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Covalent drug discovery has experienced a renaissance, with numerous electrophilic small molecules recently gaining FDA approval. Many structurally diverse electrophilic small molecules target exportin-1 (XPO1/CRM1) at cysteine 528, including the selective inhibitor of nuclear export (SINE) selinexor, which was FDA-approved as an anticancer agent in 2019. Emerging evidence supports additional pharmacological classes of XPO1 modulators targeting Cys528, including the selective inhibitors of transcriptional activation (SITAs) and probes that induce rapid degradation of XPO1. Here, we analyzed structure-activity relationships across multiple structural series of XPO1 Cys528-targeting probes. We observe that the electrophilic moiety of Cys528-targeting small molecules plays a decisive role in the cellular behavior observed, with subtle changes in electrophile structure being sufficient to convert XPO1-targeting probes to different pharmacological classes. This investigation represents a unique case study in which the electrophile functionality used to target a specific cysteine determines the pharmacological effect among diverse XPO1-targeting small molecules.
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Proteína Exportina 1 , Carioferinas , Receptores Citoplasmáticos e Nucleares , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Carioferinas/antagonistas & inibidores , Carioferinas/metabolismo , Humanos , Relação Estrutura-Atividade , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Fenótipo , Cisteína/química , Cisteína/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Hidrazinas/farmacologia , Hidrazinas/química , Hidrazinas/síntese química , Triazóis/farmacologia , Triazóis/química , Triazóis/síntese química , Estrutura MolecularRESUMO
Hierarchical polymer structures have garnered widespread application across various fields owing to their distinct surface properties and expansive surface areas. Conventional hierarchical polymer structures, however, often lack postfabrication scalability and spatial selectivity. In this study, we propose a novel strategy to prepare light-assisted hierarchical polymer structures using azopolymers (PAzo), the breath figure method, and anodic aluminum oxide (AAO) templates. Initially, the breath figure PAzo films are prepared by dripping a PAzo chloroform solution onto glass substrates in a high-humidity environment. The AAO templates are then placed on the breath figure PAzo film. Upon ultraviolet (UV) light exposure, the azobenzene groups in the azopolymers undergo trans-cis photoisomerization. This process causes the glass transition temperature (Tg) of the PAzo to become lower than room temperature, allowing the azopolymer to enter the nanopores of the AAO templates. The hierarchical azopolymer structures are then formed by using a sodium hydroxide solution to remove the templates. Furthermore, exploring the effects of PAzo concentration and UV light exposure duration on the film morphology reveals optimized conditions for hierarchical structure formation. Additionally, the water contact angles of these polymer structures are measured. The hierarchical PAzo structures exhibit higher hydrophobicity compared with the flat PAzo films and the PAzo breath figure films. Finally, patterned breath figure films can be prepared using designed photomasks, demonstrating the method's capability for spatial selectivity.
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Exosomes are extracellular vesicles generated by all cells and they carry nucleic acids, proteins, lipids, and metabolites. They mediate the exchange of substances between cells,thereby affecting biological properties and activities of recipient cells. In this review, we briefly discuss the composition of exocomes and exosome isolation. We also review the clinical applications of exosomes in cancer biology as well as strategies in exosome-mediated targeted drug delivery systems. Finally, the application of exosomes in the context of cancer therapeutics both in practice and literature are discussed.
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Exossomos , Neoplasias , Exossomos/metabolismo , Humanos , Neoplasias/terapia , Sistemas de Liberação de Medicamentos/métodos , Ensaios Clínicos como AssuntoRESUMO
Molecular glues can induce proximity between a target protein and ubiquitin ligases to induce target degradation, but strategies for their discovery remain limited. We screened 3,200 bioactive small molecules and identified that C646 requires neddylation-dependent protein degradation to induce cytotoxicity. Although the histone acetyltransferase p300 is the canonical target of C646, we provide extensive evidence that C646 directly targets and degrades Exportin-1 (XPO1). Multiple cellular phenotypes induced by C646 were abrogated in cells expressing the known XPO1C528S drug-resistance allele. While XPO1 catalyzes nuclear-to-cytoplasmic transport of many cargo proteins, it also directly binds chromatin. We demonstrate that p300 and XPO1 co-occupy hundreds of chromatin loci. Degrading XPO1 using C646 or the known XPO1 modulator S109 diminishes the chromatin occupancy of both XPO1 and p300, enabling direct targeting of XPO1 to phenocopy p300 inhibition. This work highlights the utility of drug-resistant alleles and further validates XPO1 as a targetable regulator of chromatin state.
