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OBJECTIVE: Disulfiram has been repurposed as a potential candidate to suppress various cancers. However, its anti-tumor effects and molecular mechanisms of oral squamous cell carcinoma remain unclear. In this study, we aimed to assess the anti-cancer activity and underlying mechanisms of disulfiram in the context of oral squamous cell carcinoma. MATERIALS AND METHODS: We tested the cytotoxicity of disulfiram in oral squamous cell carcinoma using a 3D culture model and a PDX model. Cell proliferation, cell death, and related signaling pathways were evaluated. Mitochondrial DNA copy number, mitochondrial respiration, mitochondrial mass, and mitochondrial complexes were analyzed. RESULTS: Disulfiram can induce excessive autophagy in oral squamous cell carcinoma cells as a result of OXPHOS deficiency. Disulfiram-induced OPA1 degradation can impair the functional cristae structure, which results in a dramatic reduction in mitochondrial respiration capability as well as ATP production. Subsequently, energy deprivation leads to excessive autophagy through AMPK activation. In addition, exogenous ATP blocked the activation of AMPK and rescued disulfiram-induced cell death. CONCLUSION: DSF targets mitochondrial inner membrane protein OPA1 to disturb the energy supply, triggering excessive autophagy, and cell death in OSCC. Our study suggests OPA1-dependent ATP generation is pharmacologically targetable in OSCC treatment.
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Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Apoptose , Autofagia , Carcinoma de Células Escamosas/tratamento farmacológico , Morte Celular , Linhagem Celular Tumoral , Proliferação de Células , Dissulfiram/farmacologia , Humanos , Neoplasias Bucais/tratamento farmacológicoRESUMO
Smilax glabra Roxb. (SGR) is known for its high nutritional and therapeutic value. However, the frequent appearance of counterfeit products causes confusion and inconsistent quality among SGR varieties. Herein, this study collected the proportion of SGR adulteration and used high-performance liquid chromatography (HPLC) to measure the astilbin content of SGR. Then Fourier-transform near-infrared (FT-NIR) technology, combined with multivariate intelligent algorithms, was used to establish partial least squares regression quantitative models for detecting SGR adulteration and measuring astilbin content, respectively. The method conducted a quantitative analysis of dual indicators through single-spectrum data acquisition (QADS) to comprehensively evaluate the authenticity and superiority of SGR. The coefficients of determination (R2) for both the calibration and prediction sets exceeded 0.96, which successfully leverages FT-NIR combined with multivariate intelligent algorithms to considerably enhance the accuracy and reliability of quantitative models. Overall, this research holds substantial value in the comprehensive quality evaluation in functional health foods.
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Algoritmos , Smilax , Espectroscopia de Luz Próxima ao Infravermelho , Smilax/química , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Cromatografia Líquida de Alta Pressão , Controle de Qualidade , Espectroscopia de Infravermelho com Transformada de Fourier , Extratos Vegetais/química , Extratos Vegetais/análise , Análise dos Mínimos QuadradosRESUMO
Abstract Background/purpose: Recurrent aphthous ulcer (RAU) is one of the most common diseases of oral mucosa, which is generally believed to be related to immunity, though the etiology is still unclear. It is suspected that allergies are directly related to RAU. So we sought to explore the relationship between hypersensitivity and RAU. Materials and methods: 40 RAU patients who were in ulceration period and 40 people who were in good health were selected from Jan 2016 to Feb 2017, matched in age and sex. The peripheral blood antigens of 40 RAU patients and 40 healthy people was tested, and serum specific IgE (sIgE) with 6 groups of antigens and total IgE (tIgE) analysis was performed to identify IgE-mediated allergic reaction possibly affecting RAU. We then investigated the food intolerance and IgG levels to discover the correlation between non-IgE mediated allergic reaction and RAU. Results: The positive cases and rate of sIgE in RAU group was higher than that of control, but the difference was not statistically significant (Pï¼0.05). Positive grade of animal fur scraps (EX1), house dust mixed (HX2) and the serum tIgE concentration of the RAU group were significantly higher than the control group (Pï¼0.05).The number of food intolerance in RAU group was significantly higher than that in control group (Pï¼0.05). Conclusion: Our findings suggested certain correlation between RAU and anaphylaxis. Daily contact allergens and food intolerance may be one of the causes of RAU. Moreover, this provides reference value for clinical diagnosis and treatment.
