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Nonylphenols (NPs) are confirmed endocrine disruptors that are banned in many countries due to correlations with human cancers. NPs pollution in surfactant oilfield chemicals (OFCs) has become an important environmental safety issue. It is significant to establish a simple, accurate and low-cost method for detection of NPs in OFCs. In this research, computer-aided molecular design technology was utilized to design NPs haptens. High affinity monoclonal antibodies against NPs were obtained using a matrix effect-enhanced screening method, with an IC50 value of 183.01 ng/mL. A colloidal gold immunochromatography assay (ICA) for detection of NPs enabled rapid on-site detection of large volumes of OFCs. Under optimal conditions, the limit of detection was 0.72-1.82 mg/kg, with a detection range of 4.49-191.28 mg/kg. The recovery was 84 %-104 %, with coefficients of variation < 13 %. As confirmed by high-performance liquid chromatography of natural positive OFCs samples, the proposed colloidal gold ICA demonstrated accuracy and reliability, with potential for fast and economical on field test.
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With the development of wireless communication technology, Ultra-Wideband (UWB) has become an important solution for indoor positioning. In complex indoor environments, the influence of non-line-of-sight (NLOS) factors leads to increased positioning errors. To improve the positioning accuracy, fuzzy iterative self-organizing data analysis clustering algorithm (ISODATA) is introduced to process a large amount of UWB data to reduce the influence of NLOS factors, and to stabilize positioning error within 2 cm, enhances the accuracy of the positioning system. To further improve the running efficiency of the algorithm, FPGA is used to accelerate the key computational part of the algorithm, compared with running on the MATLAB platform, which improves the speed about 100 times, enhances the algorithm's computational speed dramatically.
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USP7 is one of the most studied deubiquitinating enzymes, which is involved in the regulation of multiple cell signaling pathways and has been shown to be associated with the occurrence and progression of a variety of cancers. Inhibitors targeting USP7 have been studied by several teams, but most of them lack selectivity and have low activities. Herein, we reported a serious of pyrrole[2,3-d]pyrimidin-4-one derivatives through scaffold hopping of recently reported 4-hydroxypiperidine compounds. The representative compound Z33 (YCH3124) exhibited highly potent USP7 inhibition activity as well as anti-proliferative activity against four kinds of cancer cell lines. Further study revealed that YCH3124 effectively inhibited the downstream USP7 pathway and resulted in the accumulation of both p53 and p21 in a dose-dependent manner. Notably, YCH3124 disrupted cell cycle progression through restricting G1 phase and induced significant apoptosis in CHP-212 cells. In summary, our efforts provided a series of novel pyrrole[2,3-d]pyrimidin-4-one analogs as potent USP7 inhibitors with excellent anti-cancer activity.
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Polymer composite materials are increasingly used in civil aircraft structures. The failure mode and energy-absorption characteristics of polymer composite structures have garnered significant attention from academia and industry. For thin-walled polymer composite C-channels with layups of [0/90]3s, [45/-45]3s, and [45/90/-45/0]3, low-speed axial compression tests were performed to investigate the failure modes, failure mechanisms, and energy-absorbing characteristics. After parametric studies using [0] and [90] single-element models, stacked shell models of thin-walled composite C-channels were established using the Lavadèze single-layer damage constitutive model, Puck 2000, and Yamada Sun failure criteria. The results show that these thin-walled composite C-channels exhibit a stable progressive crushing process with a local buckling failure mode, encompassing local buckling, fiber break-age, matrix cracks, delamination, and corner cracking. The stacked shell model demonstrates reasonable agreement with the progressive crushing process of thin-walled composites, accurately capturing interlayer matrix failure and interface delamination cracking behavior. A comparison of the specific energy absorption (SEA) and mean crushing force (Fmean) between the simulation and test results yields a difference of less than 6%, indicating a strong correlation between the simulation results and the experimental energy-absorbing characteristics. It also shows that a deep understanding of the parameters is helpful for accurate numerical modeling.