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Cromatina , Proteína p300 Associada a E1A , Proteína Exportina 1 , Carioferinas , Receptores Citoplasmáticos e Nucleares , Humanos , Cromatina/metabolismo , Proteína p300 Associada a E1A/metabolismo , Carioferinas/metabolismo , Carioferinas/antagonistas & inibidores , Proteólise/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/metabolismoRESUMO
Cryptococcus neoformans (C. neoformans) is a pathogenic fungus that can cause life-threatening meningitis, particularly in individuals with compromised immune systems. The current standard treatment involves the combination of amphotericin B and azole drugs, but this regimen often leads to inevitable toxicity in patients. Therefore, there is an urgent need to develop new antifungal drugs with improved safety profiles. We screened antimicrobial peptides from the hemolymph transcriptome of Blaps rhynchopetera (B. rhynchopetera), a folk Chinese medicine. We found an antimicrobial peptide named blap-6 that exhibited potent activity against bacteria and fungi. Blap-6 is composed of 17 amino acids (KRCRFRIYRWGFPRRRF), and it has excellent antifungal activity against C. neoformans, with a minimum inhibitory concentration (MIC) of 0.81 µM. Blap-6 exhibits strong antifungal kinetic characteristics. Mechanistic studies revealed that blap-6 exerts its antifungal activity by penetrating and disrupting the integrity of the fungal cell membrane. In addition to its direct antifungal effect, blap-6 showed strong biofilm inhibition and scavenging activity. Notably, the peptide exhibited low hemolytic and cytotoxicity to human cells and may be a potential candidate antimicrobial drug for fungal infection caused by C. neoformans.
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Antifúngicos , Peptídeos Antimicrobianos , Besouros , Cryptococcus neoformans , Testes de Sensibilidade Microbiana , Cryptococcus neoformans/efeitos dos fármacos , Animais , Antifúngicos/farmacologia , Antifúngicos/química , Besouros/microbiologia , Besouros/efeitos dos fármacos , Peptídeos Antimicrobianos/farmacologia , Peptídeos Antimicrobianos/química , Humanos , Biofilmes/efeitos dos fármacos , Sequência de AminoácidosRESUMO
The decrease in eggshell quality seriously affects production efficiency. Guinea fowl (GF) eggs possess strong eggshells because of their unique crystal structure, and few systematic studies have compared laying hen and GF eggs. Sixty eggs were collected from both 40-week-old Dwarf Layer-White (DWL-White) laying hens and GF, and the eggshell quality, ultrastructure, bubble pores, and composition were measured. The results showed that the DWL-White eggs had a higher egg weight and a lower eggshell strength, strength per unit weight, thickness, and ratio than the GF eggs (p < 0.01). There were differences in the mammillary layer thickness ratio, the effective layer thickness ratio, the quantity of bubble pores (QBPs), the ratio of the sum of the area of bubble pores to the area of the eggshell in each image (ARBE), and the average area of bubble pores (AABPs) between the DWL-White and GF eggs (p < 0.01). The composition analysis demonstrated that there were differences in the organic matter, inorganic matter, calcium, and phosphorus between the DWL-White and GF eggs (p < 0.01). There were positive associations between the mammillary knob number in the image and the QBPs and ARBE and a negative correlation with the AABPs in the DWL-White eggs (p < 0.01). This study observed distinctions that offer new insights into enhancing eggshell quality.
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While polymer fabrics are integral to a wide range of applications, their vulnerability to mechanical damage limits their sustainability and practicality. Addressing this challenge, our study introduces a versatile strategy to develop photohealable fabrics, utilizing a composite of polystyrene (PS) and an azobenzene-containing polymer (PAzo). This combination leverages the structural stability of PS to compensate for the mechanical weaknesses of PAzo, forming the fiber structures. Key to our approach is the reversible trans-cis photoisomerization of azobenzene groups within the PAzo under UV light exposure, enabling controlled morphological alterations in the PS/PAzo blend fibers. The transition of PAzo sections from a solid to a liquid state at a low glass transition temperature (Tg â¼ 13.7 °C) is followed by solidification under visible light, thus stabilizing the altered fiber structures. In this study, we explore various PS/PAzo blend ratios to optimize surface roughness and mechanical properties. Additionally, we demonstrate the capability of these fibers for photoinduced self-healing. When damaged fabrics are clamped and subjected to UV irradiation for 20 min and pressed for 24 h, the mobility of the cis-form PAzo sections facilitates healing while retaining the overall fabric structure. This innovative approach not only addresses the critical issue of durability in polymer fabrics but also offers a sustainable and practical solution, paving the way for its application in smart clothing and advanced fabric-based materials.
