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Given the insidious and high-fatality nature of cardiovascular diseases (CVDs), the emergence of fluoride as a newly identified risk factor demands serious consideration alongside traditional risk factors. While vascular smooth muscle cells (VSMCs) play a pivotal role in the progression of CVDs, the toxicological impact of fluoride on VSMCs remains largely uncharted. In this study, we constructed fluorosis model in SD rats and A7R5 aortic smooth muscle cell lines to confirm fluoride impaired VSMCs. Fluoride aggravated the pathological damage of rat aorta in vivo. Then A7R5 were exposed to fluoride with concentration ranging from 0 to 1200 µmol/L over a 24-h period, revealing a dose-dependent inhibition of cell proliferation and migration. The further metabolomic analysis showed alterations in metabolite profiles induced by fluoride exposure, notably decreasing organic acids and lipid molecules level. Additionally, gene network analysis underscored the frequency of fluoride's interference with amino acids metabolism, potentially impacting the tricarboxylic acid (TCA) cycle. Our results also highlighted the ATP-binding cassette (ABC) transporters pathway as a central element in VSMC impairment. Moreover, we observed a dose-dependent increase in osteopontin (OPN) and α-smooth muscle actin (α-SMA) mRNA level and a dose-dependent decrease in ABC subfamily C member 1 (ABCC1) and bestrophin 1 (BEST1) mRNA level. These findings advance our understanding of fluoride as a CVD risk factor and its influence on VSMCs and metabolic pathways, warranting further investigation into this emerging risk factor.
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Aminoácidos , Proliferação de Células , Fluoretos , Músculo Liso Vascular , Ratos Sprague-Dawley , Animais , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Músculo Liso Vascular/efeitos dos fármacos , Fluoretos/farmacologia , Linhagem Celular , Aminoácidos/metabolismo , Proliferação de Células/efeitos dos fármacos , Ratos , Movimento Celular/efeitos dos fármacos , Masculino , Aorta/patologia , Aorta/efeitos dos fármacos , Aorta/metabolismo , Metabolômica , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Redes Reguladoras de Genes/efeitos dos fármacosRESUMO
BACKGROUND: Paired box 1 (PAX1) is a transcription factor and essential for the development of pharyngeal pouches-derived tissues, including thymus. PAX1 mutations are identified in Severe Combined Immunodeficiency (SCID) patients with Otofaciocervical Syndrome Type 2 (OTFCS2). However, despite the critical roles of PAX1 in embryonic development and diseases, detailed insights into its molecular mode of action are critically missing. METHODS: The repressing roles of PAX1 and SCID associated mutants on Wnt signaling pathway were investigated by luciferase reporter assays, qRT-PCR and in situ hybridization in HEK293FT, HCT116 cells and zebrafish embryos, respectively. Co-immunoprecipitation (co-IP) and western blotting assays were carried out to identify the molecular mechanisms underlying PAX1's role on Wnt signaling pathway. hESC based endoderm differentiation, flow cytometry, high-throughput sequencing data analysis, and qRT-PCR assays were utilized to determine the roles of PAX1 during endoderm differentiation. RESULTS: Here, we show that PAX1 represses canonical Wnt signaling pathway in vertebrate cells. Mechanically, PAX1 competes with SUMO E3 ligase PIASy to bind to TCF7L2, thus perturbing TCF7L2 SUMOylation level, further reducing its transcriptional activity and protein stability. Moreover, we reveal that PAX1 plays dual roles in hESC-derived definitive and foregut/pharyngeal endoderm cells, which give rise to the thymus epithelium, by inhibiting Wnt signaling. Importantly, our data show PAX1 mutations found in SCID patients significantly compromise the suppressing ability of PAX1 on Wnt signaling. CONCLUSIONS: Our study presents a novel molecular mode of action of PAX1 in regulation of canonical Wnt signaling and endoderm differentiation, thus providing insights for the molecular basis of PAX1 associated SCID, offering better understanding of the behavior of PAX1 in embryogenesis.
