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1.
Int J Mol Sci ; 25(8)2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38673944

RESUMO

It is important to search for cytostatic compounds in order to fight cancer. One of them could be 2'-methylthiamine, which is a thiamine antimetabolite with an additional methyl group at the C-2 carbon of thiazole. So far, the cytostatic potential of 2'-methylthiamine has not been studied. We have come forward with a simplified method of synthesis using commercially available substrates and presented a comparison of its effects, as boosted by oxythiamine, on normal skin fibroblasts and HeLa cancer cells, having adopted in vitro culture techniques. Oxythiamine has been found to inhibit the growth and metabolism of cancer cells significantly better than 2'-methylthiamine (GI50 36 and 107 µM, respectively), while 2'-methylthiamine is more selective for cancer cells than oxythiamine (SI = 180 and 153, respectively). Docking analyses have revealed that 2'-methylthiamine (ΔG -8.2 kcal/mol) demonstrates a better affinity with thiamine pyrophosphokinase than thiamine (ΔG -7.5 kcal/mol ) and oxythiamine (ΔG -7.0 kcal/mol), which includes 2'-methylthiamine as a potential cytostatic. Our results suggest that the limited effect of 2'-methylthiamine on HeLa arises from the related arduous transport as compared to oxythiamine. Given that 2'-methylthiamine may possibly inhibit thiamine pyrophosphokinase, it could once again be considered a potential cytostatic. Thus, research should be carried out in order to find the best way to improve the transport of 2'-methylthiamine into cells, which may trigger its cytostatic properties.


Assuntos
Simulação de Acoplamento Molecular , Oxitiamina , Humanos , Células HeLa , Oxitiamina/farmacologia , Oxitiamina/química , Oxitiamina/metabolismo , Tiamina/farmacologia , Tiamina/análogos & derivados , Tiamina/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Simulação por Computador
2.
Int J Mol Sci ; 25(7)2024 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-38612837

RESUMO

Hashimoto's thyroiditis (HT) and Graves' disease (GD) are common autoimmune endocrine disorders in children. Studies indicate that apart from environmental factors, genetic background significantly contributes to the development of these diseases. This study aimed to assess the prevalence of selected single-nucleotide polymorphisms (SNPs) of Il7R, CD226, CAPSL, and CLEC16A genes in children with autoimmune thyroid diseases. We analyzed SNPs at the locus rs3194051, rs6897932 of IL7R, rs763361 of CD226, rs1010601 of CAPSL, and rs725613 of CLEC16A gene in 56 HT patients, 124 GD patients, and 156 healthy children. We observed significant differences in alleles IL7R (rs6897932) between HT males and the control group (C > T, p = 0.028) and between all GD patients and healthy children (C > T, p = 0.035) as well as GD females and controls (C > T, p = 0.018). Moreover, the C/T genotype was less frequent in GD patients at rs6897932 locus and in HT males at rs1010601 locus. The presence of the T allele in the IL7R (rs6897932) locus appears to have a protective effect against HT in males and GD in all children. Similarly, the presence of the T allele in the CAPSL locus (rs1010601) seems to reduce the risk of HT development in all patients.


Assuntos
Doenças Autoimunes , Doença de Graves , Doença de Hashimoto , Criança , Feminino , Masculino , Humanos , Adolescente , Prevalência , Alelos , Doença de Hashimoto/genética , Polimorfismo de Nucleotídeo Único , Doença de Graves/genética , Receptores de Interleucina-7/genética , Proteínas de Transporte de Monossacarídeos , Lectinas Tipo C/genética
3.
Sci Rep ; 13(1): 22083, 2023 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-38086930

RESUMO

Some of the multiple autoimmune diseases have been already associated with IL-13 single-nucleotide polymorphisms (SNPs). However, there are only few studies regarding multiple sclerosis (MS) risk and IL-13 rs20541 (R130Q) polymorphism, and their results are conflicting. Therefore, the aim of our study was to investigate the frequency of the IL-13 gene rs20541 (R130Q) polymorphism in MS participants and its association with MS clinical subsets in the Polish population. We conducted a case‒control study including 94 relapsing remitting MS patients and 160 healthy volunteers. We genotyped the rs20541 polymorphism in the IL-13 gene and analysed the genotype frequency, age of MS onset and clinical condition (EDSS values) of the MS participants. Fisher's exact test was used for statistical analysis, and the log-linear model was applied to test for associations. Allele A, as well as the AA and AG genotypes, was observed to be significantly more common in the MS subjects. The OR (odds ratio) for the A compared to the G allele was 1.71 (1.14-2.56), whereas OR 2.33 (0.86-6.26) and OR 1.92 (1.11-3.30) were obtained for the AA and AG genotypes, respectively. We did not identify any significant associations of the studied IL-13 SNP with the investigated clinical parameters of the MS participants. Our results suggest that the rs20541 polymorphism in the IL-13 gene may play an important role in MS predisposition but not in investigated clinical parameters in MS subjects of the Polish population.


