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1.
Dis Model Mech ; 16(5)2023 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-35855640

RESUMO

When pathological hypertrophy progresses to heart failure (HF), the prognosis is often very poor. Therefore, it is crucial to find new and effective intervention targets. Here, myocardium-specific Trim44 knockout rats were generated using CRISPR-Cas9 technology. Cardiac phenotypic observations revealed that Trim44 knockout affected cardiac morphology at baseline. Rats with Trim44 deficiency exhibited resistance to cardiac pathological changes in response to stimulation via isoproterenol (ISO) treatment, including improvement of cardiac remodeling and dysfunction by morphological and functional observations, reduced myocardial fibrosis and reduced expression of molecular markers of cardiac stress. Furthermore, signal transduction validation associated with growth and hypertrophy development in vivo and in vitro demonstrated that Trim44 deficiency inhibited the activation of signaling pathways involved in myocardial hypertrophy, especially response to pathological stress. In conclusion, the present study indicates that Trim44 knockout attenuates ISO-induced pathological cardiac remodeling through blocking the AKT/mTOR/GSK3ß/P70S6K signaling pathway. This is the first study to demonstrate the function and importance of Trim44 in the heart at baseline and under pathological stress. Trim44 could be a novel therapeutic target for prevention of cardiac hypertrophy and HF.


Assuntos
Proteínas Proto-Oncogênicas c-akt , Remodelação Ventricular , Animais , Cardiomegalia/genética , Isoproterenol/metabolismo , Isoproterenol/farmacologia , Isoproterenol/uso terapêutico , Miócitos Cardíacos/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Serina-Treonina Quinases TOR/metabolismo , Remodelação Ventricular/fisiologia
2.
J Colloid Interface Sci ; 630(Pt B): 786-794, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36356446

RESUMO

Two-dimensional transition metal dichalcogenides, which display considerable theoretical capacity and large layer spacing, have been regarded as promising candidates as anode materials for sodium-ion batteries (SIBs). However, their low conductivity and large volume change during charge-discharge cycles leads to performance degradation. Herein, polyvinylpyrrolidone (PVP) is used as a soft template to synthesize PVP-derived nitrogen-doped carbon-coated MoS2 composites (MoS2/NC) by a simple hydrothermal method followed by high-temperature treatment. The as-prepared composite exhibits a flowerball-like morphology and a diameter of approximately 250 nm. The optimized MoS2/NC has the most uniform particle size and provides the best performance, with a stable capacity of 504.9 mAh g-1 after 120 cycles at a current density of 100 mA g-1. It has excellent rate performance, which can reach 524.6, 481.9, 447.7, 412.5, and 370.9 mAh g-1 at current densities of 0.1, 0.2, 0.5, 1 and 2 A g-1, respectively. The small particle size and the addition of carbonaceous materials play an important role in their excellent electrochemical properties. This study opens up a simple and effective way to synthesize high-performance two-dimensional MoS2 composite anodes for SIBs.

3.
Spectrochim Acta A Mol Biomol Spectrosc ; 286: 121988, 2023 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-36308828

RESUMO

Our previous work firstly reported that (E)-2-styrylanthracene-9,10-dione is a novel fluorescent core (EK01) with the ability of specific mitochondria imaging. In this effort, we mainly focused our attention on the structure-photophysical property relationship and application in cells imaging of this new fluorescent chemotype. A series of the structural derivatives (TZ series) were designed and synthesized by introducing some substituents onto the 2-styryl moiety. The structure-photophysical property relationship analysis suggested that TZ03 is an excellent fluorescent molecular building block with the property of fluorescent "turn-on" effect after the modification of acylation, and TZ07 is an excellent fluorescent dye with a series of advantages such as high fluorescence intensity (Fmax = 4049.0 in CH2Cl2, 25.80 µM), moderate molar extinction coefficients (3.77 × 103-5.93 × 103 mol-1∙L∙cm-1), strong fluorescence quantum yield (Φmax = 0.739 in CH2Cl2), large Stokes shift (99.0 nm-161.8 nm) and well biological tolerance. As a classical D-π-A structure, the ICT characteristic of TZ07 was analyzed through spectroscopy verification and DFT calculations. Furthermore, optimized compound TZ07 was successfully applied in the living cells imaging with the excellent selectivity to mitochondria in a green fluorescent form. It was also suggested that the mechanism of TZ07 targeting mitochondria is independent of mitochondrial membrane potential, but probably related to the mitochondrial complex I. These findings may provide some insights into the development of novel mitochondria-targeted fluorescent probes.


