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Age, ethnic background and genetic components have been identified as the established risks for prostate cancer (PCa). Pentraxin 3 (PTX3), originally identified as a pattern-recognition molecule for defence against infectious agents, has multiple functions in tissue repair and in the regulation of cancer-associated inflammation. In this study, we sought to investigate the impact of PTX3 gene variants on the development of PCa. Genotypes of four common single-nucleotide polymorphisms (SNPs) of PTX3 gene, including rs1840680, rs2305619, rs3816527 and rs2120243, were profiled among 705 PCa patients and 705 ethnicity-matched controls. In this study, we found that patients who carry at least one minor allele (C) of rs3816527 (AC and CC) tended to develop advanced forms of diseases (clinical large T stage, OR, 1.593, p = 0.032; pathologically-confirmed nodal spread, OR, 1.987, p = 0.011; metastatic tumour, OR, 3.896, p = 0.032) as compared with those homologous for the major allele (AA). Further stratification analysis showed that such association of rs3816527 with lymphatic and distal metastasis of PCa was accentuated in the younger age group (≤65 at diagnosis) but not seen in the older age group (>65 at diagnosis), suggesting an age-specific effect of PTX3 variants. Prediction of PTX3 protein structure implied that polymorphism may alter the quaternary organization and oligomerization of PTX3 protein. Moreover, our gene silencing experiments and survey of public datasets revealed that elevation of PTX3 levels in PCa was required for cell migration and associated with tumour metastasis. Our results highlight an association of PTX3 rs3816527 with the progression of PCa.
Assuntos
Proteína C-Reativa , Progressão da Doença , Predisposição Genética para Doença , Metástase Neoplásica , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata , Componente Amiloide P Sérico , Humanos , Masculino , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Componente Amiloide P Sérico/genética , Componente Amiloide P Sérico/metabolismo , Proteína C-Reativa/genética , Proteína C-Reativa/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Idoso , Pessoa de Meia-Idade , Alelos , Genótipo , Estudos de Casos e Controles , Linhagem Celular TumoralRESUMO
BACKGROUND: Perturbation of gut microbiota has been linked to chronic kidney disease (CKD), which was correlated with a sophisticated milieu of metabolic and immune dysregulation. METHODS: To clarify the underlying host-microbe interaction in CKD, we performed multi-omics measurements, including systems-level gut microbiome, targeted serum metabolome and deep immunotyping, in a cohort of patients and non-CKD controls. RESULTS: Our analyses on functional profiles of the gut microbiome showed a decrease in the diversity and abundance of carbohydrate-active enzyme (CAZyme) genes but an increase in the abundance of antibiotic resistance, nitrogen cycling enzyme and virulence factor genes in CKD. Moreover, models generated using measurements of serum metabolites (amino acids, bile acids and short-chain fatty acids) or immunotypes were predictive of renal impairment but less so than many of the functional profiles derived from gut microbiota, with the CAZyme genes being the top-performing model to accurately predict the early stage of diseases. In addition, co-occurrence analyses revealed coordinated host-microbe relationships in CKD. Specifically, the highest fractions of significant correlations were identified with circulating metabolites by several taxonomic and functional profiles of gut microbiome, while immunotype features were moderately associated with the abundance of microbiome-encoded metabolic pathways and serum levels of amino acids (e.g. B cell cluster tryptophan and B cell cluster tryptophan metabolism). CONCLUSION: Overall, our multi-omics integration revealed several signatures of systems-level gut microbiome in robust associations with host-microbe co-metabolites and renal function, which may have aetiological and diagnostic implications in CKD.
