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l-2-Hydroxyglutarate (l-2-HG) has been regarded as a tumor metabolite, and it plays a crucial role in adaptation of tumor cells to hypoxic conditions. However, the role of l-2-HG in tumor radioresistance and the underlying mechanism have not yet been revealed. Here, we found that l-2-HG exhibited to have radioresistance effect on U87 human glioblastoma cells, which could reduce DNA damage and apoptosis caused by irradiation, promote cell proliferation and migration, and impair G2/M phase arrest. Mechanistically, l-2-HG upregulated the protein level of hypoxia-inducible factor-1α (HIF-1α) and the expression levels of HIF-1α downstream target genes. The knockdown of l-2-hydroxyglutarate dehydrogenase (L2HGDH) gene promoted the tumor growth and proliferation of U87 cells in nude mice by increasing HIF-1α expression level in vivo. In addition, the low expression level of L2HGDH gene was correlated with the short survival of patients with glioma or kidney cancer. In conclusion, our study revealed the role and mechanism of l-2-HG in tumor radioresistance and may provide a new perspective for overcoming tumor radioresistance and broaden our comprehension of the role of metabolites in tumor microenvironment.
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Microplastics (MPs)/nanoplastics (NPs) are widely found in the natural environment, including soil, water and the atmosphere, which are essential for human survival. In the recent years, there has been a growing concern about the potential impact of MPs/NPs on human health. Due to the increasing interest in this research and the limited number of studies related to the health effects of MPs/NPs on humans, it is necessary to conduct a systematic assessment and review of their potentially toxic effects on human organs and tissues. Humans can be exposed to microplastics through ingestion, inhalation and dermal contact, however, ingestion and inhalation are considered as the primary routes. The ingested MPs/NPs mainly consist of plastic particles with a particle size ranging from 0.1 to 1 µm, that distribute across various tissues and organs within the body, which in turn have a certain impact on the nine major systems of the human body, especially the digestive system and respiratory system, which are closely related to the intake pathway of MPs/NPs. The harmful effects caused by MPs/NPs primarily occur through potential toxic mechanisms such as induction of oxidative stress, generation of inflammatory responses, alteration of lipid metabolism or energy metabolism or expression of related functional factors. This review can help people to systematically understand the hazards of MPs/NPs and related toxicity mechanisms from the level of nine biological systems. It allows MPs/NPs pollution to be emphasized, and it is also hoped that research on their toxic effects will be strengthened in the future.
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Microplásticos , Poluentes Químicos da Água , Humanos , Microplásticos/toxicidade , Plásticos , Atmosfera , Metabolismo Energético , Ingestão de Alimentos , Poluentes Químicos da Água/toxicidadeRESUMO
BACKGROUND: The dose-response relationship between cancers and protracted low-dose rate exposure to ionising radiation is still uncertain. This study aims to estimate quantified relationships between low-dose radiation exposures and site-specific solid cancers among Chinese medical X-ray workers. METHODS: This cohort study included 27 011 individuals who were employed at major hospitals in 24 provinces in China from 1950 to 1980 and had been exposed to X-ray equipment, and a control group of 25 782 physicians who were not exposed to X-ray equipment. Person-years of follow-up were calculated from the year of employment to the date of the first diagnosis of cancer or the end of follow-up, whichever occurred first. All cancers were obtained from medical records during 1950-1995. This study used Poisson regression models to estimate the excess relative risk (ERR) and excess absolute risk (EAR) for incidence of site-specific solid cancers associated with cumulative dose. RESULTS: 1643 solid cancers were developed, the most common being lung, liver and stomach cancer. Among X-ray workers, the average cumulative colon dose was 0.084 Gy. We found a positive relationship between cumulative organ-specific dose and liver (ERR/Gy=1.48; 95% CI 0.40 to 2.83), oesophagus (ERR/Gy=18.1; 95% CI 6.25 to 39.1), thyroid (ERR/Gy=2.96; 95% CI 0.44 to 8.18) and non-melanoma skin cancers (ERR/Gy=7.96; 95% CI 2.13 to 23.12). We found no significant relationship between cumulative organ-specific doses and other cancers. Moreover, the results showed a statistically significant EAR for liver, stomach, breast cancer (female), thyroid and non-melanoma skin cancers. CONCLUSIONS: These findings provided more useful insights into the risks of site-specific cancers from protracted low-dose rate exposure to ionising radiation.
