Light-Controlled Regulation of Dual-Enzyme Properties in YbGd-Carbon Quantum Dots Nano-Hybrid for Advanced Biosensing.

Compared to nanozymes with single enzyme activity, those with multiple enzyme activities possess broader application potential due to their diversified enzymatic functionalities. However, the multienzyme nanozymes currently face challenges of interference among different enzymatic activities during practical applications. In this study, we report the synthesis of a light-responsive YbGd-carbon quantum dots nano-hybrid, termed YbGd-CDs, which exhibits controllable enzyme-mimicking activities. This light-responsive behavior enables selective control of the enzymatic activities. Under visible light irradiation, YbGd-CDs demonstrate robust oxidase-like activity. Conversely, under dark conditions, they primarily exhibit peroxidase-like activity. Leveraging the dual-enzyme-mimicking capabilities of YbGd-CDs, we developed colorimetric assays for sensitive detection of total antioxidant capacity (TAC) in both normal and cancer cells as well as d-amino acids in human saliva. This study not only advances the synthesis of carbon-based nanozymes but also highlights their potential in biosensing applications.

The role of PALLD-STAT3 interaction in megakaryocyte differentiation and thrombocytopenia treatment.

Impaired differentiation of megakaryocytes constitutes the principal etiology of thrombocytopenia. The signal transducer and activator of transcription 3 (STAT3) is a crucial transcription factor in regulating megakaryocyte differentiation, yet the precise mechanism of its activation remains unclear. PALLD, an actin-associated protein, has been increasingly recognized for its essential functions in multiple biological processes. This study revealed that megakaryocyte/plateletspecific knockout of PALLD in mice exhibited thrombocytopenia due to diminished platelet biogenesis. In megakaryocytes, PALLD deficiency led to impaired proplatelet formation and polyploidization, ultimately weakening their differentiation for platelet production. Mechanistic studies demonstrated that PALLD bound to STAT3 and interacted with its DNA-binding domain (DBD) and Src homology 2 (SH2) domain via Immunoglobulin domain 3 (Ig3). Moreover, the absence of PALLD attenuated STAT3 Y705 phosphorylation and impeded STAT3 nuclear translocation. Based on the PALLD-STAT3 binding sequence, we designed a peptide C-P3, which can facilitate megakaryocyte differentiation and accelerate platelet production in vivo. In conclusion, this study highlights the pivotal role of PALLD in megakaryocyte differentiation and proposes a novel approach for treating thrombocytopenia by targeting the PALLD-STAT3 interaction.

Biomimetic Slippery Surface with Exclusive Liquid-Repellent and Self-Cleaning Properties for Antifouling.

The nature always offers amazing inspiration, where it is highly desirable to endow coatings on marine equipment with powerful functions. An excellent example is slippery zone of Nepenthes pitcher, which possesses novel liquid-repellent and self-cleaning performance. Therefore, this study presents an efficient fabrication method to prepare a novel coating. The coatings were fabricated by designing biomimetic textures extracted from the lunate bodies of slippery zone on polydimethylsiloxane (PDMS) and then grafting Dictyophora indusiata polysaccharide (DIP) modifier. The as-prepared slippery coatings exhibited outstanding antifouling properties against kinds of daily life pollutants such as Chlorella and coffee. This synergistic strategy was proposed combined with environmentally friendly modifier grafting and heterogeneous microstructure on the surface to broaden new probabilities for manufacturing slippery coatings with incredible protective functionality.

Roles of Nontraditional Lipid Parameters for Predicting Restenosis in Patients with Intracranial Atherosclerotic Stenosis After Endovascular Treatment.

