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5-Fluorouracil (5-FU) is a first-line treatment for colorectal cancer, but side effects such as severe diarrhea are common in clinical use and have been linked to its induction of normal cell senescence. Chloramphenicol (CAP) is an antibiotic commonly used to treat typhoid or anaerobic infections, but its senescence-related aspects have not been thoroughly investigated. Here, we used 5-FU to induce senescence in human umbilical vein endothelial cells (HUVECs) and investigated the relationship between CAP and cellular senescence at the cellular level. In a model of cellular senescence induced by 5-FU treatment, we discovered that CAP treatment reversed the rise in the percentage of senescence-associated galactosidase (SA-ß-gal)-positive cells and decreased the expression of senescence-associated proteins (p16), senescence-associated genes (p21), and senescence-associated secretory phenotypes (SASPs: IL-6, TNF-α). In addition, CAP subsequently restored the autophagic process inhibited by 5-FU and upregulated the levels of autophagy-related proteins. Mechanistically, we found that CAP restored autophagic flux by inhibiting the mTOR pathway, which in turn alleviated FU-induced cellular senescence. Our findings suggest that CAP may help prevent cellular senescence and restore autophagy, opening up new possibilities and approaches for the clinical management of colorectal cancer.
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Skin is the biggest organ of the human body, which easily gets irritated by exposure to the sun. Skin photoaging and acute photodamage are caused by intense UV-B radiation. Therefore, it is imperative to find new compounds to prevent skin damage and aging. Mercaptopurine is an immunologic agent commonly used for treating Acute lymphoblastic leukemia and inflammatory bowel disease. The beneficial effects of mercaptopurine on the skin have not been reported, and its intrinsic mechanism of action is unclear. Therefore, this study was to explore mercaptopurine when exposed to UV-B radiation in HacaT cells and C57BL6 mice aging and damage effects. The model of in vivo UV-B-induced skin damage and skin photoaging was established, and the impact of mercaptopurine on cell and animal skin was studied. The study found that mercaptopurine, on the one hand, inhibits cellular and animal senescence. On the other, it inhibits the expression of mitogen-activated protein kinase (MAPK) and the nuclear factor κB (NF-κB), which are important signaling molecules in the early UV-B reaction signaling pathway. In addition, mercaptopurine downregulates matrix metalloproteinase expression, increases collagen fiber content, and facilitates collagen synthesis. Treatment with mercaptopurine also inhibits the expression of inflammatory factors and reduces inflammatory cell infiltration of the skin. In conclusion, our study elucidates mercaptopurine's anti-photoaging and anti-inflammatory activity in cellular and animal models.
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Mercaptopurina , Envelhecimento da Pele , Animais , Humanos , Camundongos , Mercaptopurina/farmacologia , Mercaptopurina/metabolismo , Camundongos Endogâmicos C57BL , Pele/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/metabolismo , Envelhecimento , Colágeno/metabolismo , Raios Ultravioleta , FibroblastosRESUMO
A series of asymmetric ureas were synthesized by a one-pot reaction of amines and carbonyl sulfide (COS) under catalyst-free conditions. The highly selective synthesis of asymmetric urea was successfully achieved by the use of weakly nucleophilic aromatic amines and highly nucleophilic secondary aliphatic amines. Moreover, a reaction mechanism was proposed based on the detailed NMR and FTIR study. This efficient synthetic methodology provides a mild and selective method for synthesizing asymmetric urea derivatives.
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A colon tumor, one of the digestive tract malignant tumors, is harmful to human health. A potential new treatment still deserves attention. The development of a new drug needs more resources, including time and expense. Therefore, the old drug with new targets has become a current research hotspot. Fluvoxamine, as an antidepressant, could play an effect on inhibiting 5-hydroxytryptamine reuptake. In the present research, the antitumor effects and possible mechanisms of fluvoxamine are validated. The results showed that fluvoxamine significantly suppressed the migration and proliferation of tumor cells, and increased the apoptosis in vitro. Additionally, fluvoxamine significantly delays tumor development, and prompts the apoptosis in tumor tissues of mice-burdened colon tumors in vivo. The tumor suppression might be related with that fluvoxamine inhibits the expression of phosphorylated signal transducer and activator of transcription 3, matrix metalloproteinase 2, and cleaved-caspase 3. Importantly, fluvoxamine significantly reduces the expression level of programmed cell death ligand 1. This could be a possible reason that treatment with fluvoxamine drives the infiltration of T lymphocytes and M1-type macrophages in tumor tissues. Taken together, this research suggests that fluvoxamine might be a promising drug to treat colon cancer by inhibiting the proliferation and migration, inducing apoptosis, and even increasing the immune response of antitumor.
