RESUMO
Breast cancer has become the most commonly diagnosed cancer. Heterogeneous nuclear ribonucleoprotein C (HNRNPC), a reader of N6-methyladenosine (m6A), has been observed to be upregulated in various types of cancer. Nevertheless, the role of HNRNPC in breast cancer and whether it is regulated by m6A modification deserve further investigation. The expression of HNRNPC in breast cancer was examined by quantitative real-time polymerase chain reaction and western blot analysis. RNA immunoprecipitation was performed to validate the binding relationships between HNRNPC and WD repeat domain 77 (WDR77). The effects of HNRNPC and m6A regulators on WDR77 were investigated by actinomycin D assay. The experiments in vivo were conducted in xenograft models. In this research, we found that HNRNPC was highly expressed in breast cancer, and played a crucial role in cell growth, especially in the luminal subtype. HNRNPC could combine and stabilize WDR77 mRNA. WDR77 successively drove the G1/S phase transition in the cell cycle and promoted cell proliferation. Notably, this regulation axis was closely tied to the m6A modification status of WDR77 mRNA. Overall, a critical regulatory mechanism was identified, as well as promising targets for potential treatment strategies for luminal breast cancer.
Assuntos
Neoplasias da Mama , Ribonucleoproteínas Nucleares Heterogêneas Grupo C , Feminino , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Ciclo Celular/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo C/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo C/metabolismo , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , RNA Mensageiro/genética , Fatores de Transcrição/genética , AdenosinaRESUMO
Ulcerative colitis (UC) is an idiopathic, chronic inflammatory condition of the colon, characterized by repeated attacks, a lack of effective treatment options, and significant physical and mental health complications for patients. The endoplasmic reticulum (ER) is a vital intracellular organelle in maintaining cellular homeostasis. Endoplasmic reticulum stress (ERS) is induced when the body is exposed to adverse external stimuli. Numerous studies have shown that ERS-induced apoptosis plays a vital role in the pathogenesis of UC. Mogroside V (MV), an active ingredient of Monk fruit, has demonstrated excellent anti-inflammatory and antioxidant effects. In this study, we investigated the therapeutic effects of MV on dextran sulfate sodium (DSS)-induced UC and its potential mechanisms based on ERS. The results showed that MV exerted a protective effect against DSS-induced UC in mice as reflected by reduced DAI scores, increased colon length, reduced histological scores of the colon, and levels of pro-inflammatory cytokines, as well as decreased intestinal permeability. In addition, the expression of ERS pathway including BIP, PERK, eIF2α, ATF4, CHOP, as well as the apoptosis-related protein including Caspase-12, Bcl-2 and Bax, was found to be elevated in UC. However, MV treatment significantly inhibited the UC and reversed the expression of inflammation signaling pathway including ERS and ERS-induced apoptosis. Additionally, the addition of tunicamycin (Tm), an ERS activator, significantly weakened the therapeutic effect of MV on UC in mice. These findings suggest that MV may be a therapeutic agent for the treatment of DSS-induced UC by inhibiting the activation of the ERS-apoptosis pathway, and may provide a novel avenue for the treatment of UC.
Assuntos
Apoptose , Colite Ulcerativa , Sulfato de Dextrana , Estresse do Retículo Endoplasmático , Animais , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/patologia , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/metabolismo , Apoptose/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Colo/patologia , Colo/efeitos dos fármacos , Triterpenos/farmacologia , Triterpenos/uso terapêutico , Camundongos , Citocinas/metabolismo , Permeabilidade/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
Inflammatory bowel disease (IBD) is a chronic inflammatory disease involving the digestive tract, characterized by abdominal pain, diarrhea, rectal bleeding, and so on, which can make patients physically weakened and live difficultly. Although IBD has been recognized for many years, the pathogenesis of IBD has not yet been established and damage to intestinal barrier is thought to be closely associated with IBD. Intestinal barrier is an innate barrier that maintains the homeostasis of the intestinal environment and impedes pathogenic bacteria and toxins, and the endoplasmic reticulum (ER) has recently been found to be involved in maintaining the integrity of intestinal barrier. Endoplasmic reticulum stress (ERS) is a status of endoplasmic reticulum damaged when unfolded or misfolded proteins accumulate in excess of the degradation systematic clearance limit of the misfolded proteins. The regulation of ERS on protein folding synthesis and maintenance of cellular homeostasis is an important factor in influencing the integrity of the intestinal barrier. This paper mainly discusses the relationship between ERS and the intestinal barrier, aiming to understand the regulatory role of ERS on the intestinal barrier and the mechanism and to improve new solutions and notions for the treatment or prevention of IBD.
