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Tumor-specific activatable long-wavelength (LW) photosensitizers (PSs) show promise in overcoming the limitations of traditional photodynamic therapy (PDT), such as systemic phototoxicity and shallow tissue penetration. However, their insufficient LW light absorption and low singlet oxygen quantum yield (Φ 1O2) usually require high laser power density to produce thermal energy and synergistically enhance PDT. The strong photothermal radiation causing acute pain significantly reduces patient compliance and hinders the broader clinical application of LW PDT. Through the exciton dynamics dissection strategy, we have developed a series of pH-activatable cyanine-based LW PSs (LET-R, R = H, Cl, Br, I), among which the activated LET-I exhibits strong light absorption at 808â nm and a remarkable 3.2-fold enhancement in Φ 1O2 compared to indocyanine green. Transient spectroscopic analysis and theoretical calculations confirmed its significantly promoted intersystem crossing and simultaneously enhanced LW fluorescence emission characteristics. These features enable the activatable fluorescence and photoacoustic dual-modal imaging-escorted complete photodynamic eradication of tumors by the folic acid (FA)-modified LET-I probe (LET-I-FA), under the ultralow 808â nm laser power density (0.2â W cm-2) for irradiation, without the need for photothermal energy synergy. This research presents a novel strategy of dissecting exciton dynamics to screen activatable LW PSs for traceable PDT.
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Tumour-associated macrophages (TAMs), encompassing M1 and M2 subtypes, exert significant effects on osteosarcoma (OS) progression and immunosuppression. However, the impacts of TAM-derived biomarkers on the progression of OS remains limited. The GSE162454 profile was subjected to single-cell RNA (scRNA) sequencing analysis to identify crucial mediators between TAMs and OS cells. The clinical features, effects and mechanisms of these mediators on OS cells and tumour microenvironment were evaluated via biological function experiments and molecular biology experiments. Phosphodiesterase 4C (PDE4C) was identified as a pivotal mediator in the communication between M2 macrophages and OS cells. Elevated levels of PDE4C were detected in OS tissues, concomitant with M2 macrophage level, unfavourable prognosis and metastasis. The expression of PDE4C was observed to increase during the conversion process of THP-1 cells to M2 macrophages, which transferred the PDE4C mRNA to OS cells through exosome approach. PDE4C increased OS cell proliferation and mobility via upregulating the expression of collagens. Furthermore, a positive correlation was observed between elevated levels of PDE4C and increased TIDE score, decreased response rate following immune checkpoint therapy, reduced TMB and diminished PDL1 expression. Collectively, PDE4C derived from M2 macrophages has the potential to enhance the proliferation and mobility of OS cells by augmenting collagen expression. PDE4C may serve as a valuable biomarker for prognosticating patient outcomes and response rates following immunotherapy.
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Neoplasias Ósseas , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Imunoterapia , Macrófagos , Osteossarcoma , Microambiente Tumoral , Humanos , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/patologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Regulação Neoplásica da Expressão Gênica , Imunoterapia/métodos , Macrófagos/metabolismo , Macrófagos/imunologia , Metástase Neoplásica , Osteossarcoma/patologia , Osteossarcoma/imunologia , Osteossarcoma/genética , Osteossarcoma/metabolismo , Osteossarcoma/terapia , Prognóstico , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Sophora flavescens is often used in traditional Chinese medicine for skin issues, diarrhea, and vaginal itching (Plant names have been checked with http://www.the/plant/list.org on Feb 22nd, 2024). Oxymatrine (OY), a major bioactive compound from Sophora flavescens, is commonly used in China to treat ulcerative colitis, but its mechanisms are still unclear. AIM OF THE STUDY: Recent studies have found that the crosstalk between ferroptosis and inflammation is an important mechanism in the pathogenesis of UC. The aim of this study was to investigate the potential underlying mechanisms of OY treatment on DSS-induced ulcerative colitis, specifically focusing on the processes of ferroptosis and inflammation. MATERIALS AND METHODS: Bioinformatics methods were used to identify key targets of OY for ferroptosis and inflammation in ulcerative colitis, based on GEO data and FerrDb database. Then, 4% DSS solution was used to induce UC model. OY's impact on morphological changes was assessed using colon views, Hematoxylin and eosin (HE) staining, and transmission electron microscopy (TEM). Ferroptosis phenotype index and inflammations factors were detected by ELISA or chem-bio detection kits. The screen out hub related genes about ferroptosis and inflammation were verified by RT-PCR, immunohistochemistry (IHC), and western blotting (WB) respectively. RESULTS: Bioinformatics results show that there are 16 key target genes involved in ferroptosis and inflammation interaction of OY treatment for UC, such as IL6, NOS2, IDO1, SOCS1, and DUOX. The results of animal experiments show that OY could depress inflammatory factors (IL-1ß, IL-6, TNF-α, HMGB1, and NLRP3) and reduce iron deposition (Fe2+, GSH). Additionally, OY suppressed the hub genes or proteins expression involved in ferroptosis and inflammation, including IL-1ß, IL-6, NOS2, HIF1A, IDO1, TIMP1, and DUOX2. CONCLUSION: This present study combines bioinformatics, molecular biology, and animal experimental research evidently demonstrated that OY attenuates UC by improving ferroptosis and inflammation, mainly target to the expression of IL-1ß, IL-6, NOS2, HIF1A, IDO1, TIMP1, and DUOX2.