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Pessoal de Saúde , Neoplasias Induzidas por Radiação , Exposição Ocupacional , Radiação Ionizante , Feminino , Humanos , Neoplasias da Mama , Estudos de Coortes , População do Leste Asiático , Neoplasias Induzidas por Radiação/epidemiologia , Neoplasias Induzidas por Radiação/etiologia , Exposição Ocupacional/efeitos adversos , Doses de Radiação , Neoplasias Cutâneas , Raios X/efeitos adversosRESUMO
BACKGROUND: Genetic factors and muscle strength both contribute to the risk of major depressive disorder (MDD), but whether high muscle strength can offset the risk of MDD with different genetic risk is unknown. This study aims to examine whether a higher muscle strength is associated with lower risk of MDD regardless of genetic risk among middle-aged and older adults. METHODS: This cohort study obtained data from the UK Biobank, which includes 345,621 individuals aged 40-69 years (mean (standard deviation): 56.7 (7.99) years) without baseline MDD. Polygenic risk score for MDD was categorised as low, intermediate or high. The mean of the right- and left-hand grip strength values was used in the analysis and was divided into three categories. RESULTS: 9,753 individuals developed MDD within 2,752,461 person-years of follow-up. The multivariable adjusted hazard ratios (HRs) (95% confidence intervals (CIs)) of MDD across increased grip strength categories were 1.00, 0.72 (0.68-0.75) and 0.56 (0.53-0.59) (P for trend <0.0001). The HRs (95% CIs) of incident MDD across the genetic risk categories were 1.00, 1.11 (1.05-1.17) and 1.20 (1.13-1.28) (P for trend <0.0001); 4.07% of individuals with a high genetic risk and low grip strength developed MDD, and 1.72% of individuals with a low genetic risk and high grip strength developed MDD, with an HR (95% CI) of 0.44 (0.39-0.50). CONCLUSIONS: Both muscle strength and genetic risk were significantly associated with incident MDD. A higher muscle strength was associated with a lower MDD risk among individuals with a high genetic risk. Improving muscle strength should be encouraged for all individuals, including individuals with high genetic risk for MDD.
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Transtorno Depressivo Maior , Humanos , Pessoa de Meia-Idade , Idoso , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/genética , Força da Mão , Bancos de Espécimes Biológicos , Estudos de Coortes , Força Muscular/genética , Fatores de Risco , Reino Unido/epidemiologiaRESUMO
In the frame of radiotherapy treatment of cancer, radioresistance remains a major issue that still needs solutions to be overcome. To effectively improve the radiosensitivity of tumors and reduce the damage of radiation to neighboring normal tissues, radiosensitizers have been given increasing attention in recent years. As nanoparticles based on the metal element gadolinium, AGuIX nanoparticles have been shown to increase the radiosensitivity of cancers. Although it is a rare nanomaterial that has entered preclinical trials, the unclear biological mechanism hinders its further clinical application. In this study, we demonstrated the effectiveness of AGuIX nanoparticles in the radiosensitization of triple-negative breast cancer. We found that AGuIX nanoparticles increased the level of DNA damage by compromising the homologous recombination repair pathway instead of the non-homologous end joining pathway. Moreover, the results showed that AGuIX nanoparticles induced apoptosis, but the degree of apoptosis ability was very low, which cannot fully explain their strong radiosensitizing effect. Ferroptosis, the other mode of cell death, was also discovered to play a significant role in radiation sensitization, and AGuIX nanoparticles may regulate the anti-ferroptosis system by inhibiting the NRF2-GSH-GPX4 signaling pathway.