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BACKGROUND: Cathepsin S (CTSS) is a cysteine protease that played diverse roles in immunity, tumor metastasis, aging and other pathological alterations. At the cellular level, increased CTSS levels have been associated with the secretion of pro-inflammatory cytokines and disrupted the homeostasis of Ca2+ flux. Once CTSS was suppressed, elevated levels of anti-inflammatory cytokines and changes of Ca2+ influx were observed. These findings have inspired us to explore the potential role of CTSS on cognitive functions. METHODS: We conducted classic Y-maze and Barnes Maze tests to assess the spatial and working memory of Ctss-/- mice, Ctss+/+ mice and Ctss+/+ mice injected with the CTSS inhibitor (RJW-58). Ex vivo analyses including long-term potentiation (LTP), Golgi staining, immunofluorescence staining of sectioned whole brain tissues obtained from experimental animals were conducted. Furthermore, molecular studies were carried out using cultured HT-22 cell line and primary cortical neurons that treated with RJW-58 to comprehensively assess the gene and protein expressions. RESULTS: Our findings reported that targeting cathepsin S (CTSS) yields improvements in cognitive function, enhancing both working and spatial memory in behavior models. Ex vivo studies showed elevated levels of long-term potentiation levels and increased synaptic complexity. Microarray analysis demonstrated that brain-derived neurotrophic factor (BDNF) was upregulated when CTSS was knocked down by using siRNA. Moreover, the pharmacological blockade of the CTSS enzymatic activity promoted BDNF expression in a dose- and time-dependent manner. Notably, the inhibition of CTSS was associated with increased neurogenesis in the murine dentate gyrus. These results suggested a promising role of CTSS modulation in cognitive enhancement and neurogenesis. CONCLUSION: Our findings suggest a critical role of CTSS in the regulation of cognitive function by modulating the Ca2+ influx, leading to enhanced activation of the BDNF/TrkB axis. Our study may provide a novel strategy for improving cognitive function by targeting CTSS.
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Fator Neurotrófico Derivado do Encéfalo , Catepsinas , Cognição , Animais , Masculino , Camundongos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Catepsinas/efeitos dos fármacos , Catepsinas/genética , Catepsinas/metabolismo , Cognição/efeitos dos fármacos , Cognição/fisiologia , Camundongos Knockout , Receptor trkB/metabolismo , Receptor trkB/genética , Transativadores/genética , Transativadores/metabolismoRESUMO
Follicular atresia in chickens reduces the number of follicles that can further develop, leading to decrease egg laying. Endoplasmic reticulum stress (ERS) can initiate a unique pathway inducing the apoptosis of follicular granulosa cells, thus reducing egg laying. Melatonin (MEL) is involved in the regulation of follicle development, ovulation, and oocyte maturation, and is closely related to follicle fate. Mammalian target of Rapamycin (mTOR) signaling pathway plays an important role in cell growth regulation, and that there is a possible crosstalk between melatonin and mTOR activity in granular cells maturation and ovulation. This study aimed to investigate whether MEL inhibits ERS and follicular granulosa cell apoptosis by regulating ATF4 to activate mTOR signaling pathway in chickens. Frist, we established an in vitro ERS cell model using tunicamycin (TM). The results showed that different concentrations of TM exhibited dose-dependent inhibition of cell activity and induction of granulosa cells (P<0.01). Therefore, we chose 5 µg/mL of TM and a treatment time for 6 h as the optimal concentration for the following experiments. Then we investigate whether melatonin can inhibit ERS. TM treatment decreased the cell viability and Bcl-2 expression, increasing ROS levels and the mRNA expression of Grp78, ATF4, CHOP, PERK, eIF-2α, and BAX (P<0.01), whereas TM+MEL treatment significantly inhibited these changes (P<0.01). Then we explored whether melatonin protects follicular granulosa cells from ERS-induced apoptosis through the mammalian target of rapamycin (mTOR) signaling pathway by regulating ATF4, we found that ATF4 knockdown inhibited ERS by decreasing the expression of ERS-related genes and proteins and activating mTOR signaling pathway by increasing the protein expression of p4E-BP1 and pT389-S6K (P<0.001), while these changes were promoted by TM+si-ATF4+MEL treatment (P<0.01). These results indicate that MEL could alleviate TM-induced ERS by regulating ATF4 to activate mTOR signaling pathway in follicular granulosa cells, thus providing a new perspective for prolonging the laying cycle in chickens.
