RESUMO
mTORC1/2 dual inhibitors may be more effective than mTORC1 inhibitor rapamycin. However, their metabolic impacts on colon cancer cells remain unexplored. We conducted a comparative analysis of the anti-proliferative effects of rapamycin and the novel OSI-027 in colon cancer cells HCT-116, evaluating their metabolic influences through ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS/MS). Our results demonstrate that OSI-027 more effectively inhibits colon cancer cell proliferation than rapamycin. Additionally, we identified nearly 600 metabolites from the spectra, revealing significant differences in metabolic patterns between cells treated with OSI-027 and rapamycin. Through VIP value screening, we pinpointed crucial metabolites contributing to these distinctions. For inhibiting glycolysis and reducing glucose consumption, OSI-027 was likely to be more potent than rapamycin. For amino acids metabolism, although OSI-027 has a broad effect as rapamycin, their effects in degrees were not exactly the same. These findings address the knowledge gap regarding mTORC1/2 dual inhibitors and lay a foundation for their further development and research.
RESUMO
The introduction and scale-up of antiretroviral therapy (ART) have contributed to significantly improved patients with acquired immune deficiency syndrome (AIDS) quality of life and prolongs their survival. This has occurred by suppressing viral replication and recovering the CD4 cell count. However, some patients do not normalize their CD4 cell count, despite suppression of the viral load (VL). Patients with suboptimal immune recovery (SIR), as defined by a VL < 400 copies/ml with a CD4 cell count of<200 cells/µl, after ART initiation, exhibit severe immune dysfunction and have a higher risk of AIDS and non-AIDS events. In recent years, People living with HIV/AIDS (PLWHA) with first-line ART failure began to gradually switch to second-line ART. This study aimed to examine the prevalence and factors affecting SIR among PLWHA who switch to second-line ART in rural China. A 1-year retrospective cohort study was conducted among PLWHA who switched to second-line ART between January 2009 and December 2018. All patients with a VL < 400 copies/ml after 1 year of second-line ART were included. SIR was defined as a CD4 cell count <200 cells/µl and a VL < 400 copies/ml after 1 year of second-line ART. The data collected from medical records were analyzed by univariate and multivariate analyses. A total of 5294 PLWHA met the inclusion criteria, 24 died, and 1152 were lost to follow-up after 1 year of second-line ART. Among 4118 PLWHA who were followed up, 3039 with a VL < 400 copies/ml had their data analyzed, and the prevalence of SIR was 13.1%. The patients' mean age at recruitment was 47.6 ± 8.1 years and 45.3% were men. A total of 30.7% of patients were HIV-positive for >8 years and 88.2% were receiving ART before starting second-line ART for >3 years. The mean CD4 cell count was 354.8 ± 238.2 cells/µl. A multivariable analysis showed that male sex, single status (unmarried or divorced), and a low CD4 cell count were risk factors for SIR among PLWHA with second-line ART. The prevalence of SIR among PLWHA who switched to second-line ART in this retrospective cohort study is lower than that in most other studies. Several factors associated with SIR include male sex, marital status, and CD4 cell count levels in PLWHA.
Assuntos
Síndrome da Imunodeficiência Adquirida , Fármacos Anti-HIV , Infecções por HIV , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Síndrome da Imunodeficiência Adquirida/epidemiologia , Fármacos Anti-HIV/uso terapêutico , Antirretrovirais/uso terapêutico , Contagem de Linfócito CD4 , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Humanos , Masculino , Qualidade de Vida , Estudos Retrospectivos , Carga ViralRESUMO
BACKGROUND: The cyclin-dependent kinase 7 (CDK7) inhibitor THZ1 represses multiple cancer cells. However, its tumor-repressive efficiency in wild-type p53 breast cancer cells remains controversial. METHODS: We conducted various assays, including CCK8, colony formation, flow cytometry, western blotting, and lactate dehydrogenase release detection, to clarify whether p53 elevation sensitizes breast cancer cells to THZ1. RESULTS: We found that upregulating functional p53 contributes to the increased sensitivity of breast cancer cells to THZ1. Increased THZ1 sensitivity requires active p53 and an intact p53 pathway, which was confirmed by introducing exogenous wild-type p53 and the subsequent elevation of THZ1-mediated tumor suppression in breast cancer cells carrying mutant p53. We confirmed that p53 accumulates in the nucleus and mitochondria during cell death. Furthermore, we identified extensive transcriptional disruption, rather than solely CDK7 inhibition, as the mechanism underlying the nutlin-3 and THZ1-induced death of breast cancer cells. Finally, we observed the combined nutlin-3 and THZ1 treatment amplified gasdermin E cleavage. CONCLUSION: Enhanced sensitivity of breast cancer cells to THZ1 can be achieved by increasing effective p53 expression. Our approach may serve as a potential treatment for patients with breast cancer resistant to regular therapies. Video Abstract.
