RESUMO
OBJECTIVE: The effects of air pollution on metabolism have become a popular research topic, and a large number of studies had confirmed that air pollution exposure could induce insulin resistance (IR) to varying degrees, but the results were inconsistent, especially for the long-term exposures. The aim of the current study was to further investigate the potential effects of air pollution on IR. METHODS: A systematic review and meta-analysis of four electronic databases, including PubMed, Embase, Web of Science and Cochrane were conducted, searching for relevant studies published before June 10, 2023, in order to explore the potential relationships between long-term exposure to air pollution and IR. A total of 10 studies were included for data analysis, including seven cohort studies and three cross-sectional studies. Four major components of air pollution, including PM2.5 (particulate matter with an aerodynamic diameter of 2.5 µm or less), PM10 (particulate matter with an aerodynamic diameter of 10 µm or less), NO2, and SO2 were selected, and each analyzed for the potential impacts on insulin resistance, in the form of adjusted percentage changes in the homeostasis assessment model of insulin resistance (HOMA-IR). RESULTS: This systematic review and meta-analysis showed that for every 1 µg/m³ increase in the concentration of selected air pollutants, PM2.5 induced a 0.40% change in HOMA-IR (95%CI: -0.03, 0.84; I2 =67.4%, p = 0.009), while PM10 induced a 1.61% change (95%CI: 0.243, 2.968; I2 =49.1%, p = 0.001). Meanwhile, the change in HOMA-IR due to increased NO2 or SO2 exposure concentration was only 0.09% (95%CI: -0.01, 0.19; I2 =83.2%, p = 0.002) or 0.01% (95%CI: -0.04, 0.06; I2 =0.0%, p = 0.638), respectively. CONCLUSIONS: Long-term exposures to PM2.5, PM10, NO2 or SO2 are indeed associated with the odds of IR. Among the analyzed pollutants, inhalable particulate matters appear to exert greater impacts on IR.
Assuntos
Poluentes Atmosféricos , Poluição do Ar , Resistência à Insulina , Humanos , Dióxido de Nitrogênio/análise , Estudos Transversais , Exposição Ambiental/efeitos adversos , Exposição Ambiental/análise , Poluição do Ar/efeitos adversos , Poluição do Ar/análise , Poluentes Atmosféricos/toxicidade , Poluentes Atmosféricos/análise , Material Particulado/toxicidade , Material Particulado/análiseRESUMO
6:2 fluorotelomer carboxylic acid (6:2 FTCA) is a perfluorooctanoic acid (PFOA) substitute, which is supposedly less accumulative and toxic than PFOA. However, 6:2 FTCA is structurally similar to PFOA, and there had already been reports about its toxicities comparable to PFOA. The aim of the current study is to assess potential effects of developmental exposure to 6:2 FTCA on the development of kidney in chicken embryo and to investigate underlying mechanism. Fertile chicken eggs were exposed to 1.25â¯mg/kg, 2.5â¯mg/kg or 5â¯mg/kg doses of 6:2 FTCA, or 2â¯mg/kg PFOA, then incubated to hatch. Serum and kidney of hatchling chickens were collected. Blood urea nitrogen (BUN) and creatinine (Cre) levels were measured with commercially available kits. Morphology of kidney was assessed with histopathology. To further reveal molecular mechanism of observed endpoints, IGF signaling molecules were assessed in the kidney samples with qRT-PCR, results indicated that IGFBP3 is a potentially crucial molecule. Lentiviruses overexpressing or silencing IGFBP3 were designed and applied to enhance/suppress the expression of IGFBP3 in developing chicken embryo for further verification of its role in the observed effects. Disrupted nephron formation, in the manifestation of decreased glomeruli number/area and increased serum BUN/Cre levels, was observed in the animals developmentally exposed to 6:2 FTCA. Correspondingly, IGF signaling molecules (IGF1, IGF1R and IGFBP3) were affected by 6:2 FTCA exposure. Meanwhile, overexpression of IGFBP3 effectively alleviated such changes, while silencing of IGFBP3 mimicked observed effects. In conclusion, developmental exposure to 6:2 FTCA is associated with disrupted chicken embryo renal development, in which IGFBP3 seems to be a remarkable contributor, suggesting potential health risks for human and other species. Further risk assessments and mechanistic works are necessary.
