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Mercury (Hg) is a persistent soil pollutant, and its toxicity can be evaluated using soil enzyme indicators. However, a thorough understanding of how the enzyme resists and remains resilient to Hg stress is essential, as it significantly impacts the accuracy of toxicity assessments. Therefore, it is worthwhile to understand the functional stability of urease in soil under Hg pollution. This study compares the effects of Hg at different concentrations and exposure times on soil urease. Results indicate that soil urease activity was enhanced in the first two hours under low levels of Hg pollution, decreased after six hours of acute Hg pollution, and reached its maximum reduction in 24 hours. The urease in fluvo-aquic soil, with higher soil organic matter showed higher resistance to Hg acute pollution than that in red soil. Over a longer aging process, soil urease activity gradually recovered with time. Hormesis effects were observed in red soil under high Hg stress after 30 days, showing the strong resilience of urease enzyme function to Hg pollution. The ecological dose, ED10, (the Hg concentration causing a 10% reduction in soil urease activity) ranged from 0.09 to 0.59 mg kg-1 under short-term exposure, and was lower than that under a longer aging process (0.28 to 2.71 mg kg-1). Further, aging reduced the Hg ecotoxicity due to decreased Hg availability and the resilience of soil urease activity. This indicates that the risk of Hg pollution estimated by soil urease as an indicator depends on exposure time and enzyme stability. These factors need consideration in heavy metal pollution assessments using soil enzymes.
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INTRODUCTION: Inflammatory bowel disease (IBD) is a chronic idiopathic inflammatory disorder that arises from complex interactions between genetics, environment and gut microbiota. It encompasses Crohn's disease, ulcerative colitis and IBD-unclassified. The protracted course of IBD imposes a significant burden on patients' quality of life, economic productivity, social functioning, as well as treatment, hospitalisation and surgery. This study aims to conduct an umbrella review of meta-analyses to systematically evaluate the methodology's quality, potential biases and validity of all epidemiological evidence focused on risk factors for IBD while providing an overview of the evidence concerning IBD risk factors. METHODS AND ANALYSIS: We will systematically search, extract and analyse data from reported systematic reviews and meta-analyses that specifically focus on the risk factors of IBD, following the guidelines outlined in Preferred Reporting Items for Overviews of Reviews. Our search will encompass PubMed, Embase, Web of Science and the Cochrane Database of Systematic Reviews from the initial period up until April 2023 (last update), targeting systematic reviews and meta-analyses based on non-interventional studies. Inclusion criteria allow for systematic reviews and meta-analyses evaluating IBD risk factors across all countries and settings, regardless of ethnicity or sex. The identified risk factors will be categorised according to the health ecological model into innate personal traits, behavioural lifestyles, interpersonal networks, socioeconomic status and macroenvironments. To assess methodological quality for each meta-analysis included in our study, two authors will employ a measurement tool to assess the methodological quality of systematic reviews (AMSTAR)-2, Grading of Recommendations, Assessment, Development and Evaluation (GRADE) criteria along with evidence classification criteria. ETHICS AND DISSEMINATION: Ethical approval is not required for this umbrella review. We will seek to submit the results for publication in a peer-reviewed journal or present it at conferences. PROSPERO REGISTRATION NUMBER: CRD42023417175.
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Doenças Inflamatórias Intestinais , Metanálise como Assunto , Projetos de Pesquisa , Revisões Sistemáticas como Assunto , Humanos , Fatores de RiscoRESUMO
Spectroscopic exploration of sulfur-centered hydrogen bonding involving a thiol group (S-H) as the hydrogen bond donor is scarce in the literature. Herein, we have investigated 1:1 complexes of 2-fluorothiophenol (2-FTP) with methanol (MeOH) and ethanol (EtOH) in the gas phase to examine the physical characteristics and strength of the S-Hâ¯O hydrogen bond. Structures, conformations, and the strength of the S-Hâ¯O interaction are investigated by measuring the electronic and Infrared (IR) spectra of the two complexes employing resonant two-photon ionization, UV-UV hole-burning, and IR-UV double resonance spectroscopic techniques combined with quantum chemical calculations. Three conformers of 2-FTPâ¯MeOH and two conformers of 2-FTPâ¯EtOH have been detected in the experiment. A comparison of the IR spectra obtained from the experiment with those of the low-energy conformers of 2-FTPâ¯MeOH and 2-FTPâ¯EtOH predicted from the theory confirms that all the observed conformers of the two complexes are primarily S-Hâ¯O hydrogen bonded. The IR red-shifts found in the S-H stretching frequencies in 2-FTPâ¯MeOH and 2-FTPâ¯EtOH concerning that in 2-FTP are â¼76 and â¼88 cm-1, respectively, which are much larger than that was reported earlier in the 2-FTPâ¯H2O complex (30 cm-1). The strength and physical nature of different noncovalent interactions, including the S-Hâ¯O hydrogen bond existing in the complexes, are further analyzed using natural bond orbital analysis, quantum theory of atoms in molecules, and localized molecular orbital-energy decomposition analysis. The current investigation reveals that the S-Hâ¯O hydrogen bond can be strengthened by judicial choices of the hydrogen bond acceptors of higher proton affinities.