Assuntos
Estresse do Retículo Endoplasmático , Doenças Inflamatórias Intestinais , Humanos , Estresse do Retículo Endoplasmático/fisiologia , Intestinos , Doenças Inflamatórias Intestinais/metabolismo , Dobramento de Proteína , Retículo Endoplasmático/metabolismo , Mucosa Intestinal/metabolismo , Resposta a Proteínas não DobradasRESUMO
KEY MESSAGE: NtTAS14-like1 enhances osmotic tolerance through coordinately activating the expression of osmotic- and ABA-related genes. Osmotic stress is one of the most important limiting factors for tobacco (Nicotiana tabacum) growth and development. Dehydrin proteins are widely involved in plant adaptation to osmotic stress, but few of these proteins have been functionally characterized in tobacco. Here, to identify genes required for osmotic stress response in tobacco, an encoding dehydrin protein gene NtTAS14-like1 was isolated based on RNA sequence data. The expression of NtTAS14-like1 was obviously induced by mannitol and abscisic acid (ABA) treatments. Knock down of NtTAS14-like1 expression reduced osmotic tolerance, while overexpression of NtTAS14-like1 conferred tolerance to osmotic stress in transgenic tobacco plants, as determined by physiological analysis of the relative electrolyte leakage and malonaldehyde accumulation. Further expression analysis by quantitative real-time PCR indicated that NtTAS14-like1 participates in osmotic stress response possibly through coordinately activating osmotic- and ABA-related genes expression, such as late embryogenesis abundant (NtLEA5), early responsive to dehydration 10C (NtERD10C), calcium-dependent protein kinase 2 (NtCDPK2), ABA-responsive element-binding protein (NtAREB), ABA-responsive element-binding factor 1 (NtABF1), dehydration-responsive element-binding genes (NtDREB2A), xanthoxin dehydrogenase/reductase (NtABA2), ABA-aldehyde oxidase 3 (NtAAO3), 9-cis-epoxycarotenoid dioxygenase (NtNCED3). Together, this study will facilitate to improve our understandings of molecular and functional properties of plant TAS14 proteins and to improve genetic evidence on the involvement of the NtTAS14-like1 in osmotic stress response of tobacco.
Assuntos
Nicotiana , Osmorregulação , Nicotiana/genética , Desidratação , Estresse Fisiológico/genética , Ácido Abscísico/farmacologia , Ácido Abscísico/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas/genética , Plantas Geneticamente Modificadas/metabolismo , Pressão Osmótica/fisiologia , Regulação da Expressão Gênica de Plantas/genéticaRESUMO
The dysregulation of miR-125a-3p has been observed in multiple tumor types. Nevertheless, the function of miR-125a-3p in papillary thyroid carcinoma (PTC) is yet to be explored. Herein, we find that miR-125a-3p is markedly downregulated in PTC tissues, and its level is inversely related to the histological grade of PTC. Upregulation of miR-125a-3p suppresses the pulmonary metastatic ability as well as the tumor growth of PTC cell in vivo. Consistently, the colony formation ability and other metastasis-related traits of PTC cell are inhibited by miR-125a-3p transfection in vitro. In addition, we identify that matrix metalloprotease 11 (MMP11) is the direct target gene of miR-125a-3p, and that miR-125a-3p inhibits cell viability, migration, and invasiveness of PTC cell by reducing MMP11 expression in vitro. Together, these data testify that the miR-125a-3p/MMP11 axis plays vital roles in the growth and progression of human PTC cells.