Assuntos
Neoplasias da Mama , Proteína Supressora de Tumor p53 , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Fenilenodiaminas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Proteína Supressora de Tumor p53/metabolismoRESUMO
BACKGROUND: Gastric cancer is a common and lethal human malignancy worldwide and cancer cell metastasis is the leading cause of cancer-related mortality. MICAL2, a flavoprotein monooxygenase, is an important regulator of epithelial-to-mesenchymal transition. The aim of this study was to explore the effects of MICAL2 on gastric cancer cell migration and determine the underlying molecular mechanisms. METHODS: Cell migration was examined by wound healing and transwell assays. Changes in E-cadherin/ß-catenin signaling were determined by qPCR and analysis of cytoplasmic and nuclear protein fractions. E-cadherin/ß-catenin binding was determined by co-immunoprecipitation assays. Cdc42 activity was examined by pulldown assay. RESULTS: MICAL2 was highly expressed in gastric cancer tissues. The knockdown of MICAL2 significantly attenuated migratory ability and ß-catenin nuclear translocation in gastric cancer cells while LiCl treatment, an inhibitor of GSK3ß, reversed these MICAL2 knockdown-induced effects. Meanwhile, E-cadherin expression was markedly enhanced in MICAL2-depleted cells. MICAL2 knockdown led to a significant attenuation of E-cadherin ubiquitination and degradation in a Cdc42-dependent manner, then enhanced E-cadherin/ß-catenin binding, and reduced ß-catenin nuclear translocation. CONCLUSIONS: Together, our results indicated that MICAL2 promotes E-cadherin ubiquitination and degradation, leading to enhanced ß-catenin signaling via the disruption of the E-cadherin/ß-catenin complex and, consequently, the promotion of gastric cell migration. Video Abstract.
Assuntos
Antígenos CD , Caderinas , Proteínas dos Microfilamentos , Oxirredutases , Neoplasias Gástricas , beta Catenina , Proteína cdc42 de Ligação ao GTP , Antígenos CD/genética , Antígenos CD/metabolismo , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Movimento Celular/fisiologia , Proliferação de Células , Transição Epitelial-Mesenquimal , Humanos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Oxirredutases/genética , Oxirredutases/metabolismo , Transdução de Sinais , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Via de Sinalização Wnt , beta Catenina/genética , beta Catenina/metabolismo , Proteína cdc42 de Ligação ao GTP/genética , Proteína cdc42 de Ligação ao GTP/metabolismoRESUMO
Sex determination and differentiation is an important biological process for unisexual flower development. Spinach is a model plant to study the mechanism of sex determination and differentiation of dioecious plant. Till now, little is known about spinach sex determination and differentiation mechanism. MicroRNAs are key factors in flower development. Herein, small RNA sequencing was performed to explore the roles of microRNAs in spinach sex determination and differentiation. As a result, 92 known and 3402 novel microRNAs were identified in 18 spinach female and male flower samples. 74 differentially expressed microRNAs were identified between female and male flowers, including 20 female-biased and 48 male-biased expression microRNAs. Target prediction identified 22 sex-biased microRNA-target pairs, which may be involved in spinach sex determination or differentiation. Among the differentially expressed microRNAs between FNS and M03, 55 microRNAs were found to reside in sex chromosome; one of them, sol-miR2550n, was functionally studied via genetic transformation. Silencing of sol-miR2550n resulted in abnormal anther while overexpression of sol-miR2550n induced early flowering, indicating sol-miR2550n was a male-promoting factor and validating the reliability of our small RNA sequencing data. Conclusively, this work can supply valuable information for exploring spinach sex determination and differentiation and provide a new insight in studying unisexual flower development.