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MALT1 has been implicated as an upstream regulator of NF-κB signaling in immune cells and tumors. This study determined the regulatory mechanisms and biological functions of MALT1 in non-small cell lung cancer (NSCLC). In cell culture and orthotopic xenograft models, MALT1 suppression via gene expression interference or protein activity inhibition significantly impaired malignant phenotypes and enhanced radiation sensitivity of NSCLC cells. CSN5, the core subunit of COP9 signalosome, was firstly verified to stabilize MALT1 via disturbing the interaction with E3 ligase FBXO3. Loss of FBXO3 in NSCLC cells reduced MALT1 ubiquitination and promoted its accumulation, which was reversed by CSN5 interference. An association between CSN5/FBXO3/MALT1 regulatory axis and poor prognosis in NSCLC patients was identified. Our findings revealed the detail mechanism of continuous MALT1 activation in NF-κB signaling, highlighting its significance as predictor and potential therapeutic target in NSCLC.
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Complexo do Signalossomo COP9 , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa , NF-kappa B , Transdução de Sinais , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/metabolismo , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/genética , Humanos , Complexo do Signalossomo COP9/metabolismo , Complexo do Signalossomo COP9/genética , NF-kappa B/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Animais , Linhagem Celular Tumoral , Camundongos , Camundongos Nus , Ubiquitinação , Peptídeo Hidrolases/metabolismo , Peptídeo Hidrolases/genética , Progressão da Doença , Camundongos Endogâmicos BALB C , Feminino , Proteínas F-Box/metabolismo , Proteínas F-Box/genética , Peptídeos e Proteínas de Sinalização IntracelularRESUMO
Idiopathic pulmonary fibrosis treatments are limited, often with severe side effects, highlighting the need for novel options. Taraxerone has diverse biomedical properties, but its mechanism remains unclear. This study investigates taraxerone's impact and the mechanisms involved in bleomycin-induced pulmonary fibrosis in mice. After establishing a pulmonary fibrosis mouse model, taraxerone was intraperitoneally injected continuously for 14-28 days. The in vivo antifibrotic and antioxidative stress effects of taraxerone were assessed. In vitro, the influence of taraxerone on transforming growth factor-ß1-induced myofibroblast transformation and oxidative stress was investigated. Subsequently, quantitative polymerase chain reaction screened the histone deacetylase and Sirtuin family, and taraxerone's effects on SIRT1 were assessed. After SIRT1 siRNA treatment, changes in myofibroblast transformation and antioxidant capacity in response to taraxerone were observed. Acetylation and phosphorylation levels of Smad3 were evaluated. We also examined the binding levels of SIRT1 with Pho-Smad3 and Smad3, as well as the nuclear localization of Smad2/3. EX527 confirmed SIRT1's in vivo action in response to taraxerone. In vitro experiments suggested that taraxerone inhibited myofibroblast differentiation by activating SIRT1 and reducing oxidative stress. We also observed a new interaction between SIRT1 and the Smad complex. Taraxerone activates SIRT1, enabling it to bind directly to Smad3. This leads to reduced Smad complex phosphorylation and limited nuclear translocation. As a result, the transcription of fibrotic factors is reduced. In vivo validation confirms taraxerone's SIRT1-mediated antifibrotic effectiveness. This suggests that targeting SIRT1-mediated inhibition of myofibroblast differentiation could be a key strategy in taraxerone-based therapy for pulmonary fibrosis.
