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Electro-ionic soft actuators have garnered significant attention owing to their promising applications in flexible electronics, wearable devices, and soft robotics. However, achieving high actuation performance (large bending strain and fast response time) of these soft actuators under low voltage has been challenging due to issues related to ion diffusion and accumulation. In this study, an electro-ionic soft actuator is fabricated using Ti3C2Tx MXene and eutectic gallium-indium (EGaIn) composite material as the bilayer electrode and methylammonium formate/1-ethyl-3-methylimidazolium tetrafluoroborate/poly(vinylidene fluoride) (MAF-EMIMBF4/PVDF) as the ionic liquid-type electrolyte. The research results indicate that the prepared soft actuator exhibits excellent actuation performance with a peak-to-peak displacement of 35 mm and a bending strain of 0.69% (a peak-to-peak strain of 1.38%) under a low voltage (3 V). The electro-ionic soft actuator shows a wide frequency range (0.1-10 Hz), fast response time (0.35 s), and a rise time of 7.5 s. Furthermore, it demonstrates good cyclic durability, with a retention rate of 92.5% of its performance for 10 000 cycles. These excellent performances are attributed to the 3D structure of the Ti3C2Tx-EGaIn/Ti3C2Tx bilayer composite electrode, as well as the characteristics of the low viscosity, high conductivity, small ion volume, and larger volume difference between cations and anions in MAF ionic liquid. The high-performance electro-ionic soft actuator can be used in various fields such as artificial muscles, tactile devices, and soft robots.
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BACKGROUND: Ovarian cancer is insidious and usually detected in advanced stages of the disease. As the ovaries are pelvic organs, changes in their pelvic fluid metabolites may be associated with ovarian cancer. METHODS: Metabolomic changes in the pelvic fluid were detected using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in patients with ovarian cancer, ovarian cysts and uterine fibroids. Area under the curve (AUC) analysis was used to assess the diagnostic performance of lipid metabolites and blood tumor indices. The Pearson correlation algorithm was used to analyze the correlation between clinical characteristics and lipid metabolites in ovarian cancer patients. RESULTS: There were 24 lipid metabolites significantly changed in the pelvic fluid of ovarian cancer patients (p < 0.05). Palmitoylcarnitine, lipoamide, lipid metabolites, and blood tumor indices (CA15-3 and CA125) showed AUC > 0.8, with palmitoylcarnitine reaching a high of 0.942. In addition, we found that some lipid metabolites were significantly associated with the clinical stage, abdominal water volume, lymphatic metastasis, and recurrence (p < 0.05, r > 0.5). CONCLUSION: Levels of specific lipid metabolites are potential biomarkers of ovarian cancer and may play a key role in the early diagnosis and prognostic assessment of ovarian cancer. SIGNIFICANCE: Our results showed that pelvic metabolites, especially some lipid metabolites, play an important role in the diagnosis of ovarian cancer. Meanwhile, partial lipid metabolites were closely associated with the clinical presentation and prognosis of patients with ovarian cancer. We believe that our study makes a significant contribution to the literature because it provides a potential approach that is more effective for ovarian cancer detection.
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Accurately evaluating the local biomechanics of arterial wall is crucial for diagnosing and treating arterial diseases. Indentation measurement can be used to evaluate the local mechanical properties of the artery. However, the effects of the indenter's geometric structure and the analysis theory on measurement results remain uncertain. In this paper, four kinds of indenters were used to measure the pulmonary aorta, the proximal thoracic aorta and the distal thoracic aorta in pigs, and the arterial elastic modulus was calculated by Sneddon and Sirghi theory to explore the influence of the indenter geometry and analysis theory on the measured elastic modulus. The results showed that the arterial elastic modulus measured by cylindrical indenter was lower than that measured by spherical indenter. In addition, compared with the calculated results of Sirghi theory, the Sneddon theory, which does not take adhesion forces in account, resulted in slightly larger elastic modulus values. In conclusion, this study provides parametric support for effective measurement of arterial local mechanical properties by millimeter indentation technique.