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Alcaloides , Colite Ulcerativa , Sulfato de Dextrana , Ferroptose , Quinolizinas , Sophora , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Quinolizinas/farmacologia , Quinolizinas/uso terapêutico , Sophora/química , Ferroptose/efeitos dos fármacos , Animais , Alcaloides/farmacologia , Alcaloides/uso terapêutico , Camundongos , Inflamação/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Camundongos Endogâmicos C57BL , Masculino , Modelos Animais de Doenças , Colo/efeitos dos fármacos , Colo/patologia , Colo/metabolismo , Sophora flavescens , MatrinasRESUMO
The oncogenic properties of members belonging to the forkhead box (FOX) family have been extensively documented in different types of cancers. In this study, our objective was to investigate the impact of FOXP3 on glioblastoma multiforme (GBM) cells. By conducting a screen using a small hairpin RNA (shRNA) library, we discovered a significant association between FOXP3 and ferroptosis in GBM cells. Furthermore, we observed elevated levels of FOXP3 in both GBM tissues and cell lines, which correlated with a poorer prognosis. FOXP3 was found to promote the proliferation of GBM cells by inhibiting cell ferroptosis in vitro and in vivo. Mechanistically, FOXP3 not only directly upregulated the transcription of GPX4, but also attenuated the degradation of GPX4 mRNA through the linc00857/miR-1290 axis, thereby suppressing ferroptosis and promoting proliferation. Additionally, the FOXP3 inhibitor epirubicin exhibited the ability to impede proliferation and induce ferroptosis in GBM cells both in vitro and in vivo. In summary, our study provided evidences that FOXP3 facilitates the progression of glioblastoma by inhibiting ferroptosis via the linc00857/miR-1290/GPX4 axis, highlighting FOXP3 as a potential therapeutic target for GBM.
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Ferroptose , Glioblastoma , MicroRNAs , Humanos , Glioblastoma/genética , Ferroptose/genética , MicroRNAs/genética , RNA Interferente Pequeno , Fatores de Transcrição Forkhead/genética , Proliferação de Células/genética , Linhagem Celular TumoralRESUMO
Natural chemicals derived from herbal plants have recently been recognized as potentially useful treatment alternatives owing to their ability to target a wide range of important biological molecules. Cynaroside is one of these natural compounds with promising anticancer activity for numerous tumor types. Nevertheless, the anticancer effects and molecular mechanisms of action of cynaroside on colorectal cancer (CRC) remain unclear. In this study, cynaroside was found to markedly inhibit CRC cell proliferation and colony formation in vitro. Cynaroside also inhibited cell proliferation in vivo and decreased the expression of KI67, a cell nuclear antigen. RNA sequencing revealed 144 differentially expressed genes (DEGs) in HCT116 cells and 493 DEGs in RKO cells that were enriched in the cell cycle signaling pathway. Cell division cycle 25A (CDC25A), a DEG widely enriched in the cell cycle signaling pathway, is considered a key target of cynaroside in CRC cells. Cynaroside also inhibited DNA replication and arrested cells in the G1/S phase in vitro. The expression levels of CDC25A and related G1-phase proteins were significantly elevated after CDC25A overexpression in CRC cells, which partially reversed the inhibitory effect of cynaroside on CRC cell proliferation and G1/S-phase arrest. In summary, cynaroside may be used to treat CRC as it inhibits CDC25A expression.