Assuntos
Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Metaloproteinase 11 da Matriz/química , MicroRNAs/genética , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Animais , Apoptose , Biomarcadores Tumorais/genética , Movimento Celular , Proliferação de Células , Humanos , Metaloproteinase 11 da Matriz/genética , Metaloproteinase 11 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Prognóstico , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Metabolic reprogramming, immune evasion and tumor-promoting inflammation are three hallmarks of cancer that provide new perspectives for understanding the biology of cancer. We aimed to figure out the relationship of tumor glycolysis and immune/inflammation function in the context of breast cancer, which is significant for deeper understanding of the biology, treatment and prognosis of breast cancer. METHODS: Using mRNA transcriptome data, tumor-infiltrating lymphocytes (TILs) maps based on digitized H&E-stained images and clinical information of breast cancer from The Cancer Genome Atlas projects (TCGA), we explored the expression and prognostic implications of glycolysis-related genes, as well as the enrichment scores and dual role of different immune/inflammation cells in the tumor microenvironment. The relationship between glycolysis activity and immune/inflammation function was studied by using the differential genes expression analysis, gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, gene set enrichment analyses (GSEA) and correlation analysis. RESULTS: Most glycolysis-related genes had higher expression in breast cancer compared to normal tissue. Higher phosphoglycerate kinase 1 (PGK1) expression was associated with poor prognosis. High glycolysis group had upregulated immune/inflammation-related genes expression, upregulated immune/inflammation pathways especially IL-17 signaling pathway, higher enrichment of multiple immune/inflammation cells such as Th2 cells and macrophages. However, high glycolysis group was associated with lower infiltration of tumor-killing immune cells such as NKT cells and higher immune checkpoints expression such as PD-L1, CTLA4, FOXP3 and IDO1. CONCLUSIONS: In conclusion, the enhanced glycolysis activity of breast cancer was associated with pro-tumor immunity. The interaction between tumor glycolysis and immune/inflammation function may be mediated through IL-17 signaling pathway.
Assuntos
Neoplasias , Glicólise , Humanos , Inflamação , Linfócitos do Interstício Tumoral , Prognóstico , Microambiente TumoralRESUMO
Avian pathogenic Escherichia coli (APEC) can cause serious pathological changes and inflammation in chickens. Schizandrin has anti-inflammatory activity and can prevent damage to various tissues and organs. The purpose of this study was to investigate the protective effect of schizandrin on APEC-induced lung lesions in chickens and explore the potential mechanism of schizandrin protection. The schizandrin (50, 100, and 200 mg/kg) was intragastrically administered for 3 days. APEC was administered using intraperitoneal (i.p.) injection to induce lung lesions. Then, chickens were sacrificed by CO2 inhalation 24 h later and the lung tissues were collected for examining histopathological changes, wet/dry (W/D) ratio, myeloperoxidase (MPO) activity, malondialdehyde (MDA), levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, and IL-8 and activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. Our findings showed that schizandrin markedly inhibited pathological changes, pulmonary edema, MPO activity and MDA content. Moreover, schizandrin markedly reduced the levels of TNF-α, IL-1ß, IL-6 and IL-8 in lung tissue. Importantly, the mechanism responsible for these effects was attributed to the inhibitory effect of schizandrin on NF-κB and MAPK signaling activation. In conclusion, our findings reveal that schizandrin displays anti-oxidant and anti-inflammatory activity against APEC-induced lung lesions in chickens, paving the way for rational use of schizandrin as a protective agent against lung-related inflammatory disease.
RESUMO
BACKGROUND: Canine distemper virus (CDV) can cause a highly contagious disease to canid. However, how CDV affects peripheral blood lymphocyte (PBL) remains unclear. METHODS: In this study, CDV infected PBL was cultured to investigate the effect of CDV on the differentiation of lymphocytes and the mRNA expression of inflammatory cytokines in PBL. RESULTS: The results showed that CDV changed the phenotype of lymphocytes and increased the percentage of CD4+CD8+ T cells. To explore the effect of immune response of lymphocytes to CDV, the mRNA expression of pro- and anti-inflammatory cytokines was examined. Interleukin (IL-6, IL-12B), and tumor necrosis factor (TNF)-α mRNA expression was significantly increased at 12-48â¯h after CDV infection. IL-10 mRNA expression was dramatically enhanced at 12-36â¯h after CDV infection. However, IL-4 and transforming growth factor (TGF-ß) were not response to CDV infection. These results indicated that PBL differentiated intoCD4+CD8+ T cells and improved the inflammatory response to CDV infection. CONCLUSIONS: After CDV infection, PBL differentiated into CD4+CD8+ T cells and initiated inflammatory response.
