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1.
Int J Mol Sci ; 24(18)2023 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-37762427

RESUMO

Oxidative stress (OS) is a condition that occurs as a result of an imbalance between the production of reactive oxygen species (ROS) and the body's ability to detoxify and neutralize them. It can play a role in a variety of reproductive system conditions, including polycystic ovary syndrome (PCOS), endometriosis, preeclampsia, and infertility. In this review, we briefly discuss the links between oxidative stress and PCOS. Mitochondrial mutations may lead to impaired oxidative phosphorylation (OXPHOS), decreased adenosine triphosphate (ATP) production, and an increased production of ROS. These functional consequences may contribute to the metabolic and hormonal dysregulation observed in PCOS. Studies have shown that OS negatively affects ovarian follicles and disrupts normal follicular development and maturation. Excessive ROS may damage oocytes and granulosa cells within the follicles, impairing their quality and compromising fertility. Impaired OXPHOS and mitochondrial dysfunction may contribute to insulin resistance (IR) by disrupting insulin signaling pathways and impairing glucose metabolism. Due to dysfunctional OXPHOS, reduced ATP production, may hinder insulin-stimulated glucose uptake, leading to IR. Hyperandrogenism promotes inflammation and IR, both of which can increase the production of ROS and lead to OS. A detrimental feedback loop ensues as IR escalates, causing elevated insulin levels that exacerbate OS. Exploring the relations between OS and PCOS is crucial to fully understand the role of OS in the pathophysiology of PCOS and to develop effective treatment strategies to improve the quality of life of women affected by this condition. The role of antioxidants as potential therapies is also discussed.

2.
Exp Eye Res ; 168: 138-148, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29278698

RESUMO

Pseudoexfoliation syndrome (PEXS) is an age-related elastosis, strongly associated with the development of secondary glaucoma. It is clearly suggested that PEXS has a genetic component, but this has not been extensively studied. Here, a genome-wide association study (GWAS) using a DNA-pooling approach was conducted to explore the potential association of genetic variants with PEXS in a Polish population, including 103 PEXS patients without glaucoma and 106 perfectly (age- and gender-) matched controls. Individual sample TaqMan genotyping was used to validate GWAS-selected single-nucleotide polymorphism (SNP) associations. Multivariate binary logistic regression analysis was applied to develop a prediction model for PEXS. In total, 15 SNPs representing independent PEXS susceptibility loci were selected for further validation in individual samples. For 14 of these variants, significant differences in the allele and genotype frequencies between cases and controls were identified, of which 12 remained significant after Benjamini-Hochberg adjustment. The minor allele of five SNPs was associated with an increased risk of PEXS development, while for nine SNPs, it showed a protective effect. Beyond the known LOXL1 variant rs2165241, nine other SNPs were located within gene regions, including in OR11L1, CD80, TNIK, CADM2, SORBS2, RNF180, FGF14, FMN1, and RBFOX1 genes. None of these associations with PEXS has previously been reported. Selected SNPs were found to explain nearly 69% of the total risk of PEXS development. The overall risk prediction accuracy for PEXS, expressed by the area under the ROC curve (AUC) value, increased by 0.218, from 0.672 for LOXL1 rs2165241 alone to 0.89 when seven additional SNPs were included in the proposed 8-SNP prediction model. In conclusion, several new susceptibility loci for PEXS without glaucoma suggested that neuronal development and actin remodeling are potentially involved in either PEXS onset or inhibition or delay of its conversion to glaucoma.


Assuntos
Actinas/genética , Síndrome de Exfoliação/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Neurônios/fisiologia , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Casos e Controles , Feminino , Frequência do Gene , Genótipo , Humanos , Modelos Logísticos , Masculino , Análise em Microsséries , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética
3.
BMC Cancer ; 15: 570, 2015 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-26232141