Assuntos
Rim , Transdução de Sinais , Animais , Embrião de Galinha , Rim/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fluorocarbonos/toxicidade , Caprilatos/toxicidade , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina , Galinhas , Nitrogênio da Ureia Sanguínea , Creatinina/sangueRESUMO
Hexafluoropropylene oxide tetramer acid (HFPO-TeA) is an emerging environmental contaminant, with environmental presence but limited toxicological information. To investigate its potential developmental toxicities, various doses of HFPO-TeA exposure were achieved in chicken embryos via air cell injection, and the exposed embryos were incubated until hatch. Within 24 h of hatch, the hatchling chickens were assessed with electrocardiography and histopathology for toxicological evaluation. For mechanistic investigation, in ovo silencing of PPARα was achieved via lentivirus microinjection, then the morphological/functional endpoints along with protein expression levels of PPARα-regulated genes were assessed. HFPO-TeA exposure in chicken embryo resulted in developmental cardiotoxicity and hepatotoxicity. Specifically, decreased right ventricular wall thickness, increased heart rate and hepatic steatosis were observed, whereas silencing of PPARα resulted in alleviation of observed toxicities. Western blotting for EHHADH and FABPs suggested that developmental exposure to HFPO-TeA effectively increased the expression levels of both targets in hatchling chicken heart and liver tissue samples, while PPARα silencing prevented such changes, suggesting that PPARα and its downstream genes are playing critical roles in HFPO-TeA induced developmental toxicities.
Assuntos
Galinhas , Fluorocarbonos , Embrião de Galinha , Animais , Galinhas/metabolismo , PPAR alfa/genética , PPAR alfa/metabolismo , Fluorocarbonos/toxicidade , Coração , Fígado/metabolismoRESUMO
OBJECTIVES: Rheumatoid arthritis (RA) is a common autoimmune disease. However, the positive diagnosis value of the current biomarkers is unsatisfactory. Here, we aimed to identify RA-associated susceptibility genes and explore their potential as novel biomarkers for the diagnosis of RA. METHODS: Peripheral blood mononuclear cells (PBMCs) were collected from healthy controls and RA patients. RNA-seq and bioinformatics analyses were performed to identify the hub genes associated with RA. Then, the expression of hub genes was assessed in mRNA expression profiles from GEO datasets. Real time-quantitative PCR (RT-qPCR) was performed to further confirm the expression of the hub genes using the PBMCs that were collected from RA patients (n=47) and healthy controls (n=40). Finally, we evaluated the diagnostic potential of the candidate mRNAs. RESULTS: RNA-seq analyses revealed 178 dysregulated genes measured by changes in mRNAs between the healthy controls and the RA patients. We identified 3 candidate mRNAs, including ASPM, DTL and RRM2, all of which were highly expressed in RA. RRM2 showed a significant higher expression in remissive RA compared with active RA. Significant correlations were observed between DTL and IL-8, TNF-α which were tested in serum by ELISA, between RRM2 and CDAI, DAS-28, tender and swollen joints, respectively. The expression level of RRM2 was significantly higher in RA patients with the Anti-CCP- than with the Anti-CCP+. The AUC (RA vs. OA) value of RRM2 was 0.941 (p<0.0001; sensitivity=0.867; specificity=0.904). CONCLUSIONS: RRM2 showed high diagnosis efficiency for RA patients. Therefore, the findings provided a novel candidate biomarker for the diagnosis of RA.
Assuntos
Artrite Reumatoide , Leucócitos Mononucleares , Humanos , Leucócitos Mononucleares/metabolismo , Anticorpos Antiproteína Citrulinada/metabolismo , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/genética , Biomarcadores , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
OBJECTIVES: To identify disease activity scores and biomarkers that reflect magnetic resonance imaging (MRI)-determined sacroiliac joint (SIJ) inflammation in ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA). METHODS: Patients who had AS and nr-axSpA were enrolled. All the patients underwent SIJ MRI. SpondyloArthritis Research Consortium of Canada (SPARCC) method was used to score bone marrow edema in the inflammatory lesions on MRI. Radiographic assessment of the spine was performed using modified Stoke Ankylosing Spondylitis Spine Score. Clinical variables, inflammatory markers, serum alkaline phosphatase, osteocalcin (OC), C-terminal telopeptide of type I collagen (CTX-I), and procollagen I N-terminal peptide (PINP) were measured. Correlation analysis between MRI-determined SIJ inflammation scores and disease activity scores and laboratory variables was performed. RESULTS: Thirty-five patients had AS and 36had nr-axSpA. Significant differences were noted between the AS group and the nr-axSpA group in terms of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Ankylosing Spondylitis Disease Activity Score (ASDAS)-ESR, ASDAS-CRP, PINP, and SPARCC (p < .001, p = .004, p < .001, p < .001, p = .030, p < .001, respectively). MRI-determined SIJ inflammatory scores correlated with Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), OC, CTX-I, and PINP in AS (p = .036, p = .023, p = .002, p = .041, p = .004, respectively) and correlated with ESR, CRP, ASDAS-ESR, ASDAS-CRP, BASDAI, and BASFI in nr-axSpA (p = .003, p = .002, p < .001, p < .001, p = .010, p = .007, respectively). Multivariate analysis showed that PINP exhibited a positive correlation independent of the MRI inflammatory score and that age exhibited a negative correlation independent of the MRI inflammatory score. CONCLUSIONS: In AS, PINP and age independently correlated with active inflammation on SIJ MRI. PINP may be useful as a marker of objective inflammation in AS.