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Antioxidantes , Bleomicina , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Fibrose Pulmonar , Transdução de Sinais , Sirtuína 1 , Proteína Smad3 , Fator de Crescimento Transformador beta1 , Animais , Sirtuína 1/metabolismo , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Camundongos , Transdução de Sinais/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Proteína Smad3/metabolismo , Antioxidantes/farmacologia , Masculino , Fator de Crescimento Transformador beta1/metabolismo , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , Modelos Animais de Doenças , Fosforilação , AcetilaçãoRESUMO
The safe and effective delivery of messenger ribonucleic acid (mRNA) is crucial for its therapeutic effects in vivo. In this study, we developed a new type of ionizable lipid S-1, which contains an amino head, a cholesterol matrix, and a long hydrophobic carbon tail. We employed microfluidics to rapidly mix an ethanol phase containing S-1 lipid with an aqueous mRNA to form mRNA/S-1 lipid nanoparticles (LNPs, 100-200â¯nm). We observed low cytotoxicity and high transfection efficiency in RAW264.7 and HCT-116 cell lines for mRNA/S-1 LNPs, comparable to mRNA/SM-102 LNPs. Based on the obtained findings, mRNA/S-1 LNPs have good stability, low cytotoxicity, high transfection efficiency, and enhanced cellular uptake. The synthesized S-1 lipid ensures efficient assembly of lipid nanoparticles, protects mRNA from RNase degradation, and enables the delivery of mRNA into the cytoplasm for translation.
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Colesterol , Lipídeos , Nanopartículas , RNA Mensageiro , RNA Mensageiro/genética , Humanos , Colesterol/química , Lipídeos/química , Camundongos , Animais , Nanopartículas/química , Células RAW 264.7 , Células HCT116 , Transfecção/métodos , Tamanho da Partícula , Sobrevivência Celular/efeitos dos fármacosRESUMO
Artemisinin has an endoperoxide bridge structure, which can be cleaved by ferrous ions to generate various carbonyl radicals in an oxygen-independent manner, highlighting its potential for treating hypoxic tumors. In our study, we fabricated Tween 80 micelles loaded with Fe3O4 nanoparticles and artemisinin for cancer therapy. The synthesized Fe3O4 nanoparticles and drug-loaded micelles have particle sizes of about 5 nm and 80 nm, respectively, both exhibiting excellent dispersibility and stability. After uptake by MCF-7 cells, drug-loaded micelles release Fe2+ and ART into the cytoplasm, effectively inducing the generation of reactive oxygen species (ROS) in hypoxic conditions, thereby enhancing toxicity against cancer cells. In vitro and in vivo studies have demonstrated that ART and Fe3O4 nanoparticles are encapsulated in Tween 80 to form micelles, which effectively prevent premature release during circulation in the body. Although free ART and Fe3O4 nanoparticles can inhibit tumor growth, TW80-Fe3O4-ART micelles demonstrate a more pronounced inhibitory effect, with a tumor suppression rate of up to 85%. A novel strategy based on artemisinin and ferroptosis is thus offered, holding a favorable prospect for hypoxic cancer therapy.
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RATIONALE AND OBJECTIVES: We examined the effectiveness of computed tomography (CT)-based deep learning (DL) models in differentiating benign and malignant solid pulmonary nodules (SPNs) ≤ 8 mm. MATERIALS AND METHODS: The study patients (n = 719) were divided into internal training, internal validation, and external validation cohorts; all had small SPNs and had undergone preoperative chest CTs and surgical resection. We developed five DL models incorporating features of the nodule and five different peri-nodular regions with the Multiscale Dual Attention Network (MDANet) to differentiate benign and malignant SPNs. We selected the best-performing model, which was then compared to four conventional algorithms (VGG19, ResNet50, ResNeXt50, and DenseNet121). Furthermore, another five DL models were constructed using MDANet to distinguish benign tumors from inflammatory nodules and the one performed best was selected out. RESULTS: Model 4, which incorporated the nodule and 15 mm peri-nodular region, best differentiated benign and malignant SPNs. The model had an area under the curve (AUC), accuracy, recall, precision, and F1-score of 0.730, 0.724, 0.711, 0.705, and 0.707 in the external validation cohort. Model 4 also performed better than the other four conventional algorithms. Model 8, which incorporated the nodule and 10 mm peri-nodular region, was the best model for distinguishing benign tumors from inflammatory nodules. The model had an AUC, accuracy, recall, precision, and F1-score of 0.871, 0.938, 0.863, 0.904, and 0.882 in the external validation cohort. CONCLUSION: The study concludes that CT-based DL models built with MDANet can accurately discriminate among small benign and malignant SPNs, benign tumors and inflammatory nodules.