RESUMO

BACKGROUND: Tamoxifen, the most frequently used drug for treating estrogen receptor-positive breast cancer, must be converted into active metabolites to exert its therapeutic efficacy, mainly through CYP2D6 enzymes. The objective of this study was to investigate the impact of CYP2D6 polymorphisms on (Z)-endoxifen-directed tamoxifen metabolism and to assess the usefulness of CYP2D6 genotyping for identifying patients who are likely to have insufficient (Z)-endoxifen concentrations to benefit from standard therapy. METHODS: Blood samples from 279 Polish women with breast cancer receiving tamoxifen 20 mg daily were analyzed for CYP2D6 genotype and drug metabolite concentration. Steady-state plasma levels of tamoxifen and its 14 metabolites were measured by using the ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method. RESULTS: In nearly 60 % of patients, including over 30 % of patients with fully functional CYP2D6, (Z)-endoxifen concentration was below the predefined threshold of therapeutic efficacy. The most frequently observed CYP2D6 genotype was EM/PM (34.8 %), among which 83.5 % of patients had a combination of wild-type and *4 alleles. Plasma concentration of five metabolites was significantly correlated with CYP2D6 genotype. For the first time, we identified an association between decreased (E/Z)-4-OH-N-desmethyl-tamoxifen-ß-D-glucuronide levels (r (2) = 0.23; p < 10(-16)) and increased CYP2D6 functional impairment. The strongest correlation was observed for (Z)-endoxifen, whose concentration was significantly lower in groups of patients carrying at least one CYP2D6 null allele, compared with EM/EM patients. The CYP2D6 genotype accounted for plasma level variability of (Z)-endoxifen by 27 % (p < 10(-16)) and for the variability of metabolic ratio indicating (Z)-endoxifen-directed metabolism of tamoxifen by 51 % (p < 10(-43)). CONCLUSIONS: The majority of breast cancer patients in Poland may not achieve a therapeutic level of (Z)-endoxifen upon receiving a standard dose of tamoxifen. This finding emphasizes the limited value of CYP2D6 genotyping in routine clinical practice for identifying patients who might not benefit from the therapy. In its place, direct monitoring of plasma steady-state (Z)-endoxifen concentration should be performed to personalize and optimize the treatment.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Citocromo P-450 CYP2D6/genética , Tamoxifeno/análogos & derivados , Tamoxifeno/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/sangue , Cromatografia Líquida , Feminino , Humanos , Pessoa de Meia-Idade , Polônia , Medicina de Precisão , Tamoxifeno/sangue , Tamoxifeno/farmacocinética , Espectrometria de Massas em Tandem/métodos
4.
J Cell Mol Med ; 18(9): 1762-72, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24913135

RESUMO

One of the main questions regarding nonalcoholic fatty liver disease is the molecular background of the transition from simple steatosis (SS) to the inflammatory and fibrogenic condition of steatohepatitis (NASH). We examined the gene expression changes during progression from histologically normal liver to SS and NASH in models of obesity caused by hyperphagia or a high-fat diet. Microarray-based analysis revealed that the expression of 1445 and 264 probe sets was changed exclusively in SS and NASH samples, respectively, and 1577 probe sets were commonly altered in SS and NASH samples. Functional annotations indicated that transcriptome alterations that were common for NASH and SS, as well as exclusive for NASH, involved extracellular matrix (ECM)-related processes, although they differed in the type of matrix structure change. The expression of 80 genes was significantly changed in all three comparisons: SS versus control, NASH versus control and NASH versus SS. Of these genes, epithelial membrane protein 1, IKBKB interacting protein and decorin were progressively up-regulated in both SS and NASH compared to normal tissue. The molecular context of interactions of encoded 80 proteins revealed that they are highly interconnected and significantly enriched for processes involving metabolism by cytochrome P450. Validation of 10 selected mRNAs encoding genes related to ECM and cytochrome P450 with quantitative RT-PCR analysis showed consistent changes in their expression during NASH development. The expression profile of these genes has the potential to distinguish NASH from SS and normal tissue and may possibly be beneficial in the clinical diagnosis of NASH.


Assuntos
Sistema Enzimático do Citocromo P-450/genética , Matriz Extracelular/metabolismo , Fígado Gorduroso/enzimologia , Transcriptoma , Animais , Glicemia , Sistema Enzimático do Citocromo P-450/metabolismo , Diagnóstico Diferencial , Modelos Animais de Doenças , Fígado Gorduroso/diagnóstico , Humanos , Insulina/sangue , Lipídeos/sangue , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Anotação de Sequência Molecular , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase em Tempo Real
5.
Infect Immun ; 82(8): 3457-70, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24891108

RESUMO

Helicobacter pylori causes numerous alterations in gastric epithelial cells through processes that are dependent on activity of the cag type IV secretion system (T4SS). Filamentous structures termed "pili" have been visualized at the interface between H. pylori and gastric epithelial cells, and previous studies suggested that pilus formation is dependent on the presence of the cag pathogenicity island (PAI). Thus far, there has been relatively little effort to identify specific genes that are required for pilus formation, and the role of pili in T4SS function is unclear. In this study, we selected 7 genes in the cag PAI that are known to be required for T4SS function and investigated whether these genes were required for pilus formation. cagT, cagX, cagV, cagM, and cag3 mutants were defective in both T4SS function and pilus formation; complemented mutants regained T4SS function and the capacity for pilus formation. cagY and cagC mutants were defective in T4SS function but retained the capacity for pilus formation. These results define a set of cag PAI genes that are required for both pilus biogenesis and T4SS function and reveal that these processes can be uncoupled in specific mutant strains.