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Aorta Torácica , Módulo de Elasticidade , Artéria Pulmonar , Animais , Suínos , Fenômenos Biomecânicos , Aorta Torácica/fisiologia , Aorta Torácica/anatomia & histologia , Artéria Pulmonar/fisiologia , Estresse Mecânico , Artérias/fisiologiaRESUMO
A convenient method for preparing 3-aryl isoquinolines via a base-promoted tandem reaction is presented. Simply combining commercially available 2-methyl-arylaldehydes, benzonitriles, NaN(SiMe3)2, and Cs2CO3 enabled the synthesis of a variety of isoquinolines (23 examples, ≤90% yield). Among the syntheses of isoquinolines, the transition metal-free method described here is straightforward, practical, and operationally simple.
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Objective: To construct and validate radiomics models for hepatocellular carcinoma (HCC) grade predictions based on contrast-enhanced CT (CECT). Methods: Patients with pathologically confirmed HCC after surgery and underwent CECT at our institution between January 2016 and December 2020 were enrolled and randomly divided into training and validation datasets. With tumor segmentation and feature extraction, radiomic models were constructed using univariate analysis, followed by least absolute shrinkage and selection operator (LASSO) regression. In addition, combined models with clinical factors and radiomics scores (Radscore) were constructed using logistic regression. Finally, all models were evaluated using the receiver operating characteristic (ROC) curve with the area under the curve (AUC), calibration curve, and decision curve analysis (DCA). Results: In total 242 patients were enrolled in this study, of whom 170 and 72 formed the training and validation datasets, respectively. The arterial phase and portal venous phase (AP+VP) radiomics model were evaluated as the best for predicting HCC pathological grade among all the models built in our study (AUC = 0.981 in the training dataset; AUC = 0.842 in the validation dataset) and was used to build a nomogram. Furthermore, the calibration curve and DCA indicated that the AP+VP radiomics model had a satisfactory prediction efficiency. Conclusions: Low- and high-grade HCC can be distinguished with good diagnostic performance using a CECT-based radiomics model.
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Interleukin-1 receptor-associated kinase 4 (IRAK4) is a promising therapeutic target in inflammation-related diseases. However, the inhibition of IRAK4 kinase activity may lead to moderate anti-inflammatory efficacy owing to the dual role of IRAK4 as an active kinase and a scaffolding protein. Herein, we report the design, synthesis, and biological evaluation of an efficient and selective IRAK4 proteolysis-targeting chimeric molecule that eliminates IRAK4 scaffolding functions. The most potent compound, LC-MI-3, effectively degraded cellular IRAK4, with a half-maximal degradation concentration of 47.3 nM. LC-MI-3 effectively inhibited the activation of downstream nuclear factor-κB signaling and exerted more potent pharmacological effects than traditional kinase inhibitors. Furthermore, LC-MI-3 exerted significant therapeutic effects in lipopolysaccharide- and Escherichia coli-induced acute and chronic inflammatory skin models compared with kinase inhibitors in vivo. Therefore, LC-MI-3 is a candidate IRAK4 degrader in alternative targeting strategies and advanced drug development.
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Quinases Associadas a Receptores de Interleucina-1 , Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Animais , Humanos , Camundongos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Administração Oral , Lipopolissacarídeos/farmacologia , NF-kappa B/metabolismo , NF-kappa B/antagonistas & inibidores , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/química , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacocinética , Disponibilidade Biológica , Descoberta de Drogas , Proteólise/efeitos dos fármacos , Relação Estrutura-Atividade , Masculino , Camundongos Endogâmicos C57BLRESUMO
Systemic lupus erythematosus (SLE) is an autoimmune and inflammatory disease with a risk associated with hormonal and reproductive factors. However, the potential causal effects between these factors and SLE remain unclear. A two-sample Mendelian randomization study was conducted using the published summary data from the genome-wide association study database. Five independent genetic variants associated with hormonal and reproductive factors were selected as instrumental variables: age at menarche, age at natural menopause, estradiol, testosterone, and follistatin. To estimate the causal relationship between these exposure factors and disease outcome, we employed the inverse-variance weighted, weighted median, and MR-Egger methods. In addition, we carried out multiple sensitivity analyses to validate model assumptions. Inverse variance weighted showed that there was a causal association between circulating follistatin and SLE risk (OR = 1.38, 95% CI 1.03 to 1.86, P = 0.033). However, no evidence was found that correlation between AAM (OR = 1.04, 95% CI 0.77 to 1.40, P = 0.798), ANM (OR = 0.99, 95% CI 0.92 to 1.06, P = 0.721), E2 (OR = 1.40, 95% CI 0.14 to 13.56, P = 0.772), T (OR = 1.25, 95% CI 0.70 to 2.28, P = 0.459), and SLE risk. Our study revealed that elevated circulating follistatin associates with an increased risk of SLE. This finding suggests that the regulatory signals mediated by circulating follistatin may provide a potential mechanism relevant to the treatment of SLE.