Assuntos
Espondiloartrite Axial , Espondiloartrite Axial não Radiográfica , Sacroileíte , Espondilartrite , Espondilite Anquilosante , Biomarcadores , Proteína C-Reativa/análise , Estudos Transversais , Humanos , Inflamação/diagnóstico por imagem , Inflamação/patologia , Imageamento por Ressonância Magnética/métodos , Peptídeos , Pró-Colágeno , Articulação Sacroilíaca/diagnóstico por imagem , Articulação Sacroilíaca/patologia , Sacroileíte/patologia , Índice de Gravidade de Doença , Espondilartrite/diagnóstico por imagem , Espondilite Anquilosante/patologiaRESUMO
Myofibroblast apoptosis is essential for normal resolution of wound repair, including cardiac infarction repair. Impaired cardiac myofibroblast (CMF) apoptosis is associated with excessive extracellular matrix (ECM) deposition, which could be responsible for pathological cardiac fibrosis. Conventionally, angiotensin II (Ang II), a soluble peptide, is implicated in fibrogenesis because it induces cardiac fibroblast (CFb) proliferation, differentiation, and collagen synthesis. However, the role of Ang II in regulation of CMF survival and apoptosis has not been fully clarified. In this report, we cultured neonatal rat CFbs, which transform into CMFs after passage 3 (6-8 days), and investigated the effects of Ang II on CMFs challenged by TNF-α combined with cycloheximide and the underlying mechanisms. Here, we show that Ang II rapidly activates MAPKs but not AKT in CMFs and confers apoptosis resistance, as evidenced by the inhibition of caspase-3 cleavage, early apoptotic cells and late apoptotic cells. This inhibitory effect of Ang II was reversed by blockade of AT1 or inactivation of ERK1/2 or RSK1 but not AT2, indicating that activation of the prosurvival AT1/ERK1/2/RSK1 signaling pathway mediates apoptosis resistance. TGF-ß, a latent fibrotic factor, was found to have no relation to Ang II-induced apoptosis resistance in our study. Furthermore, Ang II-mediated apoptosis resistance, which was conferred by activation of the AT1/ERK1/2/RSK1 signaling pathway, was also confirmed in human adult ventricular cardiac myofibroblasts. Collectively, our findings suggest a novel profibrotic mechanism of Ang II in which it promotes myofibroblast resistance to apoptosis in addition to classical mechanisms, providing a potential novel therapeutic approach by targeting prosurvival signaling pathways. © 2018 IUBMB Life, 71(1):261-276, 2019.
Assuntos
Angiotensina II/farmacologia , Apoptose/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Miofibroblastos/efeitos dos fármacos , Receptor Tipo 1 de Angiotensina/genética , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Bloqueadores do Receptor Tipo 2 de Angiotensina II/farmacologia , Animais , Apoptose/genética , Butadienos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Cicloeximida/farmacologia , Flavonoides/farmacologia , Regulação da Expressão Gênica , Humanos , Imidazóis/farmacologia , Losartan/farmacologia , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Miocárdio/citologia , Miocárdio/metabolismo , Miofibroblastos/citologia , Miofibroblastos/metabolismo , Nitrilas/farmacologia , Cultura Primária de Células , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/metabolismo , Proteínas Quinases S6 Ribossômicas 90-kDa/antagonistas & inibidores , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
Alcohol consumption likely induces gastric carcinogenesis through deregulation of RNA polymerase (Pol) III genes and oxidative damage. Transcription factor IIB-related factor 1 (BRF1) overexpression alleviates RNA Pol III transcription inhibition through breast cancer susceptibility gene 1 (BRCA1). Myeloperoxidase (MPO) involvement in cancer is induced by alcohol-mediated oxidative damage. BRCA1/2 and MPO play key roles in DNA repair. BRCA1 and BRCA2 exert different roles in homologous recombination repair. By using human gastric cancer (GC) biopsies, we investigated the prognostic value of these proteins upon alcohol induction. In total, high expression of BRF1 (P = 0.010) and positive cell infiltration of MPO (P = 0.004) in tumor tissues as well as positive expression of BRCA1 (P < 0.001) in para-tumor tissues were more frequent in GC patients with hazardous or harmful alcohol consumption habits. BRF1 (P = 0.021), BRCA2 (P < 0.001), and MPO (P = 0.039) were independent prognostic factors for disease-free survival. BRCA1 (P = 0.005) and BRCA2 (P < 0.001) also were identified as independent prognostic factors for overall survival. Furthermore, BRCA2 was an independent unfavorable prognostic factor for disease-free survival and overall survival (P < 0.001) in GC patients who underwent platinum-based adjuvant chemotherapy. BRF1, BRCA1/2, and MPO are DNA repair-related biomarkers, induced by alcohol with prognostic value in GC patients.