Assuntos
Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular , Citocinas/metabolismo , Vírus da Cinomose Canina/patogenicidade , Cinomose/imunologia , Linfócitos/metabolismo , RNA Mensageiro/metabolismo , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Cinomose/virologia , Cães , Feminino , Interleucina-10/metabolismo , Linfócitos/imunologia , Fenótipo , Fator de Crescimento Transformador beta/metabolismoRESUMO
Canine distemper (CD) is a highly contagious disease caused by the canine distemper virus (CDV), and mortality can be as high as 100%. However, there is no specific treatment for CD. In this study, the antiviral activity of the caffeic acid against CDV was evaluated in vitro. The results showed that the IC50 of the caffeic acid against CDV at 1 and 2 h post infection (PI) is 23.3 and 32.3 µg/mL, respectively. Consistently, at 1 and 2 h PI, the caffeic acid exhibited a reduced (23.3-57.0% and 37.2-38.1%) viral inhibitory effect in vero cells. Furthermore, the caffeic acid plus Ribavirin (RBV) has greater antiviral activity against CDV than the caffeic acid or RBV individually. In addition, the caffeic acid reduced the total viral RNA synthesis by 59-86% at 24-72 h. Therefore, our data provided the experimental evidence that the caffeic acid effectively inhibited CDV infection in vero cells, which may potentially be used to treat clinical disease associated with CDV infection.
Assuntos
Antivirais/farmacologia , Ácidos Cafeicos/farmacologia , Vírus da Cinomose Canina/efeitos dos fármacos , Cinomose/tratamento farmacológico , Animais , Antivirais/administração & dosagem , Antivirais/química , Antivirais/uso terapêutico , Ácidos Cafeicos/administração & dosagem , Ácidos Cafeicos/química , Ácidos Cafeicos/uso terapêutico , Chlorocebus aethiops , Cinomose/virologia , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Concentração Inibidora 50 , RNA Viral/metabolismo , Ribavirina/farmacologia , Ribavirina/uso terapêutico , Fatores de Tempo , Células Vero/efeitos dos fármacos , Replicação Viral/efeitos dos fármacosRESUMO
Streptococcus pneumoniae (pneumococcus) is an important causative agent of acute invasive and non-invasive infections. Pneumolysin is one of a considerable number of virulence traits produced by pneumococcus that exhibits a variety of biological activities, thus making it a target of small molecule drug development. In this study, we aimed to evaluate the effect of morin, a natural compound that has no antimicrobial activity against S. pneumonia, is a potent neutralizer of pneumolysin-mediated cytotoxicity and genotoxicity by impairing oligomer formation, and possesses the capability of mitigating tissue damage caused by pneumococcus. These findings indicate that morin could be a potent candidate for a novel therapeutic or auxiliary substance to treat infections for which there are inadequate vaccines and that are resistant to traditional antibiotics.
Assuntos
Biopolímeros/metabolismo , Flavonoides/farmacologia , Streptococcus pneumoniae/metabolismo , Estreptolisinas/toxicidade , Células A549 , Animais , Proteínas de Bactérias/toxicidade , Feminino , Hemólise/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Testes de Sensibilidade Microbiana , Streptococcus pneumoniae/efeitos dos fármacosRESUMO
Avian pathogenic Escherichia coli (APEC) infections are responsible for great losses in the poultry industry. Quorum sensing (QS) acts as a global regulatory system that controls genes involved in bacterial pathogenesis, metabolism and protein biosynthesis. However, whether QS of APEC is related to cell damage has not been elucidated. In the present study, we explored the correlation between the damage of chicken type II pneumocytes induced by APEC and the autoinducer-2 (AI-2) activity of APEC. The results showed that when chicken type II pneumocytes were co-cultured with 108 CFU/ml of APEC-O78 for 6 h, the release of LDH reached the highest level (192.5 ± 13.4 U/L) (P < 0.01), and the percentages of dead cells followed the same trend in trypan blue exclusion assay. In addition, the AI-2 activity of cell-free culture fluid (CF) reached the maximum value after 6 h co-culture with 108 CFU/ml of APEC-O78. At the same time, the mRNA expressions of eight virulence genes (papC, fimA, fimC, hlyE, ompA, luxS, pfs, and qseA) of 108 CFU/ml APEC-O78 were significantly increased compared with those of 107 CFU/ml, and the mRNA expressions of four virulence genes (hlyE, tsh, iss, and luxS) of 108 CFU/ml APEC-O78 were higher than those of 109 CFU/ml (p < 0.05) after incubation for 6 h. These results suggested that AI-2-mediated QS is involved in the cell damage induced by APEC-O78, indicating AI-2 may be one new potential target for preventing chicken colibacillosis.