Assuntos
Corantes Fluorescentes , Mitocôndrias , Corantes Fluorescentes/química , Fluorescência , Diagnóstico por Imagem
4.
J Ethnopharmacol ; 301: 115799, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36216196

RESUMO

ETHNOPHARMACOLOGY RELEVANCE: Sophora flavescens is a frequently used traditional Chinese medicine (TCM) for the treatment of skin disorders, diarrhea, vaginal itching and inflammatory diseases. In particular, the root of S. flavescens combination with other herbs mainly treat eczema ailment in the clinical applications. However, a holistic network pharmacology approach to understanding the mechanism by which alkaloids in S. flavescens treat eczema has not been pursued. AIM OF THE STUDY: To examine the network pharmacological potential effect of S. flavescens on eczema, we studied the alkaloids, performed protein targets prediction and investigated interacting signal pathways. Furthermore, animal experiment was carried out to evaluate its efficacy and real-time quantitative polymerase chain reactions (RT-qPCR) analysis was explored the mechanism of action. MATERIALS AND METHODS: The detail information on alkaloids from S. flavescens were obtained from a handful of public databases on the basis of oral bioavailability (OB ≥ 30%) and drug-likeness (DL ≥ 0.18). Then, correlations between compounds and protein targets were linked using the STRING database, and targets associated with eczema were gathered by the GeneCards database. Human genes were identified and subjected to Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and Gene Ontology (GO) functional enrichment analysis. Particularly, matrine, the crucial alkaloid from S. flavescens, was estimated using a 2,4-dinitrochlorobenzene (DNCB)-induced eczema Kunming (KM) mice model, administered (50 mg/kg and 10 mg/kg) to mice for 22 days. On the last day, the activities of serum tumor necrosis factor α (TNF-α), interleukin-4 (IL-4) and histopathologic examinations were determined. For further to elucidate the mechanisms, the mRNA levels of TNF-α, STAT3, TP53, AKT1, IL-6, JUN and EGFR in dorsal skin tissues were also tested. RESULTS: Network analysis collected and identified 35 alkaloids from S. flavescens. Among them, in total 10 dominating alkaloids, including matrine, oxymatrine, sophoridine, sophocarpine, oxysophocarpine, allomatrine, sophoramine, anagyrine, cytisine and N-methylcytisine. And 71 related targets were provided of alkaloids for the treatment of eczema from S. flavescens. Furthermore, matrine dose-dependently (50 or 10 mg/kg, 22 days, apply to dorsal skin) remarkable decreased the serum levels of TNF-α and IL-4, and significantly alleviated the skin lesions. The effects of 50 mg/kg of matrine were almost identical to those of 200 mg/kg of the positive drug dexamethasone (DXM). The further RT-qPCR analyses could reveal that matrine down-regulate TNF-α, STAT3 and TP53 at transcriptional level in dorsal skin tissues. CONCLUSION: Pharmacological network analysis can utilize to illuminate the pharmacodynamic substances and the potential molecular mechanism of S. flavescens for treating eczema. Matrine, as the crucial alkaloid from S. flavescens, could be a promising drug candidate for the treatment of eczema ailment.


Assuntos
Alcaloides , Eczema , Sophora , Humanos , Camundongos , Animais , Interleucina-4 , Fator de Necrose Tumoral alfa , Farmacologia em Rede , Quinolizinas/farmacologia , Quinolizinas/uso terapêutico , Alcaloides/farmacologia , Alcaloides/uso terapêutico , Alcaloides/análise
5.
Environ Pollut ; 316(Pt 1): 120546, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36332704