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Neoplasias Colorretais , Glucosídeos , Humanos , Pontos de Checagem da Fase G1 do Ciclo Celular , Luteolina , Neoplasias Colorretais/tratamento farmacológicoRESUMO
Rationale: Primordial follicles are limited in number and cannot be regenerated, dormant primordial follicles cannot be reversed once they enter a growth state. Therefore, the length of the female reproductive lifespan depends on the orderly progression and selective activation of primordial follicles, the mechanism of which remains unclear. Methods: We used human ovarian cortical biopsy specimens, granulosa cells from diminished ovarian reserve (DOR) patients, Hdac6-overexpressing transgenic mouse model, and RNA sequencing to analyze the crucial roles of histone deacetylase 6 (HDAC6) in fertility preservation and primordial follicle activation. Results: In the present study, we found that HDAC6 was highly expressed in most dormant primordial follicles. The HDAC6 expression was reduced accompanying reproductive senescence in human and mouse ovaries. Overexpression of Hdac6 delayed the rate of primordial follicle activation, thereby prolonging the mouse reproductive lifespan. Short-term inhibition of HDAC6 promoted primordial follicle activation and follicular development in humans and mice. Mechanism studies revealed that HDAC6 directly interacted with NGF, reducing acetylation modification of NGF and thereby accelerating its ubiquitination degradation. Consequently, the reduced NGF protein level maintained the dormancy of primordial follicles. Conclusions: The physiological significance of the high expression of HDAC6 in most primordial follicles is to reduce NGF expression and prevent primordial follicle activation to maintain female fertility. Reduced HDAC6 expression increases NGF expression in primordial follicles, activating their development and contributing to reproduction. Our study provides a clinical reference value for fertility preservation.
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Desacetilase 6 de Histona , Camundongos Transgênicos , Fator de Crescimento Neural , Folículo Ovariano , Ubiquitinação , Animais , Feminino , Humanos , Camundongos , Acetilação , Células da Granulosa/metabolismo , Desacetilase 6 de Histona/metabolismo , Desacetilase 6 de Histona/genética , Fator de Crescimento Neural/metabolismo , Folículo Ovariano/metabolismoRESUMO
The telomerase reverse transcriptase promoter (TERTp) is frequently mutated in gliomas. This study sought to identify immune biomarkers of gliomas with TERTp mutations. Data from TCGA were used to identify and validate survival-associated gene signatures, and immune and stromal scores were calculated using the ESTIMATE algorithm. High stromal or immune scores in patients with TERTp-mutant gliomas correlated with shorter overall survival compared to cases with low stromal or immune scores. Among TERTp-mutant gliomas with both high immune and high stromal scores, 213 commonly shared DEGs were identified. Among 71 interacting DEGs representing candidate hub genes in a PPI network, HOXC6, WT1, CD70, and OTP showed significant ability in establishing subgroups of high- and low-risk patients. A risk model based on these 4 genes showed strong prognostic potential for gliomas with mutated TERTp, but was inapplicable for TERTp-wild-type gliomas. TERTp-mutant gliomas with high-risk scores displayed a greater percentage of naïve B cells, plasma cells, naïve CD4 T cells, and activated mast cells than low-risk score gliomas. TIDE analysis indicated that immune checkpoint blockade (ICB) therapy may benefit glioma patients with TERTp mutations. The present risk model can help predict prognosis of glioma patients with TERTp mutations and aid ICB treatment options.
