniques and their current clinical uses in COPD treatment. It then delves into the therapeutic effects reported in recent clinical studies and discusses the underlying mechanisms. Finally, the review assesses the future prospects and challenges of employing ablation technology in COPD clinical practice, aiming to provide a practical reference and a theoretical basis for its use and inspire further research.


Assuntos
Técnicas de Ablação , Doença Pulmonar Obstrutiva Crônica , Doença Pulmonar Obstrutiva Crônica/terapia , Doença Pulmonar Obstrutiva Crônica/cirurgia , Humanos , Técnicas de Ablação/métodos , Pulmão , Animais
16.
Adv Sci (Weinh) ; : e2400011, 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38698560

RESUMO

DNA is commonly employed as a substrate for the building of artificial logic networks due to its excellent biocompatibility and programmability. Till now, DNA logic circuits are rapidly evolving to accomplish advanced operations. Nonetheless, nowadays, most DNA circuits remain to be disposable and lack of field programmability and thereby limits their practicability. Herein, inspired by the Configurable Logic Block (CLB), the CLB-based erasable field-programmable DNA circuit that uses clip strands as its operation-controlling signals is presented. It enables users to realize diverse functions with limited hardware. CLB-based basic logic gates (OR and AND) are first constructed and demonstrated their erasability and field programmability. Furthermore, by adding the appropriate operation-controlling strands, multiple rounds of programming are achieved among five different logic operations on a two-layer circuit. Subsequently, a circuit is successfully built to implement two fundamental binary calculators: half-adder and half-subtractor, proving that the design can imitate silicon-based binary circuits. Finally, a comprehensive CLB-based circuit is built that enables multiple rounds of switch among seven different logic operations including half-adding and half-subtracting. Overall, the CLB-based erasable field-programmable circuit immensely enhances their practicability. It is believed that design can be widely used in DNA logic networks due to its efficiency and convenience.

17.
Chem Sci ; 15(18): 6853-6859, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38725489

RESUMO

The accumulation and deposition of amyloid fibrils, also known as amyloidosis, in tissues and organs of patients has been found to be linked to numerous devastating neurodegenerative diseases. The aggregation of proteins to form amyloid fibrils, however, is a slow pathogenic process, and is a major issue for the evaluation of the effectiveness of inhibitors in new drug discovery and screening. Here, we used microdroplet reaction technology to accelerate the amyloid fibrillation process, monitored the process to shed light on the fundamental mechanism of amyloid self-assembly, and demonstrated the value of the technology in the rapid screening of potential inhibitor drugs. Proteins in microdroplets accelerated to form fibrils in milliseconds, enabling an entire cycle of inhibitor screening for Aß40 within 3 minutes. The technology would be of broad interest to drug discovery and therapeutic design to develop treatments for diseases associated with protein aggregation and fibrillation.

18.
ACS Appl Mater Interfaces ; 16(17): 21438-21449, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38626407

RESUMO

Thrombolytic therapy is one of the most effective treatments for thrombus dissolution and recanalization of blocked vessels in thrombotic diseases. However, the application of the thrombolytic strategy has been limited due to unsatisfactory thrombolytic efficacy, relatively higher bleeding complications, and consequently restricted indications. Recombinant staphylokinase (r-SAK) is a third-generation thrombolytic agent produced by genetic engineering technology, which exhibits a better thrombolytic efficacy than urokinase and recombinant streptokinase. Inspired by the natural affinity of platelets in hemostasis and pathological thrombosis, we developed a platelet membrane (PM)-coated r-SAK (PM-r-SAK). Results from animal experiments and human in vitro studies showed that the PM-r-SAK had a thrombolytic efficacy equal to or better than its 4-fold dose of r-SAK. In a totally occluded rabbit femoral artery thrombosis model, the PM-r-SAK significantly shortened the initial recanalization time compared to the same dose and 4-fold dose of r-SAK. Regarding the recanalized vessels, the PM-r-SAK prolonged the time of reperfusion compared to the same dose and 4-fold dose of r-SAK, though the differences were not significant. An in vitro thrombolytic experiment demonstrated that the thrombolytic efficacy of PM-r-SAK could be inhibited by platelet-poor plasma from patients taking aspirin and ticagrelor. PM coating significantly improves the thrombolytic efficacy of r-SAK, which is related to the thrombus-targeting activity of the PM-r-SAK and can be inhibited by aspirin- and ticagrelor-treated plasma.


Assuntos
Plaquetas , Fibrinolíticos , Metaloendopeptidases , Trombose , Animais , Coelhos , Humanos , Trombose/tratamento farmacológico , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Fibrinolíticos/química , Fibrinolíticos/uso terapêutico , Fibrinolíticos/farmacologia , Metaloendopeptidases/metabolismo , Terapia Trombolítica , Proteínas Recombinantes/uso terapêutico , Masculino , Membrana Celular/metabolismo , Membrana Celular/efeitos dos fármacos
19.
Small Methods ; : e2400426, 2024 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-38678531

RESUMO

Extracellular vesicles (EVs), crucial in facilitating the transport of diverse molecular cargoes for intercellular communication, have shown great potential in diagnostics, therapeutics, and drug delivery. The challenge of developing effective preparation methods for EVs is heightened by their intrinsic heterogeneity and complexity. Here, a novel strategy for high EV enrichment is developed by utilizing EV-affinitive-modified cellulose nanofibrils. Specifically, modified cellulose with rich carboxyl groups has outstanding dispersing properties, able to be dispersed into cellulose nanofibrils in solution. These cellulose nanofibrils are utilized as scaffolds for the immobilization of EV-affinitive antibody of CD63 by chemical conjugation. The CD63-modified nanofibrils demonstrate a superior EV capture efficiency of 86.4% compared with other reported methods. The high performance of this system is further validated by the efficient capture of EVs from biological blood plasma, allowing the detection of bioactive markers from EV-derived miRNAs and proteins. The authors envision that these modified cellulose nanofibrils of enhanced capability on EV enrichment will open new avenues in various biomedical applications.

20.
Nat Methods ; 21(6): 1023-1032, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38664529

RESUMO

Addressing interfacial effects during specimen preparation in cryogenic electron microscopy remains challenging. Here we introduce ESI-cryoPrep, a specimen preparation method based on electrospray ionization in native mass spectrometry, designed to alleviate issues associated with protein denaturation or preferred orientation induced by macromolecule adsorption at interfaces. Through fine-tuning spraying parameters, we optimized protein integrity preservation and achieved the desired ice thickness for analyzing target macromolecules. With ESI-cryoPrep, we prepared high-quality cryo-specimens of five proteins and obtained three-dimensional reconstructions at near-atomic resolution. Our findings demonstrate that ESI-cryoPrep effectively confines macromolecules within the middle of the thin layer of amorphous ice, facilitating the preparation of blotting-free vitreous samples. The protective mechanism, characterized by the uneven distribution of charged biomolecules of varying sizes within charged droplets, prevents the adsorption of target biomolecules at air-water or graphene-water interfaces, thereby avoiding structural damage to the protein particles or the introduction of dominant orientation issues.


Assuntos
Microscopia Crioeletrônica , Manejo de Espécimes , Espectrometria de Massas por Ionização por Electrospray , Microscopia Crioeletrônica/métodos , Manejo de Espécimes/métodos , Espectrometria de Massas por Ionização por Electrospray/métodos , Proteínas/química , Humanos , Substâncias Macromoleculares/química
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