Assuntos
Células Epiteliais Alveolares/microbiologia , Células Epiteliais Alveolares/fisiologia , Escherichia coli/patogenicidade , Homosserina/análogos & derivados , Lactonas/metabolismo , Fatores de Virulência/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Galinhas , Técnicas de Cocultura , Escherichia coli/fisiologia , Homosserina/metabolismo , L-Lactato Desidrogenase/análise , Percepção de Quorum , Coloração e Rotulagem , Azul Tripano/análiseRESUMO
Cinobufagin (CBG), one active ingredient isolated from Venenum Bufonis, has been demonstrated to have immunoregulatory effect. The aim of this study was to investigate whether CBG can enhance the protective efficacy of formalin-inactivated Salmonella typhimurium (FIST) in mice. ICR mice were immunized with FIST (106 CFU/mouse) alone or mixed with CBG (10, 20, and 40 µg) or alum (200 µg) on day 1 and day 15. Two weeks after the second immunization, serum and spleen were sampled for measuring FIST-specific antibody levels, cytokine levels, and splenocyte proliferation. The results showed that CBG enhanced FIST-specific IgG and IgG2a, the levels of interferon-gamma (IFNγ) and nitric oxide (NO), and the splenocyte proliferation response induced by concanavalin A, lipopolysaccharide, and FIST. In vivo protection studies showed that CBG significantly decreased the bacterial burdens in the spleen and prolonged the survival time of FIST-immunized mice challenged with live Salmonella typhimurium. In vivo IFNγ neutralization led to a significant reduction in FIST-specific IgG2a and IFNγ levels, and in the protective efficacy in CBG/FIST-immunized mice. In conclusion, CBG enhances the protective efficacy of formalin-inactivated Salmonella typhimurium vaccine by promoting the Th1 immune response.
Assuntos
Adjuvantes Imunológicos/administração & dosagem , Bufanolídeos/administração & dosagem , Vacinas contra Salmonella/imunologia , Salmonella typhimurium/imunologia , Células Th1/imunologia , Compostos de Alúmen/administração & dosagem , Animais , Anticorpos Antibacterianos/sangue , Proliferação de Células , Citocinas/análise , Modelos Animais de Doenças , Fixadores , Formaldeído , Esquemas de Imunização , Imunoglobulina G/sangue , Leucócitos Mononucleares/imunologia , Camundongos Endogâmicos ICR , Salmonelose Animal , Vacinas contra Salmonella/administração & dosagem , Soro/imunologia , Baço/imunologia , Baço/microbiologia , Análise de Sobrevida , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/imunologiaRESUMO
Cdc27, as a core component of anaphase-promoting complex (APC), is a cell cycle regulator, which participates in control of mitotic checkpoint and surveys the mitotic spindle to maintain chromosomal integrity. It was hypothesized that polymorphisms in cdc27 gene might contribute to the susceptibility of breast cancer (BC) through influencing the mitotic progression of cells. Therefore, a hospital-based case-control study with 463 BC patients and 536 controls was implemented to investigate the association of six single-nucleotide polymorphisms (SNPs) in cdc27 and BC risk in a Chinese Han population. Among the six SNPs, two SNPs of rs11570443 and rs12601027 were positively correlated with BC risk. Individuals carrying rs11570443-CT or CC genotypes showed a higher BC risk with the OR of 1.75 (95 % confidence interval (CI) = 1.13-1.69), compared with those carrying rs11570443-TT genotype. For rs12601027, an increased BC risk was significantly associated with homozygote TT genotype (odds ratio (OR) = 1.49, 95 % CI = 1.12-1.98) compared with homozygote CC and heterozygote CT genotypes. In addition, a significant interaction effect of these two SNPs was found. The rs12601027-TT in combination with rs11570443-CT/CC genotypes showed a strongly elevated risk of BC compared with rs12601027-CC/CT and rs11570443-TT genotype (OR = 1.95, 95 % CI = 1.06-3.59). These findings suggested that polymorphisms in cdc27 may contribute to the susceptibility of BC though functional studies are needed to further elucidate the underling mechanisms of the associations.