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Neoplasias Encefálicas , Glioma , Telomerase , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Mutação , Glioma/tratamento farmacológico , Glioma/genética , Prognóstico , Telomerase/genéticaRESUMO
Introduction: The risk that a large polyp (≥10 mm) evolves into high-grade dysplasia (HGD) is relatively high compared with that of a small/diminutive polyp (<10 mm). Recently, the detection of small and diminutive polyps has been substantially improved with the advancement of endoscopy. However, further research is needed on the role of the incidence of HGD caused by the co-occurrence of small and diminutive polyps in the progression of HGD. In this study, we aim to investigate whether and how the small and diminutive polyps correlate with the incidence of HGD in the population. Methods: The pooled data were deeply analyzed from four published randomized controlled trials (RCTs) regarding colon polyp detection. All polyps detected were examined and confirmed by pathologists. The primary outcome was the composition ratio of the HGD polyps in each polyp size category. Results: Among a total of 3,179 patients with 2,730 polyps identified, there were 83 HGD polyps confirmed, and 68 patients had at least one polyp with HGD. The risk of development of HGD was lower for a single small and diminutive polyp than for one large polyp (2.18% vs. 22.22%, P < 0.0001). On the contrary, the composition ratio for HGD from small and diminutive polyps was significantly higher than that from the large ones (68.67% vs. 31.33%, P < 0.0001). The combined number of HGD presented a trend negatively correlated to size. Conclusions: Our data demonstrated that the absolute number of HGD significantly derives more from small and diminutive polyps than from the large ones, and the collective number of small and diminutive polyps per patient is indicative of his/her HGD exposure. These findings positively provide novel perspectives on the management of polyps and may further optimize the prevention of colorectal cancer. Systematic Review Registration: http://www.chictr.org.cn, identifier ChiCTR1900025235, ChiCTR1800017675, ChiCTR1800018058, and ChiCTR1900023086.
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ETHNOPHARMACOLOGICAL RELEVANCE: Bone defects are difficult to treat and have a high incidence of nonunion. The Epimedii folium-Rhizoma drynariae herbal pair (EDP) is a traditional Chinese medicine (TCM) used for treating bone diseases. However, the mechanisms by which EDP promotes osteogenesis or bone formation remain largely unclear. AIM OF THE STUDY: This study aimed to investigate the mechanism of EDP promoted bone formation in bone defects using network pharmacology and experiments. MATERIALS AND METHODS: The chemical components of EDP were analyzed by UHPLC-MS. The hub target and pathway enrichment analysis was conducted using molecular docking or network pharmacology. The pharmacological actions of EDP were determined by µCT and histopathology examination using a bone defect rat model. The effects of EDP on the mRNA expression of Bmp2, Smad2/5, Runx2, and Alp genes were measured by RT-PCR, while changes in the protein expressions of BMP2, COL1A1, SPP1, ALP, and RUNX2in the tibia tissues of the rats in response to EDP were analyzed by immunohistochemical staining or Western blot. We also performed cell viability assays, Alizarin Red and ALP staining assays, and RT-PCR to better understand how EDP affected osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). RESULTS: Identified 14 key compounds and 47 hub targets of EDP that may be involved in promoting osteogenesis to repair bone defects. And the BMP/Smad/Runx2 pathway was likely the key pathway through which EDP promoted bone defects repairing. The results of in vivo rat experiments indicated that EDP effectively promoted tibia repair in the model rats and activated the BMP/Smad/Runx2 pathway in the tibia tissue, with upregulating Bmp2, Bmpr1α, Smad2/5, Runx2, and Alp genes, and increased the protein expression of BMP2, COL1A1, RUNX2, and ALP. In vitro, EDP was found to increase the proliferation, differentiation, and mineralization in BMSCs- and also up-regulated the expression of key genes in the BMP/Smad/Runx2 pathway. CONCLUSION: This study highlighted the ability of EDP to promote the osteogenic differentiation to enable bone repair by activating the BMP/Smad/Runx2 pathway.
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Subunidade alfa 1 de Fator de Ligação ao Core , Osteogênese , Ratos , Animais , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Farmacologia em Rede , Simulação de Acoplamento Molecular , Células Cultivadas , Diferenciação CelularRESUMO
Gastrodin, the primary bioactive compound found in Gastrodia elata, has been shown to exhibit neuroprotective properties in a range of neurological disorders. However, the precise mechanisms through which gastrodin influences glioma cells remain unclear, and there is a scarcity of data regarding its specific effects. To ascertain the viability of glioma cell lines LN229, U251, and T98, the CCK-8 assay, a colony formation assay, and a 3D culture model were employed, utilizing varying concentrations of gastrodin (0, 5, 10, and 20 µM). Gastrodin exhibited a notable inhibitory effect on the growth of glioma cells, as evidenced by its ability to suppress colony formation and spheroid formation. Additionally, gastrodin induced ferroptosis in glioma cells, as it can increase the levels of reactive oxygen species (ROS) and peroxidized lipids, and reduced the levels of glutathione. Using a subcutaneous tumor model, gastrodin was found to significantly inhibit the growth of the T98 glioma cell line in vivo. Using high-throughput sequencing, PPI analysis, and RT-qPCR, we successfully identified Homeobox D10 (HOXD10) as the principal target of gastrodin. Gastrodin administration significantly enhanced the expression of HOXD10 in glioma cells. Furthermore, treatment with gastrodin facilitated the transcription of ACSL4 via HOXD10. Notably, the inhibition of HOXD10 expression impeded ferroptosis in the cells, which was subsequently restored upon rescue with gastrodin treatment. Overall, our findings suggest that gastrodin acts as an anti-cancer agent by inducing ferroptosis and inhibiting cell proliferation in HOXD10/ACSL4-dependent pathways. As a prospective treatment for gliomas, gastrodin will hopefully be effective.