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Diferenciação Celular , Endoderma , Via de Sinalização Wnt , Peixe-Zebra , Humanos , Via de Sinalização Wnt/genética , Diferenciação Celular/genética , Endoderma/metabolismo , Endoderma/citologia , Animais , Peixe-Zebra/genética , Células HEK293 , Proteína 2 Semelhante ao Fator 7 de Transcrição/metabolismo , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Células HCT116 , Fatores de Transcrição Box Pareados/metabolismo , Fatores de Transcrição Box Pareados/genéticaRESUMO
BACKGROUND: Local high-frequency percussive (HFP) massage has recently found widespread application in physical therapy. Although HFP massage reportedly improves range of motion (ROM), the mechanism underlying its action has not yet been proven. This study aimed to clarify whether a 5-minute percussive massage regimen affects muscular or connective tissues, such as the deep fascia and deep intermuscular fascia and the change in joint ROM. METHOD: The study sample was calculated using G*Power analysis program, and this study enrolled 15 healthy men who underwent 5-minute HFP massage to the medial gastrocnemius muscle. Shear-wave elastography was used to measure tissue stiffness in the deep fascia, muscle, and deep intermuscular fascia through shear-wave velocity as well as the ROM of the volunteers' ankle joint dorsiflexion before and after the HFP massage. A value of P < .05 was used to declare statistical significance, and post hoc was used to calculate the effect size using G*Power. RESULTS: Shear-wave velocity revealed a significant change in the deep fascia (P = .003; shear-wave velocity: -0.7 m/s) and significant increase in ROM of ankle dorsiflexion (P = .002; increase in ROM: 3.0°) after 5 minutes of HFP massage. However, the muscle and deep intermuscular fascia did not exhibit any significant changes. CONCLUSIONS: HFP massage for 5 minutes modified the stiffness of the deep fascia and concurrently improved the ankle joint-dorsiflexion ROM. This method can be used as an intervention to decrease stiffness of the deep fascia and increase the ROM efficiently.
Assuntos
Articulação do Tornozelo , Técnicas de Imagem por Elasticidade , Fáscia , Massagem , Músculo Esquelético , Amplitude de Movimento Articular , Humanos , Masculino , Massagem/métodos , Amplitude de Movimento Articular/fisiologia , Adulto Jovem , Músculo Esquelético/fisiologia , Fáscia/fisiologia , Articulação do Tornozelo/fisiologia , AdultoRESUMO
[Purpose] To measure the sub-sesamoid soft tissue thickness change from non-loading to self-weight loading conditions. [Participants and Methods] The study included 17 female participants for the study. A questionnaire was used to collect the demographic data and participant anamnesis, such as the presence of foot injuries and diabetes. The measured height and weight were used to calculate the body mass index. Participants were required to stand on an evaluation device from non-loading to 100% loading conditions to measure the sub-sesamoid soft tissue thickness. [Results] Significant differences were observed between the tibial and fibular sub-sesamoid soft tissue thicknesses under non-loading and all loading conditions. Significant soft tissue thinning was observed with a change from non-loading to 25% loading condition. However, no significant differences in the rate of change were observed between the tibial and fibular sub-sesamoid soft tissue thicknesses at 100% loading. [Conclusion] The sub-fibular sesamoid soft tissue was thicker than the sub-tibial sesamoid soft tissue in all loading conditions. The sub-sesamoid soft tissue thickness change was larger during initial loading stage than during the late loading stage, which may be normal in healthy females in their 20s.