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Mild traumatic brain injuries (mTBIs) are highly prevalent and can lead to chronic behavioral and cognitive deficits often associated with the development of neurodegenerative diseases. Oxidative stress and formation of reactive oxygen species (ROS) have been implicated in mTBI-mediated axonal injury and pathogenesis. However, the underlying mechanisms and contributing factors are not completely understood. In this study, we explore these pathogenic mechanisms utilizing a murine model of repetitive mTBI (r-mTBI) involving five closed-skull concussions in young adult C57BL/6J mice. We observed a significant elevation of Na+/H+ exchanger protein (NHE1) expression in GFAP+ reactive astrocytes, IBA1+ microglia, and OLIG2+ oligodendrocytes across various brain regions (including the cerebral cortex, corpus callosum, and hippocampus) after r-mTBI. This elevation was accompanied by astrogliosis, microgliosis, and the accumulation of amyloid precursor protein (APP). Mice subjected to r-mTBI displayed impaired motor learning and spatial memory. However, post-r-mTBI administration of a potent NHE1 inhibitor, HOE642, attenuated locomotor and cognitive functional deficits as well as pathological signatures of gliosis, oxidative stress, axonal damage, and white matter damage. These findings indicate NHE1 upregulation plays a role in r-mTBI-induced oxidative stress, axonal damage, and gliosis, suggesting NHE1 may be a promising therapeutic target to alleviate mTBI-induced injuries and restore neurological function.
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OBJECTIVE: To observe the effects of electroacupuncture (EA) on the expression of serum interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and the pancreatic nuclear factor-κB (NF-κB) pathway in type 2 diabetes mellitus (T2DM) rats, and to explore the possible mechanism by which EA improving the dedifferentiation of pancreatic ß-cells in the treatment of T2DM. METHODS: Among 18 SPF-grade male Wistar rats, 6 rats were randomly selected as the control group, and the remaining 12 rats were fed with high-sugar and high-fat diet combined with intraperitoneal injection of 2% streptozotocin solution (35 mg/kg) to establish T2DM model. After successful modeling, the 12 rats were randomly divided into a model group and an EA group, with 6 rats in each group. The EA group received EA at bilateral "Zusanli" (ST 36), "Sanyinjiao" (SP 6), "Weiwanxiashu" (EX-B 3), and "Pishu" (BL 20), with continuous wave, frequency of 15 Hz, current intensity of 2 mA, for 20 min each time, once a day, 6 times a week, for a total of 6 weeks. Fasting blood glucose (FBG) levels were measured before modeling and before and after intervention. After intervention, ELISA was used to detect the serum fasting insulin (FINS), IL-1ß and TNF-α levels, and the ß-cell function index (HOMA-ß) and insulin resistance index (HOMA-IR) were calculated; HE staining was used to observe the morphology of the pancreatic islets; Western blot was used to detect the protein expression of pancreatic forkhead box protein O1 (FoxO1), pancreatic and duodenal homeobox 1 (PDX-1), neurogenin 3 (NGN3), and NF-κB p65. RESULTS: After intervention, the FBG in the model group was higher than that in the control group (P<0.01), and the FBG in the EA group was lower than that in the model group (P<0.01). Compared with the control group, the model group had increased levels of serum FINS, IL-1ß, TNF-α, and HOMA-IR (P<0.01), and decreased HOMA-ß (P<0.01), reduced protein expression of pancreatic FoxO1 and PDX-1 (P<0.01), and increased protein expression of pancreatic NGN3 and NF-κB p65 (P<0.01, P<0.05). Compared with the model group, the EA group had lower serum FINS, IL-1ß, TNF-α levels, and HOMA-IR (P<0.01), higher HOMA-ß (P<0.05), increased protein expression of pancreatic FoxO1 and PDX-1 (P<0.01, P<0.05), and decreased protein expression of pancreatic NGN3 and NF-κB p65 (P<0.01, P<0.05). The control group's pancreatic islets showed no obvious abnormalities; the model group's pancreatic islets were irregular in shape and had unclear boundaries with the surrounding area, with immune cell infiltration, reduced ß-cell nuclei, disordered arrangement of islet cells, and increased intercellular spaces; the EA group showed improvements in islet morphology, immune cell infiltration, ß-cell nuclei count, and the arrangement and spacing of islet cells approaching normal. CONCLUSION: EA could lower the blood glucose levels in T2DM rats, alleviate chronic inflammatory responses in the islets, and improve the dedifferentiation of pancreatic ß-cells, which may be related to the inhibition of pancreatic NF-κB pathway expression.