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Neoplasias do Colo , Fluvoxamina , Humanos , Animais , Camundongos , Fluvoxamina/farmacologia , Fluvoxamina/uso terapêutico , Metaloproteinase 2 da Matriz , Antígeno B7-H1/metabolismo , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Linhagem Celular TumoralRESUMO
Belinostat (PXD101), a new histone deacetylase inhibitor, has shown good performance in various cancer treatments and has been approved by the FDA for the treatment of recurrent or refractory peripheral T-cell lymphoma (PTCL) in patients with drugs. PXD101 is considered to have certain anti-allergic and anti-inflammatory properties, but its beneficial effects in UVB-induced skin photoaging have not been reported. In a recent study, HacaT cells and C57BL6 mice were used to study the impact of PXD101 on UVB-induced cellular senescence and skin photoaging and to explore their potential mechanisms of action. Studies have shown that PXD101 inhibits UVB-induced HacaT cell senescence, which appears to be achieved by inhibiting activation of the UVB-induced NF-κB/p65 signaling pathway. At the same time, PXD101 inhibits the expression of MMPs. In addition, PXD101 alleviated skin damage on the dorsal skin of mice, reduced skin aging and inflammation, increased collagen fiber synthesis, and restored UVB-induced epidermal thickening. In short, we believe that PXD101 effectively inhibits cellular senescence and skin photoaging caused by UVB exposure, a potential method for developing clinical prevention and treatment of skin aging.
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Envelhecimento da Pele , Animais , Senescência Celular , Ácidos Hidroxâmicos , Camundongos , Camundongos Endogâmicos C57BL , Pele/metabolismo , Sulfonamidas , Raios Ultravioleta/efeitos adversosRESUMO
Marimastat is one of the potent inhibitors of MMP (MMPIs) with few side effects. The impact of marimastat on cellular senescence remains unexplored. Our study evaluated the marimastate effect on oxidative stress-induced cell senescence using NIH3T3 cells. Marimastate administration was found to suppress senescence-ß-galactosidase (SA-ß-gal) activity and development linked with aging. Furthermore, we observed that this effect of marimastat was closely linked with the recovery of autophagy dysfunction and mTOR suppression in H2O2-treated cells. Notably, this study demonstrated the marimastat effect on senescence inhibition for the first time.
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Senescência Celular , Peróxido de Hidrogênio , Animais , Autofagia , Peróxido de Hidrogênio/farmacologia , Ácidos Hidroxâmicos , Camundongos , Células NIH 3T3 , Estresse OxidativoRESUMO
Trifluridine, a key component of trifluridine/tipiracil, is a potential anti-cancer drug that can act effectively on refractory metastatic colorectal cancer. Chemotherapy is important for cancer treatment, but its adverse effects limit its use. Long-term side-effects caused by the drug used during chemotherapy are closely related to the accumulation of cellular senescence. However, the relationship between trifluridine and normal cell aging remains unclear. The purpose of this study is to evaluate whether trifluridine can induce the senescence of human umbilical vein endothelial cells and to explore the possible mechanism. Human umbilical vein endothelial cells were treated with trifluridine, senescence levels were measured via senescence-related acidic ß-galactosidase staining and senescence-associated secretory phenotype levels respectively. Autophagy was assessed by the protein levels of LC3II/LC3I and p62, and LC3 fusion was detected by fluorescence microscopy. Chloroquine diphosphate salt and rapamycin were used to detect the effect of trifluridine on autophagy flux and mTOR signaling pathway. Trifluridine increased the expression of senescence-associated acidic ß-galactosidase and senescence-related secretory phenotype mRNA levels in cells. In addition, also trifluridine induced cellular senescence by inhibiting autophagy and was closely related to the activation of the mTOR signaling pathway, therefore, we believe that trifluridine may be an effective mTOR activator. The findings also provide a new strategy for establishing autophagy or aging models, as well as a new theoretical basis for the use of trifluridine in clinical treatment.