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Microbioma Gastrointestinal , Metagenômica , Insuficiência Renal Crônica , Humanos , Insuficiência Renal Crônica/microbiologia , Insuficiência Renal Crônica/imunologia , Masculino , Feminino , Pessoa de Meia-Idade , Metagenômica/métodos , Estudos de Casos e Controles , Idoso , MetabolomaRESUMO
HO-3867, a synthetic curcumin analog, has displayed various tumor-suppressive characteristics and improved bioabsorption over its parent compound. However, its influences on the development of hepatocellular carcinoma (HCC) are poorly defined. To address this, we tested the anticarcinogenic impact of HO-3867 and investigated the underlying mechanisms in fighting liver cancer. Our result demonstrated that HO-3867 reduced the viability of HCC cells, accompanied by promotion of cell cycle arrest at the sub-G1 stage and apoptotic responses. Furthermore, a distinctive profile of apoptosis associated proteins, encompassing elevated heme oxygenase-1 (HO-1) level and caspase activation, was detected in HO-3867-stimulated HCC cells. In addition, such HO-3867-mediated elevation in caspase activation was dampened by pharmacological suppression of p38 activities. Taken together, our findings unveiled that HO-3867 triggered cell cycle arrest and apoptotic events in liver cancer, involving a p38-mediated activation of caspase cascades. These data highlighted a usefulness of curcumin or its analogs on the management of hepatocarcinogenesis.
Assuntos
Carcinoma Hepatocelular , Curcumina , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patologia , Curcumina/farmacologia , Apoptose , Heme Oxigenase-1 , Caspases , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
A disintegrin and metalloproteinase domain-containing protein 10 (ADAM-10) involves in the tumour progression, but the impacts of single-nucleotide polymorphism (SNP) of ADAM-10 on oral squamous cell carcinoma (OSCC) remain unclear. The aim of this study was to investigate the influence of SNP of ADAM-10 on the clinical features of OSCC in male Taiwanese. Five loci of ADAM-10 SNPs including rs653765 (C/T), rs2305421 (A/G), rs514049 (A/C), rs383902 (T/C) and rs2054096 (A/T) were genotyped by TaqMan allelic discrimination in 1138 OSCC patients and 1199 non-OSCC individuals. The ADAM-10 SNP rs2305421 GG (AOR: 1.399, 95% CI: 1.045-1.874, p = 0.024) and G allele (AOR: 1.170, 95% CI: 1.012-1.351, p = 0.034) illustrated a significantly higher genotypic frequencies in the OSCC group compared to the distribution of the ADAM-10 SNP rs2305421 AA wild type. In the subgroup analysis, the ADAM-10 SNP rs383902 TC+CC was significantly correlated to tumour size larger than T2 in betel quid chewer (AOR: 1.375, 95% CI: 1.010-1.872, p = 0.043), while the ADAM-10 SNP rs653765 CT+TT was significantly associated with tumour size larger than T2 in cigarette smoker (AOR: 1.346, 95% CI: 1.023-1.772, p = 0.034). The results from The Cancer Genome Atlas revealed highest ADAM-10 mRNA level in T2 stage of current smokers with head and neck squamous cell carcinoma (HNSCC). In conclusions, the ADAM-10 SNP rs2305421 G allele is associated with the presence of OSCC, and the ADAM-10 SNP rs383902 TC+CC and ADAM-10 SNP rs653765 CT+TT correlates to large tumour size in specific conditions.
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Proteína ADAM10 , Carcinoma de Células Escamosas , Neoplasias Bucais , Humanos , Masculino , Proteína ADAM10/genética , Carcinoma de Células Escamosas/genética , Estudos de Casos e Controles , Predisposição Genética para Doença , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
Oral squamous cell carcinoma (OSCC) is a common malignant disease associated with a high mortality rate and heterogeneous disease aetiology. Cyclin dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1), is a long noncoding RNA that has been shown to act as a scaffold, sponge, or signal hub to promote carcinogenesis. Here, we attempted to assess the effect of CDKN2B-AS1 single-nucleotide polymorphisms (SNPs) on the susceptibility to OSCC. Five CDKN2B-AS1 SNPs, including rs564398, rs1333048, rs1537373, rs2151280 and rs8181047, were analysed in 1060 OSCC cases and 1183 cancer-free controls. No significant association of these five SNPs with the risk of developing OSCC was detected between the case and control group. However, while examining the clinical characteristics, patients bearing at least one minor allele of rs1333048 (CA and CC) were more inclined to develop late-stage (stage III/IV, adjusted OR, 1.480; 95% CI, 1.129-1.940; p = 0.005) and large-size (greater than 2 cm in the greatest dimension, adjusted OR, 1.347; 95% CI, 1.028-1.765; p = 0.031) tumours, as compared with those homologous for the major allele (AA). Further stratification analyses demonstrated that this genetic correlation with the advanced stage of disease was observed only in habitual betel quid chewers (adjusted OR, 1.480; 95% CI, 1.076-2.035; p = 0.016) or cigarette smokers (adjusted OR, 1.531; 95% CI, 1.136-2.063; p = 0.005) but not in patients who were not exposed to these major habitual risks. These data reveal an interactive effect of CDKN2B-AS1 rs1333048 with habitual exposure to behavioural risks on the progression of oral cancer.