Assuntos
Adenocarcinoma/diagnóstico , Alcoolismo/complicações , Biomarcadores Tumorais/metabolismo , Reparo do DNA , Neoplasias Gástricas/diagnóstico , Adenocarcinoma/etiologia , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Adulto , Proteína BRCA2/metabolismo , Biópsia , Quimioterapia Adjuvante , DNA de Neoplasias/genética , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Peroxidase/metabolismo , Prognóstico , Neoplasias Gástricas/etiologia , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia , Fatores Associados à Proteína de Ligação a TATA/metabolismo , Resultado do Tratamento , Ubiquitina-Proteína Ligases/metabolismoRESUMO
BACKGROUND: Recently, the roles of interleukin-6 (IL-6), IL-8 and IL-10 gene polymorphisms in gastric cancer have been extensively studied, with conflicting results. Therefore, we conducted the present study to better assess the potential correlations between these interleukin gene polymorphisms and gastric cancer. METHODS: Eligible articles were searched in PubMed, Medline, Embase, Web of Science and CNKI. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to detect any potential associations between interleukin gene polymorphisms and the risk of gastric cancer. RESULTS: A total of 73 case-control studies were finally included. Significant associations with the risk of gastric cancer were only detected for the IL-8 rs4073 polymorphism in overall analyses. Further subgroup analyses according to ethnicity of participants revealed that the IL-6 rs1800796, IL-8 rs4073, IL-10 rs1800871, IL-10 rs1800872 and IL-10 rs1800896 polymorphisms were all significantly associated with the risk of gastric cancer in Asians. No positive results were found for any investigated interleukin gene polymorphisms in Caucasians. CONCLUSIONS: Our findings suggest that IL-6 rs1800796, IL-8 rs4073, IL-10 rs1800871, IL-10 rs1800872 and IL-10 rs1800896 polymorphisms may serve as genetic biomarkers of gastric cancer in Asians.
Assuntos
Predisposição Genética para Doença/genética , Interleucina-10/genética , Interleucina-6/genética , Interleucina-8/genética , Polimorfismo Genético/fisiologia , Neoplasias Gástricas/genética , Povo Asiático/genética , Estudos de Casos e Controles , Humanos , Razão de Chances , Fatores de Risco , População Branca/genéticaRESUMO
Microsomal epoxide hydrolase (mEH) is a bifunctional protein that plays a central role in the metabolism of numerous xenobiotics as well as mediating the sodium-dependent transport of bile acids into hepatocytes where they are involved in cholesterol excretion and metabolism, lipid digestion and regulating numerous signaling pathways. Previous studies have demonstrated the critical role of GATA-4 and a C/EBPα-NF/Y complex in the regulation of the mEH gene (EPHX1). In this study we show that HNF-4α and CAR/RXR also bind to the proximal promoter region and regulate EPHX1 expression. Bile acids, which inhibit the expression of HNF-4α also decrease the expression of EPHX1. Studies also established that the binding of HNF-4α was essential for the activation of EPHX1 activity by CAR suggesting the formation of a complex between these adjacent factors. The nature of this regulatory complex was further explored using a biotinylated oligonucleotide of this region in conjunction with BioMag beads and mass spectrometric analysis which demonstrated the presence of an additional inhibitory factor (PSF), confirmed by co-immunoprecipitation and ChIP analyses, which interacted with DNA-bound CAR/RXR/HNF-4α forming a 4-component regulatory complex.