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Autofagia , Trifluridina , Senescência Celular , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Serina-Treonina Quinases TOR/metabolismo , beta-Galactosidase/metabolismoRESUMO
Colon cancer is a member of malignant tumors in the digestive system. Traditional treatment strategies are ineffective and improving the treatment of colon cancer is an urgent need. Targeting programmed cell death-1 (PD-1) by monoclonal antibodies has shown some therapeutic effectiveness and has advantages. Additionally, the Stat3 inhibitor nifuroxazide was employed to promote the antitumor activity. Here, we hypothesized that combining nifuroxazide with PD-1 small interfering RNA carried by attenuated Salmonella would exert a synergistic antitumor effect on colon cancer. Indeed, treatment with this combination effectively inhibited the development of colon cancer in mice and improved the survival rate. These two novel anticancer agents worked synergistically to elicit potent antitumor immunity and achieve improved therapeutic efficacy. The underlying mechanisms are mainly involved with immune regulation and cell apoptosis. This study provides a previous framework for combining this Stat3 inhibitor with RNAi designed to block immune checkpoint signaling for cancer therapy.
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Neoplasias do Colo/terapia , Hidroxibenzoatos/farmacologia , Nitrofuranos/farmacologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , RNA Interferente Pequeno/administração & dosagem , Salmonella/química , Animais , Anti-Infecciosos/farmacologia , Apoptose , Movimento Celular , Proliferação de Células , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Terapia Combinada , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Receptor de Morte Celular Programada 1/genética , RNA Interferente Pequeno/genética , Salmonella/genética , Salmonella/crescimento & desenvolvimento , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Long noncoding RNA (lncRNA) plays an important regulatory role in tumorigenesis. This study aims to analyze the lncRNA-messenger RNA (mRNA) expression network and potential roles in colorectal cancer (CRC). The LncRNA expression profile was analyzed in CRC tissue by RNA sequencing and the functions of differentially expressed genes were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The lncRNA-mRNA network was predicted with bioinformatics. From the result, we identified 485 differential expression lncRNAs and 2383 mRNAs in CRC, GO, and KEGG analyses showed that the changes in lncRNAs were mainly associated with metabolism and transcription regulation that were different from mRNA function. Additionally, based on the predicted coexpression network, we identified that NONHSAT074176.2, downregulated in CRC tissue and cell lines, was a hub lncRNA in the development of CRC. Our results describe the lncRNA-mRNA network in detail and indicate that lncRNA NONHSAT074176.2 may be useful as a candidate diagnostic biomarker and may be a promising therapeutic target for CRC.
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Neoplasias Colorretais/genética , Redes Reguladoras de Genes , RNA Longo não Codificante/metabolismo , RNA Mensageiro/metabolismo , Neoplasias Colorretais/metabolismo , Biologia Computacional , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Análise de Sequência de RNARESUMO
This study utilized hyperspectral imaging technology combined with mathematical modeling methods to predict the protein content of rice grains. Firstly, the Kjeldahl method was used to determine the protein content of rice grains, and different preprocessing techniques were applied to the spectral information. Then, a prediction model for rice grain protein content was developed by combining the spectral data with the protein content. After performing multiplicative scatter correction (MSC) preprocessing and selecting feature wavelengths based on successive projections algorithm (SPA), the multivariate linear regression (MLR) model showed the best prediction performance, with a calibration set R2C of 0.9393, a validation set R2V of 0.8998, an RMSEV of 0.1725, and an RPD of 3.16. Finally, the quantitative protein content model was mapped pixel by pixel to visualize the distribution of rice protein, providing possibilities for non-destructive protein content detection.
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Imageamento Hiperespectral , Oryza , Proteínas de Plantas , Oryza/química , Imageamento Hiperespectral/métodos , Proteínas de Plantas/análise , Algoritmos , Grão Comestível/química , Modelos LinearesRESUMO
Growth period determination and color coordinates prediction are essential for comparing postharvest fruit quality. This paper proposes a tomato growth period judgment and color coordinates prediction model based on hyperspectral imaging technology. It utilizes the most effective color coordinates prediction model to obtain a color visual image. Firstly, hyperspectral images were taken of tomatoes at different growth periods (green-ripe, color-changing, half-ripe, and full-ripe), and color coordinates (L*, a*, b*, c, h) were obtained using a colorimeter. The sample set was divided by the sample set partitioning based on joint X-Y distances (SPXY). The support vector machine (SVM), K-nearest neighbors (KNN), and linear discriminant analysis (LDA) were used to discriminate growth period. Results show that the LDA model has the best prediction effect with a prediction set accuracy of 93.1%. In addition, effective wavelengths were selected using competitive adaptive reweighted sampling (CARS) and successive projections algorithm (SPA), and chromaticity prediction models were established using partial least squares regression (PLSR), multiple linear regression (MLR), principal component regression (PCR) and support vector machine regression (SVR) Finally, the color of each pixel of the tomato is calculated using the optimal model, generating a visual distribution image of the color coordinate. The results showed that hyperspectral imaging can non-destructively detect tomatoes' growth stage and color coordinates, providing great significance for designing a tomato quality grading system.