RESUMO

Microplastic and antibiotic contamination are considered an increasing environmental problem in aquatic systems, while little is known about the impact of microplastics and co-pollutant with antibiotics on freshwater vascular plants, particularly the effects of interactions between macrophytes. Here, we performed a mesocosm experiment to evaluate the impact of polyethylene-microplastics and their co-pollutants with ciprofloxacin on the growth and physiological characteristics of Spirodela polyrhiza and Lemna minor and the interactions between these two macrophytes. Our results showed that microplastics alone cannot significantly influence fresh weight and specific leaf area of the two test free-floating macrophytes, but the effects on photosynthetic pigments, malondialdehyde, catalase and soluble sugar contents were species-specific. Ciprofloxacin can significant adverse effects on the growth and physiological traits of the two test macrophytes and microplastic mitigated the toxicity of ciprofloxacin on the two free-floating plants to a certain extent. In addition, our studies showed that microplastics and co-pollutants can influence relative yield and competitiveness of S. polyrhiza and L. minor by directly or indirectly influencing their physiology and growth. Therefore our findings suggest that species-specific sensibility to microplastic and its co-pollutant among free-floating macrophytes may influence macrophyte population dynamics and thereby community structure and ecosystem functioning. And microplastics altered other contaminant behaviours and toxicity, and may directly or indirectly influence macrophytes interactions and community structure. The present study is the first experimental study exploring the effects of microplastics alone and with their co-pollutants on interactions between free-floating macrophytes, which can provide basic theoretical guidance for improving the stability of freshwater ecosystems.

6.
J Hazard Mater ; 443(Pt B): 130245, 2023 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-36332278

RESUMO

Bioleaching is intensively investigated for recovering valuable metals such as Li, Co, Ni and Cu. Nickel ion stress threatens the health of microorganisms when Ni2+ starts to accumulate in the leachate during the bioleaching of materials that are rich in Ni, such as spent lithium-ion batteries. The possible mechanisms underlying the response of S. thermosulfidooxidans to nickel ion stress were analyzed using a multi-scale approach. Under the condition of nickel ion stress, high concentrations of nickel ions were immobilized by extracellular polymeric substances, while concentrations of nickel ions inside the cells remained low. The intracellular adenosine triphosphate (ATP) concentration and H+-ATPase activity increased to maintain normal cell growth and metabolic activities. Scavenging abilities of S. thermosulfidooxidans for hydrogen peroxide and superoxide anion were enhanced to reduce oxidative damage induced by nickel ion stress. There were 734 differentially expressed genes identified by RNA-seq under nickel ion stress. Most of them were involved in oxidative phosphorylation, glutathione metabolism and genetic information processing, responsible for intracellular energy utilization, intracellular antioxidant capacity and DNA damage repair, respectively. The results of this study are of major significance for in-depth understanding of the mechanisms of acidophilic microorganisms' resistance to metal ions.


Assuntos
Lítio , Níquel , Níquel/toxicidade , Fontes de Energia Elétrica , Íons
7.
Water Res ; 228(Pt A): 119328, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36413832

RESUMO

Pyrolysis of pharmaceutical sludge (PS) is a promising way of safe disposal and to recover energy and resources from waste. The resulting PS biochar (PSBC) is often used as adsorbent, but has seldom been explored as catalyst. Herein we demonstrate that PSBC (0.4 g/L) could efficiently activate peroxymonosulfate (PMS) to 100% degrade 4-chlorophenol (4-CP) with rate constants of 0.42-1.70 min-1, outperforming other reported catalysts. Interestingly, the PMS activation pathway highly depended on PSBC pyrolysis temperature, which produced dominantly high-valent iron species (e.g., FeIVO2+) at low temperature but more sulfate radical (SO4·-) and hydroxyl radical (·OH) at higher temperature, e.g., 0.17, 0.23, 0.12 mmol/L of FeIVO2+ and 0.009, 0.038, 0.102 mmol/L of SO4·-/·OH were produced within 10 min by PSBC-600/PMS, PSBC-800/PMS, and PSBC-1000/PMS, respectively. Characterization, density functional theory (DFT) simulation and Pearson correlation analysis revealed that along with the increase of pyrolysis temperatures, the active sites of PSBC gradually shifted from atomically dispersed N-coordinated Fe moieties (FeNx) to iron nitrides (FexN), which activated PMS to produce FeIVO2+ and SO4·-/·OH, respectively. This study clarifies the structure-activity relationships of PSBC for PMS activation, and opens a new avenue for the treatment and utilization of PS as high value-added resources.


