RESUMO
Overexpression of T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) on T cells has been observed in smokers. However, whether and how galectin-9 (Gal-9)/TIM-3 signal between T-regulatory cells (Tregs) and type 17 helper (Th17) cells contributes to tobacco smoke-induced airway inflammation remains unclear. Here, we aimed to explore the role of the Gal-9/TIM-3 signal between Tregs and Th17 cells during chronic tobacco smoke exposure. Tregs phenotype and the expression of TIM-3 on CD4+ T cells were detected in a mouse model of experimental emphysema. The role of TIM-3 in CD4+ T cells was explored in a HAVCR2-/- mouse model and in mice that received recombinant anti-TIM3. The crosstalk between Gal-9 and Tim-3 was evaluated by coculture Tregs with effector CD4+ T cells. We also invested the expression of Gal-9 in Tregs in patients with COPD. Our study revealed that chronic tobacco smoke exposure significantly reduces the frequency of Tregs in the lungs of mice and remarkably shapes the heterogeneity of Tregs by downregulating the expression of Gal-9. We observed a pro-inflammatory but restrained phenotypic transition of CD4+ T cells after tobacco smoke exposure, which was maintained by TIM-3. The restrained phenotype of CD4+ T cells was perturbed when TIM-3 was deleted or neutralised. Tregs from the lungs of mice with emphysema displayed a blunt ability to inhibit the differentiation and proliferation of Th17 cells. The inhibitory function of Tregs was partially restored by using recombinant Gal-9. The interaction between Gal-9 and TIM-3 inhibits the differentiation of Th17 cells and promotes apoptosis of CD4+ T cells, possibly by interfering with the expression of retinoic acid receptor-related orphan receptor gamma t. The expression of Gal-9 in Tregs was reduced in patients with COPD, which was associated with Th17 response and lung function. These findings present a new paradigm that impairment of Gal-9/Tim-3 crosstalk between Tregs and Th17 cells during chronic tobacco smoke exposure promotes tobacco smoke-induced airway/lung inflammation.
Assuntos
Galectinas , Receptor Celular 2 do Vírus da Hepatite A , Camundongos Knockout , Doença Pulmonar Obstrutiva Crônica , Linfócitos T Reguladores , Células Th17 , Animais , Células Th17/imunologia , Células Th17/metabolismo , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Receptor Celular 2 do Vírus da Hepatite A/genética , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Galectinas/metabolismo , Camundongos , Humanos , Doença Pulmonar Obstrutiva Crônica/imunologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Feminino , Masculino , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Transdução de Sinais , Fumar/efeitos adversosRESUMO
The cultured meat technology has developed rapidly in recent years, but there are still many technical challenges that hinder the large-scale production and commercialization of cultured meat. Firstly, it is necessary to lay the foundation for cultured meat production by obtaining seed cells and maintaining stable cell functions. Next, technologies such as bioreactors are used to expand the scale of cell culture, and three-dimensional culture technologies such as scaffold culture or 3D printing are used to construct the three-dimensional structure of cultured meat. At the same time, it can reduce production costs by developing serum-free medium suitable for cultured meat. Finally, the edible quality of cultured meat is improved by evaluating food safety and sensory flavor, and combining ethical and consumer acceptability issues. Therefore, this review fully demonstrates the current development status and existing technical challenges of the cultured meat production technology with regard to the key points described above, in order to provide research ideas for the industrial production of cultured meat.