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Cor , Frutas , Imageamento Hiperespectral , Solanum lycopersicum , Máquina de Vetores de Suporte , Solanum lycopersicum/crescimento & desenvolvimento , Imageamento Hiperespectral/métodos , Análise Discriminante , Frutas/crescimento & desenvolvimento , Frutas/química , Análise dos Mínimos Quadrados , Análise de Componente Principal , Algoritmos , Modelos LinearesRESUMO
5-Fluorouracil (5-Fu) is a basic drug that is used to treat colorectal cancer. Patients who receive 5-Fu chemotherapy often experience side effects that affect the digestive system, such as intestinal injury and diarrhoea, which significantly affect patient compliance with anticancer treatment and quality of life. Therefore, identifying approaches to treat or prevent these side effects is urgent. Dasabuvir (DSV) is a hepatitis C virus inhibitor, but its impact on 5-Fu-induced intestinal injury remains unknown. Our study investigated the effects of DSV on 5-Fu-induced intestinal injury in HUVECs, HIECs and male BALB/c mice. We found that 5-Fu caused intestinal damage by inducing senescence, increasing inflammatory factor expression, and generating oxidative stress. Compared with 5-Fu treatment alone, DSV inhibited senescence by reducing senescence-ß-galactosidase (SA-ß-gal) activity, the senescence-associated secretory phenotype (SASP, including IL-1, IL-6, and TNF-α) and senescence marker expression levels (p16, p21, and p53). Moreover, the anti-senescence effect of DSV was achieved by inhibiting the mTOR signaling pathway. DSV increased antioxidant enzyme levels and alleviated intestinal tissue injury in mice. In addition, DSV suppressed the 5-Fu-induced increase the diarrhoea scores and ameliorated the weight loss, food intake and water intake of the mice. Overall, this study indicated that DSV could be used to treat chemotherapy-induced intestinal damage.
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Anti-Inflamatórios , Senescência Celular , Fluoruracila , Camundongos Endogâmicos BALB C , Animais , Fluoruracila/efeitos adversos , Fluoruracila/toxicidade , Humanos , Masculino , Camundongos , Senescência Celular/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Células Endoteliais da Veia Umbilical Humana , Estresse Oxidativo/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Transdução de Sinais/efeitos dos fármacos , Intestinos/efeitos dos fármacos , Intestinos/patologiaRESUMO
Oxaliplatin is currently used for chemotherapy in patients with hepatocellular carcinoma, but its increasing tolerance to tumours over time limits its clinical application. Studies have shown that high PD-L1 expression promotes the polarization of M2 macrophages. The increased infiltration of M2 macrophages, including those in HCC, is positively correlated with poor prognosis in various solid tumours. We found that oxaliplatin promoted the expression of PD-L1 in liver cancer cells, which might be attributed partly to the tolerance of tumours to oxaliplatin. Therefore, in this study, we explored the antitumour effect of attenuated Salmonella carrying siRNA-PD-L1 combined with oxaliplatin via Western blotting, immunohistochemistry, immunofluorescence, and flow cytometry. The results revealed that attenuated Salmonella carrying siRNA-PD-L1 combined with oxaliplatin more significantly inhibited tumour growth in tumour-bearing mice, suppressed the expression of PD-L1 in tumour tissue, increased the apoptosis of tumour cells and the expression of the tumour-related protein cleaved-caspase3, and increased the infiltration of M1 macrophages and T lymphocytes in tumour tissues. Moreover, the combination therapy increased the activation of T cells and the number of T lymphocytes and NK cells in the spleens of the mice and improved the overall antitumour immune response in the mice. Our results confirmed that attenuated Salmonella harbouring siRNA-PD-L1 combined with oxaliplatin had a significant antitumour effect and did not increase the incidence of toxic side effects, providing a theoretical reference for addressing oxaliplatin tolerance in the treatment of hepatocellular carcinoma.