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Fator 4 Ativador da Transcrição , Apoptose , Proteínas Aviárias , Galinhas , Estresse do Retículo Endoplasmático , Células da Granulosa , Melatonina , Transdução de Sinais , Serina-Treonina Quinases TOR , Animais , Melatonina/farmacologia , Feminino , Galinhas/fisiologia , Células da Granulosa/efeitos dos fármacos , Células da Granulosa/fisiologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/genética , Fator 4 Ativador da Transcrição/metabolismo , Fator 4 Ativador da Transcrição/genética , Proteínas Aviárias/metabolismo , Proteínas Aviárias/genética , Tunicamicina/farmacologiaRESUMO
Granular cell apoptosis is a key factor leading to follicular atresia and decreased laying rate in aged laying hens. Endoplasmic reticulum stress (ERS) induced cell apoptosis is a new type of apoptosis pathway. Previous studies have shown that the ERS pathway is involved in the regulation of follicular development and atresia, and can be regulated by mTOR. Melatonin (MEL) can protect the normal development of follicles, but the precise mechanism by which MEL regulates follicular development is not yet clear. So, we investigated the potential relationship between MEL and ERS and mTOR signaling pathway in vivo through intraperitoneal injection of MEL in aged laying hens. The results show that the laying rate, ovarian follicle number, plasma MEL, E2, LH, FSH concentrations, as well as the mRNA expression of mTOR signaling-associated genes TSC1, TSC2, mTOR, 4E-BP1, and S6K in old later-period chicken control (Old-CN) group was significantly decreased (P < 0.01). In contrast, the ERS-related of plasma and granular cell layer mRNA expression of Grp78, CHOP, and Caspase-3 was significantly increased (P < 0.01). While both of the effects were reversed by MEL. Then, aging granulosa cells were treated with MEL in vitro, followed by RNA seq analysis, and it was found that 259 and 322 genes were upregulated and downregulated. After performing GO enrichment analysis, it was found that DEGs significantly contribute to the biological processes including cell growth and apoptosis. Using pathway enrichment analysis, we found significant overrepresentation of cellular processes related to mTOR signaling and endoplasmic reticulum (ER) stress, involving genes such as GRB10, SGK1, PRKCA, RPS6KA2, RAF1, PIK3R3, FOXO1, DERL3, HMOX1, TLR7, VAMP7 and INSIG2. The obtained results of RT-PCR showed consistency with the RNA-Seq data. In summary, the underlined results revealed that MEL has significantly contributed to follicular development via activating the mTOR signaling pathway-related genes and alleviating ERS-related genes in laying hens. The current study provides a theoretical background for enhancing the egg-laying capability of hens and also providing a basis for elucidating the molecular mechanism of follicular selection.
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Galinhas , Estresse do Retículo Endoplasmático , Melatonina , Transdução de Sinais , Serina-Treonina Quinases TOR , Animais , Feminino , Melatonina/farmacologia , Melatonina/administração & dosagem , Galinhas/fisiologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/genética , Transdução de Sinais/efeitos dos fármacos , Proteínas Aviárias/metabolismo , Proteínas Aviárias/genética , Ovário/efeitos dos fármacos , Ovário/fisiologia , Envelhecimento , Células da Granulosa/efeitos dos fármacos , Células da Granulosa/fisiologiaRESUMO
Exportin-1 (XPO1/CRM1) plays a central role in the nuclear-to-cytoplasmic transport of hundreds of proteins and contributes to other cellular processes, such as centrosome duplication. Small molecules targeting XPO1 induce cytotoxicity, and selinexor was approved by the Food and Drug Administration in 2019 as a cancer chemotherapy for relapsed multiple myeloma. Here, we describe a cell-type-dependent chromatin-binding function for XPO1 that is essential for the chromatin occupancy of NFAT transcription factors and thus the appropriate activation of T cells. Additionally, we establish a class of XPO1-targeting small molecules capable of disrupting the chromatin binding of XPO1 without perturbing nuclear export or inducing cytotoxicity. This work defines a broad transcription regulatory role for XPO1 that is essential for T cell activation as well as a new class of XPO1 modulators to enable therapeutic targeting of XPO1 beyond oncology including in T cell-driven autoimmune disorders.