PURPOSE: Nontraditional lipid parameters are associated with intracranial atherosclerotic stenosis (ICAS) progression. This study aimed to investigate the association of nontraditional lipid parameters with the risk of restenosis in patients with ICAS after endovascular treatment (EVT). METHODS: This study retrospectively enrolled consecutive patients with symptomatic ICAS after successful EVT followed by at least 3 months of angiography. Participants were divided into restenosis or non-restenosis groups based on the angiographic follow-up results. The nontraditional lipid parameters were calculated from conventional lipid parameters. The COX regression models and restricted cubic splines (RCS) were used to explore the association between nontraditional lipid parameters and restenosis. RESULTS: This study recruited 222 cases with 224 lesions eligible for our study, of which 56 (25%) had restenosis. Compared with the non-restenosis group, patients in the restenosis group had higher levels of the atherogenic index of plasma (AIP) (0.211, interquartile range, IQR, 0.065-0.404 vs. 0.083, IQR, -0.052-0.265, P = 0.001), remnant cholesterol (RC) (0.55, IQR, 0.33-0.77 vs. 0.30, IQR, 0.18-0.49, P < 0.001) and Castelli's index­I (CRI-I) (4.13, IQR, 3.39-5.34 vs. 3.74, IQR, 2.94-4.81, P = 0.030). In the multivariable COX regression analysis, a 0.1 unit increase of AIP was an independent risk factor for restenosis (hazard ratio, HR = 1.20, 95% confidence interval, CI 1.05-1.35, P = 0.005) whereas such an association was not observed for RC (HR = 1.01, 95% CI 0.90-1.15, P = 0.835). The restricted cubic spline (RCS) plot revealed a linear relationship between AIP and restenosis (P for nonlinear = 0.835) but a nonlinear relationship for RC (P for nonlinear = 0.012). Patients were stratified according to tertiles (T) of AIP and RC and the risk of restenosis increased in T3 compared to T1 (HR = 3.21, 95% CI 1.35-7.62, P = 0.008 and HR = 2.99, 95% CI 1.11-8.03, P = 0.030, respectively). Furthermore, this association remained stable within each LDL­C level subgroup. CONCLUSION: The AIP and RC were positively and independently associated with restenosis in patients with ICAS after EVT.

Efficacy of radiofrequency ablation vs. transcatheter arterial embolization for hepatic hemangiomas.

OBJECTIVE: The objective of this study was to evaluate the safety and effectiveness of radiofrequency ablation (RFA) and transcatheter arterial chemoembolization (TACE) in the treatment of large hepatic hemangiomas (LHH) (5-9.9 cm in diameter). METHODS AND MATERIALS: This study retrospectively collected data from 82 patients with LHH treated at Chaoyang Central Hospital. The study analyzed the differences in postoperative efficacy, operative time, blood routine, liver and kidney function on the first day after surgery, postoperative hospitalization time and postoperative complications. RESULTS: There were statistically significant differences in indicators such as white blood cell count, alanine aminotransferase, aspartate aminotransferase and total bilirubin on the first day after surgery between the RFA group (39 cases) and the TACE group (43 cases) ( P < 0.001). Compared to RFA, LHH patients treated with TACE had a general complication rate of 39.5% (vs. 43.6%; P = 0.7), a procedure-related complication rate of 30.2% (vs. 59.0%; P = 0.009), an effective rate at 6-12 months postoperatively of 55.8% (vs. 82.1%; P = 0.01), an operating-time of 41.2 ± 14.9 min (vs. 100.8 ± 35.5 min; P < 0.001) and hospitalization costs of 17052.7 ± 1364.8 yuan (vs. 30952.1 ± 4327.6 yuan; P < 0.001). CONCLUSION: This study indicates that the efficacy of RFA in treating LHH is significantly superior to TACE. Microwave ablation and RFA appear to be safe treatments for LHH. The TACE group exhibited shorter operating-time, lower hospitalization costs and lower demands on cardiopulmonary function.

A platinum glutamate acid complex as a peroxidase mimic: high activity, controllable chemical modification, and application in biosensors.

Recent strides in nanotechnology have given rise to nanozymes, nanomaterials designed to emulate enzymatic functions. Despite their promise, challenges such as batch-to-batch variability and limited atomic utilization persist. This study introduces Pt(Glu)2, a platinum glutamic acid complex, as a versatile small-molecule peroxidase mimic. Synthesized through a straightforward method, Pt(Glu)2 exhibits robust catalytic activity and stability. Steady-state kinetics reveal a lower Km value compared to that of natural enzymes, signifying strong substrate affinity. Pt(Glu)2 was explored for controllable chemical modification and integration into cascade reactions with natural enzymes, surpassing other nanomaterials. Its facile synthesis and seamless integration enhance cascade reactions beyond the capabilities of nanozymes. In biosensing applications, Pt(Glu)2 enabled simultaneous detection of cholesterol and alkaline phosphatase in human serum with high selectivity and sensitivity. These findings illustrate the potential of small molecule mimetics in catalysis and biosensing, paving the way for their broader applications.