Sujet(s)
Diabète de type 2 , Électroacupuncture , Cellules à insuline , Interleukine-1 bêta , Facteur de transcription NF-kappa B , Rat Wistar , Animaux , Mâle , Rats , Diabète de type 2/thérapie , Diabète de type 2/métabolisme , Cellules à insuline/métabolisme , Facteur de transcription NF-kappa B/métabolisme , Humains , Interleukine-1 bêta/métabolisme , Facteur de nécrose tumorale alpha/métabolisme , Transduction du signal , Dédifférenciation cellulaire , Glycémie/métabolisme , Points d'acupuncture , Insuline/métabolismeRÉSUMÉ
Due to the presence of non-line-of-sight (NLOS) obstacles, the localization accuracy in ultra-wideband (UWB) wireless indoor localization systems is typically substantially lower. To minimize the influence of these environmental factors and improve the accuracy of indoor wireless positioning, this paper proposes a density clustering with noise combined with particle swarm optimization (DCNPSO) to improve UWB positioning. Which exploits the advantages of the density-based spatial clustering algorithm with noise (DBSCAN) and particle swarm optimization (PSO) algorithm. The experimental results show that the DCNPSO algorithm achieves 45.25% and 36.14% higher average positioning accuracy than the DBSCAN and PSO algorithms, respectively. The positioning error of this algorithm remains stable within 3 cm in static positioning and can achieve high accuracy in NLOS environments.
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Nanoplasmas induced by intense laser fields have attracted enormous attention due to their accompanied spectacular physical phenomena which are vigorously expected by the community of science and industry. For instance, the energetic electrons and ions produced in laser-driven nanoplasmas are significant for the development of compact beam sources. Nevertheless, effective confinement on the propagating charged particles, which was realized through magnetic field modulation and target structure design in big facilities, are largely absent in the microscopic regime. Here we introduce a reliable scheme to provide control on the emission direction of protons generated from surface ionization in gold nanoparticles driven by intense femtosecond laser fields. The ionization level of the nanosystem provides us a knob to manipulate the characteristics of the collective proton emission. The most probable emission direction can be precisely steered by tuning the excitation strength of the laser pulses. This work opens new avenue for controlling the ion emission in nanoplasmas and can vigorously promote the fields such as development of on-chip beam sources at micro-/nano-scales.
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USP1 has emerged as a novel and potential target for drug discovery in single therapeutic agents or combination with chemotherapy and molecular targeted therapy. In this study, based on the disclosed structure of ML323 and KSQ-4279, we designed and synthesized a series of pyrido[2,3-d]pyrimidin-7(8H)-one derivatives as potent USP1 inhibitors by cyclization strategy and the systematic structure-activity relationship exploration was conducted. The representative compounds 1k, 1m and 2d displayed excellent USP1/UAF inhibition and exhibited strong antiproliferation effect in NCI-H1299 cells. Further flow cytometry analysis revealed that they could arrest breast cancer cells MDA-MB-436 in the S phase. Inhibition mechanism study of compound 1m indicated these derivatives acted as reversible and noncompetitive USP1 inhibitors. Of note, the combination of compound 1m with PARP inhibitor olaparib generated enhanced cell killing in olaparib-resistant MDA-MB-436/OP cells, and compound 1m exhibited excellent oral pharmacokinetic properties in mice. Overall, our efforts may provide a reliable basis for the development of novel USP1 inhibitor as a single therapeutic agent and in combination with PARP inhibitors.