Assuntos
MicroRNAs , Spinacia oleracea , Flores/metabolismo , Regulação da Expressão Gênica de Plantas , MicroRNAs/genética , MicroRNAs/metabolismo , Reprodutibilidade dos Testes , Diferenciação Sexual/genética , Spinacia oleracea/genética , Spinacia oleracea/metabolismoRESUMO
BACKGROUND: Dioecious spinach (Spinacia oleracea L.), a commercial and nutritional vegetable crop, serves as a model for studying the mechanisms of sex determination and differentiation in plants. However, this mechanism is still unclear. Herein, based on PacBio Iso-seq and Illumina RNA-seq data, comparative transcriptome analysis of male and female flowers were performed to explore the sex differentiation mechanism in spinach. RESULTS: Compared with published genome of spinach, 10,800 transcripts were newly annotated; alternative splicing, alternative polyadenylation and lncRNA were analyzed for the first time, increasing the diversity of spinach transcriptome. A total of 2965 differentially expressed genes were identified between female and male flowers at three early development stages. The differential expression of RNA splicing-related genes, polyadenylation-related genes and lncRNAs suggested the involvement of alternative splicing, alternative polyadenylation and lncRNA in sex differentiation. Moreover, 1946 male-biased genes and 961 female-biased genes were found and several candidate genes related to gender development were identified, providing new clues to reveal the mechanism of sex differentiation. In addition, weighted gene co-expression network analysis showed that auxin and gibberellin were the common crucial factors in regulating female or male flower development; however, the closely co-expressed genes of these two factors were different between male and female flower, which may result in spinach sex differentiation. CONCLUSIONS: In this study, 10,800 transcripts were newly annotated, and the alternative splicing, alternative polyadenylation and long-noncoding RNA were comprehensively analyzed for the first time in spinach, providing valuable information for functional genome study. Moreover, candidate genes related to gender development were identified, shedding new insight on studying the mechanism of sex determination and differentiation in plant.
Assuntos
Spinacia oleracea , Transcriptoma , Flores/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Sequenciamento de Nucleotídeos em Larga Escala , Spinacia oleracea/genéticaRESUMO
We investigate the force measurement sensitivity in a squeezed dissipative optomechanics within the free-mass regime under the influence of shot noise (SN) from the photon number fluctuations, laser phase noise from the pump laser, thermal noise from the environment, and optical losses from outcoupling and detection inefficiencies. Generally, squeezed light could generate a reduced SN on the squeezed quadrature and an enlarged quantum backaction noise (QBA) due to the antisqueezed conjugate quadrature. With an appropriate choice of phase angle in homodyne detection, QBA is cancellable, leading to an exponentially improved measurement sensitivity for the SN-dominated regime. By now, the effects of laser phase noise that is proportional to laser power emerge. The balance between squeezed SN and phase noise can lead to an sub-SQL sensitivity at an exponentially lower input power. However, the improvement by squeezing is limited by optical losses because high sensitivity is delicate and easily destroyed by optical losses.
RESUMO
Enhanced migration potential is a common characteristic of cancer cells induced by mechanisms that are incompletely defined. The present study was designed to investigate relationship of a new discovered cytoskeleton regulator MICAL-L2 and the endogenous epidermal growth factor receptor (EGFR) signalling pathways in gastric cancer cell migration. Increased expression of MICAL-L2 in gastric cancer cells up-regulated EGFR protein level, accompanied by the increase of cell migration, whereas silencing MICAL-L2 down-regulated EGFR and inhibited cell migration. Expression of MICAL-L2 was also shown positively correlated with the activation of HSP27/cytoskeleton and HSP27/ß-catenin signalling pathways that provide key mechanisms controlling cell migration. The up-regulating effect of MICAL-L2 on EGFR is mediated through a transcription-independent mechanism that involves inhibiting EGFR protein degradation in lysosome. Further analysis indicated that Cdc42 activation contributed in maintaining the effect of MICAL-L2 on EGFR stability. Furthermore analysis of clinic specimens revealed increased expression of MICAL-L2 in carcinoma tissues and a positive correlation between MICAL-L2 and EGFR expression levels. The above results indicate that MICAL-L2 potentiates gastric cell migration via inhibiting EGFR degradation in lysosome via a Cdc42-dependent manner that leads to the activation of EGFR/HSP27 signalling pathways.