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Decades have witnessed rapid progress of polymeric materials for vascular embolic or chemoembolic applications. Commercially available polymeric embolics range from gelatin foam to synthetic polymers such as poly(vinyl alcohol). Current systems under investigation include tunable, bioresorbable microspheres composed of chitosan or poly(ethylene glycol) derivatives,in situgelling liquid embolics with improved safety profiles, and radiopaque embolics that are trackablein vivo. In this paper, we proposed a concept of 'responsive embolization'. Sevelamer, clinically proved as an inorganic phosphate binder, was ground into nanoparticles. Sevelamer nanoparticle is highly mobile and capable of swelling and aggregating in the presence of endogenous inorganic phosphate, thereby effectively occluding blood flow in the vessel as it was administered as an embolic agent for interventional therapy. Moreover, citrated sevelamer nanoparticles delayed the aggregation, preferable to penetrate deeply into the capillary system. On the rabbit VX2 liver cancer model, both sevelamer particles aggregates occlude the tumor feeding artery, but backflow was found for the pristine one, thereby citrate passivation of sevelamer nanoparticles endows it have potential from 'bench to bedside' as a new type of vascular embolic.
Assuntos
Embolização Terapêutica , Nanopartículas , Animais , Microesferas , Fosfatos , Polímeros , Coelhos , SevelamerRESUMO
Laser cutting belongs to non-contact processing, which is different from traditional turning and milling. In order to improve the machining accuracy of laser cutting, a thermal error prediction and dynamic compensation strategy for laser cutting is proposed. Based on the time-varying characteristics of the digital twin technology, a hybrid model combining the thermal elastic-plastic finite element (TEP-FEM) and T-XGBoost algorithms is established. The temperature field and thermal deformation under 12 common working conditions are simulated and analyzed with TEP-FEM. Real-time machining data obtained from TEP-FEM simulation is used in intelligent algorithms. Based on the XGBoost algorithm and the simulation data set as the training data set, a time-series-based segmentation algorithm (T-XGBoost) is proposed. This algorithm can reduce the maximum deformation at the slit by more than 45%. At the same time, by reducing the average volume strain under most working conditions, the lifting rate can reach 63% at the highest, and the machining result is obviously better than XGBoost. The strategy resolves the uncontrollable thermal deformation during cutting and provides theoretical solutions to the implementation of the intelligent operation strategies such as predictive machining and quality monitoring.
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Although clinically associated with the progression of multiple cancers, the biological function of p21-activated kinase 5 (PAK5) in breast cancer remains largely unknown. Here, we reveal that the PAK5-aspartyl aminopeptidase (DNPEP)-ubiquitin-specific protease 4 (USP4) axis is involved in breast cancer progression. We show that PAK5 interacts with and phosphorylates DNPEP at serine 119. Functionally, we demonstrate that DNPEP overexpression suppresses breast cancer cell proliferation and invasion and restricts breast cancer growth and metastasis in mice. Furthermore, we identify USP4 as a downstream target of the PAK5-DNPEP pathway; DNPEP mediates USP4 downregulation. Importantly, we verify that DNPEP expression is frequently downregulated in breast cancer tissues and is negatively correlated with PAK5 and USP4 expression. PAK5 decreases DNPEP abundance via the ubiquitin-proteasome pathway. Consistently, analyses of clinical breast cancer specimens revealed significantly increased PAK5 and USP4 levels and an association between higher PAK5 and USP4 expression and worse breast cancer patient survival. These findings suggest a pivotal role for PAK5-elicited signaling in breast cancer progression.
Assuntos
Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Glutamil Aminopeptidase/metabolismo , Proteases Específicas de Ubiquitina/metabolismo , Quinases Ativadas por p21/metabolismo , Animais , Processos de Crescimento Celular/fisiologia , Feminino , Células HEK293 , Xenoenxertos , Humanos , Células MCF-7 , Camundongos , Camundongos Nus , Metástase Neoplásica , Fosforilação , Transdução de SinaisRESUMO
Claudin-4 (CLDN4), a crucial member of tight junction proteins, is aberrantly expressed in breast cancer cells and contributes to cell migration and invasion. However, the mechanisms controlling CLDN4 expression in breast cancer are poorly understood. Here, we reported that CLDN4 expression correlated positively with p21-activated kinase 4 (PAK4) expression in human breast cancer tissues. Knockdown of PAK4 in MDA-MB-231 and ZR-75-30â¯cells suppressed CLDN4 expression and significantly inhibited cell migration and invasion. Conversely, restoration of CLDN4 expression in PAK4-knockdown cells reversed the inhibition of migration and invasion. We identified CCAAT/enhancer-binding protein ß (CEBPB) as a novel transcriptional regulator of CLDN4 and confirmed that CEBPB bound to the -1093 to -991 bp region of the CLDN4 promoter. Importantly, we found that PAK4 enhanced CEBPB phosphorylation on Thr-235. In summary, we showed that PAK4-mediated CEBPB activation upregulated CLDN4 expression to promote breast cancer cell migration and invasion. Our results might contribute to understanding the mechanisms of CLDN4 regulation and suggest PAK4-CEBPB-CLDN4 axis as a potential therapeutic target for breast cancer.