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Head and neck squamous carcinoma (HNSC) is a frequent and deadly malignancy that is challenging to manage. The existing treatment options have considerable efficacy limitations. Hence, the identification of new therapeutic targets and the development of efficacious treatments are urgent needs. Cuproptosis, a non-apoptotic programmed cell death caused by excess copper, has only very recently been discovered. The present study investigated the prognostic importance of genes involved in cuproptosis through the mRNA expression data and related clinical information of HNSC patients downloaded from public databases. Our results revealed that many cuproptosis-related genes were differentially expressed between normal and HNSC tissues in the TCGA cohort. Moreover, 39 differentially expressed genes were associated with the prognosis of HNSC patients. Then, a 24-gene signature was identified in the TCGA cohort utilizing the LASSO Cox regression model. HNSC expression data used for validation were obtained from the GEO database. Consequently, we divided patients into high- and low-risk groups based on the 24-gene signature. Furthermore, we demonstrated that the high-risk group had a worse prognosis when compared to the low-risk group. Additionally, significant differences were found between the two groups in metabolic pathways, immune microenvironment, etc. In conclusion, we found a cuproptosis-related gene signature that can be used effectively to predict OS in HNSC patients. Thus, targeting cuproptosis might be an alternative and promising strategy for HNSC patients.
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The effects of cement dosage, compaction coefficient, molding method (vertical vibration method and static pressure method), and dry-wet and freeze-thaw cycles on the mechanical strength of cement-improved loess (CIL) were studied to reveal its strength degradation law under dry-wet and freeze-thaw cycles. Results show that when using the vertical vibration molding method, the strength degradation effect of CIL can be improved by increasing the cement dosage and compaction coefficient; however, it is not obvious. Under the action of dry-wet cycle, damages, such as voids and cracks of CIL, develop continuously. Further, the strength deteriorates continuously and does not decrease after more than 15 dry-wet cycles. Therefore, the dry-wet cycle degradation system is selected by considering the most unfavorable conditions. In the process of freeze-thaw alternation, the pores and fissures of CIL develop and evolve continuously and the strength deteriorates continuously under the joint influence of water and low temperature. The strength tends to become stable after more than 12 freeze-thaw cycles. According to the safety principle, the deterioration coefficient of the freeze-thaw cycles is 0.3.
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Cinza de Carvão/química , Materiais de Construção/análise , Congelamento , Sedimentos Geológicos/química , Vibração , Resistência ao Cisalhamento , SoloRESUMO
Adrenergic nerve fibers in the tumor microenvironment promote tumor growth and represent a potential target for cancer therapy. However, the effectiveness of targeting adrenergic nerve fibers for oral squamous cell carcinoma (OSCC) therapy needs to be evaluated by preclinical data. Herein, the 4NQO-induced and orthotopic xenograft OSCC mice models were established. We demonstrated that using 6OHDA chemical denervation as well as using nebivolol adrenergic blockade could halt the oral mucosa carcinogenesis. Our preclinical studies suggested that nebivolol, which is widely used to treat cardiovascular diseases, can be repositioned as a potential candidate to treat OSCC. Remarkably, we revealed the precise effect and mechanism of nebivolol on OSCC cells proliferation, cell cycle, and cell death. Administration of nebivolol could activate the endoplasmic reticulum (ER) stress signaling pathway through increasing the expression of inducible nitric oxide synthase, which subsequently triggers the integrated stress response and cell growth arrest. Simultaneously, ER stress also induced mitochondrial dysfunction in OSCC cells. We found that the accumulation of dysfunctional mitochondria with the impaired electron transport chain caused increasing reactive oxygen species production, which ultimately resulted in OSCC cell death. Altogether, our finding suggested a novel therapeutic opportunity for OSCC by targeting adrenergic nerve fibers, and repurposing nebivolol to treat OSCC can be represented as an effective strategy.