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OBJECTIVE: We have previously shown that neutrophil extracellular traps (NETs) are present on the ocular surface of patients with ocular graft versus host disease (oGVHD), contributing to inflammation and surface disease. Therefore, we performed a clinical trial using deoxyribonuclease I (DNAase) eye drops to test the hypothesis that reducing the abundance of NETs from the ocular surface will reduce signs and symptoms of oGVHD. METHODS: A prospective, phase I or II, randomized, placebo-controlled, double-masked clinical trial was performed to determine the safety and preliminary efficacy of DNAase (0.1%) eye drops four times daily for 8 weeks in patients with oGVHD (n=58). Intent-to-treat analysis was performed to determine the change in safety outcome measures (drug tolerability and proportion of adverse events) and efficacy outcome measures (ocular surface disease index [OSDI] score and corneal staining) between baseline and week 8. RESULTS: Tolerability and adverse events were similar in the vehicle and DNAase groups. Within the DNAase group (but not the vehicle group), corneal staining showed a statistically significant and clinically meaningful reduction at week 8 (3.50 [2.75; 5.00]) compared with baseline (5.00 [3.00; 7.00]). The OSDI score also showed a statistically significant clinically meaningful reduction of 18.4 (9.16; 33.1) ( P <0.001) at week 8 compared with baseline (45.5 [31.8; 50.0]) within the DNAase group. The proportion of eyes that had improvement in subjective global assessment (SGA) and mucous discharge was significantly greater in the DNAase group (55.6% and 57.7% at weeks 4 and 8, respectively; P <0.0001 at both time points) as compared with the vehicle group (35.7% and 34.0% at weeks 4 and 8, respectively). CONCLUSIONS: Treatment of patients with oGVHD using DNAase eye drops is safe and demonstrates preliminary efficacy. Deoxyribonuclease I eye drops can potentially reduce the severity of signs and symptoms of ocular surface disease in patients with oGVHD.
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Desoxirribonuclease I , Doença Enxerto-Hospedeiro , Soluções Oftálmicas , Humanos , Desoxirribonuclease I/uso terapêutico , Desoxirribonuclease I/administração & dosagem , Masculino , Método Duplo-Cego , Feminino , Adulto , Pessoa de Meia-Idade , Estudos Prospectivos , Doença Enxerto-Hospedeiro/tratamento farmacológico , Adulto Jovem , Idoso , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Armadilhas Extracelulares/efeitos dos fármacos , Resultado do Tratamento , AdolescenteRESUMO
BACKGROUND: Black women experience a higher prevalence of poor asthma outcomes and physical inactivity than their White counterparts. Black women comprise a particularly vulnerable group of patients with asthma, with some of the highest rates of asthma in adults, high health care use (emergency department visits and hospitalizations), and the highest crude asthma mortality rate of all race or ethnicity groups. Despite recommendations to engage in regular physical activity, fewer than 15% of Black women meet the 2008 National Physical Activity Guidelines, the lowest of all racial subgroups of adults. Given the connection between physical inactivity and poor asthma outcomes, addressing physical activity among Black women with asthma is imperative. OBJECTIVE: This 2-arm randomized controlled trial aims to (1) determine the efficacy of a lifestyle walking intervention on asthma control compared to an education (control) group over 24 weeks, (2) examine the maintenance effects of the lifestyle walking intervention on asthma control at 48 weeks, (3) explore the behavioral mediators (eg, self-efficacy, social support, self-regulation, and daily physical activity levels) and contextual moderators (eg, baseline asthma severity, neighborhood environment, comorbid conditions, and social determinants of health) that contribute to treatment responsiveness, and (4) assess the reach and implementation potential of the intervention. METHODS: The proposed study (ACTION [A Lifestyle Physical Activity Intervention for Minority Women with Asthma]) delivers a 24-week lifestyle walking intervention designed for and by urban Black women with asthma. Participants (n=224) will be recruited through 2 urban health care systems that care for a diverse Black population. Patients will be randomized to one of two groups: (1) ACTION intervention (group sessions, physical activity self-monitoring-Fitbit, and text-based support for step goal setting) or (2) education control (an individual asthma education session and SMS text messages related to asthma education). Outcome assessments will take place at baseline, 12, 24, and 48 weeks. The primary outcome is