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Nanopartículas , Neoplasias , Radiossensibilizantes , Gadolínio , Humanos , Fator 2 Relacionado a NF-E2 , Nanopartículas/uso terapêutico , Neoplasias/tratamento farmacológico , Radiação Ionizante , Transdução de SinaisRESUMO
Tumour radioresistance is a major problem for cancer radiation therapy. To identify the underlying mechanisms of this resistance, we used human non-small cell lung cancer (NSCLC) cell lines and focused on the Inhibitor of Apoptosis Protein (IAP) family, which contributes to tumourigenesis and chemoresistance. We investigated the possible correlation between radioresistance in six NSCLC cell lines and IAP protein levels and tested the radiosensitizing effect of birinapant in vitro, a molecule that mimics the second mitochondria-derived activator of caspase. We found that birinapant-induced apoptosis and inhibited the proliferation of NSCLC cells after exposure to radiation. These effects were induced by birinapant downregulation of cIAP protein levels and changes of cIAP gene expression. Overall, birinapant can inhibit tumour growth of NSCLC cell lines to ironizing radiation and act as a promising strategy to overcome radioresistance in NSCLC.
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Maintenance of genome integrity is critical for faithful propagation of genetic information and the prevention of the mutagenesis induced by various DNA damage events. RecQ-mediated genome instability protein 1 (RMI1), together with Bloom syndrome protein and topoisomerase IIIα, form an evolutionarily conserved complex that is critical for the maintenance of genomic stability. Herein, we report that RMI1 depletion increases cell sensitivity to camptothecin treatment, as shown by an elevation of genotoxic stress-induced DNA double-strand breaks, a stronger activation of the DNA damage response, and a greater G2/M cell cycle delay. Our findings support that, upon DNA damage, RMI1 forms nuclear foci at the damaged regions, interacts with RAD51, and facilitates the recruitment of RAD51 to initiate homologous recombination. Our data reveal the importance of RMI1 in response to DNA double-strand breaks and shed light on the molecular mechanisms by which RMI1 contributes to maintain genome stability.-Fang, L., Sun, X., Wang, Y., Du, L., Ji, K., Wang, J., He, N., Liu, Y., Wang, Q., Zhai, H., Hao, J., Xu, C., Liu, Q. RMI1 contributes to DNA repair and to the tolerance to camptothecin.
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Camptotecina/farmacologia , Reparo do DNA/efeitos dos fármacos , Proteínas de Ligação a DNA/genética , Linhagem Celular , Linhagem Celular Tumoral , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/genética , Reparo do DNA/genética , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/genética , Células HEK293 , Células HeLa , Recombinação Homóloga/efeitos dos fármacos , Recombinação Homóloga/genética , Humanos , Rad51 Recombinase/genéticaRESUMO
Tissue and cell damage caused by ionizing radiation is often highly genotoxic. The swift repair of DNA damage is crucial for the maintenance of genomic stability and normal cell fitness. Long noncoding RNAs (lncRNAs) have been reported to play an important role in many physiological and pathological processes in cells. However, the exact function of lncRNAs in radiation-induced DNA damage has yet to be elucidated. Therefore, this study aimed to analyze the potential role of lncRNAs in radiation-induced DNA damage. We examined the expression profiles of lncRNAs and mRNAs in 293T cells with or without 8 Gy irradiation using high-throughput RNA sequencing. We then performed comprehensive transcriptomic and bioinformatic analyses of these sequencing results. A total of 18,990 lncRNAs and 16,080 mRNAs were detected in all samples. At 24 h post irradiation, 49 lncRNAs and 323 mRNAs were differentially expressed between the irradiation group and the control group. qRT-PCR was used to verify the altered expression of six lncRNAs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicated that the predicted genes were mainly involved in the histone mRNA metabolic process and Wnt signaling pathways. This study may provide novel insights for the study of lncRNAs in radiation-induced DNA damage.