RESUMO
Programmed cell death ligand 2 (PD-L2), a ligand for the receptor programmed cell death 1 (PD-1), has an identity of 34% with its twin ligand PD-L1 and exhibits higher binding affinity with PD-1 than PD-L1. However, the role of PD-L2 in non-small cell lung cancer (NSCLC) progression, especially tobacco-induced cancer progression, has not been fully understood. Here, we found that PD-L2 promoted tumor growth in murine models with recruitment of regulatory T cells (Tregs). In patients with NSCLC, PD-L2 expression level in tumor samples was higher than in counterpart normal controls and was positively associated with patients' response to anti-PD-1 treatment. Mechanismly, PD-L2 bound its receptor Repulsive guidance molecule B (RGMB) on cancer cells and activated extracellular signal-regulated kinase (Erk) and nuclear factor κB (NFκB), leading to increased production of chemokine CCL20, which recruited Tregs and contributed to NSCLC progression. Consistently, knockdown of RGMB or NFκB p65 inhibited PD-L2-induced CCL20 production, and silencing of PD-L2 repressed Treg recruitment by NSCLC cells. Furthermore, cigarette smoke and carcinogen benzo(a)pyrene (BaP) upregulated PD-L2 in lung epithelial cells via aryl hydrocarbon receptor (AhR)-mediated transcription activation, whose deficiency markedly suppressed BaP-induced PD-L2 upregulation. These results suggest that PD-L2 mediates tobacco-induced recruitment of Tregs via the RGMB/NFκB/CCL20 cascade, and targeting this pathway might have therapeutic potentials in NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Quimiocina CCL20 , Neoplasias Pulmonares , NF-kappa B , Proteína 2 Ligante de Morte Celular Programada 1 , Linfócitos T Reguladores , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Humanos , NF-kappa B/metabolismo , Animais , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Proteína 2 Ligante de Morte Celular Programada 1/metabolismo , Proteína 2 Ligante de Morte Celular Programada 1/genética , Quimiocina CCL20/metabolismo , Quimiocina CCL20/genética , Camundongos , Fumar Tabaco/efeitos adversos , Transdução de Sinais , Linhagem Celular Tumoral , Masculino , FemininoRESUMO
Breast cancer is the leading cause of cancer deaths in women worldwide. EF-24, an analog of curcumin, has been shown to possess promising anticancer effects. However, the underlying mechanism remains elusive. In the present study, the inhibitory effect of EF-24 against one breast cancer cell line, MDA-MB-231, and its anti-migration ability were assessed by MTT, wound healing, and Transwell assay. Furthermore, we found that EF-24 could induce initiation of autophagy as evidenced by fluorescence and electron microscope observation. EF-24 also induced mitochondrial apoptosis in MDA-MB-231 cells as detected by Hoechst 33342 staining, flow cytometry analysis, and western blot analysis. In addition, the early autophagy inhibitor 3-MA could reduce the cleavage of PARP protein and protect cells from EF-24-induced apoptosis, while the autophagy inducer (rapamycin) could enhance the anticancer effect of EF-24 in MDA-MB-231 cells, which suggest that EF-24 induces crosstalk between autophagy and apoptosis, which herein participate in the antiproliferative effect of EF-24 in breast cancer cells. Moreover, removal of EF-24-activated ROS with NAC significantly reversed migration ability of MDA-MB-231 cells, indicating that EF-24 exerted an inhibitory effect through a ROS-mediating pathway. These results will help to elucidate the antitumor mechanism of curcumin analogs and to explore future potential clinical applications.
Assuntos
Antineoplásicos , Neoplasias da Mama , Curcumina , Feminino , Humanos , Curcumina/farmacologia , Curcumina/uso terapêutico , Células MDA-MB-231 , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Proliferação de Células , Neoplasias da Mama/patologia , Autofagia , Apoptose , Linhagem Celular TumoralRESUMO
To eliminate the reference mirror (REF) error of the Fizeau interferometer for measuring X-ray mirrors, the reference calibration method of lateral multi-shift measurements at the hundreds-micrometer pixel level is presented. Because of the high aspect ratio of long X-ray mirrors, by shifting the surface under test (SUT) along the tangential direction with integer multiple pixels, we extend the calibration method by using the difference between multiple shifted measurements to build an augmented multi-matrix for extracting the two-dimensional (2D) absolute surface. The method can be applied to arbitrary measurement regions of the test optics, and the measurement for both the benchmark sub-aperture and calibration of the REF is accomplished in a single measuring process. Furthermore, by adjusting the shift to the millimeter scale, reference-subtracted sub-apertures can be stitched to obtain the absolute 2D map of the X-ray mirror. Experimental results show that all the 2D discrepancies reach sub-nanometer repeatability, and comparison results between the long trace profiler (LTP) and the proposed method have been performed. Therefore, the results demonstrated that the proposed method meets the requirements of X-ray mirror measurements.