a change in asthma control from baseline to week 24 as assessed by the asthma control questionnaire-6 (ACQ-6). Secondary outcomes include asthma-related quality of life, health care use, and asthma exacerbations and behavioral outcomes such as self-efficacy, self-regulation, social support, and physical activity. RESULTS: This study was funded by the National Institute of Minority Health Disparities in August 2022. We pilot-tested our recruitment and intervention procedures and began recruitment in April 2023, with the enrollment of our first participant in May 2023. The anticipated completion of the study is April 2027. CONCLUSIONS: This study will deliver a new approach to physical activity interventions in Black women with asthma and help to provide guidance for addressing physical activity within this subgroup. This study will also provide a potential framework for future studies in minoritized populations with other disease conditions associated with low levels of physical activity. TRIAL REGISTRATION: ClinicalTrials.gov NCT05726487; https://clinicaltrials.gov/study/NCT05726487. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/55700.
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In recent years, hafnium oxide (HfO2) has gained increasing interest because of its high dielectric constant, excellent thermal stability, and high band gap. Although HfO2 bulk and film materials have been prepared and well-studied, HfO2 fibers, especially hollow fibers, have been less investigated. In this study, we present a facile preparation method for HfO2 hollow fibers through a unique integration of the sol-gel process and electrospinning technique. Initially, polystyrene (PS) fibers are fabricated by using electrospinning, followed by dipping in a HfO2 precursor solution, resulting in HfO2-coated PS fibers. Subsequent thermal treatment at 800 °C ensures the selective pyrolysis of the PS fibers and complete condensation of the HfO2 precursors, forming HfO2 hollow fibers. Scanning electron microscopy (SEM) characterizations reveal HfO2 hollow fibers with rough surfaces and diminished diameters, a transformation attributed to the removal of the PS fibers and the condensation of the HfO2 precursors. Our study also delves into the influence of precursor solution molar ratios, showcasing the ability to achieve smaller HfO2 fiber diameters with reduced precursor quantities. Validation of the material composition is achieved through thermogravimetric analysis (TGA) and energy-dispersive spectroscopy (EDS) mapping. Additionally, X-ray diffraction (XRD) analysis provides insights into the crystallinity of the HfO2 hollow fibers, highlighting a higher crystallinity in fibers annealed at 800 °C compared with those treated at 400 °C. Notably, the HfO2 hollow fibers demonstrate a water contact angle (WCA) of 38.70 ± 5.24°, underscoring the transformation from hydrophobic to hydrophilic properties after the removal of the PS fibers. Looking forward, this work paves the way for extensive research on the surface properties and potential applications of HfO2 hollow fibers in areas such as filtration, energy storage, and memory devices.
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Stimuli-responsive ion nanochannels have attracted considerable attention in various fields because of their remote controllability of ionic transportation. For photoresponsive ion nanochannels, however, achieving precise regulation of ion conductivity is still challenging, primarily due to the difficulty of programmable structural changes in confined environments. Moreover, the relationship between noncontact photo-stimulation in nanoscale and light-induced ion conductivity has not been well understood. In this work, a versatile design for fabricating guard cell-inspired photoswitchable ion channels is presented by infiltrating azobenzene-cross-linked polymer (AAZO-PDAC) into nanoporous anodic aluminum oxide (AAO) membranes. The azobenzene-cross-linked polymer is formed by azobenzene chromophore (AAZO)-cross-linked poly(diallyldimethylammonium chloride) (PDAC) with electrostatic interactions. Under UV irradiation, the trans-AAZO isomerizes to the cis-AAZO, causing the volume compression of the polymer network, whereas, in darkness, the cis-AAZO reverts to the trans-AAZO, leading to the recovery of the structure. Consequently, the resultant nanopore sizes can be manipulated by the photomechanical effect of the AAZO-PDAC polymers. By adding ionic liquids, the ion conductivity of the light-driven ion nanochannels can be controlled with good repeatability and fast responses (within seconds) in multiple cycles. The ion channels have promising potential in the applications of biomimetic materials, sensors, and biomedical sciences.