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Antinéoplasiques , Prolifération cellulaire , Conception de médicament , Tests de criblage d'agents antitumoraux , Pyrimidinones , Humains , Relation structure-activité , Prolifération cellulaire/effets des médicaments et des substances chimiques , Antinéoplasiques/pharmacologie , Antinéoplasiques/synthèse chimique , Antinéoplasiques/composition chimique , Animaux , Pyrimidinones/pharmacologie , Pyrimidinones/composition chimique , Pyrimidinones/synthèse chimique , Structure moléculaire , Souris , Lignée cellulaire tumorale , Relation dose-effet des médicaments , Antienzymes/pharmacologie , Antienzymes/synthèse chimique , Antienzymes/composition chimique , Ubiquitin-specific proteases/antagonistes et inhibiteurs , Ubiquitin-specific proteases/métabolismeRÉSUMÉ
The predictive power of B-type natriuretic peptide (BNP) and left ventricular ejection fraction (LVEF) is limited by its low specificity in patients with heart failure (HF). Discovery of more novel biomarkers for HF better diagnosis is necessary and urgent. ELABELA, an early endogenous ligand for the G protein-coupled receptor APJ (Apelin peptide jejunum, Apelin receptor), exhibits cardioprotective actions. However, the relationship between plasma ELABELA and cardiac function in HF patients is unclear. To evaluate plasma ELABELA level and its diagnostic value in HF patients, a total of 335 patients with or without HF were recruited for our monocentric observational study. Plasma ELABELA and Apelin levels were detected by immunoassay in all patients. Spearman correlation analysis was used to analyze the correlation between plasma ELABELA or Apelin levels and study variables. The receiver operating characteristic curves were used to access the predictive power of plasma ELABELA or Apelin levels. Plasma ELABELA levels were lower, while plasma Apelin levels were higher in HF patients than in non-HF patients. Plasma ELABELA levels were gradually decreased with increasing New York Heart Association grade or decreasing LVEF. Plasma ELABELA levels were negatively correlated with BNP, left atrial diameter, left ventricular end-diastolic diameter, left ventricular end-systolic diameter, and left ventricular posterior wall thickness and positively correlated with LVEF in HF patients. In contrast, the correlation between plasma Apelin levels and these parameters is utterly opposite to ELABELA. The diagnostic value of ELABELA, Apelin, and LVEF for all HF patients was 0.835, 0.673, and 0.612; the sensitivity was 62.52, 66.20, and 32.97%; and the specificity was 95.92, 67.23, and 87.49%, respectively. All these parameters in HF patients with preserved ejection fraction were comparable to those in total HF patients. Overall, plasma ELABELA levels were significantly reduced and negatively correlated with cardiac function in HF patients. Decreased plasma ELABELA levels may function as a novel screening biomarker for HF. A combined assessment of BNP and ELABELA may be a good choice to increase the accuracy of the diagnosis of HF.
Sujet(s)
Apeline , Marqueurs biologiques , Défaillance cardiaque , Hormones peptidiques , Humains , Défaillance cardiaque/sang , Défaillance cardiaque/diagnostic , Mâle , Femelle , Hormones peptidiques/sang , Adulte d'âge moyen , Marqueurs biologiques/sang , Sujet âgé , Apeline/sang , Débit systolique , Courbe ROC , Peptide natriurétique cérébral/sang , Fonction ventriculaire gauche , Études de cohortesRÉSUMÉ
Methionine adenosyltransferase 2 A (MAT2A) mediates the synthesis of methyl donor S-Adenosylmethionine (SAM), providing raw materials for methylation reactions in cells. MAT2A inhibitors are currently used for the treatment of tumors with methylthioadenosine phosphorylase (MTAP) deficiency in clinical research. Methyltransferase like 3 (METTL3) catalyzes N6-methyladenosine (m6A) modification of mRNA in mammalian cells using SAM as the substrate which has been shown to affect the tumorigenesis of non-small cell lung cancer (NSCLC) from multiple perspectives. MAT2A-induced SAM depletion may have the potential to inhibit the methyl transfer function of METTL3. Therefore, in order to expand the applicability of inhibitors, improve anti-tumor effects and reduce toxicity, the combinational effect of MAT2A inhibitor AG-270 and METTL3 inhibitor STM2457 was evaluated in NSCLC. The results showed that this combination induced cell apoptosis rather than cell cycle arrest, which was non-tissue-specific and was independent of MTAP expression status, resulting in a significant synergistic anti-tumor effect. We further elucidated that the combination-induced enhanced apoptosis was associated with the decreased m6A level, leading to downregulation of PI3K/AKT protein, ultimately activating the apoptosis-related proteins. Unexpectedly, although combination therapy resulted in metabolic recombination, no significant change in methionine metabolic metabolites was found. More importantly, the combination also exerted synergistic effects in vivo. In summary, the combination of MAT2A inhibitor and METTL3 inhibitor showed synergistic effects both in vivo and in vitro, which laid a theoretical foundation for expanding the clinical application research of the two types of drugs.