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Regulação da Expressão Gênica/efeitos da radiação , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Radiação Ionizante , Biologia Computacional/métodos , Dano ao DNA , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Células HEK293 , Humanos , MicroRNAs/genética , Interferência de RNA , Reprodutibilidade dos Testes , TranscriptomaRESUMO
LncRNAs have been reported to play an important role in various diseases. However, their role in the radiation-induced intestinal injury is unknown. The goal of the present study was to analyse the potential mechanistic role of lncRNAs in the radiation-induced intestinal injury. Mice were divided into two groups: Control (non-irradiated) and irradiated. Irradiated mice were administered 14 Gy of abdominal irradiation (ABI) and were assessed 3.5 days after irradiation. Changes to the jejuna of ABI mice were analysed using RNA-Seq for alterations to both lncRNA and mRNA. These results were validated using qRT-PCR. LncRNAs targets were predicted based on analysis of lncRNAs-miRNAs-mRNAs interaction. 29 007 lncRNAs and 17 142 mRNAs were detected in the two groups. At 3.5 days post-irradiation, 91 lncRNAs and 57 lncRNAs were significantly up- and downregulated respectively. Similarly, 752 mRNAs and 400 mRNAs were significantly up- and downregulated respectively. qRT-PCR was used to verify the altered expression of four lncRNAs (ENSMUST00000173070, AK157361, AK083183, AK038898) and four mRNAs (Mboat1, Nek10, Ccl24, Cyp2c55). Gene ontology and KEGG pathway analyses indicated the predicted genes were mainly involved in the VEGF signalling pathway. This study reveals that the expression of lncRNAs was altered in the jejuna of mice post-irradiation. Moreover, it provides a resource for the study of lncRNAs in the radiation-induced intestinal injury.
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Jejuno/efeitos da radiação , MicroRNAs/genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Animais , Regulação da Expressão Gênica/efeitos da radiação , Redes Reguladoras de Genes/genética , Redes Reguladoras de Genes/efeitos da radiação , Jejuno/metabolismo , Jejuno/patologia , Camundongos , MicroRNAs/efeitos da radiação , RNA Longo não Codificante/efeitos da radiação , RNA Mensageiro/efeitos da radiação , Radiação , Fator A de Crescimento do Endotélio Vascular/genéticaRESUMO
BACKGROUND/AIMS: Circular RNAs (circRNAs) make up a large class of non-coding RNAs and play important roles in a variety of diseases, including nervous system diseases and cancers. The intestinal epithelium is sensitive to ionizing radiation, radiotherapy of abdominal or pelvic tumors or nuclear accident exposure can lead to high radiation toxicity, which can result in radiation-induced intestinal injury. The goal of this present study was to analyze the potential roles of circRNAs in radiation-induced intestinal injury. METHODS: Mice were divided into two groups: control group and irradiated group. Irradiated group was 3.5 days after 14Gy abdominal irradiation (ABI) group. We started with RNA-seq of circRNA changes in mouse jejuna after radiation and validated by RT-PCR in the following experimental. miRNAs targeted mRNAs were predicted using proprietary software based on target scan and Miranda. The network of circRNA-miRNA-mRNA was illustrated by cytoscape software. RESULTS: 2751 circRNAs were detected in the two groups. At day 3.5 post-radiation, 42 and 48 circRNAs were found to be significantly upregulated and downregulated, respectively, compared to the control (p≤0.05, Fold Change ≥2). Further, the altered expression of 10 circRNAs (chr18: 35610871-35613502+, chr15: 95864225-95894541+, chr3: 96041338-96042928-, chr5: 64096979-64108263+, chr19: 16705875-16710941-, chr5: 134491893-134500149-, chr19: 42562552-42564341+, chr5: 32640331-32664400+, chr3: 72958113-72960367- and chr8: 79343654-79372364-) were verified by RT-PCR. Compared the miRNA-targeted mRNAs with our mRNAs sequencing data, we found 14 upregulated circRNA-targeted mRNAs were also unregulated and 22 downregulated circRNAs-targeted mRNAs were also downregulated. Gene ontology and KEGG pathway analyses indicated the predicted genes were mainly involved in the MAPK signaling pathway. CONCLUSIONS: This study reveals that expression of circRNAs was altered in the jejuna of mice post-irradiation and provides a resource for the study of circRNAs in radiation-induced intestinal injury and repair.