Assuntos
Proteínas de Bactérias/metabolismo , Sistemas de Secreção Bacterianos , Fímbrias Bacterianas/metabolismo , Genes Bacterianos , Helicobacter pylori/metabolismo , Complexos Multiproteicos/metabolismo , Multimerização Proteica , Proteínas de Bactérias/genética , Linhagem Celular , Células Epiteliais/microbiologia , Fímbrias Bacterianas/genética , Técnicas de Inativação de Genes , Teste de Complementação Genética , Ilhas Genômicas , Helicobacter pylori/genética , Humanos , Complexos Multiproteicos/genética
6.
Funct Integr Genomics ; 14(1): 245-59, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24178926

RESUMO

Although mitochondrial dysfunction is implicated in the pathogenesis of obesity, the molecular mechanisms underlying obesity-related metabolic abnormalities are not well established. We performed mitochondrial quantitative proteomic and whole transcriptome analysis followed by functional annotations within liver and skeletal muscles, using fasted and non-fasted 16- and 48-week-old high-fat diet (HFD)-fed and normal diet-fed (control group) wild-type C56BL/6J mice, and hyperphagic ob/ob and db/db obese mice. Our study identified 1,675 and 704 mitochondria-associated proteins with at least two peptides in liver and muscle, respectively. Of these, 221 liver and 44 muscle proteins were differentially expressed (adjusted p values ≤ 0.05) between control and all obese mice, while overnight fasting altered expression of 107 liver and 35 muscle proteins. In the liver, we distinguished a network of 27 proteins exhibiting opposite direction of expression changes in HFD-fed and hyperphagic mice when compared to control. The network centered on cytochromes P450 3a11 (Cyp3a11) and 4a14 (Cyp4a14), and fructose-bisphosphate aldolase B (Aldob) proteins which bridged proteins cluster involved in Metabolism of xenobiotics with proteins engaged in Fatty acid metabolism and PPAR signaling pathways. Functional annotations revealed that most of the hepatic molecular alterations, which characterized both obesity and fasting, related to different aspects of energy metabolism (such as Fatty acid metabolism, Peroxisome, and PPAR signaling); however, only a limited number of functional annotations could be selected from skeletal muscle data sets. Thus, our comprehensive molecular overview revealed that both obesity and fasting states induce more pronounced mitochondrial proteome changes in the liver than in the muscles.


Assuntos
Jejum/metabolismo , Mitocôndrias Hepáticas/metabolismo , Mitocôndrias Musculares/metabolismo , Obesidade/metabolismo , Proteínas/metabolismo , Animais , Dieta Hiperlipídica , Ácidos Graxos/metabolismo , Hiperfagia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Músculo Esquelético/metabolismo , Proteínas/genética
7.
Cancers (Basel) ; 16(2)2024 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-38254888

RESUMO

This comprehensive review encompasses studies examining changes in the cervical and cervico-vaginal microbiota (CM and CVM) in relation to human papillomavirus (HPV) using next-generation sequencing (NGS) technology. HPV infection remains a prominent global health concern, with a spectrum of manifestations, from benign lesions to life-threatening cervical cancers. The CM and CVM, a unique collection of microorganisms inhabiting the cervix/vagina, has emerged as a critical player in cervical health. Recent research has indicated that disruptions in the CM and CVM, characterized by a decrease in Lactobacillus and the overgrowth of other bacteria, might increase the risk of HPV persistence and the progression of cervical abnormalities. This alteration in the CM or CVM has been linked to a higher likelihood of HPV infection and cervical dysplasia. NGS technology has revolutionized the study of the cervical microbiome, providing insights into microbial diversity, dynamics, and taxonomic classifications. Bacterial 16S rRNA gene sequencing, has proven invaluable in characterizing the cervical microbiome, shedding light on its role in HPV infections and paving the way for more tailored strategies to combat cervical diseases. NGS-based studies offer personalized insights into an individual's cervical microbiome. This knowledge holds promise for the development of novel diagnostic tools, targeted therapies, and preventive interventions for cervix-related conditions, including cervical cancer.