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The senescence of alveolar epithelial cells (AECs) and fibroblasts plays a pivotal role in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a condition lacking specific therapeutic interventions. Curculigoside (CCG), a prominent bioactive constituent of Curculigo, exhibits anti-osteoporotic and antioxidant activities. Our investigation aimed to elucidate the anti-senescence and anti-fibrotic effects of CCG in experimental pulmonary fibrosis and delineate its underlying molecular mechanisms. Our findings demonstrate that CCG attenuates bleomycin-induced pulmonary fibrosis and lung senescence in murine models, concomitantly ameliorating lung function impairment. Immunofluorescence staining for senescence marker p21, alongside SPC or α-SMA, suggested that CCG's mitigation of lung senescence correlates closely with the deceleration of senescence in AECs and fibroblasts. In vitro, CCG mitigated H2O2-induced senescence in AECs and the natural senescence of primary mouse fibroblasts. Mechanistically, CCG can upregulate SIRT1 expression, downregulating P300 expression, enhancing Trim72 expression to facilitate P300 ubiquitination and degradation, reducing the acetylation levels of antioxidant enzymes, and upregulating their expression levels. These actions collectively inhibited endoplasmic reticulum stress (ERS) and alleviated senescence. Furthermore, the anti-senescence effects and mechanisms of CCG were validated in a D-galactose (D-gal)-induced progeroid model. This study provides novel insights into the mechanisms underlying the action of CCG in cellular senescence and chronic diseases, offering potential avenues for the development of innovative drugs or therapeutic strategies.
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Background: Predicting the severity of acute pancreatitis (AP) early poses a challenge in clinical practice. While there are well-established clinical scoring tools, their actual predictive performance remains uncertain. Various studies have explored the application of machine-learning methods for early AP prediction. However, a more comprehensive evidence-based assessment is needed to determine their predictive accuracy. Hence, this systematic review and meta-analysis aimed to evaluate the predictive accuracy of machine learning in assessing the severity of AP. Methods: PubMed, EMBASE, Cochrane Library, and Web of Science were systematically searched until December 5, 2023. The risk of bias in eligible studies was assessed using the Prediction Model Risk of Bias Assessment Tool (PROBAST). Subgroup analyses, based on different machine learning types, were performed. Additionally, the predictive accuracy of mainstream scoring tools was summarized. Results: This systematic review ultimately included 33 original studies. The pooled c-index in both the training and validation sets was 0.87 (95 % CI: 0.84-0.89) and 0.88 (95 % CI: 0.86-0.90), respectively. The sensitivity in the training set was 0.81 (95 % CI: 0.77-0.84), and in the validation set, it was 0.79 (95 % CI: 0.71-0.85). The specificity in the training set was 0.84 (95 % CI: 0.78-0.89), and in the validation set, it was 0.90 (95 % CI: 0.86-0.93). The primary model incorporated was logistic regression; however, its predictive accuracy was found to be inferior to that of neural networks, random forests, and xgboost. The pooled c-index of the APACHE II, BISAP, and Ranson were 0.74 (95 % CI: 0.68-0.80), 0.77 (95 % CI: 0.70-0.85), and 0.74 (95 % CI: 0.68-0.79), respectively. Conclusions: Machine learning demonstrates excellent accuracy in predicting the severity of AP, providing a reference for updating or developing a straightforward clinical prediction tool.
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Thermoresponsive wound dressings with real-time monitoring and on-demand drug delivery have gained significant attention recently. However, such smart systems with stable temperature adjustment and drug release control are still lacking. Here, a novel smart fabric is designed for wound management with thermoresponsive drug delivery and simultaneously temperature monitoring. The triple layers of the fabrics are composed of the drug-loaded thermoresponsive nanofiber film, the MXene-optimized joule heating film, and the FPCB control chip. The precise and stable temperature stimulation can be easily achieved by applying a low voltage (0-4 V) to the heating film, achieving the temperature control ranging from 25 to 130 °C. And the temperature of the wound region can be monitored and adjusted in real time, demonstrating an accurate and low-voltage joule heating capability. Based on that, the drug-loaded film achieved precise thermoresponsive drug release and obtained significant antibacterial effects in vitro. The in vivo experiments also proved the hybrid fabric system with a notable antibacterial effect and accelerated wound healing process (about 30% faster than the conventional gauze group).