Assuntos
Poluentes Ambientais , Pirólise , Esgotos , Temperatura , Ferro , Preparações Farmacêuticas
8.
J Environ Sci (China) ; 125: 319-331, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36375917

RESUMO

Oxidation-absorption technology is a key step for NOx removal from low-temperature gas. Under the condition of low O3 concentration (O3/NO molar ratio = 0.6), F-TiO2 (F-TiO2), which is cheap and environmentally friendly, has been prepared as ozonation catalysts for NO oxidation. Catalytic activity tests performed at 120°C showed that the NO oxidation efficiency of F-TiO2 samples was higher than that of TiO2 (about 43.7%), and the NO oxidation efficiency of F-TiO2-0.15 was the highest, which was 65.3%. Combined with physicochemical characteristics of catalysts and the analysis of active species, it was found that there was a synergistic effect between F sites and oxygen vacancies on F-TiO2, which could accelerate the transformation of monomolecular O3 into multi-molecule singlet oxygen (1O2), thus promoting the selective oxidation of NO to NO2. The oxidation reaction of NO on F-TiO2-0.15 follows the Eley-Rideal mechanism, that is, gaseous NO reacts with adsorbed O3 and finally form NO2.


Assuntos
Dióxido de Nitrogênio , Oxigênio , Catálise , Oxirredução , Oxigênio/química , Titânio/química , Ozônio/química , Óxido Nítrico/química
9.
Sci Total Environ ; 857(Pt 3): 159596, 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36280073

RESUMO

An oxalate-doped hydroxyapatite (O-HAP) was hydrothermally synthesized for aqueous lead (Pb) removal based on the solubility-limiting ability of oxalate and phosphate over pH range 4-9. Free Pb2+ activities in oxalate and/or phosphate systems were controlled by oxalate to form soluble ion pairs Pb-Ox (aq) and Pb-Ox22- at pH 4-7 while in preference to persist as PbHPO4 (aq) when pH ≥ 8. Both phosphate and oxalate exhibited excellent efficiency in reducing Pb solubility, causing over 99 % of Pb precipitated from solution following oxalate < oxalate-phosphate < phosphate. The Visual MINTEQ model overestimated dissolved Pb and free Pb2+ in nearly all of the reaction systems due to the ill-defined stability constants and solubility products for Pb ion-pair formation. The addition of phosphate acting as a buffer in Pb-oxalate systems tended to lessen the spontaneous pH shifts within 24 h to equilibrate proton release from Pb precipitation and hydrolysis, indicating lower solubility products and faster kinetics of Pb-phosphate mineral formation. The TEM-EDS, FTIR and XRD identified a block-shaped Pb-oxalate mineral phase as the only precipitate at acidic pH while substituted by phosphate to form rod-shaped Pb5(PO4)3OH and Pb3(PO4)2 precipitates as pH increased. The optimum hydrothermal conditions of O-HAP were 433 K, pH 9 and P/Ox doping ratio of 0.5 for 24 h. Batch experiments revealed the endothermic process of O-HAP toward Pb with the maximum adsorption capacity reaching 2333 mg/g at a pH of 7, reaction time of 12 h, initial Pb concentration of 600 mg/L and temperature of 308 K, which were best fitted with the pseudo-second-order kinetic model and Langmuir isotherm. The synergetic mechanisms of O-HAP for Pb removal involved dissolution-precipitation, adsorption and ion exchange. This study provides an insight in developing effective remediation strategies for heavy metal contamination by interacting between low-molecular-weight organic acids and secondary mineral phases.


Assuntos
Durapatita , Poluentes Químicos da Água , Chumbo , Oxalatos , Concentração de Íons de Hidrogênio , Compostos Orgânicos , Adsorção , Cinética
10.
Nano Lett ; 2022 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-36459114

RESUMO

Strontium-containing agents have been demonstrated to elicit both bone anabolic and antiosteoporotic effects, showing great potential for the treatment of bone loss. However, an increased incidence of strontium-induced side effects restricts their clinical applications. Herein, oxidized carbon nitride nanosheets (CN) are delicately used to incorporate Sr2+ for the first time to achieve high osteogenic efficacy. The lamellar structure and enriched nitrogen species of CN provide them with a high surface area-to-volume ratio and abundant anchoring sites for Sr2+ incorporation. Importantly, Sr2+-incorporated CN (CNS) could synergistically promote osteoblast differentiation and bone regeneration at a single, very low Sr2+ dose. Mechanically, CNS could activate the FAK/RhoA signaling pathway to modulate the intracellular tension that stimulates osteoblasts differentiation. The present study will provide a new paradigm to enhance the efficacy of osteogenic metal ions by using lamellar nanocarriers.