Assuntos
Epóxido Hidrolases/genética , Regulação da Expressão Gênica , Fator 4 Nuclear de Hepatócito/metabolismo , Regiões Promotoras Genéticas/genética , Proteínas de Ligação a RNA/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores X de Retinoides/metabolismo , Sequência de Bases , Sítios de Ligação , Western Blotting , Células Cultivadas , Imunoprecipitação da Cromatina , Cromatografia de Afinidade , Receptor Constitutivo de Androstano , Ensaio de Desvio de Mobilidade Eletroforética , Epóxido Hidrolases/metabolismo , Células HeLa , Células Hep G2 , Fator 4 Nuclear de Hepatócito/genética , Humanos , Imunoprecipitação , Dados de Sequência Molecular , Fator de Processamento Associado a PTB , RNA Mensageiro/genética , Proteínas de Ligação a RNA/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores Citoplasmáticos e Nucleares/genética , Elementos de Resposta/genética , Receptores X de Retinoides/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por MatrizRESUMO
Glycyrrhetic acid (GA)-modified pullulan nanoparticles (GAP NPs) were synthesized as a novel carrier of curcumin (CUR) with a degree of substitution (DS) of GA moieties within the range of 1.2-6.2 groups per hundred glucose units. In the present study, we investigated the physicochemical characteristics, release behavior, in vitro cytotoxicity and cellular uptake of the particles. Self-assembled GAP NPs with spherical shapes could readily improve the water solubility and stability of CUR. The CUR release was sustained and pH-dependent. The cellular uptake of CUR-GAP NPs was confirmed by green fluorescence in the cells. An MTT study showed CUR-GAP NPs with higher cytotoxicity in HepG2 cells than free CUR, but GAP NPs had no significant cytotoxicity. GAP is thus an excellent carrier for the solubilization, stabilization, and controlled delivery of CUR.
Assuntos
Antineoplásicos/química , Curcumina/química , Glucanos/química , Ácido Glicirretínico/química , Nanocápsulas/química , Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Curcumina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Estabilidade de Medicamentos , Células Hep G2 , Humanos , Cinética , Tamanho da Partícula , Solubilidade , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
BACKGROUND: Hexafluoropropylene oxide trimer acid (HFPO-TA), a perfluorooctanoic acid (PFOA) substitute, exhibited strong affinity and capability to activate peroxisome proliferator activated receptor gamma (PPARγ), a lipid metabolism regulator, suggesting potential to induce metabolic toxicities. METHODS: Fertile chicken eggs were exposed to 0, 0.5, 1 or 2 mg/kg (egg weight) HFPO-TA and incubated until hatch. Serum from 0- and 3- month-old chickens were subjected to liquid chromatography ultra-high resolution mass spectrometry for HFPO-TA concentration, while liver, pancreas and adipose tissue samples were collected for histopathological assessments. In ovo PPARγ reporter and silencing system were established with lentivirus microinjection. qRT-PCR and immunohistochemistry were utilized to evaluate the expression levels of PPARγ downstream genes. RESULTS: In 3-month-old animals developmentally exposed to HFPO-TA, adipose tissue hyperplasia, hepatic steatosis, pancreas islet hypertrophy and elevated serum free fatty acid / insulin levels were observed. Results of reporter assay and qRT-PCR indicated HFPO-TA-mediated PPARγ transactivation in chicken embryo. Silencing of PPARγ alleviated HFPO-TA-induced changes, while PPARγ agonist rosiglitazone mimicked HFPO-TA-induced effects. qRT-PCR and immunohistochemistry revealed that FASN and GPD1 were upregulated following developmental exposure to HFPO-TA in 3-month-old animals. CONCLUSIONS: Developmental exposure to HFPO-TA induced persistent metabolic toxicities in chickens, in which PPARγ played a central role.
Assuntos
Fluorocarbonos , PPAR gama , Animais , PPAR gama/genética , PPAR gama/metabolismo , Fluorocarbonos/toxicidade , Embrião de Galinha , Fígado/efeitos dos fármacos , Fígado/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Galinhas , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismoRESUMO
The association of alcohol consumption and breast cancer is more pronounced in cases that are positive for estrogen receptor (ER+) than in cases that are negative (ER-). Its mechanism remains to be determined. Deregulation of RNA polymerase III (Pol III) transcription enhances cellular tRNAs and 5S rRNA production, increasing translational capacity to promote cell transformation and tumor formation. Here, we report that alcohol increases Pol III gene transcription in both normal and cancer breast cell lines. The induction in ER+ breast cancer cells (MCF-7) is significantly higher than in ER- normal breast cells (MCF-10A, MCF-10F and MCF-12A) and is correlated with ER expression. E2 causes <2-fold increase in Pol III gene transcription. The addition of ethanol to this system now produces a 10-15-fold increase. Ethanol increases ERα expression, resulting in an increase in Brf1 protein and mRNA levels. In addition, ethanol markedly stimulates phosphorylation of JNK1, but not JNK2. Inhibition of JNK1 decreases ERE-Luc reporter activity and represses expression of ERα, Brf1 and Pol III genes. Reduction of ERα by its small interfering RNA represses Brf1 and Pol III gene transcription. Ethanol with E2 produces larger and more numerous colonies. Repression of ERα or Brf1 inhibits alcohol-induced cell transformation. Together, these results support the idea that alcohol increases ERα expression through JNK1 to elevate Brf1 expression and Pol III gene transcription to bring about greater phenotypic changes. These studies demonstrate that ERα mediates Pol III gene transcription through Brf1, suggesting that ERα may play a critical role in alcohol-induced deregulation of Pol III genes in ER+ breast cancer development.