Assuntos
Subunidade Apc3 do Ciclossomo-Complexo Promotor de Anáfase/genética , Neoplasias da Mama/genética , Predisposição Genética para Doença , Adulto , Idoso , Povo Asiático , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Humanos , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
We previously reported that a novel WD-40 domain-containing protein, p44/WDR77, drives quiescent epithelial cells to re-enter the cell cycle and plays an essential role for growth of lung and prostate cancer cells. Transforming growth factor beta (TGFß) signaling is important in the maintenance of non-transformed cells in the quiescent or slowly cycling stage. However, both non-transformed proliferating cells and human cancer cells are non-responsive to endogenous TGFß signaling. The mechanism by which proliferating cells become refractory to TGFß inhibition is not well established. Here, we found that silencing p44/WDR77 increased cellular sensitivity to TGFß signaling and that this was inversely correlated with decreased cell proliferation. Smad2 or 3 phosphorylation, TGFß-mediated transcription, and TGFß2 and TGFß receptor type II (TßRII) expression were dramatically induced by silencing of p44/WDR77. These data support the hypothesis that p44/WDR77 down-regulates the expression of the TGFß ligand and its receptor, thereby leading to a cellular non-response to TGFß signaling. Finally, we found that p44/WDR77 expression was correlated with cell proliferation and decreased TGFß signaling during lung tumorigenesis. Together, these results suggest that p44/WDR77 expression causes the non-sensitivity of proliferating cells to TGFß signaling, thereby contributing to cellular proliferation during lung tumorigenesis.
Assuntos
Proliferação de Células , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo , Fator de Crescimento Transformador beta2/metabolismo , Carcinogênese , Linhagem Celular Tumoral , Humanos , Receptor do Fator de Crescimento Transformador beta Tipo IIRESUMO
Recent publications have found associations between single-nucleotide polymorphisms (SNPs) in 8q24 and the risk of breast cancer (BC) in some populations, but the conclusions are inconsistent. In order to further investigate the association between variants in this region and BC risk in Chinese population, we conducted an independent hospital-based case-control study to discern the effects of these SNPs on BC risk. We genotyped three 8q24 SNPs (rs13281615, rs6983267, and rs9642880) in 485 cases and 530 cancer-free controls. The results indicated that the rs13281615 G allele significantly increased BC risk, with an odds ratio (OR) of 1.23 (95% confidence interval (CI) = 1.03-1.46) under the allelic model. Besides, stratification analysis reported that the significant association remained in the estrogen receptor (ER)+/progesterone receptor (PR)+ subgroup with a P value of 0.007 under the allelic model (OR = 1.33, 95% CI = 1.08-1.63). For the rs9642880 variant, only a feeble association was observed for the GT genotype compared with the GG genotype (OR = 1.33, 95% CI = 1.01-1.74). In addition, there was a negligible association between rs6983267 and BC risk in the ER-/PR- subgroup. However, no significant finding was observed in the overall participants. The findings suggested that polymorphisms in 8q24 may contribute to susceptibility to BC risk. However, functional studies are warranted to further elucidate the mechanisms of the association.