11.
Rev Sci Instrum ; 93(11): 115002, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36461484

RESUMO

This paper proposes a compound data-driven control method to solve the problems of low damping resonance, different dynamic properties, and hysteresis in the large-range compliant micropositioning stage driven by a Maxwell reluctance actuator. First, in order to verify the proposed control algorithm, a reluctance-actuated, XY compliant micropositioning stage is constructed according to the principle of operation of a reluctance actuator. Second, in order to eliminate the influence of complex dynamics on the controller design, a fractional order proportional-integral feedback controller is designed using a data iterative feedback turning algorithm. Third, the finite impulse response feedforward filter is optimized using experimental data, and the on-line inverse estimation of the system frequency response function and its iterative feedforward compensation are carried out to further eliminate the influence of light damping resonance. Finally, the proposed control method is used for tracking the experiment and compared with other methods. The experimental results show that the proposed control method can better meet the requirements of high precision, fast speed, and strong anti-interference ability for large stroke micro/nanopositioning and tracking.

12.
Res Vet Sci ; 154: 59-65, 2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36463586

RESUMO

Ketosis is a metabolic disease of dairy cows in the perinatal period, ß-hydroxybutyrate (ß-HB) is the main component of ketosis. High levels of ß-HB can trigger oxidative stress and inflammatory response in dairy cows, leading to decreased milk yield and multiple postpartum diseases. Forsythin (FOR), the major constituent of the herbal medicine Forsythia, has anti-inflammatory, anti-oxidant, and antiviral effects. FOR was demonstrated to have an antioxidant effect on PC12 cells. However, the effects of FOR on ß-HB-stimulated bovine macrophages (BMs) has not been reported. Thus, the aim of the present study was to investigate the effects of FOR on ß-HB-stimulated BMs. Firstly, the CCK8 test confirmed that FOR (50, 100, 200 µg/mL) has no effect on BMs activity, and we selected these concentrations for subsequent experiments. Secondly, through detecting the oxidation indexes ROS, MDA and antioxidant indexes CAT and SOD, we confirmed the antioxidant effect of FOR on BMs. Next, qRT-PCR confirmed that FOR dramatically reduced the mRNA levels of IL-1ß and IL-6. Furthermore, the western blotting confirmed that FOR observably down-regulated ß-HB-stimulated phosphorylation of p38, ERK and Akt and up-regulated expression of Nrf2, and HO-1. Above results suggested that FOR plays antioxidant effects on ß-HB-induced BMs through p38, ERK and PI3K/Akt, Nrf2 and HO-1 signaling pathways. Therefore, we speculated that FOR may be a potential medicine to alleviate ß-HB-induced inflammatory response and provide a preliminary reference for the research and development of FOR.

13.
Resour Conserv Recycl ; : 106800, 2022 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-36465718

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic has significantly disrupted global metal mining and associated supply chains. Here we analyse the cascading effects of the metal mining disruption associated with the COVID-19 pandemic on the economy, climate change, and human health. We find that the pandemic reduced global metal mining by 10-20% in 2020. This reduction subsequently led to losses in global economic output of approximately 117 billion US dollars, reduced CO2 emissions by approximately 33 million tonnes (exceeding Hungary's emissions in 2015), and reduced human health damage by 78,192 disability-adjusted life years. In particular, copper and iron mining made the most significant contribution to these effects. China and rest-of-the-world America were the most affected. The cascading effects of the metal mining disruption associated with the pandemic on the economy, climate change, and human health should be simultaneously considered in designing green economic stimulus policies.

14.
Heliyon ; 8(11): e11905, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36458298

RESUMO

Objective: By using bioinformatics analysis, abnormal methylated differentially expressed genes (MDEGs) in Kawasaki disease (KD) were identified and a random forest diagnostic model for KD was established. Methods: The expression (GSE18606, GSE68004, GSE73461) and methylation (GSE109430) profiles was retrieved and download from Gene Expression Omnibus (GEO). We conducted enrichment analyses by using R software. In addition, we constructed a protein interaction network, and obtained 6 hub genes. We used expression profiles GSE100154 from GEO to verify the hub genes. Finally, we constructed a diagnostic model based on random forest. Results: We got a total of 55 MDEGs (43 hyper-methylated, low-expressing genes and 12 hypo-methylated, high-expressed genes). Six hub genes (CD2, IL2RB, IL7R, CD177, IL1RN, and MYL9) were identified by Cytoscape software. The area under curve (AUC) of the six hub genes was from 0.745 to 0.898, and the combined AUC was 0.967. The random forest diagnostic model showed that AUC was 0.901. Conclusion: The identification of 6 new hub genes improves our understanding of the molecular mechanism of KD, and the established model can be employed for accurate diagnosis and provide evidence for clinical diagnosis.