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Increasing evidence implicates chronic inflammation as the main pathological cause of diabetic nephropathy (DN). Exploration of key targets in the inflammatory pathway may provide new treatment options for DN. We aimed to investigate the role of Src homology 2-containing protein tyrosine phosphatase 2 (SHP2) in macrophages and its association with DN. The upregulated phosphorylation of SHP2 was detected in macrophages in both patients with diabetes and in a mouse model. Using macrophage-specific SHP2-knockout (SHP2-MKO) mice and SHP2fl/fl mice injected with streptozotocin (STZ), we showed that SHP2-MKO significantly attenuated renal dysfunction, collagen deposition, fibrosis, and inflammatory response in mice with STZ-induced diabetes. RNA-sequencing analysis using primary mouse peritoneal macrophages (MPMs) showed that SHP2 deletion mainly affected mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) signaling pathways as well as MAPK/NF-κB-dependent inflammatory cytokine release in MPMs. Further study indicated that SHP2-deficient macrophages failed to release cytokines that induce phenotypic transition and fibrosis in renal cells. Administration with a pharmacological SHP2 inhibitor, SHP099, remarkably protected kidneys in both type 1 and type 2 diabetic mice. In conclusion, these results identify macrophage SHP2 as a new accelerator of DN and suggest that SHP2 inhibition may be a therapeutic option for patients with DN.
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Diabetes Mellitus Experimental , Nefropatias Diabéticas , Proteína Tirosina Fosfatase não Receptora Tipo 11 , Animais , Humanos , Camundongos , Citocinas/metabolismo , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , Fibrose , Inflamação/patologia , Macrófagos/metabolismo , Camundongos Knockout , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismoRESUMO
Doublecortin-like kinase 1 (DCLK1) is a microtubule-associated protein kinase involved in neurogenesis and human cancer. Recent studies have revealed a novel functional role for DCLK1 in inflammatory signaling, thus positioning it as a novel target kinase for respiratory inflammatory disease treatment. In this study, we designed and synthesized a series of NVP-TAE684-based derivatives as novel anti-inflammatory agents targeting DCLK1. Bio-layer interferometry binding screening and kinase assays of the NVP-TAE684 derivatives led to the discovery of an effective DCLK1 inhibitor (a24), with an IC50 of 179.7 nM. Compound a24 effectively inhibited lipopolysaccharide (LPS)-induced inflammation in macrophages with higher potency than the lead compound. Mechanistically, compound a24 inhibited LPS-induced inflammation by inhibiting DCLK1-mediated IKKß phosphorylation. Furthermore, compound a24 showed in vivo anti-inflammatory activity in an LPS-challenged acute lung injury model. These findings suggest that compound a24 may serve as a novel candidate for the development of DCLK1 inhibitors and a potential therapeutic agent for the treatment of inflammatory diseases.