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Near-infrared (NIR) spectra of H3O+â¯Xn (X = Ar, N2, and CO, n = 1-3) in the first overtone region of OH-stretching vibrations (4800-7000 cm-1) were measured. Not only OH-stretching overtones but also several combination bands are major features in this region, and assignments of these observed bands are not obvious at a glance. High-precision anharmonic vibrational simulations based on the discrete variable representation approach were performed. The simulated spectra show good agreement with the observed ones and provide firm assignments of the observed bands, except in the case of X = CO, in which higher order vibrational mode couplings seem significant. This agreement demonstrates that the present system can be a benchmark for high precision anharmonic vibrational computations of NIR spectra. Band broadening in the observed spectra becomes remarkable with an increase of the interaction with the solvent molecule (X). The origin of the band broadening is explored by rare gas tagging experiments and anharmonic vibrational simulations of hot bands.
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Purpose: Circular RNAs (circRNAs) are newly identified endogenous non-coding RNAs that function as crucial gene modulators in the development of several diseases. By assessing the expression levels of circRNAs in peripheral blood mononuclear cells (PBMCs) from patients with chronic obstructive pulmonary disease (COPD), this study attempted to find new biomarkers for COPD screening. Patients and Methods: We confirmed altered circRNA expression in PBMCs of COPD (n=41) vs controls (n=29). Further analysis focused on the highest and lowest circRNA expression levels. The T-test is used to assess the statistical variances in circRNAs among COPD patients in the smoking and non-smoking cohorts. Additionally, among smokers, the Spearman correlation test assesses the association between circRNAs and clinical indicators. Results: Two circRNAs, hsa_circ_0042590 and hsa_circ_0049875, that were highly upregulated and downregulated in PBMCs from COPD patients were identified and verified. Smokers with COPD had lower hsa_circ_0042590 and higher hsa_circ_0049875, in comparison to non-smokers. There was a significant correlation (r=0.52, P<0.01) between the number of acute exacerbations (AEs) that smokers with COPD experienced in the previous year and the following year (r=0.67, P<0.001). Moreover, hsa_circ_0049875 was connected to the quantity of AEs in the year prior (r=0.68, P<0.0001) as well as the year after (r=0.72, P<0.0001). AUC: 0.79, 95% CI: 0.1210-0.3209, P<0.0001) for hsa_circ_0049875 showed a strong diagnostic value for COPD, according to ROC curve analysis. Hsa_circ_0042590 showed a close second with an AUC of 0.83 and 95% CI: -0.1972--0.0739 (P <0.0001). Conclusion: This research identified a strong correlation between smoking and hsa_circ_0049875 and hsa_circ_0042590 in COPD PBMCs. The number of AEs in the preceding and succeeding years was substantially linked with the existence of hsa_circ_0042590 and hsa_circ_0049875 in COPD patients who smoke. Additionally, according to our research, hsa_circ_0049875 and hsa_circ_0042590 may be valuable biomarkers for COPD diagnosis.
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Doença Pulmonar Obstrutiva Crônica , RNA Circular , Humanos , RNA Circular/genética , Leucócitos Mononucleares/metabolismo , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/metabolismo , Biomarcadores/metabolismoRESUMO
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by the infiltration of inflammatory cells and proliferation of synovial cells. It can cause cartilage and bone damage as well as disability and is regarded as an incurable chronic disease. Available therapies cannot prevent the development of diseases due to the high toxicity of the therapeutic agents and the inefficient drug delivery. Ferroptosis, an iron-dependent manner of lipid peroxidative cell death, indicates great potential for RA therapy due to ability to damage the infiltrated inflammatory cells and proliferated fibroblast-like synoviocytes. Here, we use macrophages as vector to deliver Fe3O4 nanoparticles and sulfasalazine (SSZ) for ferroptosis and photothermal therapy of RA. The inherent property of migration towards the inflamed joints under the guidance of inflammatory factors enables macrophages to targetedly deliver the payload into the RA. Upon the irradiation of the near infrared light, the Fe3O4 nanoparticles convert the light into heat to damage the proliferated synovium. Meanwhile, the iron released from Fe3O4 nanoparticles works with SSZ to generate synergetic ferroptosis effect. The resident inflammatory cells and proliferated synovium are efficiently damaged by the ferroptosis and photothermal effect, showing pronounced therapeutic effect for RA.