8.
PLoS Pathog ; 7(9): e1002237, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21909278

RESUMO

Colonization of the human stomach by Helicobacter pylori is an important risk factor for development of gastric cancer. The H. pylori cag pathogenicity island (cag PAI) encodes components of a type IV secretion system (T4SS) that translocates the bacterial oncoprotein CagA into gastric epithelial cells, and CagL is a specialized component of the cag T4SS that binds the host receptor α5ß1 integrin. Here, we utilized a mass spectrometry-based approach to reveal co-purification of CagL, CagI (another integrin-binding protein), and CagH (a protein with weak sequence similarity to CagL). These three proteins are encoded by contiguous genes in the cag PAI, and are detectable on the bacterial surface. All three proteins are required for CagA translocation into host cells and H. pylori-induced IL-8 secretion by gastric epithelial cells; however, these proteins are not homologous to components of T4SSs in other bacterial species. Scanning electron microscopy analysis reveals that these proteins are involved in the formation of pili at the interface between H. pylori and gastric epithelial cells. ΔcagI and ΔcagL mutant strains fail to form pili, whereas a ΔcagH mutant strain exhibits a hyperpiliated phenotype and produces pili that are elongated and thickened compared to those of the wild-type strain. This suggests that pilus dimensions are regulated by CagH. A conserved C-terminal hexapeptide motif is present in CagH, CagI, and CagL. Deletion of these motifs results in abrogation of CagA translocation and IL-8 induction, and the C-terminal motifs of CagI and CagL are required for formation of pili. In summary, these results indicate that CagH, CagI, and CagL are components of a T4SS subassembly involved in pilus biogenesis, and highlight the important role played by unique constituents of the H. pylori cag T4SS.


Assuntos
Proteínas de Bactérias/fisiologia , Fímbrias Bacterianas/fisiologia , Ilhas Genômicas , Infecções por Helicobacter/fisiopatologia , Helicobacter pylori/metabolismo , Interações Hospedeiro-Patógeno/fisiologia , Sequência de Aminoácidos , Antígenos de Bactérias/metabolismo , Proteínas de Bactérias/metabolismo , Helicobacter pylori/patogenicidade , Humanos , Estômago/microbiologia
9.
BMC Cancer ; 13: 510, 2013 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-24171766

RESUMO

BACKGROUND: Breast cancer is the most common type of cancer and the second leading cause of cancer-death among women in Poland. The known high-risk mutations account for 25% of familial aggregation cases and 5% of total breast cancer predisposition. Genome-wide association studies have identified a number of common low-penetrance genetic variants, but their contribution to disease risk differs between populations. METHODS: To verify selected associations with breast cancer susceptibility among Polish women, the replication study was performed, included 1424 women with breast cancer and 1788 healthy persons. Sixteen single-nucleotide polymorphisms (SNPs) were analyzed using TaqMan SNP Genotyping Assays. Allele frequency differences were tested using chi2-test implemented in PLINK v1.07 and Cochran-Armitage trend test was performed using R software. RESULTS: Significant differences (Bonferroni corrected p-valuecor ≤ 0.0197) in the frequency of alleles distribution between all cancer and control subjects were observed for four (rs2736098, rs13281615, rs1219648, rs2981582) out of 16 SNPs. The same result was obtained for group of patients without high-risk BRCA1/2 mutations. The rs1219648 (p-valuecor ≤ 6.73E-03) and rs2981582 (p-valuecor ≤ 6.48E-03) SNPs showed significant association with both familial and sporadic cancers. Additionally, rs2736098 (p-valuecor ≤ 0.0234) was associated with only sporadic cancers; also in group without carriers of high-risk mutation. All these associations revealed their significance also in Cochran-Armitage trend test. Opposite to other SNPs, rs2736098 was associated with a decreased risk of breast cancer. CONCLUSION: The association of four known susceptibility SNPs, representing three individual loci, with breast cancer risk in Polish women was confirmed. One of them (rs2736098) seems to be specific for the Polish population. Due to the population differences in allele frequencies, identification of general genetic risk factors requires sets of association studies conducted on different populations.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença , Variação Genética , Penetrância , Adolescente , Adulto , Idoso , Alelos , Feminino , Genes BRCA1 , Genes BRCA2 , Estudo de Associação Genômica Ampla , Heterozigoto , Humanos , Desequilíbrio de Ligação , Pessoa de Meia-Idade , Mutação , Polônia , Polimorfismo de Nucleotídeo Único , Risco , População Branca/genética , Adulto Jovem
10.
Antioxidants (Basel) ; 12(11)2023 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-38001836