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Doenças do Jejuno/metabolismo , Jejuno/metabolismo , Sistema de Sinalização das MAP Quinases , RNA não Traduzido/metabolismo , Lesões Experimentais por Radiação/metabolismo , Animais , Doenças do Jejuno/patologia , Jejuno/patologia , Masculino , Camundongos , Lesões Experimentais por Radiação/patologiaRESUMO
BACKGROUND/AIMS: SirT1, a conserved NAD+-dependent deacetylase, has been implicated in modulating cell survival and stress responses, and it appears to play an important role in tumorigenesis and cancer resistance to chemoradiotherapy. The mechanism of SirT1 in cancer chemoradiotherapy remains to be further elucidated, which could provide potential targets for cancer therapy. METHODS: We performed colony formation, immunofluorescence microscopy, flow cytometry, RNA interference, and western blotting assays to determine whether SirT1 regulates radiation sensitization and which mechanisms and/or pathways it takes in lung cancer cell lines A549 and H460. RESULTS: Initially, the expression of SirT1 was found to be negatively correlated with radiosensitivity in lung cancer cell lines A549 and H460. RNA interference with siSirT1 against SirT1 specifically reduced SirT1 expression and induced radiosensitivity both in A549 and H460 cell lines. In contrast, the radiosensitivity was significantly reduced once SirT1 was activated by resveratrol. Immunofluorescence assay and apoptosis analysis indicated that the effect of SirT1 on the radiosensitivity observed in the A549 and H460 cell lines was mainly achieved by regulating DNA damage repair and apoptosis processes. Furthermore, the expression of SirT1 negatively modulated the expression of apoptosis-related protein NF-κB and its downstream regulator of Smac. CONCLUSION: Our results indicate that SirT1 regulates apoptosis and radiation sensitization in lung cancer cell lines A549 and H460 via the SirT1/NF-κB/Smac pathway.
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Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Mitocondriais/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Sirtuína 1/metabolismo , Células A549 , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Proteínas Reguladoras de Apoptose , Linhagem Celular Tumoral , Dano ao DNA/efeitos da radiação , Expressão Gênica/efeitos da radiação , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Tolerância a Radiação/efeitos dos fármacos , Radiação Ionizante , Resveratrol , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/genética , Estilbenos/farmacologiaRESUMO
The oncogenic microRNA-21 contributes to the pathogenesis of multiple myeloma. Ibrutinib (also referred to as PCI-32765), an inhibitor of Bruton's tyrosine kinase, while its effects on multiple myeloma have not been well described. Here, we show that microRNA-21 is an oncogenic marker closely linked with progression of multiple myeloma. Moreover, ibrutinib attenuates microRNA-21 expression in multiple myeloma cells by inhibiting nuclear factor-κB and signal transducer and activator of transcription 3 signaling pathways. Taken together, our results suggest that ibrutinib is a promising potential treatment for multiple myeloma. Further investigation of mechanisms of ibrutinib function in multiple myeloma will be necessary to evaluate its use as a novel multiple myeloma treatment.