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Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , RNA Longo não Codificante , Humanos , Carcinoma de Células Escamosas/genética , Neoplasias Bucais/genética , Fatores de Risco , Polimorfismo de Nucleotídeo Único/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço , RNA Longo não Codificante/genéticaRESUMO
BACKGROUND: Perturbation of gut symbiosis has been linked to childhood allergic diseases. However, the underlying host-microbe interaction connected with specific phenotypes is poorly understood. METHODS: To address this, integrative analyses of stool metagenomic and metabolomic profiles associated with IgE reactions in 56 children with mite-sensitized airway allergies (25 with rhinitis and 31 with asthma) and 28 nonallergic healthy controls were conducted. RESULTS: We noted a decrease in the number and abundance of gut microbiome-encoded carbohydrate-active enzyme (CAZyme) genes, accompanied with a reduction in species richness, in the asthmatic gut microflora but not in that from allergic rhinitis. Such loss of CAZymes was consistent with the observation that a CAZyme-linked decrease in fecal butyrate was found in asthmatics and negatively correlated with mite-specific IgE responses. Different from the CAZymes, we demonstrated an increase in α diversity at the virulome levels in asthmatic gut microbiota and identified phenotype-specific variations of gut virulome. Moreover, use of fecal metagenomic and metabolomic signatures resulted in distinct effects on differentiating rhinitis and asthma from nonallergic healthy controls. CONCLUSION: Overall, our integrative analyses reveal several signatures of systems-level gut microbiome in robust associations with fecal metabolites and disease phenotypes, which may be of etiological and diagnostic implications in childhood airway allergies.
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Asma , Microbioma Gastrointestinal , Rinite Alérgica , Rinite , Humanos , Imunoglobulina E/metabolismo , FenótipoRESUMO
Alterations in the gut microbiota composition and their associated metabolic dysfunction exist in psoriasis. However, the impact of biologics on shaping gut microbiota is not well known. This study aimed to determine the association of gut microorganisms and microbiome-encoded metabolic pathways with the treatment in patients with psoriasis. A total of 48 patients with psoriasis, including 30 cases who received an IL-23 inhibitor (guselkumab) and 18 cases who received an IL-17 inhibitor (secukinumab or ixekizumab) were recruited. Longitudinal profiles of the gut microbiome were conducted by using 16S rRNA gene sequencing. The gut microbial compositions dynamically changed in psoriatic patients during a 24-week treatment. The relative abundance of individual taxa altered differently between patients receiving the IL-23 inhibitor and those receiving the IL-17 inhibitor. Functional prediction of the gut microbiome revealed microbial genes related to metabolism involving the biosynthesis of antibiotics and amino acids were differentially enriched between responders and non-responders receiving IL-17 inhibitors, as the abundance of the taurine and hypotaurine pathway was found to be augmented in responders treated with the IL-23 inhibitor. Our analyses showed a longitudinal shift in the gut microbiota in psoriatic patients after treatment. These taxonomic signatures and functional alterations of the gut microbiome could serve as potential biomarkers for the response to biologics treatment in psoriasis.