RESUMO

BACKGROUND: The prevalence of Hashimoto's thyroiditis (HT) among women with polycystic ovary syndrome (PCOS) is higher than in the general female population, but the factors predisposing to the coexistence of these disorders remain unclear. This study employed whole genome sequencing of mitochondrial DNA to identify genetic variants potentially associated with the development of PCOS and HT and predisposing to their joint occurrence. RESULTS: A total of 84 women participated, including patients with PCOS, HT, coexisting PCOS and HT (PCOS + HT) and healthy women. Both Fisher's exact and Mann-Whitney U statistical analyses were performed to compare the frequency of variants between groups. Ten differentiating variants were common to both analyses in PCOS + HT vs. PCOS, one in PCOS + HT vs. HT, and six in PCOS + HT vs. control. Several variants differentiating the PCOS + HT group from PCOS and controls were identified, located both in the mitochondrial genes (including the MT-CYB, MT-ND1, MT-ND2, MT-ND4, MT-ND6, MT-CO1, MT-CO3) and the D-loop region. Only two variants differentiated PCOS + HT and HT groups. One variant (13237a in MT-ND5) was common for all three comparisons and underrepresented in the PCOS + HT group. Functional enrichment analysis showed 10 pathways that were unique for the comparison of PCOS + HT and PCOS groups, especially related to ATP production and oxidative phosphorylation, and one pathway, the NADH-quinone oxidoreductase, chain M/4, that was unique for the comparison of PCOS + HT and control groups. Notably, nine pathways shared commonality between PCOS + HT vs. PCOS and PCOS + HT vs. control, related to the biogenesis and assembly of Complex I. CONCLUSION: This study provides novel insights into the genetic variants associated with oxidative stress in women with coexisting PCOS and HT. Mitochondrial dysfunction and oxidative stress appear to play a role in the pathogenesis of both conditions. However, more mitochondrial variants were found to differentiate women with both PCOS and HT from those with PCOS alone than from those with HT alone.

11.
Front Immunol ; 14: 1193293, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37545519

RESUMO

A large body of evidence indicates that women with polycystic ovary syndrome (PCOS) have a higher risk of developing Hashimoto's thyroiditis (HT) than healthy individuals. Given the strong genetic impact on both diseases, common predisposing genetic factors are possibly involved but are not fully understood. Here, we performed whole-exome sequencing (WES) for 250 women with sporadic PCOS, HT, combined PCOS and HT (PCOS+HT), and healthy controls to explore the genetic background of the joint occurrence of PCOS and HT. Based on relevant comparative analyses, multivariate logistic regression prediction modeling, and the most informative feature selection using the Monte Carlo feature selection and interdependency discovery algorithm, 77 variants were selected for further validation by TaqMan genotyping in a group of 533 patients. In the allele frequency test, variants in RAB6A, GBP3, and FNDC7 genes were found to significantly (padjusted < 0.05) differentiated the PCOS+HT and PCOS groups, variant in HIF3A differentiated the PCOS+HT and HT groups, whereas variants in CDK20 and CCDC71 differentiated the PCOS+HT and both single disorder groups. TaqMan genotyping data were used to create final prediction models, which differentiated between PCOS+HT and PCOS or HT with a prediction accuracy of AUC = 0.78. Using a 70% cutoff of the prediction score improved the model parameters, increasing the AUC value to 0.87. In summary, we demonstrated the polygenic burden of both PCOS and HT, and many common and intersecting signaling pathways and biological processes whose disorders mutually predispose patients to the development of both diseases.


Assuntos
Doença de Hashimoto , Síndrome do Ovário Policístico , Humanos , Feminino , Síndrome do Ovário Policístico/genética , Síndrome do Ovário Policístico/epidemiologia , Predisposição Genética para Doença , Sequenciamento do Exoma , Doença de Hashimoto/genética , Doença de Hashimoto/epidemiologia , Frequência do Gene , Proteínas Repressoras/genética , Proteínas Reguladoras de Apoptose/genética
12.
Biomedicines ; 10(6)2022 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-35740457

RESUMO

The aim of this study is to determine the molecular differences between the urothelial transcriptomes of the bladder body and trigone. The transcriptomes of the bladder body and trigonal epithelia were analyzed by massive sequencing of total epithelial RNA. The profiles of urothelial and urinal microbiomes were assessed by amplicon sequencing of bacterial 16S rRNA genes in 17 adolescent females with pain and micturition dysfunction and control female subjects. The RNA sequencing identified 10,261 differentially expressed genes (DEGs) in the urothelia of the bladder body and trigone, with the top 1000 DEGs at these locations annotated to 36 and 77 of the Reactome-related pathways in the bladder body and trigone, respectively. These pathways represented 11 categories enriched in the bladder body urothelium, including extracellular matrix organization, the neuronal system, and 15 categories enriched in the trigonal epithelium, including RHO GTPase effectors, cornified envelope formation, and neutrophil degranulation. Five bacterial taxa in urine differed significantly in patients and healthy adolescent controls. The evaluation of their transcriptomes indicated that the bladder body and trigonal urothelia were functionally different tissues. The molecular differences between the body and trigonal urothelia responsible for clinical symptoms in adolescents with bladder pain syndrome/interstitial cystitis remain unclear.