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Lesão Pulmonar Aguda , Quinases Semelhantes a Duplacortina , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Lipopolissacarídeos/farmacologia , Proteínas Serina-Treonina Quinases , Inflamação/tratamento farmacológico , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológicoRESUMO
The relationship between the expression of the SATB2 and CDX2 proteins and common molecular changes and clinical prognosis in colorectal cancer (CRC) still needs further clarification. We collected 1180 cases of CRC and explored the association between the expression of SATB2 and CDX2 and clinicopathological characteristics, molecular alterations, and overall survival of CRC using whole-slide immunohistochemistry. Our results showed that negative expression of SATB2 and CDX2 was more common in MMR-protein-deficient CRC than in MMR-protein-proficient CRC (15.8% vs. 6.0%, P = 0.001; 14.5% vs. 4.0%, P = 0.000, respectively). Negative expression of SATB2 and CDX2 was more common in BRAF-mutant CRC than in BRAF wild-type CRC (17.2% vs. 6.1%, P = 0.003; 13.8% vs. 4. 2%; P = 0.004, respectively). There was no relationship between SATB2 and/or CDX2 negative expression and KRAS, NRAS, and PIK3CA mutations. The lack of expression of SATB2 and CDX2 was associated with poor histopathological features of CRC. In multivariate analysis, negative expression of SATB2 (P = 0.030), negative expression of CDX2 (P = 0.043) and late clinical stage (P = 0.000) were associated with decreased overall survival of CRC. In conclusion, the lack of SATB2 and CDX2 expression in CRC was associated with MMR protein deficiency and BRAF mutation, but not with KRAS, NRAS and PIK3CA mutation. SATB2 and CDX2 are prognostic biomarkers in patients with CRC.
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Adenocarcinoma , Neoplasias Encefálicas , Neoplasias Colorretais , Proteínas de Ligação à Região de Interação com a Matriz , Síndromes Neoplásicas Hereditárias , Deficiência de Proteína , Humanos , Proteínas Proto-Oncogênicas B-raf/genética , Reparo de Erro de Pareamento de DNA/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Adenocarcinoma/genética , Neoplasias Colorretais/patologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Mutação , Fator de Transcrição CDX2/genética , Fator de Transcrição CDX2/metabolismo , Proteínas de Ligação à Região de Interação com a Matriz/genética , Proteínas de Ligação à Região de Interação com a Matriz/metabolismoRESUMO
Molecular-targeted therapies for lung squamous cell carcinoma (LSCC) are limited mainly because targetable oncogenic aberrations are absent in LSCC. Recent genomic analyses have revealed that the fibroblast growth factor (FGF) signaling pathway plays a fundamental role in LSCC progression via cancer cell proliferation and angiogenesis. In the present study, we designed, expressed, and purified a fibroblast growth factor receptor fragment (FGFR1-Fc) fusion protein using NS/0 cells. In FGF2-FGFR1 overexpressed NCI-H1703 cells, the FGFR1-Fc fusion protein effectively inhibited proliferation and invasion and arrested the cell cycle at the G0-G1 phase. In NCI-H1703 cells treated with the FGFR1-Fc fusion protein, the phosphorylation levels of FGFR1, FRS2, ERK, and AKT were significantly reduced. Using an siRNA assay, we demonstrated that FGF2-FGFR1 is the major anti-tumor target of FGFR1-Fc fusion the FGFR1-Fc fusion protein, which also significantly inhibited proliferation and invasion by NCI-H1703 cells via the FGF2-FGFR1 signaling pathway. In addition, the FGFR1-Fc fusion protein significantly inhibited angiogenesis in an embryonic chorioallantoic membrane model. The FGFR1-Fc fusion protein may be an effective therapeutic candidate for LSCC.
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Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Imunoglobulina G , Neoplasias Pulmonares , Proteínas Recombinantes de Fusão , Humanos , Fator 2 de Crescimento de Fibroblastos , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Proliferação de Células , Carcinoma de Células Escamosas/genética , Neoplasias Pulmonares/tratamento farmacológico , Pulmão/metabolismo , Linhagem Celular TumoralRESUMO
BACKGROUND: Acute lung injury (ALI) is a critical inflammatory response syndrome that rapidly develops into acute respiratory distress syndrome (ARDS). Currently, no effective therapeutic modalities are available for patients with ALI/ARDS. According to recent studies, inhibiting both the release of pro-inflammatory cytokines and the formation of reactive oxygen species (ROS) as early as possible may be a promising therapy for ALI. RESULTS: In this study, a ROS-responsive nano-delivery system based on oxidation-sensitive chitosan (Ox-CS) was fabricated for the simultaneous delivery of Ce NPs and RT. The in vitro experiments have shown that the Ox-CS/Ceria-Resatorvid nanoparticles (Ox-CS/CeRT NPs) were rapidly and efficiently internalised by inflammatory endothelial cells. Biological evaluations validated the significant attenuation of ROS-induced oxidative stress and cell apoptosis by Ox-CS/CeRT NPs, while maintaining mitochondrial function. Additionally, Ox-CS/CeRT NPs effectively inhibited the release of pro-inflammatory factors. After intraperitoneal (i.p.) administration, Ox-CS/CeRT NPs passively targeted the lungs of LPS-induced inflamed mice and released the drug activated by the high ROS levels in inflammatory tissues. Finally, Ox-CS/CeRT NPs significantly alleviated LPS-induced lung injury through inhibiting both oxidative stress and pro-inflammatory cytokine expression. CONCLUSIONS: The created Ox-CS/CeRT NPs could act as a prospective nano-delivery system for a combination of anti-inflammatory and anti-oxidant therapy of ALI.