15.
J Vis Exp ; (189)2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36468709

RESUMO

An abdominal aortic aneurysm (AAA) is a life-threatening cardiovascular disease that occurs worldwide and is characterized by irreversible dilation of the abdominal aorta. Currently, several chemically induced murine AAA models are used, each simulating a different aspect of the pathogenesis of AAA. The calcium phosphate-induced AAA model is a rapid and cost-effective model compared to the angiotensin II- and elastase-induced AAA models. The application of CaPO4 crystals to the mouse aorta results in elastic fiber degradation, loss of smooth muscle cells, inflammation, and calcium deposition associated with aortic dilation. This article introduces a standard protocol for the CaPO4-induced AAA model. The protocol includes material preparation, the surgical application of the CaPO4 to the adventitia of the infrarenal abdominal aorta, the harvesting of aortas to visualize aortic aneurysms, and histological analyses in mice.


Assuntos
Aneurisma da Aorta Abdominal , Camundongos , Animais , Aneurisma da Aorta Abdominal/induzido quimicamente , Aorta Abdominal , Modelos Animais de Doenças , Fosfatos de Cálcio
16.
Comput Biol Med ; 152: 106346, 2022 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-36470146

RESUMO

BACKGROUND: Uterine carcinosarcoma (UCS) is an invasive variant of endometrial cancer. The complicated heterogeneity and low frequency of UCS suggest the relevant research is lack. There is an urgent need to further explore the pathogenic mechanism and identify new biomarkers of UCS from different angels to improve its diagnosis and prognosis. OBJECTIVE: This study is to explore the importance of alternative splicing (AS) events in UCS, construct AS-based prognosis model and excavate key splicing factors (SFs). METHOD: UCS related gene transcriptome data and AS events data were collected from The Cancer Genome Atlas (TCGA) and TCGA SpliceSeq database. The AS events related to survival were determined by Cox regression analysis, Least absolute shrinkage and selection operator (Lasso) regression analysis and optimal subset analysis. The corresponding risk score was calculated and its efficiency on prognosis was evaluated by Kaplan-Meier (K-M) survival estimate and validated by the receiver operating characteristic (ROC) curve. The prognosis model was constructed with risk score and clinic characters as independent variables to predict patients' survival. On the other hand, Kendall test was applied to inspect the correlation between the SFs and the prognosis-related AS events and a AS-SF network was constructed. Finally, the key SFs were screened through network nodes analysis and survival analysis. RESULT: Seven AS events the most related to survival were detected and the risk score was obtained. K-M survival estimate and ROC curve validation suggested the risk score was effective. Then Cox model was constructed based on the risk score and a nomogram model was obtained which provided the highest prediction accuracy of 95%. Through the AS-SF network analysis, 16 SFs were screened, among which four survival-related SFs were eventually obtained. CONCLUSION: The prognosis model could predict the survival rate of UCS patients by their clinical characters and AS-based risk score. And four newly discovered SFs could reveal the molecular mechanism of UCS and act as the potential drug targets and prognosis biomarkers.

17.
J Biol Chem ; : 102766, 2022 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-36470425

RESUMO

Epidermal growth factor receptor (EGFR) signaling is frequently dysregulated in various cancers. The ubiquitin ligase Cbl (Casitas B-lineage lymphoma proto-oncogene) regulates degradation of activated EGFR through ubiquitination and acts as an adaptor to recruit proteins required for trafficking. Here, we used Stable Isotope Labeling with Amino Acids in Cell Culture (SILAC) mass spectrometry (MS) to compare Cbl complexes with or without epidermal growth factor (EGF) stimulation. We identified over a hundred novel Cbl interactors, and a secondary siRNA screen found that knockdown of Flotillin-2 (FLOT2) led to increased phosphorylation and degradation of EGFR upon EGF stimulation in HeLa cells. In PC9 and H441 cells, FLOT2 knockdown increased EGF-stimulated EGFR phosphorylation, ubiquitination, and downstream signaling, reversible by EGFR inhibitor erlotinib. CRISPR knockout (KO) of FLOT2 in HeLa cells confirmed EGFR downregulation, increased signaling, and increased dimerization and endosomal trafficking. Furthermore, we determined that FLOT2 interacted with both Cbl and EGFR. EGFR downregulation upon FLOT2 loss was Cbl-dependent, as co-knockdown of Cbl and Cbl-b restored EGFR levels. Additionally, FLOT2 overexpression decreased EGFR signaling and growth. Overexpression of wild type (WT) FLOT2, but not the soluble G2A FLOT2 mutant, inhibited EGFR phosphorylation upon EGF stimulation in HEK293T cells. FLOT2 loss induced EGFR-dependent proliferation and anchorage-independent growth. Lastly, FLOT2 KO increased tumor formation and tumor volume in nude mice and NSG mice, respectively. Together, these data demonstrated that FLOT2 negatively regulated EGFR activation and dimerization, as well as its subsequent ubiquitination, endosomal trafficking, and degradation, leading to reduced proliferation in vitro and in vivo.