Assuntos
Povo Asiático/genética , Neoplasias da Mama/genética , Cromossomos Humanos Par 8/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo RealRESUMO
CONTEXT: Ginsenoside Rh2, an active component of ginseng, exhibits immunoregulatory and anti-inflammatory properties. Rh2-B1, a sulfated derivative, was prepared to enhance its water solubility. We studied the effect of Rh2-B1 on CTLL-2, a CD8⺠cytotoxic T cell line that was known for protecting against viral infection. OBJECTIVE: We aimed to investigate the effect of Rh2-B1 on interferon (IFN)-γ production and cell proliferation and its possible mechanism. MATERIALS AND METHODS: Enzyme-linked immunosorbent assay (ELISA) was employed to analyze the IFN-γ concentration of the whole blood and the supernatant of CTLL-2 cell culture. Cell proliferation assay was conducted using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Western blots were used to evaluate changes in signal transduction pathways in CTLL-2 cells. RESULTS: Rh2-B1 was able to enhance IFN-γ production from whole blood culture of Balb/c mice. We then evaluated the effect of Rh2-B1 on a cytotoxic T cell line, CTLL-2 for cell proliferation, IFN-γ production and its molecular mechanism. Rh2-B1 promoted cell proliferation and IFN-γ production of CTLL-2 cells. It also induced activation of p38 mitogen-activated protein kinase (MAPK) and extracellular-signal-regulated kinases (ERK), but inhibited p56 Lck and transducer and activator of transcription 5 (STAT5) expression. The effect was blocked by the specific p38 MAPK inhibitor SB203580 and ERK inhibitor U0126. CONCLUSION: Rh2-B1 could stimulate cell proliferation and IFN-γ production by activating the p38 MAPK- and ERK-dependent signaling pathways in cytotoxic T cells. This may be a novel medicine for treatment of viral infections.
Assuntos
Anti-Inflamatórios/farmacologia , Linfócitos T CD8-Positivos/imunologia , Ginsenosídeos/farmacologia , Interferon gama/imunologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia , Animais , Linfócitos T CD8-Positivos/patologia , Sistema de Sinalização das MAP Quinases/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Viroses/tratamento farmacológico , Viroses/imunologia , Viroses/patologiaRESUMO
Avian pathogenic Escherichia coli (APEC) is the causative agent of chicken colibacillosis. Paeoniflorin, a natural ingredient extracted from Paeonia lactiflora, has a variety of pharmacological effects including anti-inflammatory and immunomodulatory. However, its effects and mechanism in APEC-induced acute lung injury (ALI) in chicken is not clear. The aim of this study was to investigate the protective effect of paeoniflorin on APEC-induced ALI and its possible mechanism. Paeoniflorin (25, 50, and 100 mg/kg) was administered by gavage for 5 d starting at 9 d of age and the chicken were infected with APEC by intraperitoneal injection at 12 d of age. The tissues were collected after APEC infection for 36 h for analysis. The results showed that paeoniflorin significantly alleviated the symptoms, increased the survival rate and body weight gain of APEC-infected chicken, and improved the histopathological damages, and reduced APEC loads in lung tissues. In addition, paeoniflorin restored the gene expression of ZO-1, Occludin and Claudin-3 during APEC infection. Moreover, paeoniflorin pretreatment significantly affected the endocannabinoid system (ECs) by increasing DAGL, decreasing MAGL, increasing secretion of 2-AG. Then, paeoniflorin significantly decreased the secretion of IL-1ß, IL-6 and TNF-α in lung tissues, and decreased the mRNA expression of CXCL8, CXCL12, CCL1, CCL5, and CCL17. In addition, paeoniflorin significantly reduced the phosphorylation levels of PI3K, AKT, P65, and IκB. In summary, we found that paeoniflorin inhibited APEC-induced ALI, and its mechanism may be through affecting ECs and inhibiting the activation of PI3K/AKT and NF-κB signaling pathways, which provides a new idea for the prevention and treatment of chicken colibacillosis.