Assuntos
Biomarcadores Tumorais/metabolismo , Movimento Celular , Proteínas dos Microfilamentos/metabolismo , Neoplasias Gástricas/patologia , Proteína cdc42 de Ligação ao GTP/metabolismo , Apoptose , Proliferação de Células , Receptores ErbB/química , Receptores ErbB/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Prognóstico , Estabilidade Proteica , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Células Tumorais CultivadasRESUMO
BACKGROUND: Hypoxia, a major condition associated with the tumor microenvironment, stimulates the migration of cancer cells. SOX2 is a powerful transcription factor that shows higher expression in several cancers, however, its role in hypoxia-induced breast cancer cell migration remains largely elusive. METHODS: The human breast cancer cell lines MDA-MB-231 and MDA-MB-468 were cultured under hypoxic conditions. The cell migration rate was determined using the wound-healing and transwell assays. The protein levels of SOX2, NEDD9 and HIF-1α were evaluated via western blotting analysis. The NEDD9 mRNA levels were evaluated using qPCR. The activation of Rac1 was detected with the pulldown assay. The binding of SOX2 to the NEDD9 promoter was checked using the luciferase reporter assay. We also transfected breast cancer cells with specific siRNA for SOX2, NEDD9 or the Rac1 inactive mutant (T17 N) to investigate the role of SOX2, NEDD9 and Rac1 in the response to hypoxia. RESULTS: Hypoxia markedly increased SOX2 protein levels in a time-dependent manner. SiRNA-mediated disruption of SOX2 inhibited cell migration under hypoxic conditions. Hypoxia also significantly augmented the NEDD9 mRNA and protein levels. Interestingly, SOX2 is a positive transcriptional regulator of NEDD9. Knockdown of SOX2 inhibited hypoxia-induced NEDD9 mRNA and protein expressions. Furthermore, hypoxia-induced upregulation of Rac1 activity and HIF-1α expression was attenuated by SOX2 or NEDD9 silencing, and Rac1-T17 N abolished HIF-1α expression as well as cell migration in cells subjected to hypoxia. CONCLUSIONS: Our results highlight the essential role of SOX2 in breast cancer cell motility. The upregulation of SOX2 under hypoxic conditions may facilitate NEDD9 transcription and expression, and subsequent activation of Rac1 and HIF-1α expression. This could accelerate breast cancer cell migration.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias da Mama/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Fatores de Transcrição SOXB1/genética , Proteínas rac1 de Ligação ao GTP/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Fatores de Transcrição SOXB1/metabolismo , Transdução de Sinais , Hipóxia Tumoral , Proteínas rac1 de Ligação ao GTP/metabolismoRESUMO
Molecule interacting with CasL 1 (MICAL1) is a multidomain flavoprotein mono-oxygenase that strongly involves in cytoskeleton dynamics and cell oxidoreduction metabolism. Recently, results from our laboratory have shown that MICAL1 modulates reactive oxygen species (ROS) production, and the latter then activates phosphatidyl inositol 3-kinase (PI3K)/protein kinase B (Akt) signalling pathway which regulates breast cancer cell invasion. Herein, we performed this study to assess the involvement of MICAL1 in breast cancer cell proliferation and to explore the potential molecular mechanism. We noticed that depletion of MICAL1 markedly reduced cell proliferation in breast cancer cell line MCF-7 and T47D. This effect of MICAL1 on proliferation was independent of wnt/ß-catenin and NF-κB pathways. Interestingly, depletion of MICAL1 significantly inhibited ROS production, decreased p-ERK expression and unfavourable for proliferative phenotype of breast cancer cells. Likewise, MICAL1 overexpression increased p-ERK level as well as p-ERK nucleus translocation. Moreover, we investigated the effect of MICAL1 on cell cycle-related proteins. MICAL1 positively regulated CDK4 and cyclin D expression, but not CDK2, CDK6, cyclin A and cyclin E. In addition, more expression of CDK4 and cyclin D by MICAL1 overexpression was blocked by PI3K/Akt inhibitor LY294002. LY294002 treatment also attenuated the increase in the p-ERK level in MICAL1-overexpressed breast cancer cells. Together, our results suggest that MICAL1 exhibits its effect on proliferation via maintaining cyclin D expression through ROS-sensitive PI3K/Akt/ERK signalling in breast cancer cells.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias da Mama/genética , Proliferação de Células/genética , Ciclina D/genética , Proteínas do Citoesqueleto/genética , Proteínas com Domínio LIM/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Cromonas/farmacologia , Feminino , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Células MCF-7 , Proteínas dos Microfilamentos , Oxigenases de Função Mista , Morfolinas/farmacologia , Proteínas de Neoplasias/genética , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Arsenic trioxide (As2O3), a traditional remedy in Chinese medicine, has been used in acute promyelocytic leukemia (APL) research and clinical treatment. Previous studies have shown that As2O3 exerts its potent antitumor effects in solid tumors by regulating cell proliferation and survival. The aim of this study was to investigate whether As2O3 inhibited gastric cancer cell migration and angiogenesis by regulating FOXO3a expression. We found that As2O3 reduced gastric cancer cell viability in a dose-dependent manner and also inhibited cell migration and angiogenesis in vitro. Western blotting and immunofluorescence showed that As2O3 downregulated the levels of p-AKT, upregulated FOXO3a expression in the nucleus, and attenuated downstream Vascular endothelial growth factor (VEGF) and Matrix metallopeptidase 9 (MMP9) expression. Moreover, we demonstrated that knockdown of FOXO3a significantly reversed the inhibition of As2O3 and promoted cell migration and angiogenesis in vitro. Further, As2O3 significantly inhibited xenograft tumor growth and angiogenesis by upregulating FOXO3a expression in vivo. However, knockdown of FOXO3a attenuated the inhibitory effect of As2O3 in xenograft tumors, and increased microvessel density (MVD) and VEGF expression. Our results demonstrated that As2O3 inhibited migration and angiogenesis of gastric cancer cells by enhancing FOXO3a expression.