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Radiation-induced gastrointestinal damage is a common acute radiation syndrome. Previous studies have highlighted that Galectin-1 and Interleukin-6 (IL-6) are associated with flaking of small intestinal villi and intestinal radioresistance. Therefore, our goal is to study whether gut bacteria regulated by galectin-1 or IL-6 can mitigate radiation-induced small intestine damage. In this study, differences between galectin-1, sgp130-regulated and wild-type (WT) mice were analyzed by microbiome array. The effects of the Firmicutes/Bacteroidetes (F/B) ratio and the proportion of bacterial distribution at the phylum level were observed after 18 Gy whole abdomen radiation. Fecal microbiota transplantation was used to implant radioresistant gut flora into WT mice, and the number of viable small intestinal crypt foci was observed by immunohistochemistry. Fecal transplantation from galectin-1 knockout and sgp130 transgenic mice, with higher radiation resistance, into WT mice significantly increased the number of surviving small intestinal crypts. This radiation resistance, generated through gene regulation, was not affected by the F/B ratio. We initially found that the small intestinal villi of WT mice receiving radioresistant mouse fecal bacteria demonstrated better repair outcomes after radiation exposure. These results indicate the need for a focus on the identification and application of superior radioresistant bacterial strains. In our laboratory, we will further investigate specific radioresistant bacterial strains to alleviate acute side effects of radiation therapy to improve the patients' immune ability and postoperative quality of life.
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Galectina 1 , Microbioma Gastrointestinal , Humanos , Camundongos , Animais , Galectina 1/farmacologia , Interleucina-6/farmacologia , Receptor gp130 de Citocina , Qualidade de Vida , Intestino DelgadoRESUMO
In this work, a series of novel coumarin-based derivatives were designed and synthesized as tubulin polymerization inhibitors targeting the colchicine binding site, and their antiproliferative activities against MGC-803, HCT-116 and KYSE30 cells were evaluated. Among them, the compound I-3 (MY-1442) bearing a 6-methoxy-1,2,3,4-tetrahydroquinoline group exhibited most potent inhibitory activities on MGC-803 (IC50 = 0.034 µM), HCT-116 (IC50 = 0.081 µM) and KYSE30 cells (IC50 = 0.19 µM). Further mechanism studies demonstrated that compound I-3 (MY-1442) could directly bind to the colchicine binding site of ß-tubulin to inhibit tubulin polymerization and microtubules at the cellular level. The results of molecular docking indicated there were well binding interactions between compound I-3 (MY-1442) and the colchicine binding site of ß-tubulin. Compound I-3 (MY-1442) also exhibited effective anti-proliferation, pro-apoptosis, and anti-migration abilities against gastric cancer cells MGC-803. Additionally, compound I-3 (MY-1442) could regulate the expression of cell cycle- and apoptosis-related proteins. Importantly, compound I-3 (MY-1442) could significantly inhibit tumor growth in the MGC-803 xenograft tumor model with a TGI rate of 65.5 % at 30 mg/kg/day. Taken together, this work suggested that the coumarin skeleton exhibited great potential to be a key pharmacophore of tubulin polymerization inhibitors for the discovery of anticancer agents.
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Antineoplásicos , Neoplasias Gástricas , Humanos , Colchicina/farmacologia , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/química , Simulação de Acoplamento Molecular , Neoplasias Gástricas/tratamento farmacológico , Polimerização , Proliferação de Células , Sítios de Ligação , Cumarínicos/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Ensaios de Seleção de Medicamentos AntitumoraisRESUMO
Purpose: The purpose of this study was to evaluate the feasibility of radiofrequency ablation (RFA) for thyroid nodules with cytological atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS, Bethesda III). Materials and methods: A total of 28 adults presenting with 30 initial Bethesda III nodules underwent thyroid RFA at a single medical center. Thyroid nodules with Bethesda IV or V according to the second aspiration were excluded. All RFA procedures were performed using the free-hand, 'moving-shot' technique under local anesthesia. Clinical features and demographics, RFA details, nodule volume reduction rate (VRR), and complications were analyzed. Results: The mean age of patients was 47.6 years, 82.1% of whom were females. Mean nodule volumes at pre-RFA, and at 6 months and 12 months post-RFA were 7.92, 2.42, and 1.25 mL, respectively, with a VRR of 77.9% at 6 months, and 87.4% at 12 months. Post-RFA complications were noted in two patients, one with transient vocal cord palsy and another with isthmus minor rupture. Conclusion: RFA may be another safe alternative except for active surveillance or surgical excision for AUS/FLUS nodules with low-suspicion Thyroid Imaging Reporting and Data System features for patients who are unsuitable or strongly refuse surgery. Long-term results remain uncertain, thus further follow-up study is necessary.