Assuntos
Neoplasias da Mama/enzimologia , Receptor alfa de Estrogênio/fisiologia , Etanol/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , RNA Polimerase III/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Regiões Promotoras Genéticas , Transcrição Gênica/efeitos dos fármacosRESUMO
The products of Pol III genes (RNA polymerase III-dependent genes), such as tRNAs and 5S rRNA, are elevated in both transformed and tumor cells suggesting that they play a crucial role in tumorigenesis. An increase in Brf1 (TFIIIB-related factor 1), a subunit of TFIIIB, augments Pol III gene transcription and is sufficient for cell transformation and tumor formation. We have demonstrated that enhancement of Brf1 and Pol III gene expression is associated with the occurrences of hepatocellular carcinoma (HCC) in mice. This suggests that Brf1 may be a key molecule during HCC development. Diethylnitrosamine (DEN), a chemical carcinogen, has been used to induce HCC in rodents. To determine the role of Brf1 and the epigenetic-regulating events in cell proliferation and transformation, hepatocytes were treated with DEN. The results indicate that DEN increases proliferation and transformation of AML-12 cells. DEN enhanced Brf1 expression and tRNA(Leu) and 5S rRNA transcription, as well as H3S10ph (phosphorylation of histone H3 serine 10). Interestingly, DEN-induced Pol III gene transcription and H3S10ph in tumor cells of liver are significantly higher than in non-tumor cells. Inhibition of H3S10ph by H3S10A attenuates the induction of Brf1 and Pol III genes. Further analysis indicates that H3S10ph occupies the promoters of Brf1 and Pol III genes to modulate their expression. Blocking H3S10ph represses cell proliferation and transformation. These results demonstrate that DEN induces H3S10ph, which mediate Brf1 expression, including but not limited Brf1-dependent genes, to upregulate Pol III gene transcription, resulting in an increase in cell proliferation and transformation.
Assuntos
Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos dos fármacos , Dietilnitrosamina/farmacologia , Regulação Neoplásica da Expressão Gênica , Histonas/metabolismo , RNA Polimerase III/genética , Serina/metabolismo , Alquilantes/farmacologia , Animais , Apoptose , Western Blotting , Fator 1 de Resposta a Butirato , Adesão Celular , Células Cultivadas , Hepatócitos/citologia , Hepatócitos/metabolismo , Histonas/genética , Camundongos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosforilação , Regiões Promotoras Genéticas/genética , RNA Polimerase III/metabolismo , RNA Mensageiro/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcrição GênicaRESUMO
Proinflammatory M1 activation of hepatic macrophages (HM) is critical in pathogenesis of hepatitis, but its mechanisms are still elusive. Our earlier work demonstrates the role of ferrous iron (Fe(2+)) as a pathogen-associated molecular pattern-independent agonist for activation of IκB kinase (IKK) and NF-κB in HM via activation and interaction of p21(ras), transforming growth factor ß-activated kinase-1 (TAK1), and phosphatidylinositol 3-kinase (PI3K) in caveosomes. However, iron-induced signaling upstream of these kinases is not known. Here we show that Fe(2+) induces generation of superoxide anion (O(2)()) in endosomes, reduces protein-tyrosine phosphatase (PTP) activity, and activates Src at 2â¼10 min of Fe(2+) addition to rat primary HM culture. Superoxide dismutase (SOD) blocks O(2)() generation, PTP inhibition, and Src activation. Fe(2+)-induced p21(ras) activity is abrogated with the Src inhibitor PP2 and SOD. Fe(2+) stimulates Lys(63)-linked polyubiquitination (polyUb) of TRAF6 in caveosomes, and a dominant negative K63R mutant of ubiquitin or SOD prevents iron-induced TRAF6 polyUb and TAK1 activation. These results demonstrate that Fe(2+)-generated O(2)() mediates p21(ras) and TAK1 activation via PTP inhibition and Lys(63)-polyUb of TRAF6 in caveosomes for proinflammatory M1 activation in HM.