18.
Trends Neurosci ; 2022 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-36470706

RESUMO

In a recent study, Strickland and McDannald dissected the role of brainstem networks in threat prediction. Using probabilistic threat discrimination in rats, the authors demonstrated that brainstem neurons estimate threat probability and generate positive aversive prediction errors after unexpected outcomes. Their findings suggest that, beyond organizing defensive behaviors, brainstem neurons are involved in threat prediction computations.

19.
Biomater Sci ; 2022 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-36472132

RESUMO

Craniomaxillofacial bone defects seriously affect the physical and mental health of patients. Bone marrow mesenchymal stem cells (BMSCs) are "gold standard" cells used for bone repair. However, the collection of BMSCs is invasive, and the osteogenic capacity is limited with age. Human umbilical cord mesenchymal stem cells (hUCMSCs) are promising alternative seed cells for bone tissue engineering. Our group previously used high-throughput sequencing technology and bioinformatics methods to detect circ-CTTN (hsa-circ_0003376) molecules, which may play an essential role in the osteogenic differentiation of hUCMSCs. In this study, osteogenic induction in vitro showed that the overexpressing circ-CTTN (OE group) exhibits a more pronounced osteogenic phenotype. The levels of osteogenesis-related genes in the OE group were highly expressed. The gelatin-methacrylate (GelMA) hydrogel possessed excellent biocompatibility and was used to load hUCMSCs. In the rat calvarial defect, the OE group presented a larger bone healing volume and denser bone trabecular distribution than other groups. So far, the overexpression of circ-CTTN could enhance the osteogenic differentiation of hUCMSCs and accelerate bone reconstruction. Our research could provide a new strategy and a strong theoretical basis for promoting hUCMSC clinical application in bone tissue engineering.

20.
J Hazard Mater ; 445: 130499, 2022 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-36455318

RESUMO

Soil cadmium (Cd) contamination can reduce wheat yield and quality, thus threatening food security and human health. Herein, morphological physiology, Cd accumulation and distribution, proteomic and metabolomic analyses were performed (using wheat cultivars 'Luomai23' (LM, Cd-sensitive) and 'Zhongyu10' (ZY, Cd-tolerant) at the seedling stage with sand culture) to reveal Cd tolerance mechanism. Cd inhibited wheat growth, caused oxidative stress, hindered carbon and nitrogen metabolism, and altered the quantity and composition of root exudates. The root Cd concentration was lower in ZY than in LM by about 35% under 15 µM Cd treatments. ZY reduced Cd uptake through root exudation of amino acids and alkaloids. ZY also reduced Cd accumulation through specific up-regulation (twice) of major facilitator superfamily (MFS) proteins. Furthermore, ZY enhanced Cd cell wall fixation and vacuolar compartmentalization by increasing pectin contents, hemicellulose1 contents, and adenosine triphosphate binding cassette subfamily C member 1 (ABCC1) transporter expression, thus reducing the Cd organelle fraction of ZY by about 12% and 44% in root and shoot, respectively, compared with LM. Additionally, ZY had enhanced resilience to Cd due to increased antioxidant capacity, plasma membrane stability, nitrogen metabolism, and endoplasmic reticulum homeostasis, indicating that the increased Cd tolerance could be because of multi-level coordination. These findings provide a reference for exploring the molecular mechanism of Cd tolerance and accumulation, providing a basis for safe utilization of Cd-contaminated soil by breeding Cd-tolerant and low Cd-accumulating wheat varieties.

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