Assuntos
Neoplasias da Mama/metabolismo , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Claudina-4/metabolismo , Transdução de Sinais , Quinases Ativadas por p21/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proteína beta Intensificadora de Ligação a CCAAT/genética , Linhagem Celular Tumoral , Movimento Celular , Claudina-4/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Fosforilação , Quinases Ativadas por p21/genéticaRESUMO
Discerning the modular nature of human diseases through computational approaches calls for diverse data. The finding sites of diseases, like other disease phenotypes, possess rich information in understanding disease genetics. Yet, analysis of the rich knowledge of disease finding sites has not been comprehensively investigated. In this study, we built a large-scale disease organ network (DON) based on 76,561 disease-organ associations (for 37,615 diseases and 3492 organs) extracted from the United Medical Language System (UMLS) Metathesaurus. We investigated how phenotypic organ similarity among diseases in DON reflects disease gene sharing. We constructed a disease genetic network (DGN) using curated disease-gene associations and demonstrated that disease pairs with higher organ similarities not only are more likely to share genes, but also tend to share more genes. Based on community detection algorithm, we showed that phenotypic disease clusters on DON significantly correlated with genetic disease clusters on DGN. We compared DON with a state-of-art disease phenotype network, disease manifestation network (DMN), that we have recently constructed, and demonstrated that DON contains complementary knowledge for disease genetics understanding.
Assuntos
Biologia Computacional/métodos , Doença , Algoritmos , Bases de Dados Genéticas , Doença/classificação , Doença/genética , Humanos , Fenótipo , Unified Medical Language SystemRESUMO
OBJECTIVES: A significant number of researches have evidenced that occupational lead (Pb) exposure increased risks of cardiovascular disease. However, evidences about the potential effects of Pb on the cardiac conduction system are sparse and inconclusive. Besides, ryanodine receptors (RyRs) induced dysfunction of cardiac excitation contraction coupling which is considered to be one of the mechanisms in cardiovascular diseases. Therefore, we examined the association between occupational Pb exposure and ECG conduction abnormalities, as well as RyRs in Pb-induced ECG abnormalities. METHODS: We investigated 529 Pb smelter workers, and measured blood lead (BPb), zinc protoporphyrin (ZPP), ECG outcomes and RyR expression levels. Based on BPb levels, the workers were divided into three groups: the BPb not elevated group, the BPb elevated group and the Pb poisoning group. Descriptive and multivariable analyses were performed. RESULTS: Compared with the BPb not elevated group, the Pb poisoning group had a higher incidence of high QRS voltage, and a lower level of RyR1 gene expression (p<0.05). Further unconditional multivariable logistic regression analyses showed that high QRS voltage was positively related to BPb (OR=1.045, 95% CI 1.014 to 1.078) and inversely associated with RyR1 expression (OR=0.042, 95% CI 0.002 to 0.980) after adjusting for potential confounders. In addition, multiple linear regression analyses showed that the QTc interval was positively associated with ZPP (ß=0.299, 95% CI 0.130 to 0.468) after adjusting for potential confounders. CONCLUSIONS: Our study provided evidences that occupational exposure to Pb may be associated with worse ECG outcomes (high QRS voltage), which might be related to decreased levels of RyR1.