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Produtos Biológicos , Microbioma Gastrointestinal , Psoríase , Humanos , Interleucina-17 , RNA Ribossômico 16S , Psoríase/metabolismo , Interleucina-23RESUMO
MOTIVATION: We proposed a wiSDOM (web-based inclusionary analysis Suite for Disease-Oriented Metagenomics) R Shiny application which comprises six functional modules: (i) initial visualization of sampling effort and distribution of dominant bacterial taxa among groups or individual samples at different taxonomic levels; (ii) statistical and visual analysis of α diversity; (iii) analysis of similarity (ANOSIM) of ß diversity on UniFrac, Bray-Curtis, Horn-Morisita or Jaccard distance and visualizations; (iv) microbial biomarker discovery between two or more groups with various statistical and machine learning approaches; (v) assessment of the clinical validity of selected biomarkers by creating the interactive receiver operating characteristic (ROC) curves and calculating the area under the curve (AUC) for binary classifiers; and lastly (vi) functional prediction of metagenomes with PICRUSt or Tax4Fun. RESULTS: The performance of wiSDOM has been evaluated in several of our previous studies for exploring microbial biomarkers and their clinical validity as well as assessing the alterations in bacterial diversity and functionality. The wiSDOM can be customized and visualized as per users' needs and specifications, allowing researchers without programming background to conduct comprehensive data mining and illustration using an intuitive browser-based interface. AVAILABILITY AND IMPLEMENTATION: The browser-based R Shiny interface can be accessible via (https://lun-ching.shinyapps.io/wisdom/) and freely available at (https://github.com/lunching/wiSDOM). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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SUMMARY: In this article, we introduce a hierarchical clustering and Gaussian mixture model with expectation-maximization (EM) algorithm for detecting copy number variants (CNVs) using whole exome sequencing (WES) data. The R shiny package 'HCMMCNVs' is also developed for processing user-provided bam files, running CNVs detection algorithm and conducting visualization. Through applying our approach to 325 cancer cell lines in 22 tumor types from Cancer Cell Line Encyclopedia (CCLE), we show that our algorithm is competitive with other existing methods and feasible in using multiple cancer cell lines for CNVs estimation. In addition, by applying our approach to WES data of 120 oral squamous cell carcinoma (OSCC) samples, our algorithm, using the tumor sample only, exhibits more power in detecting CNVs as compared with the methods using both tumors and matched normal counterparts. AVAILABILITY AND IMPLEMENTATION: HCMMCNVs R shiny software is freely available at github repository https://github.com/lunching/HCMM_CNVs.and Zenodo https://doi.org/10.5281/zenodo.4593371. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Carcinoma de Células Escamosas , Neoplasias Bucais , Humanos , Sequenciamento do Exoma , Variações do Número de Cópias de DNA , Neoplasias Bucais/genética , Software , Algoritmos , Análise por ConglomeradosRESUMO
BACKGROUND/PURPOSE: Genetic and environmental factors play significant roles in the pathogenesis of Parkinson's disease (PD). Recently, 17 novel risk loci of PD were identified in a meta-analysis of genome-wide association study (GWAS) in the European populations. In order to clarify if these risk loci are associated with PD in Taiwanese population, we conducted a case-control study including 14 of the novel risk loci and analyzed the genetic distribution and allele frequency. METHODS: A total of 2798 subjects were recruited in this study. Genotyping was performed in 672 PD patients and 609 healthy controls by using Mass ARRAY, and data of another 1517 healthy controls from Taiwan Biobank were also examined. RESULTS: Our results show that the dominant models of ITPKB rs4653767 (OR (95% CI) = 0.832 (0.699, 0.990), p = 0.038), IL1R2 rs34043159 (OR (95% CI) = 0.812 (0.665, 0.992), p = 0.041) and COQ7 rs11343 (OR (95% CI) = 0.304 (0.180, 0.512), p < 0.001) were associated with PD. In allelic analysis, the T allele of IL1R2 rs34043159 (OR (95% CI) = 0.873 (0.772, 0.987), p = 0.03) and T allele of COQ7 rs11343 (OR (95% CI) = 0.098 (0.040, 0.238), p < 0.001) showed lower risk of PD. After Bonferroni correction, only dominant model and T allele of COQ7 rs11343 showed significantly reduced the risk of PD. CONCLUSION: This study suggests that ITPKB, IL1R2 and COQ7 have influence on the risk of PD in Taiwan.