Assuntos
Ablação por Radiofrequência , Neoplasias da Glândula Tireoide , Nódulo da Glândula Tireoide , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Masculino , Nódulo da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/patologia , Seguimentos , Biópsia por Agulha Fina/métodosRESUMO
OBJECTIVE: To investigate the clinical and immunological features of primary Sjögren's syndrome (pSS) patients with positive anti-centromere protein B (CENP-B) antibody. METHODS: In this cross-sectional study, the general clinical data, radiographic examination and labial salivary gland biopsy data, and serum immunological and biochemical data of patients diagnosed with pSS from January 2016 to August 2022 were evaluated. The included patients were divided into the anti-CENP-B antibody positive and negative groups. Intergroup differences were analyzed with SPSS 23.0 software. Subgroup analysis was further performed by dividing the anti-CENP-B antibody positive group into the single anti-CENP-B antibody positive and with other auto-antibodies positive groups to determine the characters related to anti-CENP-B antibody. RESULTS: In this study, 288 patients with pSS were evaluated, including 75 patients with anti-CENP-B antibody positive and 213 with anti-CENP-B antibody negative. Univariate analysis showed that compared with the anti-CENP-B antibody negative group, the patients of the anti-CENP-B antibody positive group were older, had lower proportion of the patients with salivary gland enlargement and higher proportion of autoimmune liver disease. As for immunological indicators, the positive proportions of anti-SSA/Ro60, anti-Ro52, and anti-SSB antibodies were significantly lower. Moreover, the immunoglobulin (Ig) G and rheumatoid factor levels were significantly lower, while the IgM level was significantly higher in the patients of the anti-CENP-B antibody positive group. As for serum biochemical indicators, for the patients of the anti-CENP-B antibody positive group, the level of total protein (TP) was lower, the albumin/globulin ratio was higher, and the levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), lactate dehydrogenase (LDH) were higher. Subgroup analysis showed that the levels of TP and IgA in the patients of the single anti-CENP-B antibody positive group were significantly lower than those of the patients with other autoantibodies positive group. CONCLUSION: The pSS patients with anti-CENP-B antibody positive have unique clinical and immunological features of lower disease activity, less likely to involve salivary gland, higher risk for autoimmune liver disease, and higher levels of liver function indicators. Anti-CENP-B antibody may be a marker for a distinct subset of polyautoimmunity in Sjögren's syndrome.
Assuntos
Hepatopatias , Síndrome de Sjogren , Humanos , Estudos Transversais , Anticorpos Antinucleares , AutoanticorposRESUMO
Purpose: The purpose of this study was to evaluate the feasibility of radiofrequency ablation (RFA) for thyroid nodules with cytological atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS, Bethesda III). Materials and methods: A total of 28 adults presenting with 30 initial Bethesda III nodules underwent thyroid RFA at a single medical center. Thyroid nodules with Bethesda IV or V according to the second aspiration were excluded. All RFA procedures were performed using the free-hand, 'moving-shot' technique under local anesthesia. Clinical features and demographics, RFA details, nodule volume reduction rate (VRR), and complications were analyzed. Results: The mean age of patients was 47.6 years, 82.1% of whom were females. Mean nodule volumes at pre-RFA, and at 6 months and 12 months post-RFA were 7.92, 2.42, and 1.25 mL, respectively, with a VRR of 77.9% at 6 months, and 87.4% at 12 months. Post-RFA complications were noted in two patients, one with transient vocal cord palsy and another with isthmus minor rupture. Conclusion: RFA may be another safe alternative except for active surveillance or surgical excision for AUS/FLUS nodules with low-suspicion Thyroid Imaging Reporting and Data System features for patients who are unsuitable or strongly refuse surgery. Long-term results remain uncertain, thus further follow-up study is necessary.