Assuntos
Intoxicação por Chumbo/genética , Intoxicação por Chumbo/fisiopatologia , Chumbo/sangue , Exposição Ocupacional , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Adulto , Estudos Transversais , Eletrocardiografia , Sistema de Condução Cardíaco/fisiopatologia , Humanos , Intoxicação por Chumbo/sangue , Modelos Lineares , Modelos Logísticos , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/diagnóstico , Masculino , Análise Multivariada , Protoporfirinas/sangue , Adulto JovemRESUMO
Manganese-based (chemically formulated of KMnF3) nanocrystal was evaluated as a liver-specific contrast agent for MR imaging and its imaging performance was also compared with those of two commercial hepatobiliary contrast media (Gd-EOB-DTPA and MnDPDP). KMnF3 nanocrystal was post-treated using a plasma technique to cause severe defects, leading to appropriate water dispersibility and high relaxivity. Severely defective KMnF3 nanocrystal (SD-KMnF3) has characteristic high tolerance, as evidenced by cytotoxicity on the macrophage cell, and acute and subchronic toxicity on the healthy mouse. SD-KMnF3 showed better hepatic MR imaging as the T 1 relaxation time of the liver decreased to only 17% of the control group, compared to 22% of the control group for Gd-EOB-DTPA (P < 0.01) and 42% of the control group for MnDPDP (P < 0.001). As applied to MR imaging of the allograft orthotopic model of liver cancer, statistical studies demonstrated that SD-KMnF3 significantly improved the tumor's contrast-to-noise ratio, compared with Gd-EOB-DTPA (P < 0.01) and MnDPDP (P < 0.01) by spin-echo pulse sequence, and even better performance (P < 0.001) by gradient-echo sequence. Our findings indicate that SD-KMnF3 could serve as a hepatic contrast agent for imaging liver cancer such as hepatocarcinoma or metastatic lesions.
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Magnetic nanoparticles (NPs) are emerging as promising candidates for the next generation of image contrast agents and their performance is largely dependent on physicochemical properties. In this paper, a new type of 'top-down' fabrication technique was developed to synthesize ultrasmall magnetic NPs as a contrast enhancer. In a detailed, home-made oxygen plasma generator, fragments of larger KMnF3 NPs (22 nm) were broken down into smaller (<5 nm) particles with enhanced hydrophilicity. As massive activated oxygen species were produced during the process, the plasma was able to severely etch the NPs, and vacuum UV light irradiated them heavily as well, leaving them with weak crystallinity, splitting them into ultrafine particles. Also their surface transformed from hydrophobic to hydrophilic by oxidizing the passivated ligand, evidenced by the spectroscopy and microscopy results. The fragmented NPs are characteristic of unprecedented high longitudinal relaxivity (r1 = 35.52 mM-1.s-1) and appropriate biocompatibility. In a healthy mouse, the ultrafine NPs did not exert observable toxicity, this was evaluated by histology of the main organs and hemogram analysis, including kidney and liver function analysis. More interestingly, the ultrasmall NPs had a very long circulation time, as its blood half-life was around 20 h. When applied as a contrast enhancer for MRI of the patient-derived tumor xenograft model, the accumulation of KMnF3 NPs within the tumor had an average of 12.13% ID per gram, which greatly shortened the relaxation time of the tumor. Therefore the control-to-noise ratio was significantly enhanced, relative to the same dosage of Gadopentetetic acid (Magvenist) (P < 0.001). Our primary results demonstrate that fragmentation of the NPs via our home-made oxygen plasma technique might be an effective route for fabricating ultrasmall NPs, and benefit their contrast effect when applied as MRI enhancers for clinical diagnosis of tumors.