Assuntos
Proteínas Mitocondriais/genética , Oxigenases de Função Mista/genética , Doença de Parkinson , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Receptores Tipo II de Interleucina-1 , Estudos de Casos e Controles , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Doença de Parkinson/genética , Polimorfismo de Nucleotídeo Único , Receptores Tipo II de Interleucina-1/genética , TaiwanRESUMO
Deoxyshikonin (DSK), a phytochemical constituent, has been documented to elicit various oncostatic properties alone or in combination with established therapeutics. However, its role in restraining oral squamous cell carcinoma (OSCC) is mostly unclear. Here, we examined the tumor-suppressive effect of DSK and explored the molecular mechanisms underlying DSK's activities on controlling oral cancer. Our results showed that DSK dose-dependently lessened the cell viability of tongue cancer cell lines, involving induction of cell cycle arrest at the sub-G1 phase and apoptotic cell death. Moreover, a unique signature of apoptosis-related proteins, including augmented nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) expression and caspase activation, was observed in DSK-treated tongue cancer cell lines. Furthermore, DSK-mediated upregulation of HO-1 and cleavage of caspase-9 and -3 were significantly inhibited by pharmacological blockage of p38 kinase. Collectively, these data revealed that DSK halted cell cycle progression and elicited cell apoptosis in tongue cancer cell lines, reshaping a p38-dependent profile of apoptotic proteome. Our findings provided novel insights into the therapeutic implications of a natural compound on the management of OSCC.
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Carcinoma de Células Escamosas , Neoplasias Bucais , Neoplasias da Língua , Apoptose , Proteínas Reguladoras de Apoptose/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Heme Oxigenase-1/metabolismo , Humanos , Neoplasias Bucais/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Naftoquinonas , Neoplasias da Língua/tratamento farmacológico , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Dysbiosis of oral microbiome may dictate the progression of oral squamous cell carcinoma (OSCC). Yet, the composition of oral microbiome fluctuates by saliva and distinct sites of oral cavity and is affected by risky behaviors (smoking, drinking and betel quid chewing) and individuals' oral health condition. To characterize the disturbances in the oral microbial population mainly due to oral tumorigenicity, we profiled the bacteria within the surface of OSCC lesion and its contralateral normal tissue from discovery (n = 74) and validation (n = 42) cohorts of male patients with cancers of the buccal mucosa. Significant alterations in the bacterial diversity and relative abundance of specific oral microbiota (most profoundly, an enrichment for genus Fusobacterium and the loss of genus Streptococcus in the tumor sites) were identified. Functional prediction of oral microbiome shown that microbial genes related to the metabolism of terpenoids and polyketides were differentially enriched between the control and tumor groups, indicating a functional role of oral microbiome in formulating a tumor microenvironment via attenuated biosynthesis of secondary metabolites with anti-cancer effects. Furthermore, the vast majority of microbial signatures detected in the discovery cohort was generalized well to the independent validation cohort, and the clinical validity of these OSCC-associated microbes was observed and successfully replicated. Overall, our analyses reveal signatures (a profusion of Fusobacterium nucleatum CTI-2 and a decrease in Streptococcus pneumoniae) and functions (decreased production of tumor-suppressive metabolites) of oral microbiota related to oral cancer.
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Disbiose/imunologia , Detecção Precoce de Câncer/métodos , Microbiota/imunologia , Mucosa Bucal/microbiologia , Neoplasias Bucais/diagnóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico , Adulto , Idoso , Estudos de Coortes , DNA Bacteriano/isolamento & purificação , Progressão da Doença , Disbiose/diagnóstico , Disbiose/microbiologia , Disbiose/patologia , Fusobacterium nucleatum/genética , Fusobacterium nucleatum/imunologia , Fusobacterium nucleatum/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Mucosa Bucal/imunologia , Mucosa Bucal/patologia , Neoplasias Bucais/imunologia , Neoplasias Bucais/microbiologia , Neoplasias Bucais/patologia , Prognóstico , RNA Ribossômico 16S/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/microbiologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Streptococcus pneumoniae/genética , Streptococcus pneumoniae/imunologia , Streptococcus pneumoniae/isolamento & purificação , Microambiente Tumoral/imunologiaRESUMO
Cell surface glycosylation has been known as an important modification process that can be targeted and manipulated by malignant cells to escape from host immunosurveillance. We previously showed that the blood group branched I antigen on the leukemia cell surface can regulate the cell susceptibility against natural killer (NK) cell-mediated cytotoxicity through interfering target-NK interaction. In this work, we first identified N-linkage as the major glycosylation linkage type for branched I glycan formation on leukemia cells, and this linkage was responsible for cell sensitivity against therapeutic NK-92MI targeting. Secondly, by examining different leukemia cell surface death receptors, we showed death receptor Fas had highest expressions in both Raji and TF-1a cells. Mutations on two Fas extracellular N-linkage sites (118 and 136) for glycosylation impaired activation of Fas-mediated apoptosis during NK-92MI cytotoxicity. Last, we found that the surface I antigen expression levels enable leukemia cells to respond differently against NK-92MI targeting. In low I antigen expressing K-562 cell, reduction of I antigen presence greatly reduced leukemia cell susceptibility against NK-92MI targeting. But in other high I antigen expressing leukemia cells, similar reduction in I antigen expression did not affect cell susceptibility.