13.
Front Immunol ; 12: 606620, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33746952

RESUMO

Polycystic ovary syndrome (PCOS) and Hashimoto's thyroiditis (HT) are endocrine disorders that commonly occur among young women. A higher prevalence of HT in women with PCOS, relative to healthy individuals, is observed consistently. Combined occurrence of both diseases is associated with a higher risk of severe metabolic and reproductive complications. Genetic factors strongly impact the pathogenesis of both PCOS and HT and several susceptibility loci associated with a higher risk of both disorders have been identified. Furthermore, some candidate gene polymorphisms are thought to be functionally relevant; however, few genetic variants are proposed to be causally associated with the incidence of both disorders together.


Assuntos
Predisposição Genética para Doença , Doença de Hashimoto/epidemiologia , Doença de Hashimoto/etiologia , Síndrome do Ovário Policístico/epidemiologia , Síndrome do Ovário Policístico/etiologia , Alelos , Doenças Autoimunes/epidemiologia , Doenças Autoimunes/etiologia , Autoimunidade/genética , Feminino , Estudos de Associação Genética/métodos , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Prevalência
14.
Biology (Basel) ; 10(6)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070617

RESUMO

Despite great efforts, most of the genetic factors contributing to the risk of colorectal cancer (CRC) remain undetermined. Including small but homogenous populations in genome-wide association studies (GWAS) can help us discover new common risk variants specific to the studied population. In this study, including 465 CRC patients and 1548 controls, a pooled DNA samples-based GWAS was conducted in search of genetic variants associated with CRC in a Polish population. Combined with a new method of selecting single-nucleotide polymorphisms (SNPs) for verification in individual DNA samples, this approach allowed the detection of five new susceptibility loci not previously reported for CRC. The discovered loci were found to explain 10% of the overall risk of developing CRC. The strongest association was observed for rs10935945 in long non-coding RNA LINC02006 (3q25.2). Three other SNPs were also located within genes (rs17575184 in NEGR1, rs11060839 in PIWIL1, rs12935896 in BCAS3), while one was intergenic (rs9927668 at 16p13.2). An expression quantitative trait locus (eQTL) bioinformatic analysis suggested that these polymorphisms may affect transcription factor binding sites. In conclusion, four of the identified variants were located within genes likely involved in tumor invasiveness and metastasis. Therefore, they could possibly be markers of poor prognosis in CRC patients.

15.
J Mol Med (Berl) ; 86(2): 233-42, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17952395

RESUMO

Barrett's esophagus represents a well-defined precursor lesion of esophageal adenocarcinoma, although only a subset of patients with these lesions advances to invasive cancer. Currently, reliable markers predicting neoplastic progression in Barrett's esophagus are lacking. The only clinically useful risk factor is the presence of dysplasia in Barrett's epithelium, but its use as a prognostic marker of disease progression has several significant limitations. Thus, identification of biomarkers of potential prognostic value in dysplasia development in Barrett's esophagus is highly important. The aim of the study was to determine if expression levels of selected genes support histologic diagnosis of dysplastic changes in Barrett's esophagus. Upon rigorous sampling and independent histopathologic examination of endoscopic specimens by two experienced gastrointestinal pathologists, 56 patients with Barrett's esophagus (16 negative for dysplasia, 15 with indefinite, 21 with low-grade, and 4 with high-grade dysplasia) were selected for molecular analysis. The relative mRNA levels of ten selected genes were estimated by quantitative real-time polymerase chain reaction (PCR) analysis. Although expression of nine genes showed trends toward down- or upregulation during progression from Barrett's esophagus without dysplasia to Barrett's esophagus with high-grade dysplasia, only a decrease in S100A2 mRNA levels was statistically significant (P<0.05). However, there was considerable variation among individuals and significant overlapping of ranges. Furthermore, detailed, comparative analysis of serial samples from Barrett's mucosa and normal squamous epithelium shows large intra-individual variability of gene expression levels. In conclusion, expression of this set of ten genes cannot be used as a molecular marker aiding histological examination of dysplasia in Barrett's esophagus. Significant inter- and intra-patient variations of gene expression levels makes use of the selected genes impractical.