Assuntos
Antineoplásicos/farmacologia , Trióxido de Arsênio/farmacologia , Proteína Forkhead Box O3/genética , Regulação Neoplásica da Expressão Gênica , Neovascularização Patológica/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Proteína Forkhead Box O3/antagonistas & inibidores , Proteína Forkhead Box O3/metabolismo , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Nus , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Hypoxia/reoxygenation (H/R) in human umbilical vein endothelial cells (HUVECs) induces oxidative stress and eventually leads to vascular injury. OBJECTIVE: The aim of this study was to examine the effect of melatonin on HUVECs injured by H/R and explore the underlying mechanisms. MATERIALS AND METHODS: A model of HUVECs under hypoxia/reoxygenation was established. Cell migration and adhesive ability was measured by wound healing and adhesion assays. Cell proliferation was measured by EdU assay. Production of reactive oxygen species (ROS) was evaluated by CM-H2DCFDA staining. Actin cytoskeleton rearrangement was examined by immunofluorescence. Western blotting analysis were used to analyze P38 and HSP27 phosphorylation levels. RESULTS: H/R inhibited HUVEC proliferation, cell migratory and adhesive capacities, whereas melatonin (1~100 µM) inhibited these effects in a dose-dependent manner. Melatonin alone did not affect HUVEC viability, however, it inhibited the increase in ROS production and cytoskeleton disruption elicited by H/R, and it dose-dependently prevented H/R-induced upregulation of P38 and HSP27 phosphorylation. In addition, the ROS scavenger N-acetyl-L-cysteine markedly inhibited increased phosphorylation levels of P38 and HSP27 under H/R. CONCLUSIONS: Melatonin may have a potential clinical effect in trials of H/R-induced vascular injury through its antioxidant property.
RESUMO
BACKGROUND: Despite the fact that melatonin treatment shows some promise in gastric cancer, the molecular mechanisms of gastric cancer cells in response to melatonin remains to be determined. METHODS: The SGC-7901 gastric cancer cells were treated with different concentrations of melatonin for 24 and 48 h. Cell viability was determined by MTT assay, Hoechst 33258 staining and FACS analysis were used to detect apoptotic cells. The contents and activation of apoptosis-related proteins HSP27, Akt and P38 were evaluated by immunoblotting analysis. Then we treated SGC-7901 cells with HSP27-specific siRNA, PI3K inhibitor LY294002 or P38 inhibitor SB203580 to investigate the role of HSP27, Akt and P38 in the anti-apoptotic response of SGC-7901 cells to melatonin. RESULTS: Melatonin suppressed cell viability and stimulated apoptosis of gastric cancer SGC-7901 cells dose-dependently. Mechanistically, the observed apoptosis was accompanied by the melatonin-induced phosphorylation of HSP27. HSP27-specific siRNA transfection effectively reduced HSP27 phosphorylation and augmented melatonin-induced apoptosis, indicating that HSP27 is resistant to melatonin-induced apoptosis. Moreover, melatonin increased PI3K/Akt activation, LY294002 abrogated HSP27 activation and promoted cell apoptosis induced by melatonin. Furthermore, melatonin increased P38 activity, and P38 inhibitor SB203580 inhibited melatonin-induced PI3K/Akt, HSP27 activation and accelerated cell apoptosis. CONCLUSION: In contrast to the well-established anti-cancer properties of melatonin, our study revealed clearly a distinguishable anti-apoptotic pathway induced by melatonin, that is, HSP27 plays a crucial role in apoptotic resistance in melatonin-treated gastric cancer cells, and its activation is most likely via the activation of P38/PI3K/Akt signaling.