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Melanoma, the most perilous form of skin cancer, is known for its inherent resistance to chemotherapy. Even with advances in tumor immunotherapy, the survival of patients with advanced or recurrent melanomas remains poor. Over time, melanoma tumor cells may produce excessive angiogenic factors, necessitating the use of combinations of angiogenesis inhibitors, including broad-spectrum options, to combat melanoma. Among these inhibitors, Endostatin is one of the most broad-spectrum and least toxic angiogenesis inhibitors. We found Endostatin significantly increased the infiltration of CD8+ T cells and reduced the infiltration of M2 tumor-associated macrophages (TAMs) in the melanoma tumor microenvironment (TME). Interestingly, we also observed high expression levels of programmed death 1 (PD-1), an essential immune checkpoint molecule associated with tumor immune evasion, within the melanoma tumor microenvironment despite the use of Endostatin. To address this issue, we investigated the effects of a plasmid expressing Endostatin and PD-1 siRNA, wherein Endostatin was overexpressed while RNA interference (RNAi) targeted PD-1. These therapeutic agents were delivered using attenuated Salmonella in melanoma-bearing mice. Our results demonstrate that pEndostatin-siRNA-PD-1 therapy exhibits optimal therapeutic efficacy against melanoma. We found that pEndostatin-siRNA-PD-1 therapy promotes the infiltration of CD8+ T cells and the expression of granzyme B in melanoma tumors. Importantly, combined inhibition of angiogenesis and PD-1 significantly suppresses melanoma tumor progression compared with the inhibition of angiogenesis or PD-1 alone. Based on these findings, our study suggests that combining PD-1 inhibition with angiogenesis inhibitors holds promise as a clinical strategy for the treatment of melanoma.
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Melanoma , Neoplasias Cutâneas , Humanos , Camundongos , Animais , Endostatinas/genética , Endostatinas/uso terapêutico , Endostatinas/metabolismo , Receptor de Morte Celular Programada 1/genética , Fator A de Crescimento do Endotélio Vascular/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Cutâneas/terapia , Neoplasias Cutâneas/tratamento farmacológico , Inibidores da Angiogênese/uso terapêutico , Plasmídeos , Salmonella/genética , Microambiente TumoralRESUMO
The treatment of hepatocellular carcinoma (HCC) remains a major challenge in the medical field. Lenvatinib, a multi-target tyrosine kinase inhibitor, has demonstrated anti-HCC effects by targeting and inhibiting pathways such as vascular endothelial growth factor receptor 1-3 (VEGFR1-3). However, the therapeutic efficacy of Lenvatinib is subject to various influences, with the hypoxic microenvironment of the tumor being a pivotal factor. Consequently, altering the hypoxic milieu of the tumor emerges as a viable strategy to augment the efficacy of Lenvatinib. Hypoxia-inducible factor-1α (HIF-1α), synthesized by tumor cells in response to oxygen-deprived conditions, regulates the expression of resistance genes, promotes tumor angiogenesis and cell proliferation, enhances tumor cell invasion, and confers resistance to radiotherapy and chemotherapy. Thus, we constructed a self-designed siRNA targeting HIF-1α to suppress its expression and improve the efficacy of Lenvatinib in treating HCC. The therapeutic efficacy of siRNA-HIF-1α in combination with Lenvatinib on HCC were evaluated through in vivo and in vitro experiments. The results showed that the recombinant Salmonella delivering siRNA-HIF-1α in combination with Lenvatinib effectively inhibited tumor growth and prolonged the survival of tumor-bearing mice. This treatment approach reduced cell proliferation and angiogenesis in HCC tissues while promoting tumor cell apoptosis. Additionally, this combined therapy significantly increased the infiltration of T lymphocytes and M1 macrophages within the tumor microenvironment, as well as elevated the proportion of immune cells in the spleen, thereby potentiating the host's immune response against the tumor.