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Apoptose , Carcinome pulmonaire non à petites cellules , Synergie des médicaments , Tumeurs du poumon , Methionine adenosyltransferase , Methyltransferases , Animaux , Humains , Souris , Antinéoplasiques/pharmacologie , Apoptose/effets des médicaments et des substances chimiques , Carcinome pulmonaire non à petites cellules/traitement médicamenteux , Carcinome pulmonaire non à petites cellules/anatomopathologie , Carcinome pulmonaire non à petites cellules/métabolisme , Lignée cellulaire tumorale , Antienzymes/pharmacologie , Tumeurs du poumon/traitement médicamenteux , Tumeurs du poumon/anatomopathologie , Tumeurs du poumon/métabolisme , Methionine adenosyltransferase/métabolisme , Methionine adenosyltransferase/antagonistes et inhibiteurs , Methionine adenosyltransferase/génétique , Methyltransferases/métabolisme , Methyltransferases/antagonistes et inhibiteurs , Souris de lignée BALB C , Souris nude , Tests d'activité antitumorale sur modèle de xénogreffeRÉSUMÉ
Objective: This study aimed to investigate the diagnostic value of a combination of anti-extractable nuclear antigens (anti-ENA) antibodies, anti-cardiolipin antibodies (ACA), and anti-ß2-glycoprotein 1 (anti-ß2 GPI) antibodies in patients with systemic lupus erythematosus (SLE). Methods: A total of 646 SLE patients diagnosed in our hospital between January 2020 and April 2023 were randomly selected as study subjects, while 2075 non-SLE subjects during the same period were selected as the control group. The levels of anti-extractable nuclear antigen (ENA) antibody, ACA, and anti-ß2 GPI antibodies were measured, and their diagnostic value for SLE was analyzed using binary logistic regression and receiver operating characteristic (ROC) analysis. Results: The rates of positive anti-RNP, anti-Sm, anti-Sjögren's syndrome (SS-A), and anti-SS-B antibodies in the SLE patient group were significantly higher than those in the control group, with all differences being statistically significant (P < 0.01). The rates of positive ACA, as well as the levels of ACA IgA, ACA IgG, and ACA IgM, were significantly higher in the SLE patients group compared to the control group, with statistically differences (P < 0.05). Similarly, the rates of positive anti-ß2 GPI antibodies, anti-ß2 GPI antibody IgA, IgG, and IgM, were significantly higher in the SLE patient group compared to the control group, with all differences being statistically significant (P < 0.01). Gender, age, positive anti-JO1 antibodies, positive anti-RNP antibodies, positive anti-SS-A antibodies, positive ACA, high level ACA IgG and ACA IgM, positive anti-ß2 GPI antibodies, and high level of anti-ß2 GPI antibody IgA were identified as independent risk factors for the development of SLE (P < 0.05). The combined use of age, sex, anti-ENA antibodies, ACA, and anti-ß2 GPI antibodies yielded a sensitivity of 82.12% (80.41%-83.71%) and a specificity of 80.03% (76.77%-82.93%) for the diagnosis of SLE. Conclusion: The combination of age, sex, anti-ENA antibodies, ACA, and anti-ß2 GPI antibodies shows high diagnostic value for SLE and holds potential for clinical application as an auxiliary diagnostic tool for SLE.
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Agents that inhibit bromodomain and extra-terminal domain (BET) proteins have been actively tested in the clinic as potential anticancer drugs. NEDD8-activating enzyme (NAE) inhibitors, represented by MLN4924, target the only activation enzyme in the neddylation pathway that has been identified as an attractive target for cancer therapy. In this study, we focus on the combination of BET inhibitors (BETis) and NAE inhibitors (NAEis) as a cancer therapeutic strategy and investigate its underlying mechanisms to explore and expand the application scope of both types of drugs. The results showed that this combination synergistically inhibited the proliferative activity of tumor cells from different tissues. Compared to a single drug, combination therapy had a weak effect on cycle arrest but significantly enhanced cell apoptosis. Furthermore, the growth of NCI-H1975 xenografts in nude mice was significantly inhibited by the combination without obvious body weight loss. Research on the synergistic mechanism demonstrated that combination therapy significantly increased the mRNA and protein levels of the proapoptotic gene BIM. The inhibition and knockout of BIM significantly attenuated the apoptosis induced by the combination, whereas the re-expression of BIM restored the synergistic effects, indicating that BIM induction plays a critical role in mediating the enhanced apoptosis induced by the co-inhibition of BET and NAE. Together, the enhanced transcription mediated by miR-17-92 cluster inhibition and reduced degradation promoted the increase in BIM levels, resulting in a synergistic effect. Collectively, these findings highlight the need for further clinical investigation into the combination of BETi and NAEi as a promising strategy for cancer therapy.