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Lesão Pulmonar Aguda , Nanopartículas , Síndrome do Desconforto Respiratório , Humanos , Camundongos , Animais , Antioxidantes/uso terapêutico , Espécies Reativas de Oxigênio/farmacologia , Células Endoteliais , Lipopolissacarídeos/farmacologia , Estudos Prospectivos , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/induzido quimicamente , Pulmão , Nanopartículas/uso terapêutico , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Síndrome do Desconforto Respiratório/tratamento farmacológicoRESUMO
PURPOSE: The cross-limb (CL) technique is a commonly used endovascular treatment for addressing unfavorable anatomical features in patients with abdominal aortic aneurysm (AAA). The configuration of CL stent-graft plays a critical role in determining the postoperative hemodynamic properties and physiological behaviors, which ultimately impact the efficacy and safety of endovascular AAA treatment. This study aims to investigate the relationship between hemodynamics and CL stent-graft configuration from a hemodynamic perspective. METHODS: Five distinct geometric models of cross-limb (CL) stent-graft configurations were constructed by optimizing the real clinical computed tomography angiography (CTA) data. These models varied in main body lengths and cross angles and were used to perform numerical simulations to analyze various hemodynamic parameters. Flow pattern, distribution of wall shear stress (WSS)-related parameters, localized normalized helicity (LNH), pressure drop, and the displacement force of all models were examined in this paper. RESULTS: In patient-specific cases, helical flow and WSS increase with the main body. However, it also generated secondary flow in localized areas, leading to increased oscillation in the WSS direction. Notably, increasing the stent graft's main body length or decreasing the cross angle reduced the displacement force exerted on the stent-graft. Reducing the cross angle did not significantly alter the hemodynamic characteristics. CONCLUSION: In the clinical practice of CL deployment, it is crucial to carefully consider the stent-graft configuration and the patient specific to achieve optimal postoperative outcomes. This study provides valuable insights for guiding stent selection and treatment planning in patients with abdominal aortic aneurysm undergoing CL techniques, from a hemodynamic perspective.
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The identification of potential epigenetic targets for a known bioactive compound is essential and promising as more and more epigenetic drugs are used in cancer clinical treatment and the availability of chemogenomic data related to epigenetics increases. In this study, we introduce a novel epigenetic target identification strategy (ETI-Strategy) that integrates a multi-task graph convolutional neural network prior model and a protein-ligand interaction classification discriminating model using large-scale bioactivity data for a panel of 55 epigenetic targets. Our approach utilizes machine learning techniques to achieve an AUC value of 0.934 for the prior model and 0.830 for the discriminating model, outperforming inverse docking in predicting protein-ligand interactions. When comparing with other open-source target identification tools, it was found that only our tool was able to accurately predict all the targets corresponding to each compound. This further demonstrates the ability of our strategy to take full advantage of molecular-level information as well as protein-level information in molecular activity prediction. Our work highlights the contribution of machine learning in the identification of potential epigenetic targets and offers a novel approach for epigenetic drug discovery and development.Communicated by Ramaswamy H. Sarma.