Assuntos
Fígado/metabolismo , Lisina/química , Macrófagos/metabolismo , Proteína Oncogênica p21(ras)/metabolismo , Fator 6 Associado a Receptor de TNF/química , Quinases da Família src/metabolismo , Animais , Ânions/química , Ativação Enzimática , Ferro/química , Ferro/metabolismo , Masculino , Modelos Biológicos , Estresse Oxidativo , Poliubiquitina/química , Proteínas Tirosina Fosfatases/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais , Superóxidos/química , Ubiquitina/químicaRESUMO
Introduction: The existing findings about the association between polyunsaturated fatty acid (PUFA) status (especially long-chain n-3 PUFAs) and the risk of preclinical or clinical type 1 diabetes (T1D) in children are controversial. This review aimed to evaluate the definite association. Material and methods: Three databases were systematically viewed until July, 2019 to identify relevant articles, without language restriction. Any observational study or randomized controlled trial reporting the risk estimates of preclinical or clinical T1D for PUFA status in infants and children was enrolled. Regardless of the statistical heterogeneity assessed by the I2 statistic, we pooled the odds ratios (ORs), relative risks (RRs) or hazard ratios (HRs) with 95% confidence intervals (CI) through random-effects models. Results: Five observational studies were enrolled in the meta-analysis. The status of n-3 PUFAs was negatively and significantly associated with the risk of preclinical, but not clinical, T1D (pooled RR = 0.85; 95% CI: 0.73-0.99) with substantial heterogeneity (I2 = 72.2%). However, no such association was found between n-6 PUFA status and the risk of preclinical or clinical T1D. Conclusions: The meta-analysis suggests that n-3 PUFA might play a potential protective role in the cause of preclinical T1D, and n-3 PUFA intake may be beneficial, since the n-3 PUFA status was associated with a significant decrease in the risk of preclinical T1D in children. Nevertheless, more well-designed prospective studies are necessary to determine whether dietary or supplemental intake of specific n-3 PUFA alters the risk of preclinical T1D.
RESUMO
Background: Hypoglycaemia has been linked to an increased risk of cardiac arrhythmias by causing autonomic and metabolic alterations, which may be associated with detrimental outcomes in individuals with diabetes(IWD), such as cardiovascular diseases (CVDs) and mortality, especially in multimorbid or frail people. However, such relationships in this population have not been thoroughly investigated. For this reason, we conducted a systematic review and meta-analysis. Methods: Relevant papers published on PubMed, Embase, Cochrane, Web of Knowledge, Scopus, and CINHAL complete from inception to December 22, 2022 were routinely searched without regard for language. All of the selected articles included odds ratio, hazard ratio, or relative risk statistics, as well as data for estimating the connection of hypoglycaemia with cardiac arrhythmia, CVD-induced death, or total death in IWD. Regardless of the heterogeneity assessed by the I2 statistic, pooled relative risks (RRs) and 95% confidence intervals (CI) were obtained using random-effects models. Results: After deleting duplicates and closely evaluating all screened citations, we chose 60 studies with totally 5,960,224 participants for this analysis. Fourteen studies were included in the arrhythmia risk analysis, and 50 in the analysis of all-cause mortality. Hypoglycaemic patients had significantly higher risks of arrhythmia occurrence (RR 1.42, 95%CI 1.21-1.68), CVD-induced death (RR 1.59, 95% CI 1.24-2.04), and all-cause mortality (RR 1.68, 95% CI 1.49-1.90) compared to euglycaemic patients with significant heterogeneity. Conclusion: Hypoglycaemic individuals are more susceptible to develop cardiac arrhythmias and die, but evidence of potential causal linkages beyond statistical associations must await proof by additional specifically well planned research that controls for all potential remaining confounding factors.