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Antinéoplasiques , Tumeurs , Animaux , Humains , Souris , Antinéoplasiques/pharmacologie , Apoptose , Lignée cellulaire tumorale , Cyclopentanes/pharmacologie , Souris nude , Protéine-11 analogue à Bcl-2/métabolismeRÉSUMÉ
Mycotoxins, as secondary metabolites produced by fungi, have been the focus of researchers in various countries and are considered to be one of the major risk factors in agricultural products. There is an urgent need for a rapid, simple and high-performance method to detect residues of harmful mycotoxins in agricultural foods. We have developed a gold nanoparticle-based multiplexed immunochromatographic strip biosensor that can simultaneously detect fifteen mycotoxins in cereal samples. With this optimized procedure, five representative mycotoxins, deoxynivalenol (DON), zearalenone (ZEN), T-2 toxin (T-2), tenuazonic acid (TEA) and alternariol (AOH) were detected in the range of 0.91-4.77, 0.04-0.56, 0.11-0.68, 0.12-1.02 and 0.09-0.75 ng/mL, respectively. The accuracy and stability of these measurements were demonstrated by analysis of spiked samples with recoveries of 91.8%-115.3% and coefficients of variation <8.7%. In addition, commercially available samples of real cereals were tested using the strips and showed good agreement with the results verified by LC-MS/MS. Therefore, Our assembled ICA strips can be used for the simultaneous detection of 5 mycotoxins and their analogs (15 mycotoxins in total) in grain samples, and the results were consistent between different types of cereal foods, this multiplexed immunochromatographic strip biosensor can be used as an effective tool for the primary screening of mycotoxin residues in agricultural products.
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Nanoparticules métalliques , Mycotoxines , Mycotoxines/analyse , Or/analyse , Or/composition chimique , Chromatographie en phase liquide , Contamination des aliments/analyse , Nanoparticules métalliques/analyse , Nanoparticules métalliques/composition chimique , Spectrométrie de masse en tandem , Grains comestibles/microbiologieRÉSUMÉ
ETHNOPHARMACOLOGICAL RELEVANCE: Liujunzi formula has been used to treat liver cancer in China for many years, but its underlying mechanism remains unclear. We previously found that decreased expression of miR-122-3p was associated with liver cancer. In this study, we aimed to explore the target of miR-122-3p and the effect of the Liujunzi formula on miR-122-3p and its downstream events in liver cancer. MATERIAL AND METHODS: Bioinformatics pinpointed potential targets of miR-122-3p. The actual target was confirmed by miRNA mimic/inhibitor transfections and a dual-luciferase reporter assay. RNA-seq looked at downstream genes impacted by this target. Flow cytometry checked for changes in T cell apoptosis levels after exposing them to liver cancer cells. Gene expression was measured by RT-qPCR, western blotting, and immunofluorescence staining. RESULTS: Cell experiments found the Liujunzi extract (LJZ) upregulated miR-122-3p and in a dose-dependent manner. Bioinformatics analysis found UBE2I was a potential target of miR-122-3p, which was validated through experiments using miRNA mimics/inhibitors and a dual-luciferase reporter assay. RNA-seq data implicated the NF-κB pathway as being downstream of the miR-122-3p/UBE2I axis, further confirmed by forcing overexpression of UBE2I. Bioinformatic evidence suggested a link between UBE2I and T cell infiltration in liver cancer. Given that the NF-κB pathway drives PD-L1 expression, which can inhibit T cell infiltration, we investigated whether PD-L1 is a downstream effector of miR-122-3p/UBE2I. This was corroborated through mining public databases, UBE2I overexpression studies, and tumor-T cell co-culture assays. In addition, we also confirmed that LJZ downregulates UBE2I and NF-κB/PD-L1 pathways through miR-122-3p. LJZ also suppressed SUMOylation in liver cancer cells and protected PD-1+ T cells from apoptosis induced by co-culture with tumor cells. Strikingly, a miR-122-3p inhibitor abrogated LJZ's effects on UBE2I and PD-L1, and UBE2I overexpression rescued the LJZ-mediated effects on NF-κB and PD-L1. CONCLUSIONS: miR-122-3p targets UBE2I, thereby suppressing the NF-κB signaling cascade and downregulating PD-L1 expression, which potentiates anti-tumor immune responses. LJZ bolsters anti-tumor immunity by modulating the miR-122-3p/UBE2I/NF-κB/PD-L1 axis in liver cancer cells.