Assuntos
Lesão Pulmonar Aguda , Galinhas , Infecções por Escherichia coli , Glucosídeos , Monoterpenos , NF-kappa B , Fosfatidilinositol 3-Quinases , Doenças das Aves Domésticas , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Animais , Lesão Pulmonar Aguda/prevenção & controle , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/veterinária , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Glucosídeos/farmacologia , Glucosídeos/administração & dosagem , Monoterpenos/farmacologia , Monoterpenos/administração & dosagem , Doenças das Aves Domésticas/prevenção & controle , Doenças das Aves Domésticas/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , NF-kappa B/metabolismo , NF-kappa B/genética , Infecções por Escherichia coli/veterinária , Infecções por Escherichia coli/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinases/genética , Proteínas Aviárias/metabolismo , Proteínas Aviárias/genética , Relação Dose-Resposta a Droga , Escherichia coli/efeitos dos fármacosRESUMO
Drought stress inhibits seed germination, plant growth and development of tobacco, and seriously affects the yield and quality of tobacco leaves. However, the molecular mechanism underlying tobacco drought stress response remains largely unknown. In this study, integrated analysis of transcriptome and metabolome was performed on the germinated seeds of a cultivated variety K326 and its EMS mutagenic mutant M28 with great drought tolerance. The result showed that drought stress inhibited seed germination of the both varieties, while the germination rate of M28 was faster than that of K326 under drought stress. Besides, the levels of phytohormone ABA, GA19, and zeatin were increased by drought stress in M28. Five vital pathways were identified through integrated transcriptomic and metabolomic analysis, including zeatin biosynthesis, aspartate and glutamate synthesis, phenylamine metabolism, glutathione metabolism, and phenylpropanoid synthesis. Furthermore, 20 key metabolites in the above pathways were selected for further analysis of gene modular-trait relationship, and then four highly correlated modules were found. Then analysis of gene expression network was carried out of Top30 hub gene of these four modules, and 9 key candidate genes were identified, including HSP70s, XTH16s, APX, PHI-1, 14-3-3, SCP, PPO. In conclusion, our study uncovered some key drought-responsive pathways and genes of tobacco during seeds germination, providing new insights into the regulatory mechanisms of tobacco drought stress response.
Assuntos
Germinação , Transcriptoma , Germinação/genética , Secas , Zeatina/metabolismo , Sementes/metabolismo , Metaboloma , Regulação da Expressão Gênica de Plantas , Estresse Fisiológico/genéticaRESUMO
In the previous study, we found that peimine has good anti-inflammatory effects in vivo. However, the anti-inflammatory mechanism of peimine remains unclear. We, therefore, assessed the effects of peimine on inflammatory cytokines in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. We found that peimine (0-25 mg/L) significantly inhibited tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1ß, and increased IL-10 production. Furthermore, peimine significantly inhibited the phosphorylation of p38, ERK and c-jun N-terminal kinase (JNK) as well as decreased p65 and IκB. The present results indicate that peimine inhibits the production of inflammatory cytokines induced by LPS through blocking MAPKs and NF-κB signaling pathways.
Assuntos
Cevanas/farmacologia , Citocinas/imunologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/imunologia , Fator de Transcrição RelA/imunologia , Animais , Linhagem Celular , Citocinas/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/imunologia , Quinase I-kappa B/imunologia , Lipopolissacarídeos/toxicidade , Sistema de Sinalização das MAP Quinases/imunologia , Macrófagos/metabolismo , CamundongosRESUMO
Xiang-Qi-Tang (XQT) is a Chinese herbal formula containing Cyperus rotundus, Astragalus membranaceus and Andrographis paniculata. Alpha-Cyperone (CYP), astragaloside IV (AS-IV) and andrographolide (AND) are the three major active components in this formula. XQT may modulate the inflammatory or coagulant responses. We therefore assessed the effects of XQT on lipopolysaccharide (LPS)-induced inflammatory model of rat cardiac microvascular endothelial cells (RCMECs). XQT, CYP, AS-IV and AND inhibited the production of tumor necrosis factor alpha (TNF-α), intercellular cell adhesion molecule-1 (ICAM-1) and plasminogen activator inhibitor-1 (PAI-1), and up-regulated the mRNA expression of Kruppel-like factor 2 (KLF2). XQT and CYP inhibited the secretion of tissue factor (TF). To further explore the mechanism, we found that XQT, or its active components CYP, AS-IV and AND significantly inhibited extracellular signal-regulated kinase (ERK), c-jun NH2-terminal kinase (JNK) and p38 phosphorylation protein expression as well as decreased the phosphorylation levels of nuclear factor κB (NF-κB) p65 proteins in LPS-stimulated RCMECs. These results suggested that XQT and its active components inhibited the expression of inflammatory and coagulant mediators via mitogen-activated protein kinase (MAPKs) and NF-κB signaling pathways. These findings may contribute to future research on the action mechanisms of this formula, as well as therapy for inflammation- or coagulation-related diseases.