RESUMO
Studies have shown that the inhibition of phosphatase and tensin homolog deleted on chromosome 10 (PTEN)was neuroprotective against ischemia/reperfusion(I/R) injury. Bisperoxovanadium (bpV), a derivative of vanadate, is a well-established inhibitor of PTEN. However, its function islimited due to its general inadequacy in penetrating cell membranes. Mxene(Ti3C2Tx) is a novel two-dimensional lamellar nanomaterial with an excellent ability to penetrate the cell membrane. Yet, the effects of this nanomaterial on nervous system diseases have yet to be scrutinized. Here, Mxene(Ti3C2Tx) was used for the first time to carry bpV(HOpic), creating a new nanocomposite Mxene-bpV that was probed in a cerebral I/R injury model. The findings showed that this synthetic Mxene-bpV was adequately stable and can cross the cell membraneeasily. We observed that Mxene-bpV treatment significantly increased the survival rate of oxygen glucose deprivation/reperfusion(OGD/R)--insulted neurons, reduced infarct sizes and promoted the recovery of brain function after mice cerebral I/R injury. Crucially, Mxene-bpV treatment was more therapeutically efficient than bpV(HOpic) treatment alone over the same period. Mechanistically, Mxene-bpV inhibited the enzyme activity of PTEN in vitro and in vivo. It also promoted the expression of phospho-Akt (Ser473) by repressing PTEN and then activated the Akt pathway to boost cell survival. Additionally, in PTEN transgenic mice, Mxene-bpV suppressed I/R-induced inflammatory response by promoting M2 microglial polarization through PTEN inhibition. Collectively, the nanosynthetic Mxene-bpV inhibited PTEN' enzymatic activity by activating Akt pathway and promoting M2 microglial polarization, and finally exerted neuroprotection against cerebral I/R injury.
Assuntos
Microglia , Fármacos Neuroprotetores , PTEN Fosfo-Hidrolase , Proteínas Proto-Oncogênicas c-akt , Traumatismo por Reperfusão , Transdução de Sinais , Compostos de Vanádio , Animais , Microglia/efeitos dos fármacos , Microglia/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Camundongos , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Compostos de Vanádio/farmacologia , Compostos de Vanádio/química , PTEN Fosfo-Hidrolase/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/patologia , Polaridade Celular/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Nanocompostos/químicaRESUMO
PURPOSE: The purpose of this study was to study the effects of the severity of preoperative bone marrow oedema (BME) on the postoperative short-term outcomes following bone marrow stimulation (BMS) for osteochondral lesions of the talus (OLTs) and to propose a new metric that combines volume and signal density to evaluate BME. METHODS: Sixty-five patients with symptomatic OLTs (<100 mm2) and preoperative BME, who received BMS in our institution from April 2017 to July 2021 with follow-ups of 3, 6 and 12 months, were analysed retrospectively. The area, volume and signal value of the BME were collected on preoperative magnetic resonance imaging. The enroled patients were divided into two groups according to the BME index (BMEI), which was defined as the product of oedema relative signal intensity and the relation of oedema volume to total talar volume. Visual analogue scale, American Orthopedic Foot and Ankle Society (AOFAS), Tegner, Foot and Ankle Ability Measure (FAAM)-activities of daily living (ADL) and Sports scores were assessed before surgery and at each follow-up. The relationship between the scores and the volume, relative signal intensity and BMEI was explored. RESULTS: Sixty-five patients with preoperative BME were divided into the mild (n = 33) and severe (n = 32) groups based on the BMEI. A significant difference was found for each score with the general linear model for repeated measures through all follow-up time points (p < 0.001). For the preoperative and 12-month postoperative changes of the enroled patients, 53 patients (81.5%) exceeded the minimal clinically important difference of AOFAS and 26 (40.0%) exceeded that of FAAM-sports in this study. The mild group showed significantly more improvement in AOFAS scores at 12 months (89.6 ± 7.0 vs. 86.2 ± 6.2) and FAAM-ADL scores at 6 months (83.6 ± 7.6 vs. 79.7 ± 7.7) and 12 months (88.5 ± 8.5 vs. 84.4 ± 7.7) than the severe group (p < 0.05). No significant difference of all the scores between the groups was found at 3 months. No significant correlation was found in each group between BMEI and clinical outcomes. CONCLUSION: The severity of the preoperative BME negatively affected short-term clinical outcomes following arthroscopic BMS for OLTs. Worse clinical outcomes were shown at postoperative 6 and 12 months in patients with a high preoperative BMEI, which could be a favourable parameter for assessing the severity of BME and assist in developing personalised rehabilitation plans and determining the approach and timing of surgery. LEVEL OF EVIDENCE: Level III.