Assuntos
Meios de Contraste/química , Imageamento por Ressonância Magnética/métodos , Nanopartículas/química , Oxigênio/química , Gases em Plasma/química , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Sobrevivência Celular/efeitos dos fármacos , Meia-Vida , Humanos , Cinética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/toxicidade , Nanopartículas/ultraestrutura , Células RAW 264.7RESUMO
Mediator of DNA damage checkpoint protein 1 (MDC1) is essential for DNA damage response. However, the role of MDC1 in modulating gene transcription independently of DNA damage and the underlying mechanisms have not been fully defined. Androgen receptor (AR) is the central signaling pathway in prostate cancer (PCa) and its target genes are involved in both promotion and suppression of PCa. Here, we functionally identified MDC1 as a co-activator of AR. We demonstrate that MDC1 facilitates the association between AR and histone acetyltransferase GCN5, thereby increasing histone H3 acetylation level on cis-regulatory elements of AR target genes. MDC1 knockdown promotes PCa cells growth and migration. Moreover, depletion of MDC1 results in decreased expression of a subset of the endogenous androgen-induced target genes, including cell cycle negative regulator p21 and PCa metastasis inhibitor Vinculin, in AR positive PCa cell lines. Finally, the expression of MDC1 and p21 correlates negatively with aggressive phenotype of clinical PCa. These studies suggest that MDC1 as an epigenetic modifier regulates AR transcriptional activity and MDC1 may function as a tumor suppressor of PCa, and provide new insight into co-factor-AR-signaling pathway mechanism and a better understanding of the function of MDC1 on PCa.
Assuntos
Regulação Neoplásica da Expressão Gênica , Proteínas Nucleares/metabolismo , Coativadores de Receptor Nuclear/metabolismo , Neoplasias da Próstata/genética , Receptores Androgênicos/metabolismo , Transativadores/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Animais , Animais Geneticamente Modificados , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Movimento Celular , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/fisiologia , Drosophila/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/fisiologia , Células HEK293 , Humanos , Masculino , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Elementos de Resposta , Ativação Transcricional , Fatores de Transcrição de p300-CBP/metabolismoRESUMO
Atrazine (ATR, 2-chloro-4-ethylamino-6-isopropylamino-s-triazine) is used worldwide as a herbicide, and its presence in the environment has resulted in documented human exposure. A lack of strong evidence for genetic heritability of idiopathic Parkinson's disease has focused attention on environmental toxicants in the disease etiology, particularly agrichemicals. Parkinson's disease is associated with advanced age and is characterized by the degeneration of dopaminergic neurons, but it is unclear whether specific neuronal damage could result from insults during development. The juvenile period is particularly vulnerable to environmental agent, therefore, we evaluated the effects of a 28-day exposure to ATR on the dopaminergic system in pubertal rats. Sprague-Dawley rats were treated orally with ATR at 50, 100, and 200 mg/kg bw, daily from postnatal days 27 to 54. In this study, we examined the hypothesis that pubertal exposure to ATR would disrupt the development of the nigrostriatal dopamine (DA) system. The content of DA and levodopa (L-DA) were examined in striatum samples by HPLC-FL, and the mRNA and protein expression of tyrosine hydroxylase, orphan nuclear hormone receptor (Nurr1), Nurr1 interacting protein (NuIP), and cyclin-dependent kinase inhibitors of the Cip̲Kip family (p57kip2) were examined in samples of the nigrostriatum by use of fluorescence Real-Time quantitative polymerase chain reaction (PCR). Exposure of juvenile rats to the high dose of ATR led to reduced levels of DA and L-DA, genes expression of NuIP, Nurr1, and p57kip2 in animals.
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Atrazina/toxicidade , Dopamina/metabolismo , Exposição Ambiental , Maturidade Sexual/efeitos dos fármacos , Animais , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Levodopa/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Aprendizagem Espacial/efeitos dos fármacos , NataçãoRESUMO
Cetuximab (Erbitux, C225) is a chimeric monoclonal antibody that binds to the extracellular domain of epidermal growth factor receptor (EGFR), inhibiting tumor growth, invasion, angiogenesis and metastasis. However, the mechanisms underlying the effect of Cetuximab in human oral squamous cell carcinoma (OSCC) remain unclear. Here, we report that Cetuximab modulates EGFR protein stability through the ubiquitin/proteasome pathway, resulting in the inhibition of human OSCC growth. Cetuximab significantly inhibited the migration and invasion of human OSCC cells by blocking epithelial/mesenchymal transition (EMT) and the AKT and ERK pathways. Furthermore, Cetuximab-inhibited cell growth by modulating the expression of integrin ß5. Taken together, these results provide novel insights into the mechanism of Cetuximab action and suggest potential therapeutic strategies for OSCC.