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Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , MicroRNAs/genética , Mieloma Múltiplo/genética , NF-kappa B/metabolismo , Pirazóis/farmacologia , Pirimidinas/farmacologia , Fator de Transcrição STAT3/metabolismo , Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia , Idoso , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Piperidinas , Regiões Promotoras Genéticas/genética , Ligação Proteica/efeitos dos fármacos , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismoRESUMO
BACKGROUND: Cytokine-based cancer therapies have attracted a great deal of attention in recent years. Unfortunately, resistance to treatment limits the efficacy of these therapeutics. Therefore, the aim of our study was to explore the mechanism of IL-2-based therapy for hepatocellular carcinoma in an attempt to increase the efficiency of this treatment option. METHODS: HepG2 cells were treated with IL-2. Then, siRNA against TZA was used to transfected into HepG2 cells. Cellular apoptosis was measured via MTT assay, TUNEL assay and caspase-3 activity. Cellular proliferation was evaluated via EdU assay and western blotting. Cellular migration was detected via Transwell assay. Mitochondrial function was monitored by mitochondrial potential analysis, ROS staining, immunofluorescence and western blotting. Pathway blocker and activator were used to establish the role of JNK/F-actin/mitochondrial fission signaling pathway in HepG2 cells stress response. RESULTS: Our study found that IL-2 treatment significantly reduced the viability, mobility and proliferation of HepG2 cells in vitro. We also demonstrated that IL-2 treatment was accompanied by an increase in the expression of transcriptional co-activator with PDZ-binding motif (TAZ). Interestingly, genetic ablation of TAZ in the presence of IL-2 further promoted apoptosis, inhibited mobility, and arrested proliferation in HepG2 cells. At the molecular level, IL-2 administration activated excessive mitochondrial fission via the JNK/F-actin pathway; these effects were further enhanced by TAZ deletion. Mechanistically, TAZ knockdown further increased the expression of mitochondrial fission-related proteins such as Drp1, Mff and Fis. The augmented mitochondrial fission stimulated ROS overproduction, mediated redox imbalance, interrupted mitochondrial energy generation, reduced mitochondrial membrane potential, promoted leakage of the pro-apoptotic molecule cyt-c into the nucleus, and initiated caspase-9-related mitochondrial death. Further, we demonstrated that the anti-proliferative and anti-metastatic effects of IL-2 in HepG2 cells were enhanced by TAZ deletion, suggesting that IL-2 sensitizes HepG2 cells to IL-2-based cytokine therapy. However, JNK/F-actin pathway blockade could abrogate the inhibitory effects of TAZ deletion on HepG2 migration, proliferation and survival. CONCLUSIONS: Taken together, our data indicate that the anti-tumor effects of IL-2-based therapies may be enhanced by TAZ deletion in a JNK/F-actin pathway-dependent manner. This finding provides a novel combinatorial therapeutic approach for treating hepatocellular carcinoma that might significantly increase the efficacy of cytokine-based therapies in a clinical setting.
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Colorectal cancer is the most commonly reported gastrointestinal malignancy, with a recent, rapid increase of the annual incidence all over the world. Enhancing the radiosensitivity of cancer cells while preserving the health of normal cells is one of the most important tasks in clinical radiobiology. However, resistance to radiotherapy for colorectal cancer greatly decreases the therapeutic outcome. Melatonin (N-acetyl-5-methoxytryptamine), a natural secretory product that the pineal gland in the brain normally produces, has been reported to have anticancer properties. In the study, we investigated the combination of melatonin with radiotherapy as a treatment for colorectal cancer. We firstly explored the anti-tumor activity of melatonin combined with ionizing radiation (IR) against colorectal carcinoma in vitro. It was found that melatonin effectively inhibited human colorectal carcinoma cell line HCT 116 cellular proliferation, colony formation rate and cell migration counts following IR. Increasing the radiosensitivity of colorectal cancer cells by melatonin treatment was found to be associated with cell cycle arrest in the G2/M phase, downregulation of proteins involved in DNA double-strand break repair and activation of the caspase-dependent apoptotic pathway. Moreover, we also investigated the combined effect of IR and melatonin on colorectal tumor in vivo. Results from a tumor xenograft showed that melatonin plus IR treatment significantly suppressed tumor cell growth compared with melatonin or IR alone, resulting in a much higher tumor inhibition rate for the combined treatment. The data suggested that melatonin combined with IR could improve the radiosensitivity of colorectal cancer and thus enhance the therapeutic effect of the patients, implying melatonin could function as a potential sensitizer in tumor radiotherapy.