RESUMO
A new phenolic compound oleiphenol (1), and a new dihydrochalcone oleifechalcone (2) along with seven known compounds (3-9) were isolated from the fruit shell of Camellia oleifera Abel. The planar structures of compounds 1 and 2 were determined on the basis of extensive spectroscopic analyses (IR, UV, NMR, and HR-ESI-MS) and comparison with literature data. The absolute configurations of the new structures were determined by ECD calculations and chemical methods. In addition, compounds 1-9 underwent a series of pharmacological activity tests, including cytotoxic, anti-inflammatory, anti-RSV and antioxidant activities.
Assuntos
Camellia , Frutas , Flavonoides/farmacologia , Camellia/química , Antioxidantes/farmacologia , Antioxidantes/química , Espectroscopia de Ressonância MagnéticaRESUMO
BACKGROUND: Aristolochic acid nephropathy (AAN) is a rapidly progressive interstitial nephropathy caused by Aristolochic acid (AA). AAN is associated with the development of nephropathy and urothelial carcinoma. It is estimated that more than 100 million people worldwide are at risk of developing AAN. However, the underlying mechanisms driving renal deterioration in AAN remain poorly understood, and the treatment options are limited. METHODS: We obtained GSE27168 and GSE136276 series matrix data from the Gene Expression Omnibus (GEO) related to AAN. Using the R Studio environment, we applied the limma package and WGCNA package to identify co-differently expressed genes (co-DEGs). By GO/KEGG/GSVA analysis, we revealed common biological pathways. Subsequently, co-DEGs were subjected to the String database to construct a protein-protein interaction (PPI) network. The MCC algorithms implemented in the Cytohubba plugin were employed to identify hub genes. The hub genes were cross-referenced with the transcription factor (TF) database to identify hub TFs. Immune infiltration analysis was performed to identify key immune cell groups by utilizing CIBERSORT. The expressions of AAN-associated hub TFs were verified in vivo and in vitro. Finally, siRNA intervention was performed on the two TFs to verify their regulatory effect in AAN. RESULTS: Our analysis identified 88 co-DEGs through the "limma" and "WGCNA" R packages. A PPI network comprising 53 nodes and 34 edges was constructed with a confidence level >0.4. ATF3 and c-JUN were identified as hub TFs potentially linked to AAN. Additionally, expressions of ATF3 and c-JUN positively correlated with monocytes, basophils, and vessels, and negatively correlated with eosinophils and endothelial cells. We observed a significant increase in protein and mRNA levels of these two hub TFs. Furthermore, it was found that siRNA intervention targeting ATF3, but not c-JUN, alleviated cell damage induced by AA. The knockdown of ATF3 protects against oxidative stress and inflammation in the AAN cell model. CONCLUSION: This study provides novel insights into the role of ATF3 in AAN. The comprehensive analysis sheds light on the molecular mechanisms and identifies potential biomarkers and drug targets for AAN treatment.