In vitro interaction of naphthoquine with ivermectin, atovaquone, curcumin, and ketotifen in the asexual blood stage of Plasmodium falciparum 3D7.

Naphthoquine is a promising candidate for antimalarial combination therapy. Its combination with artemisinin has demonstrated excellent efficacy in clinical trials conducted across various malaria-endemic areas. A co-formulated combination of naphthoquine and azithromycin has also shown high clinical efficacy for malaria prophylaxis in Southeast Asia. Developing new combination therapies using naphthoquine will provide additional arsenal responses to the growing threat of artemisinin resistance. Furthermore, due to its long half-life, the possible interaction of naphthoquine with other drugs also needs attention. However, studies on its pharmacodynamic interactions with other drugs are still limited. In this study, the in vitro interactions of naphthoquine with ivermectin, atovaquone, curcumin, and ketotifen were evaluated in the asexual stage of Plasmodium falciparum 3D7. By using the combination index analysis and the SYBR Green I-based fluorescence assay, different interaction patterns of selected drugs with naphthoquine were revealed. Curcumin showed a slight but significant synergistic interaction with naphthoquine at lower effect levels, and no antagonism was observed across the full range of effect levels for all tested ratios. Atovaquone showed a potency decline when combined with naphthoquine. For ivermectin, a significant antagonism with naphthoquine was observed at a broad range of effect levels below 75% inhibition, although no significant interaction was observed at higher effect levels. Ketotifen interacted with naphthoquine similar to ivermectin, but significant antagonism was observed for only one tested ratio. These findings should be helpful to the development of new naphthoquine-based combination therapy and the clinically reasonable application of naphthoquine-containing therapies. IMPORTANCE: Pharmacodynamic interaction between antimalarials is not only crucial for the development of new antimalarial combination therapies but also important for the appropriate clinical use of antimalarials. The significant synergism between curcumin and naphthoquine observed in this study suggests the potential value for further development of new antimalarial combination therapy. The finding of a decline in atovaquone potency in the presence of naphthoquine alerts to a possible risk of treatment or prophylaxis failure for atovaquone-proguanil following naphthoquine-containing therapies. The observation of antagonism between naphthoquine and ivermectin raised a need for concern about the applicability of naphthoquine-containing therapy in malaria-endemic areas with ivermectin mass drug administration deployed. Considering the role of atovaquone-proguanil as a major alternative when first-line artemisinin-based combination therapy is ineffective and the wide implementation of ivermectin mass drug administration in malaria-endemic countries, the above findings will be important for the appropriate clinical application of antimalarials involving naphthoquine-containing therapies.

PHE1-based IgG-like antibody platform provides a novel strategy for enhanced T-cell immunotherapy.

Introduction: Bispecific antibodies (BsAbs) can simultaneously target two epitopes of different antigenic targets, bringing possibilities for diversity in antibody drug design and are promising tools for the treatment of cancers and other diseases. T-cell engaging bsAb is an important application of the bispecific antibody, which could promote T cell-mediated tumor cell killing by targeting tumor-associated antigen (TAA) and CD3 at the same time. Methods: This study comprised antibodies purification, Elisa assay for antigen binding, cytotoxicity assays, T cell activation by flow cytometry in vitro and xenogenic tumor model in vivo. Results: We present a novel bsAb platform named PHE-Ig technique to promote cognate heavy chain (HC)-light chain (LC) pairing by replacing the CH1/CL regions of different monoclonal antibodies (mAbs) with the natural A and B chains of PHE1 fragment of Integrin ß2 based on the knob-in-hole (KIH) technology. We had also verified that PHE-Ig technology can be effectively used as a platform to synthesize different desired bsAbs for T-cell immunotherapy. Especially, BCMA×CD3 PHE-Ig bsAbs exhibited robust anti-multiple myeloma (MM) activity in vitro and in vivo. Discussion: Moreover, PHE1 domain was further shortened with D14G and R41S mutations, named PHE-S, and the PHE-S-based BCMA×CD3 bsAbs also showed anti BCMA+ tumor effect in vitro and in vivo, bringing more possibilities for the development and optimization of different bsAbs. To sum up, PHE1-based IgG-like antibody platform for bsAb construction provides a novel strategy for enhanced T-cell immunotherapy.

LOXL2-induced PEAR1 Ser891 phosphorylation suppresses CD44 degradation and promotes triple-negative breast cancer metastasis.