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Neoplasias Colorretais/patologia , Raios gama , Melatonina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Carcinogênese/patologia , Ciclo Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Dano ao DNA , Células HCT116 , Humanos , Masculino , Camundongos NusRESUMO
Garcinol, a natural histone acetyltransferase inhibitor, has been reported to exhibit significant anti-proliferative activity in various cancer cell types. However, no information is available about the anti-cancer effects of garcinol on gallbladder carcinoma cells (GBC). In this study, GBC cells (GBC-SD and NOZ) were treated by garcinol and subjected to Cell Counting Kit-8 (CCK-8), and GBC-SD cells were selected for further transwell chamber assay, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis. Our results indicated that garcinol could significantly inhibit the growth of GBC cells in a dose- and time-dependent manner. It also inhibited the invasion of GBC-SD cells in a dose-dependent manner. Garcinol treatment decreased the activity of matrix metalloproteinase 2 (MMP2) and MMP9 by the downregulation of mRNA levels, and these two enzymes are critical to tumor invasion. Treatment with garcinol also decreased Stat3 and Akt activation in GBC-SD cells. Taken together, the effects of garcinol on GBC-SD cells may be associated with the suppression of Stat3 and Akt signaling pathways, which may contribute to inhibiting their downstream targets such as mRNA levels of MMP2 and MMP9.
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Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Vesícula Biliar/tratamento farmacológico , Garcinia/química , Terpenos/farmacologia , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células , Relação Dose-Resposta a Droga , Neoplasias da Vesícula Biliar/patologia , Humanos , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Invasividade Neoplásica/prevenção & controle , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Fator de Transcrição STAT3/metabolismo , Terpenos/administração & dosagem , Terpenos/isolamento & purificação , Fatores de TempoRESUMO
We sought to reassess the association of PLCE1 rs2274223 and susceptibility to esophageal cancer (EC) through a meta-analysis of published case-control studies. Using the PubMed and Embase, we identified nine articles including fourteen case-control studies (15,225 cases and 23,620 controls). ORs and 95 % confidence intervals (CIs) of GG vs. AA, GG + GA vs. AA, GG vs. GA + AA, G vs. A, and AG vs. AA genetic models were estimated for each study. All of the genetic models indicated a statistically significant positive association with EC risk. The association appeared most pronounced for carriers of GG genotype (GG vs. AA: OR, 1.35; 95 % CI, 1.17 to 1.57), and weakest for individuals carrying GA genotype (GA vs. AA: OR, 1.13; 95 % CI, 1.05 to 1.23). Stratification analyses showed similar results in the population of Asians and in esophageal squamous cell carcinoma (ESCC). This meta-analysis provides strong statistical evidence for an elevated risk of EC associated with PLCE1 rs2274223. The association remains significant in Asian population and ESCC. Further investigations are warranted to validate these findings.
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Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Predisposição Genética para Doença , Fosfoinositídeo Fosfolipase C/genética , Povo Asiático/genética , Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago , Estudos de Associação Genética , Humanos , Fatores de RiscoRESUMO
The proposed method focuses on speaker disentanglement in the context of depression detection from speech signals. Previous approaches require patient/speaker labels, encounter instability due to loss maximization, and introduce unnecessary parameters for adversarial domain prediction. In contrast, the proposed unsupervised approach reduces cosine similarity between latent spaces of depression and pre-trained speaker classification models. This method outperforms baseline models, matches or exceeds adversarial methods in performance, and does so without relying on speaker labels or introducing additional model parameters, leading to a reduction in model complexity. The higher the speaker de-identification score (DeID), the better the depression detection system is in masking a patient's identity thereby enhancing the privacy attributes of depression detection systems. On the DAIC-WOZ dataset with ComparE16 features and an LSTM-only model, our method achieves an F1-Score of 0.776 and a DeID score of 92.87%, outperforming its adversarial counterpart which has an F1Score of 0.762 and 68.37% DeID, respectively. Furthermore, we demonstrate that speaker-disentanglement methods are complementary to text-based approaches, and a score-level fusion with a Word2vec-based depression detection model further enhances the overall performance to an F1-Score of 0.830.