Assuntos
Ácidos Aristolóquicos , Nefropatias , Fatores de Transcrição , Ácidos Aristolóquicos/toxicidade , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Nefropatias/induzido quimicamente , Nefropatias/genética , Animais , Camundongos , Humanos , Fator 3 Ativador da Transcrição/genética , Fator 3 Ativador da Transcrição/metabolismo , Mapas de Interação de ProteínasRESUMO
BACKGROUND: Breast cancer is the major cause of death in females globally. Chemokine-like factor like MARVEL transmembrane domain containing 7 (CMTM7) is reported as a tumor suppressor and is involved in epidermal growth factor receptor degradation and PI3K/AKT signaling in previous studies. However, other molecular mechanisms of CMTM7 remain unclear. METHODS: The expression level of CMTM7 in breast cancer cells and tissues was detected by qRT-PCR and western blot, and the methylation of CMTM7 promoter was detected by BSP sequencing. The effect of CMTM7 was verified both in vitro and in vivo, including MTT, colony formation, EdU assay, transwell assay and wound healing assay. The interaction between CMTM7 and CTNNA1 was investigated by co-IP assay. The regulation of miR-182-5p on CMTM7 and TCF3 on miR-182-5p was detected by luciferase reporter assay and ChIP analysis. RESULTS: This study detected the hypermethylation levels of the CMTM7 promoter region in breast cancer tissues and cell lines. CMTM7 was performed as a tumor suppressor both in vitro and in vivo. Furthermore, CMTM7 was a direct miR-182-5p target. Besides, we found that CMTM7 could interact with Catenin Alpha 1 (CTNNA1) and regulate Wnt/ß-catenin signaling. Finally, transcription factor 3 (TCF3) can regulate miR-182-5p. We identified a feedback loop with the composition of miR-182-5p, CMTM7, CTNNA1, CTNNB1 (ß-catenin), and TCF3, which play essential roles in breast cancer progression. CONCLUSION: These findings reveal the emerging character of CMTM7 in Wnt/ß-catenin signaling and bring new sights of gene interaction. CMTM7 and other elements in the feedback loop may serve as emerging targets for breast cancer therapy.
Assuntos
Neoplasias da Mama , MicroRNAs , Feminino , Humanos , MicroRNAs/genética , Neoplasias da Mama/genética , beta Catenina/genética , beta Catenina/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Linhagem Celular Tumoral , Via de Sinalização Wnt/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Quimiocinas/metabolismo , Proteínas com Domínio MARVEL/genética , Proteínas com Domínio MARVEL/metabolismoRESUMO
Articular cartilage (AC) is most susceptible to degeneration in knee osteoarthritis (OA); however, the existing treatments for OA do not target the core link of the pathogenesis-"decreased tissue cell function activity and extracellular matrix (ECM) metabolic disorders" for effective intervention. iMSC hold lower heterogeneity and great promise in biological research and clinical applications. Rps6ka2 may play an important role in the iMSC to treat OA. In this study, the CRISPR/Cas9 gene editing Rps6ka2-/- iMSC were obtained. Effect of Rps6ka2 on iMSC proliferation and chondrogenic differentiation was evaluated in vitro. An OA model was constructed in mice by surgical destabilization of medial meniscus (DMM). The Rps6ka2-/- iMSC and iMSC were injected into the articular cavity twice-weekly for 8 weeks. In vitro experiments showed that Rps6ka2 could promote iMSC proliferation and chondrogenic differentiation. In vivo results further confirmed that Rps6ka2 could improve iMSC viability to promote ECM production to attenuate OA in mice.
Assuntos
Cartilagem Articular , Osteoartrite do Joelho , Camundongos , Animais , Osteoartrite do Joelho/genética , Osteoartrite do Joelho/terapia , Osteoartrite do Joelho/metabolismo , Cartilagem Articular/metabolismo , Diferenciação Celular/genética , Matriz Extracelular , Condrócitos/metabolismo , Modelos Animais de DoençasRESUMO
BACKGROUND: Salt stress severely restricts rapeseed growth and productivity. Hemin can effectively alleviate salt stress in plants. However, the regulatory effect of Hemin on rapeseed in salt stress is unclear. Here, we analyzed the response and remediation mechanism of Hemin application to rapeseed before and after 0.6% (m salt: m soil) NaCl stress. Experiment using two Brassica napus (AACC, 2n = 38) rapeseed varieties Huayouza 158R (moderately salt-tolerant) and Huayouza 62 (strongly salt-tolerant). To explore the best optional ways to improve salt stress resistance in rapeseed. RESULTS: Our findings revealed that exogenous application of Hemin enhanced morph-physiological traits of rapeseed and significantly attenuate the inhibition of NaCl stress. Compared to Hemin (SH) treatment, Hemin (HS) significantly improved seedlings root length, seedlings height, stem diameter and accumulated more dry matter biomass under NaCl stress. Moreover, Hemin (HS) significantly improved photosynthetic efficiency, activities of antioxidant enzymes such as superoxide dismutase (SOD), peroxidase (POD), ascorbate peroxidase (APX), and decreased electrolyte leakage (EL) and malondialdehyde (MDA) content, thus resulting in the alleviation of oxidative membrane damage. Hemin (HS) showed better performance than Hemin (SH) under NaCl stress. CONCLUSION: Hemin could effectively mitigate the adverse impacts of salt stress by regulating the morph-physiological, photosynthetic and antioxidants traits of rapeseed. This study may provide a basis for Hemin to regulate cultivated rapeseed salt tolerance and explore a better way to alleviate salt stress.