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Anticorpos Monoclonais Humanizados/farmacologia , Carcinoma de Células Escamosas/patologia , Receptores ErbB/antagonistas & inibidores , Neoplasias da Língua/patologia , Actinas/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/toxicidade , Carcinoma de Células Escamosas/secundário , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cetuximab , Inibidores de Cisteína Proteinase/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Cadeias beta de Integrinas/efeitos dos fármacos , Leupeptinas/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Invasividade Neoplásica , Neovascularização Patológica/patologia , Proteína Oncogênica v-akt/antagonistas & inibidores , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Ubiquitina/efeitos dos fármacosRESUMO
Atrazine (2-chloro-4-ethylamino-6-isopropylamino-s-triazine) is used worldwide as a herbicide, and its presence in the environment has resulted in documented human exposure. Atrazine has been shown to cause dopaminergic neurotoxicity. The juvenile period is particularly vulnerable to environmental agents, but only few studies have investigated the long-term effects of atrazine following exposure during the pubertal development. Therefore, we evaluated the effects of a 41-day exposure to atrazine on the dopaminergic system in rats. Sprague-Dawley rats were treated orally with atrazine at 25 or 50mg/kg bw, daily from postnatal day 22 to 62. The content of dopamine (DA) was examined in striatum samples by HPLC-FL, and the mRNA and protein expression of tyrosine hydroxylase (TH), orphan nuclear hormone (Nurr1), dopamine transporter (DAT) and vesicular monoaminetransporter 2 (VMAT2) were examined in samples of the ventral mid-brain by use of fluorescence PCR and Western-blot analysis when the rats reached the age of one year. Exposure of juvenile rats to the high dose of atrazine led to reduced levels of DA and mRNA of Nurr1 in one-year-old animals. This study shows that the long-term adverse effects of atrazine on the dopaminergic system have a special relevance after juvenile exposure.
Assuntos
Envelhecimento/efeitos dos fármacos , Atrazina/toxicidade , Dopamina/metabolismo , Poluentes Ambientais/toxicidade , Herbicidas/toxicidade , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Administração Oral , Envelhecimento/metabolismo , Animais , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Relação Dose-Resposta a Droga , Feminino , Masculino , Mesencéfalo/efeitos dos fármacos , Mesencéfalo/metabolismo , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
High atrazine (2-chloro-4-ethytlamino-6-isopropylamine-1,3,5-triazine; ATR) contents in the environment threaten the health conditions of organisms. We examined the effects of ATR exposure on Sprague-Dawley rats during gestation and on the dopaminergic neurons of offspring during lactation. Pregnant dams were orally treated with 0 mg/kg/day to 50 mg/kg/day of ATR from gestational day 5 to postnatal day 22. Afterward, neither offspring nor dams received ATR. Dopamine (DA) content was examined in striatum samples by HPLC-FL; the mRNA expressions of tyrosine hydroxylase (TH), orphan nuclear hormone (Nurr1), dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT2) in the ventral midbrain samples were examined by fluorescence PCR when the offspring reached one year of age. After the pregnant rats were exposed to ATR, the DA concentrations and mRNA levels of Nurr1 were decreased in their offspring. Decreased Nurr1 levels were also accompanied by changes in the mRNA levels of VMAT2, which controls the transport and reuptake of DA.