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ETHNOPHARMACOLOGICAL RELEVANCE: Leech, as a traditional Chinese medicine for the treatment of blood circulation and blood stasis, was also widely used to cure pulmonary fibrosis in China. In clinical practice, some traditional Chinese medicine preparation such as Shui Zhi Xuan Bi Hua Xian Tang and Shui Zhi Tong Luo Capsule composed of leech, could improve the clinical symptoms and pulmonary function in patients with idiopathic pulmonary fibrosis (IPF). However, the material basis of the leech in the treatment of IPF were not yet clear. AIM OF THE STUDY: Screen out the components of leech that have the anti-pulmonary fibrosis effects, and further explore the therapeutic mechanism of the active components. MATERIALS AND METHODS: In this study, the different molecular weight components of leech extract samples were prepared using the semi-permeable membranes with different pore sizes. The therapeutic effects of the leech extract groups with molecular weight greater than 10 KDa (>10 KDa group), between 3 KDa and 10 KDa (3-10 KDa group), and less than 3 KDa (<3 KDa group) on pulmonary fibrosis were firstly investigated by cell proliferation and cytotoxicity assay (MTT), cell wound healing assay, immunofluorescence staining (IF) and Western blot (WB) assay through the TGF-ß1-induced fibroblast cell model. Then bleomycin-induced pulmonary fibrosis (BML-induced PF) mouse model was constructed to investigate the pharmacological activities of the active component group of leech extract in vivo. Pathological changes of the mouse lung were observed by hematoxylin-eosin staining (H&E) and Masson's trichrome staining (Masson). The hydroxyproline (HYP) content of lung tissues was quantified by HYP detection kit. The levels of extracellular matrix-related fibronectin (FN) and collagen type â (Collagen â ), pyruvate kinase M2 (PKM2) monomer and Smad7 protein were determined via WB method. PKM2 and Smad7 protein were further characterized by IF assays. RESULTS: Using TGF-ß1-induced HFL1 cell line as a PF cell model, the in vitro results demonstrated that the >10 KDa group could significantly inhibited the cell proliferation and migration, downregulated the expression level of cytoskeletal protein vimentin and α-smooth muscle actin (α-SMA), and reduced the deposition of FN and Collagen â . In the BML-induced PF mouse model, the >10 KDa group significantly reduced the content of HYP, downregulated the expression levels of FN and Collagen â in lung tissues, and delayed the pathological changes of lung tissue structure. The results of WB and IF assays further indicated that the >10 KDa group could up-regulate the expression level of PKM2 monomer and Smad7 protein in the cellular level, thereby delaying the progression of pulmonary fibrosis. CONCLUSIONS: Our study revealed that the >10 KDa group was the main material basis of the leech extract that inhibited pulmonary fibrosis through TGF-ß1/Smad3 signaling pathway.
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Fibrose Pulmonar Idiopática , Fator de Crescimento Transformador beta1 , Camundongos , Animais , Humanos , Fator de Crescimento Transformador beta1/metabolismo , Proteína Smad7/metabolismo , Proteína Smad7/farmacologia , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/tratamento farmacológico , Colágeno Tipo I/metabolismo , Bleomicina , Modelos Animais de Doenças , Transdução de SinaisRESUMO
Iron oxide nanoparticles (Fe3O4 NPs) have been reported to be a promising agent for cancer therapy due to their outstanding ability in catalyzing the Fenton reaction and causing peroxidation. Generally, particles with size of hundreds of nanometers exhibit enhanced accumulation in tumor due to the enhanced permeation and retention effect. However, the large size hinders penetration within the dense collagen matrix. Here, we propose a multistage system to realize pH-responsive size switch for efficient drug delivery. In this system, ultrasmall Fe3O4 (â¼4 nm) NPs are simultaneously modified with hydrophilic mPEG and hydrophobic N,N-dibutylethylenediamine (DBE) to form pH-responsive self-assembled iron oxide aggregations (SIOA). In the acidic tumor microenvironment, the protonation of DBE makes it transit from the hydrophobic to hydrophilic state, causing the disassembly of the SIOA and the release of loaded doxorubicin. The multistage Fe3O4 NPs demonstrate enhanced accumulation and efficient diffusion within the tumor, holding a promise for drug delivery and cancer therapy.