Assuntos
Brassica napus , Brassica rapa , Plântula , Hemina/farmacologia , Cloreto de Sódio/farmacologia , Antioxidantes/farmacologia , Estresse SalinoRESUMO
Zika Virus (ZIKV) infection is a global threat. Other than the congenital neurological disorders it causes, ZIKV infection has been reported to induce cardiac complications. However, the precise treatment plans are unclear. Thus, illustrating the pathogenic mechanism of ZIKV in the heart is critical to providing effective prevention and treatment of ZIKV infection. The mechanism of autophagy has been reported recently in Dengue virus infection. Whether or not autophagy participates in ZIKV infection and its role remains unrevealed. This study successfully established the in vitro cardiomyocytes and in vivo mouse models of ZIKV infection to investigate the involvement of autophagy in ZIKV infection. The results showed that ZIKV infection is both time and gradient-dependent. The key autophagy protein, LC3B, increased remarkably after ZIKV infection. Meanwhile, autophagic flux was detected by immunofluorescence. Applying autophagy inhibitors decreased the LC3B levels. Furthermore, the number of viral copies was quantified to evaluate the influence of autophagy during infection. We found that autophagy was actively involved in the ZIKV infection and the inhibition of autophagy could effectively reduce the viral copies, suggesting a potential intervention strategy for reducing ZIKV infection and the undesired complications caused by ZIKV.
Assuntos
Infecção por Zika virus , Zika virus , Animais , Camundongos , Replicação ViralRESUMO
Clear cell renal cell carcinoma (ccRCC) has poor clinical outcomes and necessitates new treatment options. Epidermal growth factor receptor (EGFR) is a potential therapeutic target, due to the associations with various carcinomas' progression. Arctigenin, a natural compound of Arctium lappa, has been shown to display anticancer abilities in various carcinomas. Cellular assays and combination studies were conducted using arctigenin and anti-ccRCC drugs. In vivo efficacy of arctigenin was determined using ccRCC xenograft mouse model. Immunoblotting and biochemistry analysis were applied to investigate the signaling affected by arctigenin. Arctigenin inhibits growth, migration, and survival of ccRCC cells while sparing normal kidney cells. Arctigenin acts synergistically with 5-FU and sorafenib but not temsirolimus in inhibiting ccRCC cells. Synergism of arctigenin with 5-FU and sorafenib was further shown in ccRCC xenograft mouse model. The combination of arctigenin with clinical anti-RCC drugs completely inhibits tumor growth without tumor progression even for an extended time period. Mechanistically, arctigenin inhibits migration in a RhoA-dependent manner while inhibits growth via suppressing EGFR-mediated signaling pathways. Our findings suggest that arctigenin performs well to add to current treatment in ccRCC and confirm the value to target EGFR to improve therapy in RCC.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Animais , Camundongos , Carcinoma de Células Renais/patologia , Sorafenibe/farmacologia , Receptores ErbB/metabolismo , Receptores ErbB/farmacologia , Receptores ErbB/uso terapêutico , Neoplasias Renais/patologia , Fluoruracila/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Proteína rhoA de Ligação ao GTP/metabolismo , Proteína rhoA de Ligação ao GTP/farmacologia , Proteína rhoA de Ligação ao GTP/uso terapêuticoRESUMO
BACKGROUND: Genome-wide association studies (GWAS) are an effective way to explore genotype-phenotype associations in humans, animals, and plants. Various GWAS methods have been developed based on different genetic or statistical assumptions. However, no single method is optimal for all traits and, for many traits, the putative single nucleotide polymorphisms (SNPs) that are detected by the different methods do not entirely overlap due to the diversity of the genetic architecture of complex traits. Therefore, multi-tool-based GWAS strategies that combine different methods have been increasingly employed. To take this one step further, we propose an ensemble-like GWAS strategy (E-GWAS) that statistically integrates GWAS results from different single GWAS methods. RESULTS: E-GWAS was compared with various single GWAS methods using simulated phenotype traits with different genetic architectures. E-GWAS performed stably across traits with different genetic architectures and effectively controlled the number of false positive genetic variants detected without decreasing the number of true positive variants. In addition, its performance could be further improved by using a bin-merged strategy and the addition of more distinct single GWAS methods. Our results show that the numbers of true and false positive SNPs detected by the E-GWAS strategy slightly increased and decreased, respectively, with increasing bin size and when the number and the diversity of individual GWAS methods that were integrated in E-GWAS increased, the latter being more effective than the bin-merged strategy. The E-GWAS strategy was also applied to a real dataset to study backfat thickness in a pig population, and 10 candidate genes related to this trait and expressed in adipose-associated tissues were identified. CONCLUSIONS: Using both simulated and real datasets, we show that E-GWAS is a reliable and robust strategy that effectively integrates the GWAS results of different methods and reduces the number of false positive SNPs without decreasing that of true positive SNPs.