Assuntos
Esôfago de Barrett/diagnóstico , Neoplasias Esofágicas/etiologia , Esofagoscopia , Esôfago/patologia , Marcadores Genéticos , Testes Genéticos , Variação Genética , Técnicas de Diagnóstico Molecular , Esôfago de Barrett/complicações , Esôfago de Barrett/genética , Esôfago de Barrett/patologia , Fatores Quimiotáticos/genética , Progressão da Doença , Regulação para Baixo , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Feminino , Perfilação da Expressão Gênica , Testes Genéticos/métodos , Genótipo , Humanos , Masculino , Fenótipo , Valor Preditivo dos Testes , Prognóstico , RNA Mensageiro/análise , Reprodutibilidade dos Testes , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas S100/genética , Índice de Gravidade de Doença
16.
J Clin Med ; 8(8)2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31344832

RESUMO

A certain minimum plasma concentration of (Z)-endoxifen is presumably required for breast cancer patients to benefit from tamoxifen therapy. In this study, we searched for DNA variants that could aid in the prediction of risk for insufficient (Z)-endoxifen exposure. A metabolic ratio (MR) corresponding to the (Z)-endoxifen efficacy threshold level was adopted as a cutoff value for a genome-wide association study comprised of 287 breast cancer patients. Multivariate regression was used to preselect variables exhibiting an independent impact on the MR and develop models to predict below-threshold MR values. In total, 15 single-nucleotide polymorphisms (SNPs) were significantly associated with below-threshold MR values. The strongest association was with rs8138080 (WBP2NL). Two alternative models for MR prediction were developed. The predictive accuracy of Model 1, including rs7245, rs6950784, rs1320308, and the CYP2D6 genotype, was considerably higher than that of the CYP2D6 genotype alone (AUC 0.879 vs 0.758). Model 2, which was developed using the same three SNPs as for Model 1 plus rs8138080, appeared as an interesting alternative to the full CYP2D6 genotype testing. In conclusion, the four novel SNPs, tested alone or in combination with the CYP2D6 genotype, improved the prediction of impaired tamoxifen-to-endoxifen metabolism, potentially allowing for treatment optimization.

17.
Acta Biochim Pol ; 53(1): 169-78, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16496041

RESUMO

hnRNP K protein, which localizes to the nucleus, cytoplasm and mitochondria, is involved in the various cellular processes that compose gene expression. We used a SAGE-based assay to profile RNAs associated with hnRNP K protein in rat mitochondria. RNA was isolated from mitoplasts obtained from highly purified and RNase-treated mitochondria. Total RNA and RNA associated with hnRNP K protein were then used as input material for generating two SAGE libraries. Mitochondrion-derived tags isolated from the total mitoplast RNA library represented 86.3%, while those isolated from the library constructed from RNA associated with hnRNP K protein represented only 28.2% of selected tags. Thus, an unexpected number of nuclear-encoded RNAs were purified from mitochondria. Many of these transcripts were co-purified with hnRNP K protein, and high levels of nuclear-encoded RNAs co-immunoprecipitating with K protein corresponded to elevated hnRNP K protein levels of the organelle. The most abundant RNAs that were co-purified with hnRNP K protein represented transcripts originating from satellite I DNA. While satellite I RNA levels were higher in the nucleus and cytoplasm than in mitochondria, the most abundant binding of satellite I transcripts to hnRNP K protein was found in mitochondria. The role of satellite I RNA in mitochondria remains to be elucidated.


Assuntos
Ribonucleoproteínas Nucleares Heterogêneas Grupo K/química , Mitocôndrias/metabolismo , RNA Satélite/genética , Animais , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Biblioteca Gênica , Técnicas Genéticas , Humanos , Proteínas de Membrana/química , Ligação Proteica , Ratos , Receptor de Insulina/metabolismo , Canais de Translocação SEC
18.
Int J Biochem Cell Biol ; 37(9): 1815-28, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16009324