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Doxorrubicina , Compostos Férricos , Neoplasias , Humanos , Doxorrubicina/química , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Sistemas de Liberação de Medicamentos , Microambiente TumoralRESUMO
The temporal interference stimulation is a new technique to modulate brain activity by applying multiple channels of voltage-controlled current source (VCCS) simultaneously to the receptor surface. In this paper, the envelopes of the overlapped current waves at several areas of the receptor were analyzed and discussed with different circuit structures of VCCS. A complementary differential current source (CDCS) was designed to fit the best circuit topology based on the analysis of the enhanced Howland current source structure. Experiments were conducted by injecting current to a swine tissue using the CDCS and conventional VCCS and acquiring the voltage waveform data from different parts of the tissue. The waveforms were compared and analyzed, revealing that the conventional VCCS may generate an interference envelope in unexpected regions, while the CDCS did not. The CDCS design approach in this paper provides a new solution for temporal interference stimulation VCCS.
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Encéfalo , Estimulação Elétrica , Animais , Suínos , Encéfalo/fisiologiaRESUMO
Currently, the treatment for sepsis-induced acute lung injury mainly involves mechanical ventilation with limited use of drugs, highlighting the urgent need for new therapeutic options. As a pivotal aspect of acute lung injury, the pathologic activation and apoptosis of endothelial cells related to oxidative stress play a crucial role in disease progression, with NOX4 and Nrf2 being important targets in regulating ROS production and clearance. Echinacoside, extracted from the traditional Chinese herbal plant Cistanche deserticola, possesses diverse biological activities. However, its role in sepsis-induced acute lung injury remains unexplored. Moreover, although some studies have demonstrated the regulation of NOX4 expression by SIRT1, the specific mechanisms are yet to be elucidated. Therefore, this study aimed to investigate the effects of echinacoside on sepsis-induced acute lung injury and oxidative stress in mice and to explore the intricate regulatory mechanism of SIRT1 on NOX4. We found that echinacoside inhibited sepsis-induced acute lung injury and oxidative stress while preserving endothelial function. In vitro experiments demonstrated that echinacoside activated SIRT1 and promoted its expression. The activated SIRT1 was competitively bound to p22 phox, inhibiting the activation of NOX4 and facilitating the ubiquitination and degradation of NOX4. Additionally, SIRT1 deacetylated Nrf2, promoting the downstream expression of antioxidant enzymes, thus enhancing the NOX4-Nrf2 axis and mitigating oxidative stress-induced endothelial cell pathologic activation and mitochondrial pathway apoptosis. The SIRT1-mediated anti-inflammatory and antioxidant effects of echinacoside were validated in vivo. Consequently, the SIRT1-regulated NOX4-Nrf2 axis may represent a crucial target for echinacoside in the treatment of sepsis-induced acute lung injury.
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Silicosis is a severe worldwide occupational hazard, characterized with lung tissue inflammation and irreversible fibrosis caused by crystalline silicon dioxide. As the most common and abundant internal modification of messenger RNAs or noncoding RNAs, N6-methyladenosine (m6A) methylation is dysregulated in the chromic period of silicosis. However, whether m6A modification is involved in the early phase of silica-induced pulmonary inflammation and fibrosis and its specific effector cells remains unknown. In this study, we established a pulmonary inflammation and fibrosis mouse model by silica particles on day 7 and day 28. Then, we examined the global m6A modification level by m6A dot blot and m6A RNA methylation quantification kits. The key m6A regulatory factors were analyzed by RTqPCR, Western blot, and immunohistochemistry (IHC) in normal and silicosis mice. The results showed that the global m6A modification level was upregulated in silicosis lung tissues with the demethylase FTO suppression after silica exposure for 7 days and 28 days. METTL3, METTL14, ALKBH5, and other m6A readers had no obvious differences between the control and silicosis groups. Then, single-cell sequencing analysis revealed that thirteen kinds of cells were recognized in silicosis lung tissues, and the mRNA expression of FTO was downregulated in epithelial cells, endothelial cells, fibroblasts, and monocytes. These results were further confirmed in mouse lung epithelial cells (MLE-12) exposed to silica and in the peripheral blood mononuclear cells of silicosis patients. In conclusion, the high level of global m6A modification in the early stage of silicosis is induced by the downregulation of the demethylase FTO, which may provide a novel target for the diagnosis and treatment of silicosis.