Assuntos
Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Humanos , Animais , Suínos , Estudo de Associação Genômica Ampla/métodos , Estudos de Associação Genética , FenótipoRESUMO
5-Bis[(2-fluorophenyl)methylene]-4-piperidinone (EF-24) is a curcumin analog, which was identified for its physiochemical stability and diverse pharmacological functions. In the present study, EF-24 was added to the breast cancer cell line MCF-7 and its cellular effects were characterized. The results indicated that EF-24 possessed antiproliferative and antimigratory activities on MCF-7 cells as determined by MTT assay, wound healing, and transwell assay, respectively. In addition, the autophagosomal vesicles could be detected by acridine orange staining and electron microscope analysis in EF-24-treated cells. Conversion of LC3-I to LC3-II was also investigated following EF-24 treatment of the cells. However, the expression analysis of p62 and LC3 revealed that EF-24 could inhibit autophagic flux in MCF-7 cells. Confocal microscopy suggested that EF-24 could inhibit the degradation of autophagic vesicles by blocking the fusion of autophagosomes with lysosomes. EF-24 could also induce apoptosis of MCF-7 cells as determined by Hoechst 33342 staining, flow cytometry analysis, and western blot analysis. Moreover, treatment of the cells with the autophagy inhibitor 3-MA enhanced the PARP1 cleavage of EF-24-treated MCF-7 cells, which indicated the crosstalk between autophagy and apoptosis in breast cancer cells. Additional investigation of EF-24 should be performed in future studies to assess its antiproliferation and antimigratory effects on MCF-7 cells. However, the current results provide a solid foundation for the potential in vivo anticancer activity of this compound.
Assuntos
Neoplasias da Mama , Curcumina , Humanos , Feminino , Células MCF-7 , Curcumina/farmacologia , Proliferação de Células , Autofagia , Linhagem Celular Tumoral , Neoplasias da Mama/tratamento farmacológico , ApoptoseRESUMO
BACKGROUND AND OBJECTIVES: Addictive behaviors are serious factors for mental health and usually increase during public crises. We identified the vulnerable characteristics for bad prognosis of addictive internet use across different periods of the coronavirus disease 2019 (COVID-19) pandemic. METHODS: Self-reported questionnaires were delivered in three waves through jdh.com during the outbreak (n = 17,960), remission (n = 15,666), and dynamic zero (n = 12,158) periods of COVID-19 pandemic in China. Internet addiction degree was assessed using the Internet Addiction Test. The different progression groups were divided using a latent class growth model among 1679 longitudinal participants. Risk factors for bad progression were identified by two-step logistic regression. RESULTS: A total of 40.16% of participants reported an increase in the addictive degree of internet use compared with prepandemic. Across different COVID-19 periods, the overall trend of addictive internet use was downward among general Chinese study participants (Mslope = -1.56). Childhood traumatic experiences, deterioration of physical health, depression, and anxiety during remission and dynamic periods were the main risk factors for the bad progression of pandemic-induced addictive internet use. DISCUSSION AND CONCLUSIONS: Addictive internet use was remitted following relaxed control policies during the COVID-19 pandemic. Negative childhood experiences and bad mental status during the recovery period were harmful to coping with pandemic-related addictive internet use. SCIENTIFIC SIGNIFICANCE: Our findings profiled the general trend of addictive internet use and the vulnerable characteristics of its bad progression across different periods of the first wave of COVID-19 pandemic in China. Our findings provide valuable insights for preventing the long-term adverse effects of negative public events on Internet addiction.