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Ferroptose , Glioma , Humanos , Ferroptose/genética , Regulação para Cima , Genes Homeobox , Glioma/tratamento farmacológico , Glioma/genética , Glioma/metabolismo , Linhagem Celular TumoralRESUMO
To explore the potential mechanism of Gegen Qinlian decoction (GGQL) in the treatment of COVID-19 comorbid with diabetes mellitus (DM) through network pharmacology and molecular docking, and to provide theoretical guidance for clinical transformation research. Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform was used to screen the active compounds and targets of GGQL, the targets of COVID-19 comorbid with DM were searched based on Genecards database. Protein-protein interaction network was constructed using String data platform for the intersection of compounds and disease targets, the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis of the intersection targets was performed using DAVID database. Cytoscape software was used to construct the "compound target-pathway (C-T-P)" of GGQL in the treatment of COVID-19 comorbid with DM, the molecular docking platform was used to complete the simulated docking of key compounds and targets. We obtained 141 compounds from GGQL, revealed 127 bioactive compounds and 283 potential targets of GGQL. Quercetin, kaempferol and formononetin in GGQL play a role by modulating the targets (including AR, GSK3B, DPP4, F2, and NOS3). GGQL might affect diverse signaling pathways related to the pathogenesis of coronavirus disease - COVID-19, AGE-RAGE signaling pathway in diabetic complications, IL-17 signaling pathway, human cytomegalovirus infection and Th17 cell differentiation. Meanwhile, molecular docking showed that the selected GGQL core active components had strong binding activity with the key targets. This study revealed that GGQL play a role in the treatment of COVID-19 comorbid with DM through multi-component, multi-target and multi-pathway mode of action, which provided good theoretical basis for further verification research.
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COVID-19 , Diabetes Mellitus , Medicamentos de Ervas Chinesas , Humanos , Simulação de Acoplamento Molecular , Farmacologia em Rede , Medicina Tradicional ChinesaRESUMO
AIM: Diabetes osteoporosis (DOP) is a chronic bone metabolic disease induced by diabetes, whose morbidity continues to increase. Epimedium brevicornum Maxim (EB), a popular Chinese traditional medicine, has been used to treat bone diseases in China for thousands of years. But its material basis and specific mechanism of action are not clear. METHODS: Epimedium brevicornum crude polysaccharide (EPE) is the main component, in this research the characterized the structure of EBPC1 purified from EPE was detected and its effects on cell proliferation, differentiation, and cytoskeletal in osteoblasts induced by high glucose. RESULTS: The molecular weight of EBPC1 was 10.5 kDa. It was mainly comprised of glucose and galactose, and the backbone of EBPC1 wasâ4)-α-D-Galp-(1â4)-α-D-Galp-(1â6)-ß-D-Galp-(1â6)-ß-D-Galp-(1â4)-α-D-Glcp-(1â4)-α-D-Glcp-(1â. The results from in vitro experiments revealed that EBPC1 significantly increased alkaline phosphatase (ALP) activity and mineralized nodule formation in primary osteoblasts, also significantly up-regulated expression of Alp mRNA and Runx2 mRNA in the presence of EBPC1 pretreatment. Moreover, EBPC1 modulated apoptosis via the regulation of Bax/Bcl2. CONCLUSION: These results indicate that EBPC1 treatment can promote osteogenesis during DOP, which can ameliorate apoptosis by regulating Bax/Bcl2 and accelerating osteogenesis in osteoblasts.