RESUMO
BACKGROUND: Molecules Interacting with CasL (MICAL1), a multidomain flavoprotein monoxygenase, is strongly involved in the mechanisms that promote cancer cell proliferation and survival. Activation of MICAL1 causes an up-regulation of reactive oxygen species (ROS) in HeLa cells. ROS can function as a signaling molecule that modulates protein phosphorylation, leading to malignant phenotypes of cancer cells such as invasion and metastasis. Herein, we tested whether MICAL1 could control cell migration and invasion through regulating ROS in breast cancer cell lines. METHODS: The effects of depletion/overexperssion of MICAL1 on cell invasion rate were measured by matrigel-based transwell assays. The contents of ROS in breast cancer cells were evaluated by CM2-DCFHDA staining and enhanced lucigenin chemiluminescence method. RAB35 activity was assessed by pulldown assay. The relationship of RAB35 and MICAL1 was evaluated by immunofluorescence, coimmunoprecipitation, immunoblotting and co-transfection techniques. Immunoblotting assays were also used to analyze Akt phosphorylation level. RESULTS: In this study, we found that depletion of MICAL1 reduced cell migration and invasion as well as ROS generation. Phosphorylation of Akt was also attenuated by MICAL1 depletion. Likewise, the over-expression of MICAL1 augmented the generation of ROS, increased Akt phosphorylation, and favored invasive phenotype of breast cancer cells. Moreover, we investigated the effect of EGF signaling on MICAL1 function. We demonstrated that EGF increased RAB35 activation and activated form of RAB35 could bind to MICAL1. Silencing of RAB35 repressed ROS generation, prevented Akt phosphorylation and inhibited cell invasion in response to EGF. CONCLUSIONS: Taken together, our results provide evidence that MICAL1 plays an essential role in the activation of ROS/Akt signaling and cell invasive phenotype and identify a novel link between RAB35 and MICAL1 in regulating breast cancer cell invasion. These findings may provide a basis for designing future therapeutic strategy for blocking breast cancer metastasis.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias da Mama/patologia , Movimento Celular/fisiologia , Proteínas do Citoesqueleto/metabolismo , Proteínas com Domínio LIM/metabolismo , Invasividade Neoplásica/patologia , Proteínas rab de Ligação ao GTP/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Sobrevivência Celular , Proteínas do Citoesqueleto/genética , Feminino , Células HeLa , Humanos , Proteínas com Domínio LIM/genética , Proteínas dos Microfilamentos , Oxigenases de Função Mista , Invasividade Neoplásica/genética , Estresse Oxidativo/fisiologia , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas rab de Ligação ao GTP/genéticaRESUMO
PURPOSE: Folic acid supplementation has been suggested to reduce the risk of preterm birth. However, results from previous epidemiologic studies have been inconclusive. We investigated the hypothesis that folic acid supplementation and dietary folate intake during pre- and post-conception reduces the risk of preterm birth. METHODS: We analyzed data from a birth cohort study conducted between 2010 and 2012 in Lanzhou, China, including 10,179 pregnant women with live singleton births. RESULTS: Compared to non-users, folic acid supplement users with >12-week duration had a reduced risk of preterm birth (OR 0.67, 95 % CI 0.55-0.83) with a significant dose-response relationship (P for trend = 0.01). A similar pattern was observed for spontaneous preterm birth. Stronger associations were seen for ever use of folic acid supplement and very preterm birth (OR 0.50, 95 % CI 0.36-0.69) and spontaneous very preterm birth (OR 0.42, 95 % CI 0.29-0.63). Dietary folate intake during preconception and pregnancy were also associated with reduced risk of preterm birth (OR 0.68, 95 % CI 0.56-0.83, OR 0.57, 95 % CI 0.47-0.70 for the highest quartiles, respectively), particularly for spontaneous very preterm (OR 0.41, 95 % CI 0.24-0.72, OR 0.26, 95 % CI 0.15-0.47 for the highest quartiles, respectively). There were also decreased risks of preterm birth observed per 10-µg increase in dietary folate intake, and similar associations were found after stratification by folic acid supplementation status. CONCLUSIONS: Our results suggest that folic acid supplementation and higher dietary folate intake during preconception and pregnancy reduces the risk of preterm birth, and the protective effect varies by preterm subtypes.