Assuntos
Comportamento Aditivo , COVID-19 , Humanos , COVID-19/epidemiologia , Pandemias , Uso da Internet , Comportamento Aditivo/epidemiologia , Comportamento Aditivo/psicologia , Fatores de Risco , China/epidemiologia , InternetRESUMO
There is growing contamination of copper (Cu) in the marine environment, particularly after the ban of organotin compounds and the increase of the use of Cu-based antifouling paints. Although there are increasing research interests in temperature-dependent chemical toxicity to aquatic organisms, most existing studies focused on acute impacts of chemicals at high concentrations. This study aimed to investigate the interacting effect of temperature and copper exposure at environmentally relevant concentrations on survival and development in the marine copepod Tigriopus japonicus with a partial life-cycle toxicity test. Expressions of five stress response genes in the copepod, namely two glutathione S-transferases (GST-S and GST-O), two heat shock proteins (HSP70 and HSP90), and glutathione reductase (GR) were also investigated. The copepod's survival was significantly impaired at 15 °C after development to adult stage, while its developmental time reduced significantly with increasing temperature. Copper at the two environmentally relevant test concentrations had no significant impacts on these apical endpoints whereas the interaction between Cu and temperature was more significant in modulating gene expressions. GST-S, GST-O and HSP90 genes in copepods exposed to 100 µg Cu L-1 were significantly upregulated at 20 °C. At 32 °C, most genes were either insignificantly expressed or down-regulated, compared to the control, likely suggesting that thermal stress inhibited the copepod's antioxidative defense system. Overall, the results revealed that the joint Cu and thermal stresses have significantly elicited antioxidative system in the copepods. It clearly demonstrated the need for more fundamental studies about potential impacts of different environmental factors such as temperature on chemical toxicity under realistic scenario of marine pollution.
Assuntos
Copépodes , Poluentes Químicos da Água , Animais , Cobre/toxicidade , Cobre/metabolismo , Copépodes/genética , Temperatura , Testes de Toxicidade/métodos , Antioxidantes/metabolismo , Poluentes Químicos da Água/toxicidade , Poluentes Químicos da Água/metabolismoRESUMO
A chemical investigation of 95% ethanol extract from the stem and branch of Tripterygium wilfordii has resulted in the isolation and characterization of two new compounds, one neolignan (1) and one phenylalanine derivative (2), as well as four known compounds (3-6). The structures of the new compounds were determined based on extensive spectroscopic analyses. The absolute configuration of compound 1 was defined by X-ray crystallographic analyses and electronic circular dichroism calculation. In addition, compounds 2 and 4-6 exhibited inhibitory effects against NO production in LPS-induced RAW 264.7 macrophages with the IC50 value ranging from 3.51 µM to 30.40 µM.
Assuntos
Óxido Nítrico , Tripterygium , Camundongos , Animais , Células RAW 264.7 , Tripterygium/química , Folhas de Planta/química , Macrófagos , Estrutura MolecularRESUMO
Two new pregnane glycosides (1 and 2), together with four known ones (3- 6), were isolated from the roots of Cynanchum auriculatum Royle ex Wight (Asclepiadaceae). On the basis of detailed spectroscopic analysis and chemical method, the structures of new compounds were characterized to be metaplexigenin 3-O-ß-D-cymaropyranosyl- (1â4)-α-L-diginopyranosyl-(1â4)-ß-D-cymaropyranoside (1), metaplexigenin 3-O-α-L-diginopyranosyl-(1â4)-ß-D-cymaropyranoside (2). All the isolated compounds (1-6) were tested for their in vitro inhibitory activity against the growth of human colon cancer cell lines HCT-116. Compounds 5 and 6 showed significant cytoxicities with IC50 values of 43.58 µM and 52.21 µM.