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Médicaments issus de plantes chinoises , Tumeurs du foie , microARN , Ubiquitin-conjugating enzymes , microARN/génétique , microARN/métabolisme , Tumeurs du foie/traitement médicamenteux , Tumeurs du foie/génétique , Humains , Ubiquitin-conjugating enzymes/génétique , Ubiquitin-conjugating enzymes/métabolisme , Médicaments issus de plantes chinoises/pharmacologie , Apoptose/effets des médicaments et des substances chimiques , Facteur de transcription NF-kappa B/métabolisme , Lignée cellulaire tumorale , Régulation de l'expression des gènes tumoraux/effets des médicaments et des substances chimiques , Transduction du signal/effets des médicaments et des substances chimiques , Cellules HepG2 , Tolérance immunitaire/effets des médicaments et des substances chimiquesRÉSUMÉ
CONTENT: Ubiquitin, a ubiquitous small protein found in all living organisms, is crucial for tagging proteins earmarked for degradation and holds pivotal importance in biomedicine. Protein functionality is intricately linked to its structure. To comprehend the impact of diverse temperatures on ubiquitin protein structure, our study delved into the energy landscape, hydrogen bonding, and overall structural stability of ubiquitin protein at varying temperatures. Through meticulous analysis of root mean square deviation and root mean square fluctuation, we validated the robustness of the simulation conditions employed. Within our simulated system, the bonding energy and electrostatic potential energy exhibited linear augmentation, while the van der Waals energy demonstrated a linear decline. Additionally, our findings highlighted that the α-Helix secondary structure of the ubiquitin protein gradually transitions toward helix destabilization under high-temperature conditions. The secondary structure of ubiquitin protein experiences distinct changes under varying temperatures. The outcomes of our molecular simulations offer a theoretical framework that enhances our comprehension of how temperature impacts the structural stability of ubiquitin protein. These insights contribute not only to a deeper understanding of iniquity's behavior but also hold broader implications in the realm of biomedicine and beyond. METHODS: All the MD simulations were performed using the GROMACS software with GROMOS96 force field and SPC for water. The ubiquitin protein was put in the center of a cubic box with a length of 8 nm, a setting that allowed > 0.8 nm in the minimal distance between the protein surface and the box wall. To remove the possible coordinate collision of the configurations, in the beginning, the steepest descent method was used until the maximum force between atoms was under 100 kJ/mol·nm with a 0.01 nm step size. Minimization was followed by 30 ps of position-restrained MD simulation. The protein was restrained to its initial position, and the solvent was freely equilibrated. The product phase was obtained with the whole system simulated for 10 ns without any restraint using an integral time step of 1 fs with different temperatures. The cutoff for short-range electronic interaction was set to 1.5 nm. The long-range interactions were treated with a particle-mesh Ewald (PME) method with a grid width of 1.2 nm.
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Simulation de dynamique moléculaire , Ubiquitine , Température , Protéines membranaires , Conformation moléculaireRÉSUMÉ
Transition metal sulfides (TMSs) are considered as promising anode materials for sodium-ion batteries (SIBs) due to their high theoretical capacities. However, the relatively low electrical conductivity, large volume variation, and easy aggregation/pulverization of active materials seriously hinder their practical application. Herein, okra-like NiS2/FeS2 particles encapsulated in multichannel N-doped carbon nanofibers (NiS2/FeS2@MCNFs) are fabricated by a coprecipitation, electrospinning, and carbonization/sulfurization strategy. The combined advantages arising from the hollow multichannel structure in carbon skeleton and heterogeneous NiS2/FeS2 particles with rich interfaces can provide facile ion/electron transfer paths, ensure boosted reaction kinetics, and help maintain the structural integrity, thereby resulting in a high reversible capacity (457 mA h g-1 at 1 A g-1), excellent rate performance (350 mA h g-1 at 5 A g-1), and outstanding long-term cycling stability (93.5% retention after 1100 cycles). This work provides a facile and efficient synthetic strategy to develop TMS-based heterostructured anode materials with high-rate and stable sodium storage properties.