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Citotoxicidade Imunológica/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Células Matadoras Naturais/imunologia , Receptor fas/imunologia , Apoptose/imunologia , Células Cultivadas , Glicosilação , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Mutação , Receptor fas/genéticaRESUMO
Melatonin is an indole produced by the pineal gland at night under normal light or dark conditions, and its levels, which are higher in children than in adults, begin to decrease prior to the onset of puberty and continue to decline thereafter. Apart from circadian regulatory actions, melatonin has significant apoptotic, angiogenic, oncostatic, and antiproliferative effects on various cancer cells. Particularly, the ability of melatonin to inhibit skeletomuscular sarcoma, which most commonly affects children, teenagers, and young adults, is substantial. In the past few decades, the vast majority of references have focused on the concept of epithelial-mesenchymal transition involvement in invasion and migration to allow carcinoma cells to dissociate from each other and to degrade the extracellular matrix. Recently, researchers have applied this idea to sarcoma cells of mesenchymal origin, e.g., osteosarcoma and Ewing sarcoma, with their ability to initiate the invasion-metastasis cascade. Similarly, interest of the effects of melatonin has shifted from carcinomas to sarcomas. Herein, in this state-of-the-art review, we compiled the knowledge related to the molecular mechanism of antimetastatic actions of melatonin on skeletomuscular sarcoma as in childhood and during adolescence. Utilization of melatonin as an adjuvant with chemotherapeutic drugs for synergy and fortification of the antimetastatic effects for the reinforcement of therapeutic actions are considered.
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Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Melatonina/metabolismo , Neoplasias Musculares/metabolismo , Neoplasias Musculares/patologia , Adolescente , Animais , Criança , Humanos , Invasividade Neoplásica , Metástase Neoplásica , Transdução de SinaisRESUMO
The inhibitory effect of melatonin on cancer cell dissemination is well established, yet the functional involvement of lncRNAs in melatonin signaling remains poorly understood. In this study, we identified a melatonin-attenuated lncRNA acting as a potential melatonin-regulated oral cancer stimulator (MROS-1). Downregulation of MROS-1 by melatonin suppressed TPA-induced oral cancer migration through replenishing the protein expression of prune homolog 2 (PRUNE2), which functioned as a tumor suppressor in oral cancer. Melatonin-mediated MROS-1/PRUNE2 expression and cell motility in oral cancer were regulated largely through the activation of JAK-STAT pathway. In addition, MROS-1, preferentially localized in the nuclei, promoted oral cancer migration in an epigenetic mechanism in which it modulates PRUNE2 expression by interacting with a member of the DNA methylation machinery, DNA methyltransferase 3A (DNMT3A). Higher methylation levels of PRUNE2 promoter were associated with nodal metastases and inversely correlated with PRUNE2 expression in head and neck cancer. Collectively, these findings suggest that MROS-1, serving as a functional mediator of melatonin signaling, could predispose patients with oral cancer to metastasize and may be implicated as a potential target for antimetastatic therapies.