CD44 is associated with a high risk of metastasis, recurrence, and drug resistance in various cancers. Here we report that platelet endothelial aggregation receptor 1 (PEAR1) is a CD44 chaperone protein that protected CD44 from endocytosis-mediated degradation and enhances cleavage of the CD44 intracellular domain (CD44-ICD). Furthermore, we found that lysyl oxidase-like protein 2 (LOXL2), an endogenous ligand of PEAR1, bound to the PEAR1-EMI domain and facilitated the interaction between PEAR1 and CD44 by inducing PEAR1 Ser891 phosphorylation in a manner that was independent of its enzyme activity. Levels of PEAR1 protein and PEAR1 phosphorylation at Ser891 were increased in patients with triple-negative breast cancer (TNBC), were positively correlated with expression of LOXL2 and CD44, and were negatively correlated with overall survival. The level of PEAR1 Ser891 phosphorylation was identified as the best independent prognostic factor in TNBC patients. The prognostic efficacy of the combination of PEAR1 phosphorylation at Ser891 and CD44 expression was superior to that of PEAR1 phosphorylation at Ser891 alone. Blocking the interaction between LOXL2 and PEAR1 with monoclonal antibodies significantly inhibited TNBC metastasis, representing a promising therapeutic strategy for TNBC.

Metformin promotes the normalization of abnormal blood vessels after radiofrequency ablation deficiency in hepatocellular carcinoma by microRNA-302b-3p targeting thioredoxin-interacting protein.

Metformin has shown great promise in the treatment of HCC. Radiofrequency ablation (RFA) deficiency results in recurrence and metastasis of remaining HCC tumors. Here, we aimed to investigate the role and mechanism of metformin in HCC after RFA deficiency. HCC cell line Hep-G2 was selected to simulate RFA deficiency and named HepG2-H cells. After treating cells with different concentrations of metformin (2.5, 5, 10 µM) or transfecting related plasmids, cell proliferation, migration, invasion, apoptosis and angiogenesis were detected, in vitro permeability test was performed, and an angiogenesis-related protein VEGFA was analyzed. The residual HCC model after RFA deficiency was established in mice. Metformin was administered by gavage to detect changes in tumor volume and weight, and CD31 staining was used to observe microvessels. The targeting relationship between miR-302b-3p and TXNIP was demonstrated by the bioinformatics website, dual-luciferase reporter assay, and RNA pull-down assay. The results found that metformin inhibited RFA deficiency-induced growth and angiogenesis of HCC cells in vitro. miR-302b-3p counteracted the therapeutic effect of metformin on RFA deficiency. miR-302b-3p targeted regulation of TXNIP. The up-regulation of TXNIP reversed the effects of overexpression of miR-302b-3p on RFA-deficient HCC cells. Metformin inhibited RFA-deficiency-induced HCC growth and tumor vascular abnormalities in vivo. Overall, metformin promotes the normalization of abnormal blood vessels after RFA deficiency in HCC by miR-302b-3p targeting TXNIP, which can be used to prevent the progression of HCC after RFA.

Effect of acid and in vitro digestion on conformation and IgE-binding capacity of major oyster allergen Cra g 1 (tropomyosin)

Introduction and Objectives: The production and consumption of oysters is increasing annually because it can provide essential nutrients and benefit for human health, leading to frequent occurrence of severe allergic reactions observed in sensitized individuals. The aim of the present study was to investigate the effects of acid and protease treatment on the conformation and IgE-binding capacity of recombinant Crassostrea gigas tropomyosin (Cra g 1). Results: Under acidic conditions, Cra g 1 did not undergo degradation, however, the changes obvious in the intensity of CD signal and ANS-binding fluorescence were observed, which was associated with a decrease in antibody reactivity. In simulated gastrointestinal fluid (SGF) and simulated intestinal fluid (SIF) digestion system, acid-treated Cra g 1 was relatively resistant to digestion, but the degradative patterns were very different. Moreover, owing to alterations of secondary structure and hydrophobic surface of the protein during digestive processing, antigenicity of acid-induced Cra g 1 reduced in SGF while it increased significantly in SIF. Conclusion: To our knowledge, this is the first study reporting that antigenicity of acid-treated oyster tropomyosin increased after SIF digestion. These results revealed that treatment with acid and pepsin, rather than trypsin, was an effective way of reducing IgE-binding capacity of tropomyosin from oyster

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