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Carcinoma Hepatocelular , Subunidade alfa do Fator 1 Induzível por Hipóxia , Neoplasias Hepáticas , Compostos de Fenilureia , Quinolinas , RNA Interferente Pequeno , Terapêutica com RNAi , Salmonella , Animais , Camundongos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/terapia , Linhagem Celular Tumoral , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/terapia , Compostos de Fenilureia/uso terapêutico , Quinolinas/uso terapêutico , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/uso terapêutico , Microambiente Tumoral , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Terapia Combinada , Terapêutica com RNAi/métodosRESUMO
Radiation therapy is a primary treatment for hepatocellular carcinoma (HCC), but its effectiveness can be diminished by various factors. The over-expression of PD-L1 has been identified as a critical reason for radiotherapy resistance. Previous studies have demonstrated that nifuroxazide exerts antitumor activity by damaging the Stat3 pathway, but its efficacy against PD-L1 has remained unclear. In this study, we investigated whether nifuroxazide could enhance the efficacy of radiotherapy in HCC by reducing PD-L1 expression. Our results showed that nifuroxazide significantly increased the sensitivity of tumor cells to radiation therapy by inhibiting cell proliferation and migration while increasing apoptosis in vitro. Additionally, nifuroxazide attenuated the up-regulation of PD-L1 expression induced by irradiation, which may be associated with increased degradation of PD-L1 through the ubiquitination-proteasome pathway. Furthermore, nifuroxazide greatly enhanced the efficacy of radiation therapy in H22-bearing mice by inhibiting tumor growth, improving survival, boosting the activation of T lymphocytes, and decelerating the ratios of Treg cells in spleens. Importantly, nifuroxazide limited the increased expression of PD-L1 in tumor tissues induced by radiation therapy. This study confirms, for the first time, that nifuroxazide can augment PD-L1 degradation to improve the efficacy of radiation therapy in HCC-bearing mice.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Nitrofuranos , Animais , Camundongos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/radioterapia , Antígeno B7-H1 , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/radioterapia , HidroxibenzoatosRESUMO
Graphene oxide (GO) has attracted intensive interest in the biomedical field in recent years. We investigate whether the use of functional graphene oxide as an efficient delivery system for delivering specific molecular antitumor therapeutics in vivo could achieve a more excellent antitumor effect. Constitutive activation of signal transducer and activator of transcription 3 (Stat3) promotes survival in a wide spectrum of human cancers. In this paper, we study the in vivo behavior of graphene oxide chemically functionalized with polyethylenimine and polyethylene glycol (GO-PEI-PEG) as a plasmid-based Stat3-specific small interfering RNA (siRNA) carrier in mouse malignant melanoma. The in vivo results indicate significant regression in tumor growth and tumor weight after plasmid-based Stat3 siRNA delivered by GO-PEI-PEG treatment. Moreover, there was no significant side effect from GO-PEI-PEG treatment according to histological examination and blood chemistry analysis in mice. Thus, our work is the first success of using GO-PEI-PEG as a promising carrier for plasmid Stat3 siRNA delivery and down-regulation of Stat3 by a polymer-mediated vehicle and suggests the great promise of graphene in biomedical applications such as cancer treatment.
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Terapia Genética/métodos , Grafite/química , Melanoma/patologia , Nanotecnologia/métodos , Óxidos/química , Plasmídeos/metabolismo , RNA Interferente Pequeno/metabolismo , Fator de Transcrição STAT3/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células , Citometria de Fluxo , Melanoma/terapia , Melanoma Experimental , Camundongos , Nanoestruturas/química , Transplante de Neoplasias , Neoplasias/terapia , Polietilenoglicóis/química , Polietilenoimina/química , TransfecçãoRESUMO
Fatigue driving is one of the leading causes of traffic accidents, so fatigue driving detection technology plays a crucial role in road safety. The physiological information-based fatigue detection methods have the advantage of objectivity and accuracy. Among many physiological signals, EEG signals are considered to be the most direct and promising ones. Most traditional methods are challenging to train and do not meet real-time requirements. To this end, we propose an end-to-end temporal and graph convolution-based (MATCN-GT) fatigue driving detection algorithm. The MATCN-GT model consists of a multi-scale attentional temporal convolutional neural network block (MATCN block) and a graph convolutional-Transformer block (GT block). Among them, the MATCN block extracts features directly from the original EEG signal without a priori information, and the GT block processes the features of EEG signals between different electrodes. In addition, we design a multi-scale attention module to ensure that valuable information on electrode correlations will not be lost. We add a Transformer module to the graph convolutional network, which can better capture the dependencies between long-distance electrodes. We conduct experiments on the public dataset SEED-VIG, and the accuracy of the MATCN-GT model reached 93.67%, outperforming existing algorithms. Furthermore, compared with the traditional graph convolutional neural network, the GT block has improved the accuracy rate by 3.25%. The accuracy of the MATCN block on different subjects is higher than the existing feature extraction methods.