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Melatonina , Neoplasias Bucais , RNA Longo não Codificante , Linhagem Celular Tumoral , Movimento Celular , DNA Metiltransferase 3A , Humanos , Melatonina/farmacologia , Neoplasias Bucais/induzido quimicamente , Neoplasias Bucais/genéticaRESUMO
Osteoarthritis (OA), the most common arthritis worldwide, is a degenerative joint disease characterized by progressive cartilage breakdown, subchondral remodeling, and synovial inflammation. Although conventional pharmaceutical therapies aimed to prevent further cartilage loss and joint dysfunction, there are no ideal strategies that target the pathogenesis of OA. Melatonin exhibits a variety of regulatory properties by binding to specific receptors and downstream molecules and exerts a myriad of receptor-independent actions via intracellular targets as a chondrocyte protector, an anti-inflammation modulator, and a free radical scavenger. Melatonin also modulates cartilage regeneration and degradation by directly/indirectly regulating the expression of main circadian clock genes, such as transcriptional activators [brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein (Bmal) and circadian locomotor output cycles kaput (Clock)], transcriptional repressors [period circadian regulator (Per)1/2, cryptochrome (Cry)1/2, and Dec2], and nuclear hormone receptors [Rev-Erbs and retinoid acid-related orphan receptors (Rors)]. Owing to its effects on cartilage homeostasis, we propose a potential role for melatonin in the prevention and therapy of OA via the modulation of circadian clock genes, mitigation of chondrocyte apoptosis, anti-inflammatory activity, and scavenging of free radicals.
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Relógios Circadianos , Melatonina , Osteoartrite , Apoptose , Condrócitos , Humanos , Melatonina/farmacologia , Osteoartrite/tratamento farmacológicoRESUMO
Background: Although associations between low protein diet (LPD) and changes of gut microbiota have been reported; however, systematic discernment of the effects of LPD on diet-microbiome-host interaction in patients with chronic kidney disease (CKD) is lacking. Methods: We searched PUBMED and EMBASE for articles published on changes of gut microbiota associated with implementation of LPD in CKD patients until July 2021. Independent researchers extracted data and assessed risks of bias. We conducted meta-analyses of combine p-value, mean differences and random effects for gut microbiota and related metabolites. Study heterogeneity was measured by Tau2 and I2 statistic. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results: Five articles met inclusion criteria. The meta-analyses of gut microbiota exhibited enrichments of Lactobacillaceae (meta-p= 0.010), Bacteroidaceae (meta-p= 0.048) and Streptococcus anginosus (meta-p< 0.001), but revealed depletion of Bacteroides eggerthii (p=0.017) and Roseburia faecis (meta-p=0.019) in LPD patients compared to patients undergoing normal protein diet. The serum IS levels (mean difference: 0.68 ug/mL, 95% CI: -8.38-9.68, p= 0.89) and pCS levels (mean difference: -3.85 ug/mL, 95% CI: -15.49-7.78, p < 0.52) did not change between groups. We did not find significant differences on renal function associated with change of microbiota between groups (eGFR, mean difference: -7.21 mL/min/1.73 m2, 95% CI: -33.2-18.79, p= 0.59; blood urea nitrogen, mean difference: -6.8 mg/dL, 95% CI: -46.42-32.82, p= 0.74). Other clinical (sodium, potassium, phosphate, albumin, fasting sugar, uric acid, total cholesterol, triglycerides, C-reactive protein and hemoglobin) and anthropometric estimates (body mass index, systolic blood pressure and diastolic blood pressure) did not differ between the two groups. Conclusions: This systematic review and meta-analysis suggested that the effects of LPD on the microbiota were observed predominantly at the families and species levels but minimal on microbial diversity or richness. In the absence of global compositional microbiota shifts, the species-level changes appear insufficient to alter metabolic or clinical outputs.
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Dieta com Restrição de Proteínas , Microbioma Gastrointestinal/fisiologia , Insuficiência Renal Crônica/microbiologia , Disbiose/epidemiologia , Disbiose/etiologia , Humanos , Internacionalidade , Insuficiência Renal Crônica/dietoterapia , Insuficiência Renal Crônica/epidemiologiaRESUMO
First discovered on the natural killer (NK) cell, the cell surface inhibitory receptor sialic acid-binding immunoglobulin-like lectin-7 (Siglec-7) is known for regulating many important biological activities. However, the detail regulatory mechanism for Siglec-7 expression in NK cells currently remains unclear. In this study, we aimed to investigate how cell surface Siglec-7 expression is regulated and found that, in both NK cell lines and peripheral NK cells, transcription was the main regulatory step. Furthermore, when NK-92MI and peripheral NK cells were treated with DNA methyltransferase (DNMT) inhibitor, the CpG island, with 9 CpG sites, in 5' Siglec-7 promoter became noticeably hypomethylated, and Siglec-7 expression increased in both RNA transcript and surface protein. Within this CpG island, we identified both CpG 8 and CpG 9 as two key regulators responsible for Siglec-7 expression. Additionally, by using histone deacetylases (HDAC) inhibitor, butyric acid, we showed that Siglec-7 expression was also subjected to the histone modification. And a combined treatment with both 5-azacytidine and butyric acid showed an additive effect on Siglec-7 transcript expression in peripheral NK cells.