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Diabetes Mellitus , Epimedium , Osteoporose , Humanos , Epimedium/química , Osteogênese , Proteína X Associada a bcl-2/metabolismo , Osteoporose/metabolismo , Diferenciação Celular , Osteoblastos , Polissacarídeos/química , RNA Mensageiro/metabolismo , Diabetes Mellitus/metabolismoRESUMO
Immune and stromal cells contribute to glioma progression by infiltrating the tumor microenvironment. We used clinical characteristics, RNA sequencing data and the ESTIMATE algorithm to obtain stromal and immune scores for alpha thalassemia retardation syndrome X-linked (ATRX)-mutation-type (ATRX-mt) and ATRX-wildtype (ATRX-wt) glioma tissues from The Cancer Genome Atlas. To identify specific immune biomarkers of glioma, we compared the gene expression profiles of ATRX-wt glioma tissues with high vs. low immune/stromal scores, and discovered 162 differentially expressed genes. The protein-protein interaction network based on these results contained 80 interacting genes, of which seven (HOXA5, PTPN2, WT1, HOXD10, POSTN, ADAMDEC1 and MYBPH) were identified as key prognostic genes via LASSO and Cox regression analyses. A risk model constructed using the expression of these seven genes could predict survival for ATRX-wt glioma patients, but was ineffective for ATRX-mt patients. T cells and macrophages were more prevalent in low-risk than in high-risk glioma tissues. Immune checkpoint blockade treatment was highly beneficial for patients with low risk scores. High-risk gliomas were predicted to be more sensitive to rapamycin, dasatinib, 5-fluorouracil and gemcitabine. Thus, our model can be used for the diagnosis, prognostic prediction and treatment planning of ATRX-wt glioma patients.
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Neoplasias Encefálicas , Glioma , Humanos , Inibidores de Checkpoint Imunológico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Proteína Nuclear Ligada ao X/genética , Proteína Nuclear Ligada ao X/metabolismo , Glioma/tratamento farmacológico , Glioma/genética , Glioma/metabolismo , Prognóstico , Microambiente TumoralRESUMO
tRNA-derived small RNAs (tDRs) are dysregulated in several diseases, including pancreatic cancer (PC). However, only a limited number of tDRs involved in PC progression are known. Herein, a novel tDR, 5'-tRF-19-Q1Q89PJZ (tRF-19-Q1Q89PJZ), was verified in PC plasma using RNA and Sanger sequencing. tRF-19-Q1Q89PJZ was downregulated in PC tissues and plasma, which was related to advanced clinical characteristics and poor prognosis. tRF-19-Q1Q89PJZ overexpression inhibited the malignant activity of PC cells in vitro, while tRF-19-Q1Q89PJZ inhibition produced an opposite effect. The differentially expressed genes induced by tRF-19-Q1Q89PJZ overexpression were enriched in "pathways in cancer" and "glycolysis". Mechanistically, tRF-19-Q1Q89PJZ directly sponged hexokinase 1 (HK1) mRNA and inhibited its expression, thereby suppressing glycolysis in PC cells. HK1 restoration relieved the inhibitory effect of tRF-19-Q1Q89PJZ on glycolysis in PC cells and on their proliferation and mobility in vitro. tRF-19-Q1Q89PJZ upregulation inhibited PC cell proliferation and metastasis in vivo and suppressed HK1 expression in tumor tissues. Furthermore, tRF-19-Q1Q89PJZ expression was attenuated under hypoxia. Collectively, these findings indicate that tRF-19-Q1Q89PJZ suppresses the malignant activity of PC cells by regulating HK1-mediated glycolysis. Thus, tRF-19-Q1Q89PJZ may serve as a key target for PC therapy.
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Hexoquinase , Neoplasias Pancreáticas , Humanos , Hexoquinase/genética , Hexoquinase/metabolismo , Linhagem Celular Tumoral , Neoplasias Pancreáticas/metabolismo , Glicólise , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias PancreáticasRESUMO
Ar-turmerone, a compound isolated from turmeric seeds, has exhibited anti-malignant, anti-aging and anti-inflammatory properties. Here, we assessed the effects of ar-turmerone on glioma cells. U251, U87 and LN229 glioma cell lines were treated with different concentrations of ar-turmerone (0, 50, 100 and 200 µM), and their viability and mobility were evaluated using Cell Counting Kit 8, colony formation, wound healing and Transwell assays. The effects of ar-turmerone on U251 glioma cell proliferation were also assessed using a subcutaneous implantation tumor model. High-throughput sequencing, bioinformatic analyses and quantitative real-time polymerase chain reactions were used to identify the key signaling pathways and targets of ar-turmerone. Ar-turmerone reduced the proliferation rate and mobility of glioma cells in vitro and arrested cell division at G1/S phase. Cathepsin B was identified as a key target of ar-turmerone in glioma cells. Ar-turmerone treatment reduced cathepsin B expression and inhibited the cleavage of its target protein P27 in glioma cells. On the other hand, cathepsin B overexpression reversed the inhibitory effects of ar-turmerone on glioma cell proliferation, mobility progression in vitro and in vivo. In conclusion, ar-turmerone suppressed cathepsin B expression and P27 cleavage, thereby inhibiting the proliferation and mobility of glioma cells.