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Background: Moderate renal artery stenosis (50-70%) may lead to uncontrolled hypertension and eventually cause irreversible damage to renal function. However, the clinical criteria for interventional treatment are still ambiguous in this condition. This study investigated the impact of the position and degree of renal artery stenosis on hemodynamics near the renal artery to assess the short-term and long-term risks associated with this disease. Methods: Calculation models with different degrees of stenosis (50%, 60%, and 70%) located at different positions in the right renal artery were established based on the computed tomography angiography (CTA) of a personalized case. And computational fluid dynamics (CFD) was used to analyze hemodynamic surroundings near the renal artery. Results: As the degree of stenosis increases and the stenosis position is far away from the aorta, there is a decrease in renal perfusion. An analysis of the wall shear stress (WSS)-related parameters indicated areas near the renal artery (downstream of the stenosis and the entrance of the right renal artery) with potential long-term risks of thrombosis and inflammation. Conclusion: The position and degree of stenosis play a significant role in judging short-term risks associated with renal perfusion. Moreover, clinicians should consider not only short-term risks but also independent long-term risk factors, such as certain regions of 50% stenosis with adequate renal perfusion may necessitate prompt intervention.
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Retrosynthesis prediction is crucial in organic synthesis and drug discovery, aiding chemists in designing efficient synthetic routes for target molecules. Data-driven deep retrosynthesis prediction has gained importance due to new algorithms and enhanced computing power. Although existing models show certain predictive power on the USPTO-50K benchmark data set, no one considers the effects of byproducts during the prediction process, which may be due to the lack of byproduct information in the benchmark data set. Here, we propose a novel two-stage retrosynthesis reaction prediction framework based on byproducts called RPBP. First, RPBP predicts the byproduct involved in the reaction based on the product molecule. Then, it handles an end-to-end prediction problem based on the prediction of reactants by product and byproduct. Unlike other methods that first identify the potential reaction center and then predict reactant molecules, RPBP considers additional information from byproducts, such as reaction reagents, conditions, and sites. Interestingly, adding byproducts reduces model learning complexity in natural language processing (NLP). Our RPBP model achieves 54.7% and 66.6% top-1 retrosynthesis prediction accuracy when the reaction class is unknown and known, respectively. It outperforms existing methods for known-class reactions, thanks to the rich chemical information in byproducts. The prediction of four kinase drugs from the literature demonstrates the model's practicality and potential to accelerate drug discovery.
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Soft fingertips have distinct intrinsic features that allow robotic hands to offer adjustable and manageable stiffness for grasping. The stability of the grasp is determined by the contact stiffness between the soft fingertip and the object. Within this work, we proposed a line vector representation method based on the Winkler Model and investigated the contact stiffness between soft fingertips and objects to achieve control over the gripping force and fingertip displacement of the gripper without the need for sensors integrated in the fingertip. First, we derived the stiffness matrix of the soft fingertip, analyzed the contact stiffness, and constructed the global stiffness matrix; then, we established the grasp stiffness matrix based on the contact stiffness model, allowing for the analysis and evaluation of the soft fingertip's manipulating process. Finally, our experiment demonstrated that the variation in object orientation caused by external forces can indicate the contact force status between the fingertip and the object. This contact force status is determined by the contact stiffness. The position error between the theoretical work and tested data was less than 9%, and the angle error was less than 5.58%. The comparison between the theoretical contact stiffness and the experimental results at the interface indicate that the present model for the contact stiffness is appropriate and the theoretical contact stiffness is consistent with the experiment data.
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Conventional oral therapy for ulcerative colitis (UC) is associated with premature release or degradation of drugs in the harsh gastrointestinal environment, resulting in reduced therapeutic effectiveness. Consequently, the present study aims to develop a dual-targeted delivery system with a nanoparticle-in-microparticle (nano-in-micro) structure. The prepared Asiatic Acid-loaded delivery system (AA/CDM-BT-ALG) has pH-sensitive properties. Cellular uptake evaluation confirms that nanoparticles exhibit targeted absorption by macrophages and Caco-2 cells through mannose (Man) receptor and biotin-mediated endocytosis, respectively. Therefore, this mechanism effectively enhances intracellular drug concentration. Additionally, the biodistribution study conducted on the gastrointestinal tract of mice indicates that the colon of the microspheres group shows higher fluorescence intensity with longer duration than the other groups. This finding indicates that the microspheres exhibit selective accumulation in areas of colon inflammation. In vivo experiments in colitis mice showed that AA/CDM-BT-ALG significantly alleviates the histopathological characteristics of the colon, reduced neutrophil, and macrophage infiltration, and decreases pro-inflammatory cytokine expression. Furthermore, the effect of AA/CDM-BT-ALG on colitis is validated to be closely related to the TLR4/MyD88/NF-κB signaling pathway. The present findings suggest that the development of a dual-targeted delivery system is accomplished effectively, with the potential to serve as a drug-controlled release system for treating UC.