Assuntos
Doenças Cardiovasculares , Diabetes Mellitus , Hipoglicemia , Humanos , Diabetes Mellitus/epidemiologia , Hipoglicemia/complicações , Arritmias Cardíacas/epidemiologia , Arritmias Cardíacas/etiologia , HipoglicemiantesRESUMO
BACKGROUND: This meta-analysis was conducted given the contradictory findings from studies on the influence of diabetes duration or age at onset on mortality in patients with insulin-dependent diabetes mellitus (IDDM). METHODS: Electronic databases (PubMed, Embase, Cochrane, Web of Knowledge, Scopus, and CINHAL) were comprehensively searched to identify relevant studies until October 31, 2022. All of the selected articles contained statistics on hazard ratios, relative risks (RRs), or odds ratios, or data for estimating the association between diabetes duration or age at onset and total mortality in IDDM patients. Regardless the heterogeneity assessed by the I2 statistic, pooled RRs and 95% confidence intervals (CI) for total mortality were acquired via random effect meta-analysis with inverse variance weighting. RESULTS: This meta-analysis finally included 19 studies involving 122, 842 individuals. Both age at onset and diabetes duration were positively associated with an increased mortality rate in IDDM patients. Specifically, the pooled RRs for age at onset and diabetes duration were 1.89 (95%CI 1.43-2.50) and 1.89 (95%CI 1.16-3.09) respectively. Subgroup analyses revealed that only prepubertal onset was associated with a greater survival advantage than pubertal or postpubertal onset. CONCLUSIONS: The findings of this meta-analysis and systematic review suggest that a later age at onset or longer diabetes duration is associated with increased risk of total mortality in IDDM patients. However, this conclusion shall be interpreted with caution due to the possibility of residual confounding and be confirmed in the future by well-designed studies.
RESUMO
Perfluorooctanoic acid (PFOA) is a widespread persistent organic pollutant. Fertile chicken eggs were exposed to PFOA and incubated to hatch. At three time points post hatch (0-, 1- and 3-months old), chickens were subjected to electrocardiography and sacrificed. Serum was subjected to LC-MS/MS for PFOA concentration, and organs were subjected to histopathological assessments. Additionally, PPARα-silencing lentivirus was co-applied with PFOA exposure, and the corresponding phenotypes were evaluated. Western blotting was performed to assess expressions of FABPs and pSMAD2 in heart and liver samples. Considerable amount of PFOA were detected in hatchling chicken serum, but not in one-month-old or three-month-old chicken serum. PFOA exposure resulted in developmental cardiotoxicity and hepatotoxicity in hatchling chickens. Meanwhile, one-month-old chickens still exhibited elevated heart rate, but classical cardiac remodeling (thicker right ventricular wall) were observed in exposed animals. Three-month-old chickens exhibited similar results as one-month-old ones. PPARα silencing only had partial protective effects in hatchling chickens, but the protective effects seemed to increase as chickens aged. Western blotting results indicated that L-FABP was involved in PFOA-induced hepatotoxicity, while pSMAD2 was involved in PFOA-induced cardiotoxicity. In summary, developmental exposure to PFOA resulted in persistent cardiotoxicity, but not hepatotoxicity. PPARα participates in both cardiotoxicity and hepatotoxicity.
Assuntos
Galinhas , Fluorocarbonos , Animais , Galinhas/metabolismo , Cardiotoxicidade , PPAR alfa/genética , PPAR alfa/metabolismo , Cromatografia Líquida , Peroxissomos/metabolismo , Espectrometria de Massas em Tandem , Caprilatos/toxicidade , Caprilatos/metabolismo , Fluorocarbonos/toxicidade , Fluorocarbonos/metabolismo , Proliferação de Células , Fígado/metabolismoRESUMO
BACKGROUND: Infertility is caused by heterogeneous risks, but most of them are unexplained. The sperm DNA Fragmentation Index (DFI) was increasingly acknowledged as a parameter for the evaluation of male infertility. This study aimed to investigate the association between sperm DFI and laboratory and clinical outcomes in a population with unexplained infertility. METHODS: The clinical data of an infertile population was collected for the selection of reproductive patients with unexplained infertility. The authors classified the patients with normal sperm parameters in a control group (DFI < 25%) and an observation group (DFI ≥ 25%) and compared the difference in basal characteristics, laboratory, and clinical outcomes between the two groups. The authors conducted a correlation analysis to examine the relationship between DFI and the number of D3 good-quality embryos, as well as the clinical pregnancy rate and live birth rate. A total of 176 cases were enrolled in the retrospective study. RESULTS: The observation group (n = 88) showed advanced male age, lower sperm concentration, progressive motility, and morphology assessment than the control group. In addition, lower No. of D3 good-quality embryos, clinical pregnancy rate, and the live birth rate were shown in the observation group. A negative correlation between the DFI and No. of D3 good-quality embryos (rs = -0.347, p < 0.001) or live birth rate (rs = -0.185, p = 0.028) was shown. CONCLUSIONS: Sperm DFI was a good indicator for the prediction of D3 good-quality embryos in unexplained infertility couples, but it did not provide sufficient information regarding clinical pregnancy outcome but live pregnancy outcome.