RESUMO

Insulin is the most potent anabolic hormone. The greatest sensitivity to insulin is exhibited by muscle, liver and adipose cells. To study links between insulin and mitochondrial function over the course of cellular quiescence and differentiation, we quantified mitochondrial RNA and DNA in L6 myoblasts and HTC-IR hepatocytes cultured under low-serum conditions in the presence of insulin. The expression of the whole set of mitochondrial genes was determined using reverse transcriptase (RT)-real time PCR. Cell proliferation was assayed by the incorporation of (3)H-thymidine and myoblast differentiation was analyzed by morphological and biochemical markers of myogenesis. Low growth factor concentration in medium decreased proliferation of both cell types and induced differentiation of myoblasts. The expression of all mitochondrial genes decreased in quiescent hepatocytes whereas it increased in quiescent differentiated myotubes, as compared with proliferating cells, similarly to reflecting the expression of the insulin receptor gene, both in myoblasts and hepatocytes. The kinetics of mitochondrial RNA levels were similar to the expression patterns of two nuclear genes, subunit e of mitochondrial ATP-synthase and uncoupling protein-2; however, they did not reflect changes in mitochondrial DNA content. Insulin accelerated myogenesis and expression of both mitochondrial and nuclear genes in differentiated myotubes but not in quiescent hepatocytes. Our studies prove that myogenesis may require the orchestrated transcriptional activation of both mitochondrial and nuclear genes and provide additional evidence confirming the regulatory impact of insulin on the function of muscle mitochondria.


Assuntos
DNA Mitocondrial/metabolismo , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Mitocôndrias Musculares/genética , Desenvolvimento Muscular/fisiologia , Mioblastos/efeitos dos fármacos , RNA/metabolismo , Animais , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Expressão Gênica , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Canais Iônicos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Proteínas de Membrana Transportadoras/metabolismo , Proteínas Mitocondriais/metabolismo , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Mioblastos/metabolismo , RNA Mitocondrial , Ratos , Proteína Desacopladora 2
19.
FEMS Immunol Med Microbiol ; 44(2): 143-50, 2005 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-15866208

RESUMO

Helicobacter pylori vacuolating cytotoxin VacA causes multiple effects on epithelial cell function and morphology, but the effects of VacA on signal transduction pathways and the cytoskeleton have not been investigated in detail. In this study, we analyzed the effects of native VacA on HeLa and AGS cell adhesion to fibronectin and laminin under serum-free conditions. Confocal microscopic examination revealed increased number of cells with rounded morphology and inhibition of actin fiber formation, in the presence of VacA. VacA binds to fibronectin in vitro in a dose-dependent manner. This interaction was partly inhibited by a peptide containing an arginine-glycine-aspartic acid motif. The adhesion of HeLa cells to fibronectin, but not to laminin, was decreased in the presence of VacA. Thus, VacA may interact with fibronectin and influence integrin receptor-induced cell signaling and cytoskeleton-dependent cell functions.


Assuntos
Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/farmacologia , Adesão Celular , Fibronectinas/metabolismo , Helicobacter pylori/patogenicidade , Adesão Celular/efeitos dos fármacos , Linhagem Celular , Citoesqueleto/metabolismo , Citoesqueleto/ultraestrutura , Células HeLa , Helicobacter pylori/metabolismo , Humanos , Transdução de Sinais
20.
PLoS One ; 9(8): e105371, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25144769

RESUMO

The mitochondrial amidoxime reducing component mARC is the fourth mammalian molybdenum enzyme. The protein is capable of reducing N-oxygenated structures, but requires cytochrome b5 and cytochrome b5 reductase for electron transfer to catalyze such reactions. It is well accepted that the enzyme is involved in N-reductive drug metabolism such as the activation of amidoxime prodrugs. However, the endogenous function of the protein is not fully understood. Among other functions, an involvement in lipogenesis is discussed. To study the potential involvement of the protein in energy metabolism, we tested whether the mARC protein and its partners are regulated due to fasting and high fat diet in mice. We used qRT-PCR for expression studies, Western Blot analysis to study protein levels and an N-reductive biotransformation assay to gain activity data. Indeed all proteins of the N-reductive system are regulated by fasting and its activity decreases. To study the potential impact of these changes on prodrug activation in vivo, another mice experiment was conducted. Model compound benzamidoxime was injected to mice that underwent fasting and the resulting metabolite of the N-reductive reaction, benzamidine, was determined. Albeit altered in vitro activity, no changes in the metabolite concentration in vivo were detectable and we can dispel concerns that fasting alters prodrug activation in animal models. With respect to high fat diet, changes in the mARC proteins occur that result in increased N-reductive activity. With this study we provide further evidence that the endogenous function of the mARC protein is linked with lipid metabolism.


Assuntos
Citocromo-B(5) Redutase/metabolismo , Citocromos b5/metabolismo , Dieta Hiperlipídica , Jejum , Proteínas Mitocondriais/metabolismo , Oxirredutases/metabolismo , Animais , Benzamidinas/metabolismo , Linhagem Celular Tumoral , Ativação Enzimática , Humanos , Hiperfagia/metabolismo , Metabolismo dos Lipídeos , Masculino , Camundongos
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