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Colite Ulcerativa , Colite , Nanopartículas , Camundongos , Humanos , Animais , Colite Ulcerativa/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Células CACO-2 , Distribuição Tecidual , Colite/tratamento farmacológico , Colo/metabolismo , Colo/patologia , Nanopartículas/química , Modelos Animais de DoençasRESUMO
Purpose: The purpose of this study was to investigate the ex vivo and in vivo biomechanical characteristic of cornea in myopic eyes. Methods: Fifty-one corneal stromal lenticules were obtained from myopic eyes during the SMILE procedure and were tested by a biaxial tensile system within 24 hours postoperatively. The material properties of the lenticules were described using stress-strain curves and were compared among axial length (AL) <26 mm and AL ≥ 26 mm group. Pre-operative stress-strain index (SSI) parameters were used to evaluate the biomechanical properties of the cornea in vivo. Results: Compared with AL < 26 mm, the tangent modulus significantly decreased in horizontal and vertical directions when AL ≥ 26 mm (P < 0.05); SSI also significantly decreased when AL ≥ 26 mm (P < 0.05). Anisotropic parameter is positively correlated with AL (r = 0.307, P < 0.05). Compared with AL < 26 mm, anisotropic parameter significantly increased when AL ≥ 26 mm (P < 0.05). SSI was negatively correlated with AL (r = -0.380, P < 0.05) in the AL < 26 mm group but not in the AL ≥ 26 mm group (P > 0.05). Compared with 26 mm ≤ AL < 27 mm group, the tangent modulus significantly decreased in the horizontal direction (P < 0.05) but not in the vertical direction when 27 mm ≤ AL < 28 mm (P > 0.05). Conclusions: The biomechanical properties of cornea decreased with the increase of AL. Tangent modulus significantly decreased in the horizontal direction compared with vertical direction. AL should be taken into account during calculation of corneal biomechanical parameters in order to improve validity.
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Córnea , Miopia , Humanos , Anisotropia , Substância Própria/cirurgia , Miopia/cirurgia , Fenômenos BiomecânicosRESUMO
α/ßKlotho coreceptors simultaneously engage fibroblast growth factor (FGF) hormones (FGF19, FGF21 and FGF23)1,2 and their cognate cell-surface FGF receptors (FGFR1-4) thereby stabilizing the endocrine FGF-FGFR complex3-6. However, these hormones still require heparan sulfate (HS) proteoglycan as an additional coreceptor to induce FGFR dimerization/activation and hence elicit their essential metabolic activities6. To reveal the molecular mechanism underpinning the coreceptor role of HS, we solved cryo-electron microscopy structures of three distinct 1:2:1:1 FGF23-FGFR-αKlotho-HS quaternary complexes featuring the 'c' splice isoforms of FGFR1 (FGFR1c), FGFR3 (FGFR3c) or FGFR4 as the receptor component. These structures, supported by cell-based receptor complementation and heterodimerization experiments, reveal that a single HS chain enables FGF23 and its primary FGFR within a 1:1:1 FGF23-FGFR-αKlotho ternary complex to jointly recruit a lone secondary FGFR molecule leading to asymmetric receptor dimerization and activation. However, αKlotho does not directly participate in recruiting the secondary receptor/dimerization. We also show that the asymmetric mode of receptor dimerization is applicable to paracrine FGFs that signal solely in an HS-dependent fashion. Our structural and biochemical data overturn the current symmetric FGFR dimerization paradigm and provide blueprints for rational discovery of modulators of FGF signalling2 as therapeutics for human metabolic diseases and cancer.