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Neoplasias Encefálicas , Glioma , Humanos , Catepsina B , Linhagem Celular Tumoral , Glioma/patologia , Proliferação de Células , Apoptose , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologiaRESUMO
Chemodynamic therapy (CDT) is a highly tumor-specific treatment, while its efficacy is compromised by the intratumoral Fenton reaction efficiency, which is determined by the following reaction factors, including the availability of Fenton ions (e.g., Fe2+), the amount of H2O2, and the degree of acidity. Synchronous optimization of these factors is a big challenge for efficient CDT. Herein, a strategy of comprehensively optimizing Fenton reaction factors was developed for traceable multistage augmented CDT by charge-reversal theranostics. The customized pH-responsive poly(ethylene)glycol-poly(ß-amino esters) (PEG-PAE) micelle (PM) was prepared as the carrier. Glucose oxidase (GOx), Fe2+, and pH-responsive second near-infrared (NIR-II) LET-1052 probe were coloaded by PM to obtain the final theranostics. The activity of metastable Fe2+ remained by the unsaturated coordination with PEG-PAE. Then tumor accumulation and exposure of Fe2+ were achieved by charge-reversal cationization of PEG-PAE, which was further enhanced by a GOx catalysis-triggered pH decrease. Together with the abundant H2O2 generation and pH decrease through GOx catalysis, the limiting factors of the Fenton reaction were comprehensively optimized, achieving the enhanced CDT both in vitro and in vivo. These findings provide a strategy for comprehensively optimizing intratumoral Fenton reaction factors to overcome the intrinsic drawbacks of current CDT.
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Peróxido de Hidrogênio , Medicina de Precisão , Catálise , Ésteres , Glucose OxidaseRESUMO
Sinapine thiocyanate (ST), an alkaloid existed extensively in seeds of cruciferous plants, exhibits a number of pharmacological effects, including anti-inflammatory and anti-malignancy properties. However, it is still unknown what effects and molecular mechanisms ST has on colorectal cancer (CRC). In the current study, it was indicated that ST inhibited proliferation, colony formation, and apoptosis in vitro, as well as arrested the G1 phase of CRC cells. There was a significant repressive effects of ST on invasion and migration of CRC cells in vitro. RNA-sequencing indicated that 750 differentially expressed genes existed in CRC cells after ST treatment, and enrichment analysis demonstrated that ST obviously decreased the activation of keratinization pathways. Among DEGs enriched in keratinization, keratin 6A (KRT6A) was decreased the most significant, as well as its target gene S100 calcium-binding protein A2 (S100A2). Low expression of KRT6A and S100A2 signatures indicated a favorable prognosis in CRC patients. Moreover, we found overexpression of KRT6A relieved the inhibitory effects of ST in CRC cells. Furthermore, ST inhibited the CRC cell proliferation in vivo, and reduced KRT6A and KI67 expression in xenograft tumor. Taken together, we demonstrated that ST exhibited anti-CRC properties by inhibiting KRT6A/S100A2 axis. It is possible that ST can be used as a treatment for CRC.
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Neoplasias , Tiocianatos , Humanos , Queratina-6 , Apoptose , Fatores Quimiotáticos , Proteínas S100RESUMO
The effects of oenothein B(OEB) on the proliferation, apoptosis, invasion, and migration of breast cancer MCF-7 and MDA-MB-231 cells were investigated by cell culture in vitro, network pharmacology, and molecular docking. In vitro cell experiments revealed that OEB inhibited the proliferation and colony formation ability, and promoted the apoptosis and formation of apoptotic bodies in breast cancer cells, as well as inhibited the invasion and migration of breast cancer cells. The targets of OEB were obtained using SwissTargetPrediction database and breast cancer targets were obtained from GeneCards. The targets of OEB and breast cancer were entered separately in Venny 2.1 software to obtain the Venn diagram of common targets of OEB and breast cancer. The common targets of OEB and breast cancer were input into STRING database to construct a protein-protein interaction(PPI) network, which was entered into Cytoscape 3.7.2 software for network topology analysis. Key targets were screened according to protein association strength, and analyzed for KEGG pathway enrichment. Molecular docking of OEB to key targets using AutoDock software revealed that OEB stably bound to the active pocket of P53, while OEB promoted the expression of P53 protein. MCF-7 and MDA-MB-231 cell viability and migration ability increased after silencing P53, and this change was reversed after treatment with OEB. Therefore, this study showed that OEB inhibited the proliferation, migration, and invasion of breast cancer MCF-7 and MDA-MB-231 cells, and promoted the apoptosis of breast cancer MCF-7 and MDA-MB-231 cells, which may be related to the targeted regulation of P53.