Assuntos
Dieta , Suplementos Nutricionais , Ácido Fólico/administração & dosagem , Nascimento Prematuro/prevenção & controle , Adulto , Índice de Massa Corporal , China , Estudos de Coortes , Relação Dose-Resposta a Droga , Exercício Físico , Feminino , Humanos , Fenômenos Fisiológicos da Nutrição Materna , Gravidez , Fatores de Risco , Fatores Socioeconômicos , Adulto JovemRESUMO
BACKGROUND: Early studies have suggested that biomass cooking fuels were associated with increased risk of low birth weight (LBW). However it is unclear if this reduced birth weight was due to prematurity or intrauterine growth restriction (IUGR). METHODS: In order to understand the relationship between various cooking fuels and risk of LBW and small for gestational age (SGA), we analyzed data from a birth cohort study conducted in Lanzhou, China which included 9,895 singleton live births. RESULTS: Compared to mothers using gas as cooking fuel, significant reductions in birth weight were observed for mothers using coal (weight difference = 73.31 g, 95 % CI: 26.86, 119.77) and biomass (weight difference = 87.84 g, 95 % CI: 10.76, 164.46). Using biomass as cooking fuel was associated with more than two-fold increased risk of LBW (OR = 2.51, 95 % CI: 1.26, 5.01), and the risk was mainly seen among preterm births (OR = 3.43, 95 % CI: 1.21, 9.74). No significant associations with LBW were observed among mothers using coal or electromagnetic stoves for cooking. CONCLUSIONS: These findings suggest that exposure to biomass during pregnancy is associated with risk of LBW, and the effect of biomass on LBW may be primarily due to prematurity rather than IUGR.
Assuntos
Peso ao Nascer , Carvão Mineral/estatística & dados numéricos , Culinária/estatística & dados numéricos , Recém-Nascido de Baixo Peso , Nascimento Prematuro/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Adulto , Biomassa , China/epidemiologia , Carvão Mineral/efeitos adversos , Estudos de Coortes , Radiação Eletromagnética , Feminino , Retardo do Crescimento Fetal/epidemiologia , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Gás Natural/estatística & dados numéricos , Gravidez , Adulto JovemRESUMO
Studies investigating the relationship between maternal passive smoking and the risk of preterm birth have reached inconsistent conclusions. A birth cohort study that included 10,095 nonsmoking women who delivered a singleton live birth was carried out in Lanzhou, China, between 2010 and 2012. Exposure to passive smoking during pregnancy was associated with an increased risk of very preterm birth (<32 completed weeks of gestation; odds ratio = 1.98, 95% confidence interval: 1.41, 2.76) but not moderate preterm birth (32-36 completed weeks of gestation; odds ratio = 0.98, 95% confidence interval: 0.81, 1.19). Risk of very preterm birth increased with the duration of exposure (P for trend = 0.0014). There was no variability in exposures by trimester. The associations were consistent for both medically indicated and spontaneous preterm births. Overall, our findings support a positive association between passive smoking and the risk of very preterm birth.
Assuntos
Nascimento Prematuro/etiologia , Poluição por Fumaça de Tabaco/efeitos adversos , Adolescente , Adulto , China/epidemiologia , Escolaridade , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Masculino , Idade Materna , Paridade , Gravidez , Nascimento Prematuro/epidemiologia , Fatores de Risco , Inquéritos e Questionários , Poluição por Fumaça de Tabaco/estatística & dados numéricos , População Urbana/estatística & dados numéricos , Adulto JovemRESUMO
BACKGROUND AND OBJECTIVE: Time series data plays a crucial role in the realm of the Internet of Things Medical (IoMT). Through machine learning (ML) algorithms, online time series classification in IoMT systems enables reliable real-time disease detection. Deploying ML algorithms on edge health devices can reduce latency and safeguard patients' privacy. However, the limited computational resources of these devices underscore the need for more energy-efficient algorithms. Furthermore, online time series classification inevitably faces the challenges of concept drift (CD) and catastrophic forgetting (CF). To address these challenges, this study proposes an energy-efficient Online Time series classification algorithm that can solve CF and CD for health devices, called OTCD. METHODS: OTCD first detects the appearance of concept drift and performs prototype updates to mitigate its impact. Afterward, it standardizes the potential space distribution and selectively preserves key training parameters to address CF. This approach reduces the required memory and enhances energy efficiency. To evaluate the performance of the proposed model in real-time health monitoring tasks, we utilize electrocardiogram (ECG) and photoplethysmogram (PPG) data. By adopting various feature extractors, three arrhythmia classification models are compared. To assess the energy efficiency of OTCD, we conduct runtime tests on each dataset. Additionally, the OTCD is compared with state-of-the-art (SOTA) dynamic time series classification models for performance evaluation. RESULTS: The OTCD algorithm outperforms existing SOTA time series classification algorithms in IoMT. In particular, OTCD is on average 2.77% to 14.74% more accurate than other models on the MIT-BIH arrhythmia dataset. Additionally, it consumes low memory (1 KB) and performs computations at a rate of 0.004 GFLOPs per second, leading to energy savings and high time efficiency. CONCLUSION: Our proposed algorithm, OTCD, enables efficient real-time classification of medical time series on edge health devices. Experimental results demonstrate its significant competitiveness, offering promising prospects for safe and reliable healthcare.