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Microglial Na/H exchanger-1 (NHE1) protein, encoded by Slc9a1, plays a role in white matter demyelination of ischemic stroke brains. To explore underlying mechanisms, we conducted single cell RNA-seq transcriptome analysis in conditional Slc9a1 knockout (cKO) and wild-type (WT) mouse white matter tissues at 3 days post-stroke. Compared to WT, Nhe1 cKO brains expanded a microglial subgroup with elevated transcription of white matter myelination genes including Spp1, Lgals3, Gpnmb, and Fabp5. This subgroup also exhibited more acidic pHi and significantly upregulated CREB signaling detected by ingenuity pathway analysis and flow cytometry. Moreover, the Nhe1 cKO white matter tissues showed enrichment of a corresponding oligodendrocyte subgroup, with pro-phagocytosis and lactate shuffling gene expression, where activated CREB signaling is a likely upstream regulator. These findings demonstrate that attenuation of NHE1-mediated H+ extrusion acidifies microglia/macrophage and may underlie the stimulation of CREB1 signaling, giving rise to restorative microglia-oligodendrocyte interactions for remyelination.
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Encéphale , Microglie , Échangeur-1 de sodium-hydrogène , Animaux , Souris , Encéphale/métabolisme , Récepteur-1 de la chimiokine CX3C/métabolisme , Macrophages/métabolisme , Microglie/métabolisme , Oligodendroglie/métabolisme , Transduction du signal/génétique , Échangeur-1 de sodium-hydrogène/métabolismeRÉSUMÉ
Contamination of oilfield chemicals (OFCs) by benzo[a]pyrene (B[a]P) is increasingly becoming a severe environmental security issue. There is an urgent need to develop a rapid and accurate method for B[a]P detection in OFCs. In this study, B[a]P hapten was designed using computer aided molecular design. A high-affinity, specific, and matrix-insensitive monoclonal antibody (mAb) with IC50 values of 6.77 ng/mL was obtained. Based on this mAb, we developed a rapid gold nanoparticle-based immunochromatographic strip assay (GICA) with double T-line mode for on-site detection of B[a]P in OFCs samples. The GICA exhibited excellent detection performance in OFCs samples with strong acidity, strong alkalinity, and deep color. Under optimal conditions, the proposed method detected B[a]P in OFCs at 0.42-300 mg/kg, and limit of detection was 0.23-1.07 mg/kg. The recovery rate was 88-106% with a coefficient of variation of 1.46-6.35%. Confirmed by natural positive OFCs samples and high-performance liquid chromatography, this GICA is accurate and reliable, with great potential for rapid and cost-effective on-site detection.
Sujet(s)
Or , Nanoparticules métalliques , Or/composition chimique , Benzo[a]pyrène , Analyse coût-bénéfice , Champs de pétrole et de gaz , Nanoparticules métalliques/composition chimique , Chromatographie d'affinité , Dosage immunologique/méthodes , Anticorps monoclonaux , Limite de détectionRÉSUMÉ
Amitraz (AMT) is a broad-spectrum formamidine insecticide and acaricide. In this study, we produced an anti-AMT monoclonal antibody (mAb) with high performance. The half-maximal inhibitory concentration of the anti-AMT mAb was 4.418 ng/mL, the cross reactivity with other insecticides was negligible, and an affinity constant was 2.06 × 109 mmol/L. Additionally, we developed an immunochromatographic assay for the rapid detection of AMT residues in oranges, tomatoes, and eggplants. The cut-off values were 2000 µg/kg in oranges and tomato samples and 1000 µg/kg in eggplant samples and the calculated limits of detection were 14.521 µg/kg, 6.281 µg/kg, and 3.518 µg/kg in oranges, tomatoes, and eggplants, respectively, meeting the detection requirements for AMT in fruits and vegetables. The recovery rates ranged between 95.8 % and 105.2 %, consistent with the recovery rates obtained via LC-MS/MS. Our developed immunochromatographic assay can effectively, accurately, and rapidly determine AMT residues in oranges, tomatoes, and eggplants.