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Neoplasias da Mama , Humanos , Feminino , Proliferação de Células , Neoplasias da Mama/tratamento farmacológico , Proteína Supressora de Tumor p53/genética , Simulação de Acoplamento MolecularRESUMO
The pancreatic stellate cells (PSCs) play an important role in the development of pancreatic cancer (PC) through mechanisms that remain unclear. Exosomes secreted from PSCs act as mediators for communication in PC. This study aimed to explore the role of PSC-derived exosomal small RNAs derived from tRNAs (tDRs) in PC cells. Exosomes from PSCs were extracted and used to detect their effects on PC cell proliferation, migration and invasion. Exosomal tDRs profiling was performed to identify PSC-derived exosomal tDRs. ISH and qRT-PCR were used to examine the tRF-19-PNR8YPJZ levels and clinical value in clinical samples. The biological function of exosomal tRF-19-PNR8YPJZ was determined using the CCK-8, clone formation, wound healing and transwell assays, subcutaneous tumour formation and lung metastatic models. The relationship between the selected exosomal tRF-19-PNR8YPJZ and AXIN2 was determined by RNA sequencing, luciferase reporter assay. PSC-derived exosomes promoted the proliferation, migration, and invasion of PC cells. Novel and abundant tDRs are found to be differentially expressed in PANC-1 cells after treatment with PSC-derived exosomes, such as tRF-19-PNR8YPJZ. PC tissue samples showed markedly higher levels of tRF-19-PNR8YPJZ than normal controls. Patients with PC exhibiting high tRF-19-PNR8YPJZ expression had a highly lymph node invasion, metastasis, perineural invasion, advanced clinical stage and poor overall survival. Exosomal tRF-19-PNR8YPJZ from PSCs targeted AXIN2 in PC cells and decreased its expression, thus activating the Wnt pathway and promoting proliferation and metastasis. Exosomal tRF-19-PNR8YPJZ from PSCs promoted proliferation and metastasis in PC cells via AXIN2.
Assuntos
Exossomos , MicroRNAs , Neoplasias Pancreáticas , Humanos , Células Estreladas do Pâncreas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Neoplasias Pancreáticas/patologia , Exossomos/metabolismo , Proliferação de Células/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Proteína Axina/genética , Proteína Axina/metabolismo , Neoplasias PancreáticasRESUMO
Gastric cancer (GC) is a common and highly malignant tumor of the digestive tract. Members of the focused fucosyltransferase (FUT) family participate in the advancement of various types of cancer. However, research of FUT family members in the progression of GC known to be limited. The purpose of the research was to determine the function of important affiliates of the FUT family in GC and to explore its impacts on the proliferation and migration of GC cells and molecular mechanisms. For the study, fucosyltransferase11 (FUT11) was confirmed to be the only affiliate of the FUT family that was upmodulated in GC tissues and linked to poor survival according to GEPIA data. Furthermore, compared with adjacent noncancerous tissues, the expression of FUT11 was increased in GC tissues. The elevated FUT11 expression suggested that the overall survival (OS) rate of GC is low. Inhibition of FUT11 significantly reduced the proliferation and migration and suppressed the PI3K/AKT pathway by down-regulated collagen type VI alpha 3 chain (COL6A3) in GC cells. The present study has demonstrated that reinstating the expression of COL6A3 in gastric cancer (GC) cells can counteract the inhibitory impact of FUT11 knockdown on the proliferation and migration of GC cells. In conclusion, FUT11 may serve as a novel biomarker for GC, as it modulates GC cell proliferation and migration through the PI3K/AKT signaling pathway.