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Speech signals are valuable biomarkers for assessing an individual's mental health, including identifying Major Depressive Disorder (MDD) automatically. A frequently used approach in this regard is to employ features related to speaker identity, such as speaker-embeddings. However, over-reliance on speaker identity features in mental health screening systems can compromise patient privacy. Moreover, some aspects of speaker identity may not be relevant for depression detection and could serve as a bias factor that hampers system performance. To overcome these limitations, we propose disentangling speaker-identity information from depression-related information. Specifically, we present four distinct disentanglement methods to achieve this - adversarial speaker identification (SID)-loss maximization (ADV), SID-loss equalization with variance (LEV), SID-loss equalization using Cross-Entropy (LECE) and SID-loss equalization using KL divergence (LEKLD). Our experiments, which incorporated diverse input features and model architectures, have yielded improved F1 scores for MDD detection and voice-privacy attributes, as quantified by Gain in Voice Distinctiveness GV D and De-Identification Scores (DeID). On the DAIC-WOZ dataset (English), LECE using ComparE16 features results in the best F1-Scores of 80% which represents the audio-only SOTA depression detection F1-Score along with a GV D of -1.1 dB and a DeID of 85%. On the EATD dataset (Mandarin), ADV using raw-audio signal achieves an F1-Score of 72.38% surpassing multi-modal SOTA along with a GV D of -0.89 dB dB and a DeID of 51.21%. By reducing the dependence on speaker-identity-related features, our method offers a promising direction for speech-based depression detection that preserves patient privacy.
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A high level of reduced glutathione is a major factor contributing to the radioresistance observed in solid tumors. To address this radioresistance associated with glutathione, a cinnamaldehyde (CA) polymer prodrug, referred to as PDPCA, is fabricated. This prodrug is created by synthesizing a pendent CA prodrug with acetal linkages in a hydrophobic block, forming a self-assembled into a core-shell nanoparticle in aqueous media. Additionally, it encapsulates all-trans retinoic acid (ATRA) for synchronous delivery, resulting in PDPCA@ATRA. The PDPCA@ATRA nanoparticles accumulate reactive oxygen species through both endogenous and exogenous pathways, enhancing ferroptosis by depleting glutathione. This approach demonstrates efficacy in overcoming tumor radioresistance in vivo and in vitro, promoting the ferroptosis, and enhancing the cytotoxic T lymphocyte (CTL) response for lung tumors to anti-PD-1 (αPD-1) immunotherapy. Furthermore, this study reveals that PDPCA@ATRA nanoparticles promote ferroptosis through the NRF2-GPX4 signaling pathway, suggesting the potential for further investigation into the combination of radiotherapy and αPD-1 immune checkpoint inhibitors in cancer treatment.
Assuntos
Acroleína/análogos & derivados , Ferroptose , Neoplasias Pulmonares , Pró-Fármacos , Humanos , Nanomedicina , Imunoterapia , Glutationa , Pró-Fármacos/farmacologia , Espécies Reativas de Oxigênio , Linhagem Celular TumoralRESUMO
The genetic influence on human vocal pitch in tonal and non-tonal languages remains largely unknown. In tonal languages, such as Mandarin Chinese, pitch changes differentiate word meanings, whereas in non-tonal languages, such as Icelandic, pitch is used to convey intonation. We addressed this question by searching for genetic associations with interindividual variation in median pitch in a Chinese major depression case-control cohort and compared our results with a genome-wide association study from Iceland. The same genetic variant, rs11046212-T in an intron of the ABCC9 gene, was one of the most strongly associated loci with median pitch in both samples. Our meta-analysis revealed four genome-wide significant hits, including two novel associations. The discovery of genetic variants influencing vocal pitch across both tonal and non-tonal languages suggests the possibility of a common genetic contribution to the human vocal system shared in two distinct populations with languages that differ in tonality (Icelandic and Mandarin).