Assuntos
Antígenos de Diferenciação Mielomonocítica/genética , Epigênese Genética/imunologia , Células Matadoras Naturais/imunologia , Lectinas/genética , Antígenos de Diferenciação Mielomonocítica/metabolismo , Azacitidina/farmacologia , Ácido Butírico/farmacologia , Linhagem Celular , Ilhas de CpG/genética , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/imunologia , Epigênese Genética/efeitos dos fármacos , Código das Histonas/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/metabolismo , Lectinas/metabolismo , Regiões Promotoras Genéticas/genética , RNA-Seq , Transcrição Gênica/efeitos dos fármacos , Transcrição Gênica/imunologiaRESUMO
Matrix metalloproteinases (MMPs) play a major role in extracellular matrix remodeling and are involved in tumor cell invasion. Cancers such as childhood leukemia are characterized by their capacity to infiltrate different organs. MMP production by leukemic cells may indicate a leukemic subtype or subpopulation with a more invasive phenotype. Therefore, clarifying the action mechanisms of MMPs as prognostic predictors or MMP targeting as a therapeutic strategy is necessary. MMP-targeting drugs have been developed for the treatment of hematological malignancies. In this review, we highlight current advances in understanding the molecular mechanisms and pathological characteristics of various MMPs, as well as recent therapeutic advances targeting MMPs in childhood leukemia. Several studies have been conducted on the therapeutic efficacy of MMP inhibitors in cancer, such as collagen peptidomimetics, nonpeptidomimetic inhibitors of MMP active sites, bisphosphonates, and tetracycline derivatives. Here, we conclude that more clinical trials are necessary to estimate the role of selective MMP inhibitors in the treatment and prevention of childhood leukemia.
Assuntos
Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/terapia , Metaloproteinases da Matriz/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Animais , Criança , HumanosRESUMO
BACKGROUND: Childhood asthma is a multifactorial inflammatory condition of the airways, associated with specific changes in respiratory microbiome and circulating metabolome. METHODS: To explore the functional capacity of asthmatic microbiome and its intricate connection with the host, we performed shotgun sequencing of airway microbiome and untargeted metabolomics profiling of serum samples in a cohort of children with mite-sensitized asthma and non-asthmatic controls. RESULTS: We observed higher gene counts and sample-to-sample dissimilarities in asthmatic microbiomes, indicating a more heterogeneous community structure and functionality among the cases than in controls. Moreover, we identified airway microbial species linked to changes in circulating metabolites and IgE responses of the host, including a positive correlation between Prevotella sp oral taxon 306 and dimethylglycine that were both decreased in patients. Several control-enriched species (Eubacterium sulci, Prevotella pallens, and Prevotella sp oral taxon 306) were inversely correlated with total and allergen-specific IgE levels. Genes related to microbial carbohydrate, amino acid, and lipid metabolism were differentially enriched, suggesting that changes in microbial metabolism may contribute to respiratory health in asthmatics. Pathway modules relevant to allergic responses were differentially abundant in asthmatic microbiome, such as enrichments for biofilm formation by Pseudomonas aeruginosa, membrane trafficking, histidine metabolism, and glycosaminoglycan degradation, and depletions for polycyclic aromatic hydrocarbon degradation. Further, we identified metagenomic and metabolomic markers (eg, Eubacterium sulci) to discriminate cases from the non-asthmatic controls. CONCLUSIONS: Our dual-omics data reveal the connections between respiratory microbes and circulating metabolites perturbed in mite-sensitized pediatric asthma, which may be of etiological and diagnostic implications.