Assuntos
Algoritmos , Eletrocardiografia , Aprendizado de Máquina , Humanos , Fotopletismografia , Internet das Coisas , Processamento de Sinais Assistido por Computador , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/classificação , Monitorização Fisiológica/instrumentação , Monitorização Fisiológica/métodosRESUMO
BACKGROUND: Observational studies have found associations between hypertensive disorders of pregnancy and an increased risk of cognitive dysfunction and reduced brain volume. However, the results of observational studies may have been influenced by confounding factors. This study applied two-sample Mendelian randomization (MR) to explore the causal associations of hypertensive disorders of pregnancy with cognition, dementia, and brain structure. METHODS: Summary data on hypertensive disorders of pregnancy and their main subtypes, cognition, dementia, and brain structure were obtained from recent European genome-wide association studies. We computed the inverse-variance weighted, MR-Egger, and weighted median MR estimates. Cochran's Q statistics and the MR-Egger intercept test were used to quantify the heterogeneity and horizontal pleiotropy of the instrumental variables. RESULTS: Genetically predicted preeclampsia or eclampsia was inversely associated with gray matter volume [betaâ=â-0.072; 95% confidence interval (CI)â=â-0.131 to -0.014; P â=â1.53â×â10 -2 ]; possibly with brain volume (betaâ=â-0.064; 95% CIâ=â-0.117 to -0.012; P â=â1.68â×â10 -2 ). However, the association of hypertensive pregnancy disorders or gestational hypertension with brain structure was not significant. We did not find any significant association between hypertensive disorders of pregnancy, gestational hypertension, or preeclampsia or eclampsia and cognition and dementia-related outcomes. CONCLUSION: This study provided genetic evidence supporting an association between preeclampsia or eclampsia and reduced brain volume. This supports the view of PE as a risk factor for gray matter volume reduction.
Assuntos
Demência , Eclampsia , Hipertensão Induzida pela Gravidez , Pré-Eclâmpsia , Feminino , Gravidez , Humanos , Hipertensão Induzida pela Gravidez/genética , Pré-Eclâmpsia/genética , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Encéfalo/diagnóstico por imagem , Cognição , Demência/epidemiologia , Demência/genéticaRESUMO
Rheumatoid arthritis (RA) is a persistent autoimmune condition with no identified cure currently. Recently, scientists have applied metabolomics to investigate altered metabolic profiles and unique diseases-associated metabolic signatures. Herein, we applied metabolomics approach to analyze serum samples of 41 RA patients and 42 healthy controls (HC) with the aim to characterize RA patients' metabolic profile, investigate related underlying pathological processes, and identify target metabolites. By utilizing ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry, we found 168 proposed metabolites and 45 vital metabolic pathways. Our analysis revealed that deoxyinosine (DI), a metabolite of the purine metabolic pathway, was the most significant reduced metabolite in RA patients. Furthermore, through targeted detection, we confirmed lower concentration of DI in RA patients' peripheral blood. Moreover, DI inhibited lipopolysaccharide-induced inflammation both in vitro and in vivo. We further assessed DI's therapeutic potential in a collagen-induced arthritis (CIA) murine model. The results revealed that DI attenuated CIA, as evidenced by significantly lowered clinical scores of arthritis, alleviated joint swelling, and mitigated bone destruction. Moreover, we elucidated the underlying mechanism by which DI increased the population of myeloid-derived suppressor cells (MDSCs) and suppressed the proliferation of induced T cells. Collectively, these findings suggested that DI potentially ameliorated RA by inducing immunosuppressive MDSCs. The study provides key observations on RA pathogenesis and may contribute to developing novel therapeutic strategies for this debilitating condition.