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Atrazina/toxicidade , Neurônios Dopaminérgicos/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Herbicidas/toxicidade , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Proteínas Vesiculares de Transporte de Monoamina/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Corpo Estriado/metabolismo , Dopamina/análise , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Feminino , Lactação , Masculino , Exposição Materna/efeitos adversos , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Gravidez , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo , Proteínas Vesiculares de Transporte de Monoamina/genéticaRESUMO
Breast cancer (BC) has been the focus of numerous studies aimed at identifying novel biological markers for its early detection. PIWI-interacting RNAs (piRNAs), a subset of small non-coding RNAs, have emerged as potential markers due to their aberrant expression in various cancers. PiRNAs have recently gained attention due to their aberrant expression in various cancers, including BC. PiRNAs, exhibit diverse biological activities, such as epigenetic regulation of gene and protein expression and their association with cell proliferation and metastasis has been well-established. As the field of non-coding RNAs rapidly evolves, there is great anticipation that therapies targeting piRNAs will advance swiftly. This review will delve into the various biological functions of piRNAs, such as gene suppression, transposon silencing, and epigenetic regulation of genes. The review will also highlight the role of piRNAs as either progenitors or suppressors in cancers, with a particular focus on BC. Lastly, it will touch upon the potential of piRNAs as biomarkers and therapeutic targets for BC.
Assuntos
Biomarcadores Tumorais , Neoplasias da Mama , RNA Interferente Pequeno , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Neoplasias da Mama/metabolismo , Feminino , RNA Interferente Pequeno/uso terapêutico , RNA Interferente Pequeno/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Epigênese Genética/genética , AnimaisRESUMO
BACKGROUND: This study aimed to determine the risk factors of hallux valgus angle among preprofessional adolescent dancesport athletes. METHODS: A total of 275 athletes, (73 males and 202 females) aged between the ages of 11 and 18 years, participated in this study. A cross-sectional questionnaire was used to survey their demographic characteristics (sex and age), training information (starting age, weekly training time, and athletic career [number of years of training at this specific dancesport school]), and measured their height and weight. The hallux valgus angle was measured based on foot photographs. The chi-square test was used to compare the difference with prevalence of hallux valgus between male and female athletes. A normal distribution test was performed, and based on the test results, unpaired t-test and multiple logistic regression were conducted to identify training factors for the hallux valgus in this cohort. RESULTS: Chi-square test showed higher prevalence of hallux valgus in female elite adolescent dancesport athletes than males. The t-test results did not show any significant differences between the hallux valgus group and non-hallux valgus groups with start age, athletic career, and weekly training time. Multiple logistic regression analysis with hallux valgus as the dependent variable revealed that the female sex was a strong predictor of a higher prevalence of hallux valgus (odds ratio [OR]: 3.954, 95% confidence interval 95% CI: 2.193-7.131, and p < 0.001). Weekly training time was also entered into the multiple logistic regression model (OR: 1.033, 95% CI: 1.001-1.067, and p = 0.041). CONCLUSIONS: Our findings revealed that the prevalence of hallux valgus in adolescent dancesport athletes was higher in females than in males. Longer weekly training time was also a risk factor for hallux valgus. Training factors should be considered in preventive programs for elite adolescent dancesport athletes, and special attention should be paid to female athletes.
Assuntos
Hallux Valgus , Humanos , Feminino , Masculino , Adolescente , Hallux Valgus/epidemiologia , Prevalência , Estudos Transversais , Criança , Fatores de Risco , Atletas/estatística & dados numéricos , Fatores Sexuais , Inquéritos e QuestionáriosRESUMO
Protein SUMOylation, a post-translational modification, intricately regulates diverse biological processes including gene expression, cell cycle progression, signaling pathway transduction, DNA damage response, and RNA metabolism. This modification contributes to the acquisition of tumorigenicity and the maintenance of cancer hallmarks. In malignancies, protein SUMOylation is triggered by various cellular stresses, promoting tumor initiation and progression. This augmentation is orchestrated through its specific regulatory mechanisms and characteristic biological functions. This review focuses on elucidating the fundamental regulatory mechanisms and pathological functions of the SUMO pathway in tumor pathogenesis and malignant evolution, with particular emphasis on the tumorigenic potential of SUMOylation. Furthermore, we underscore the potential therapeutic benefits of targeting the SUMO pathway, paving the way for innovative anti-tumor strategies by perturbing this dynamic and reversible modifying process.