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Condução de Veículo , Humanos , Acidentes de Trânsito , Algoritmos , Eletrodos , EletroencefalografiaRESUMO
5-Fluorouracil (5-FU) is a conventional and effective drug for colorectal cancer patients, and it is an important part of combined chemotherapy and adjuvant chemotherapy. Chemotherapy intestinal mucositis (CIM) is a severe side effect caused by 5-FU that, induces cancer treatment failure and affects patients' quality of life. The mechanism of 5-FU-induced CIM is related to normal cell senescence induced by 5-FU. Peficitinib, a Janus Kinase (JAK) inhibitor, treats inflammatory disorders, including rheumatoid arthritis, psoriasis, and inflammatory bowel disease. However, the therapeutic role and underlying mechanism of peficitinib in CIM remain unclear. The main objective of our research was to investigate the effects of peficitinib on 5-FU-induced senescence and intestinal damage in human umbilical vein endothelial (HUVEC) cells, human intestinal epithelial (HIEC) cells and BABL/C mice. The results showed that 5-FU caused intestinal damage by inducing aging and increasing inflammation and oxidative stress. Peficitinib alleviated aging by reducing senescence-beta-galactosidase (SA-ß-gal) activity and the protein levels of aging indicators (p53, p21, p16). Moreover, peficitinib reversed the changes in senescence-associated secretory phenotype (SASP) expression caused by 5-FU. Besides, 5-FU induced release of inflammatory factors and oxidative stress indicators was reversed by peficitinib. Additionally, the combination of peficitinib and 5-FU reinforced the anticancer curative intent of 5-FU in two colorectal cancer cell lines (HCT116 cells and SW620 cells). In conclusion, peficitinib alleviates mucositis by alleviating aging, reducing inflammatory accumulation and oxidative stress and enhancing the antitumor activity of 5-FU.
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Neoplasias Colorretais , Mucosite , Humanos , Camundongos , Animais , Fluoruracila/uso terapêutico , Mucosite/induzido quimicamente , Qualidade de Vida , Estresse Oxidativo , Senescência Celular , Neoplasias Colorretais/metabolismo , Mucosa IntestinalRESUMO
5-Fluorouracil (5-Fu) is the preferred drug in colorectal cancer treatment. Although 5-Fu treatment contributes to the increase in survival rates, long-term use of 5-Fu causes severe intestinal damage, eventually decreasing long-term survival. There is no standardtreatmentfor intestinal damage induced by 5-Fu. Our previous study found that 5-Fu-induced intestinal damage was connected to an increase in senescent cells, and antiaging drugs could relieve some adverse side effects caused by 5-Fu. Hence, it is essential to discover novel, potential antiaging therapeutic drugs for 5-Fu side effect treatment. According to the current study, Atorvastatincalcium (Ator) alleviated cellular senescence in human intestinal epithelial cells (HUVECs) and human umbilical vein endothelial cells (HIECs) caused by oxidative stress and 5-Fu. 5-Fu resulted in an increase in SA-ß-Gal-positive cells, synchronously increased expression of aging-related proteins (p16), aging-related genes (p53, p21), and the senescence-associated secretory phenotype (SASP: IL-1ß, IL-6, TNF-α), while Atorvastatincalcium (Ator) reversed the increase in these indicators. In the BALB/c mouse model, we confirmed that intestinal damage caused by 5-Fu is related to the increase in senescent cells and drug-induced inflammation, with the therapeutic effects of Ator. In addition, Ator increased the sensitivity of 5-Fu to chemotherapy in vitro and in vivo. Combination therapy significantly reduced HCT116 cell viability. Furthermore, Ator and 5-Fu present a cooperative effect on preventing the growth of tumors in CRC xenograft nude mice. In conclusion, our study demonstrates the value of Ator for treating intestinal damage. Moreover, Ator combined with 5-Fu increased the antitumor ability in CRC cells. Additionally, we provide a novel therapeutic protocol for CRC.