Assuntos
Esclerose Múltipla , Humanos , Estudos de Casos e Controles , Predisposição Genética para Doença , Genótipo , Interleucina-13/genética , Esclerose Múltipla/genética , Polônia , Polimorfismo de Nucleotídeo Único
4.
Molecules ; 28(22)2023 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-38005248

RESUMO

Cytostatic and pro-apoptotic effects of selenium steroid derivatives against HeLa cells were determined. The highest cytostatic activity was shown by derivative 4 (GI50 25.0 µM, almost complete growth inhibition after three days of culture, and over 97% of apoptotic and dead cells at 200 µM). The results of our study (cell number measurements, apoptosis profile, relative expression of apoptosis-related APAF1, BID, and mevalonate pathway-involved HMGCR, SQLE, CYP51A1, and PDHB genes, and computational chemistry data) support the hypothesis that tested selenosteroids induce the extrinsic pathway of apoptosis by affecting the cell membrane as cholesterol antimetabolites. An additional mechanism of action is possible through a direct action of derivative 4 to inhibit PDHB expression in a way similar to steroid hormones.


Assuntos
Citostáticos , Humanos , Células HeLa , Citostáticos/farmacologia , Apoptose , Colesterol/metabolismo
5.
Int J Mol Sci ; 24(6)2023 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-36982588

RESUMO

Since the role of sialome-Siglec axis has been described as a regulatory checkpoint of immune homeostasis, the promotion of stimulatory or inhibitory Siglec-related mechanisms is crucial in cancer progression and therapy. Here, we investigated the effect of tamoxifen on the sialic acid-Siglec interplay and its significance in immune conversion in breast cancer. To mimic the tumour microenvironment, we used oestrogen-dependent or oestrogen-independent breast cancer cells/THP-1 monocytes transwell co-cultures exposed to tamoxifen and/or ß-estradiol. We found changes in the cytokine profiles accompanied by immune phenotype switching, as measured by the expression of arginase-1. The immunomodulatory effects of tamoxifen in THP-1 cells occurred with the altered SIGLEC5 and SIGLEC14 genes and the expression of their products, as confirmed by RT-PCR and flow cytometry. Additionally, exposure to tamoxifen increased the binding of Siglec-5 and Siglec-14 fusion proteins to breast cancer cells; however, these effects appeared to be unassociated with oestrogen dependency. Our results suggest that tamoxifen-induced alterations in the immune activity of breast cancer reflect a crosstalk between the Siglec-expressing cells and the tumour's sialome. Given the distribution of Siglec-5/14, the expression profile of inhibitory and activatory Siglecs in breast cancer patients may be useful in the verification of therapeutic strategies and predicting the tumour's behaviour and the patient's overall survival.


Assuntos
Neoplasias , Tamoxifeno , Humanos , Tamoxifeno/farmacologia , Antígenos CD/metabolismo , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/metabolismo , Células THP-1 , Estrogênios/farmacologia
6.
Int J Mol Sci ; 23(24)2022 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-36555722

RESUMO

Prediabetes is an intermediate state of hyperglycemia during which glycemic parameters are above normal levels but below the T2D threshold. T2D and its precursor prediabetes affect 6.28% and 7.3% of the world's population, respectively. The main objective of this paper was to create and compare two polygenic risk scores (PRSs) versus changes over time (Δ) in metabolic parameters related to prediabetes and metabolic complications. The genetics of 446 prediabetic patients from the Polish Registry of Diabetes cohort were investigated. Seventeen metabolic parameters were measured and compared at baseline and after five years using statistical analysis. Subsequently, genetic polymorphisms present in patients were determined to build a T2D PRS (68 SNPs) and an obesity PRS (21 SNPs). Finally, the association among the two PRSs and the Δ of the metabolic traits was assessed. After a multiple linear regression with adjustment for age, sex, and BMI at a nominal significance of (p < 0.05) and adjustment for multiple testing, the T2D PRS was found to be positively associated with Δ fat mass (FM) (p = 0.025). The obesity PRS was positively associated with Δ FM (p = 0.023) and Δ 2 h glucose (p = 0.034). The comparison of genotype frequencies showed that AA genotype carriers of rs10838738 were significantly higher in Δ 2 h glucose and in Δ 2 h insulin. Our findings suggest that prediabetic individuals with a higher risk of developing T2D experience increased Δ FM, and those with a higher risk of obesity experience increased Δ FM and Δ two-hour postprandial glucose. The associations found in this research could be a powerful tool for identifying prediabetic individuals with an increased risk of developing T2D and obesity.


Assuntos
Diabetes Mellitus Tipo 2 , Obesidade , Estado Pré-Diabético , Humanos , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Glucose , Obesidade/complicações , Obesidade/genética , Estado Pré-Diabético/complicações , Estado Pré-Diabético/genética , Fatores de Risco , Herança Multifatorial
7.
Pharmacogenomics J ; 22(5-6): 276-283, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35963939

RESUMO

This pilot study is aimed at implementing an approach for comprehensive clinical pharmacogenomics (PGx) profiling. Fifty patients with cardiovascular diseases and 50 healthy individuals underwent whole-exome sequencing. Data on 1800 PGx genes were extracted and analyzed through deep filtration separately. Theoretical drug induced phenoconversion was assessed for the patients, using sequence2script. In total, 4539 rare variants (including 115 damaging non-synonymous) were identified. Four publicly available PGx bioinformatics algorithms to assign PGx haplotypes were applied to nine selected very important pharmacogenes (VIP) and revealed a 45-70% concordance rate. To ensure availability of the results at point-of-care, actionable variants were stored in a web-hosted database and PGx-cards were developed for quick access and handed to the study subjects. While a comprehensive clinical PGx profile could be successfully extracted from WES data, available tools to interpret these data demonstrated inconsistencies that complicate clinical application.


Assuntos
Algoritmos , Farmacogenética , Humanos , Sequenciamento do Exoma , Fluxo de Trabalho , Projetos Piloto
8.
Adv Med Sci ; 67(2): 250-256, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35785598

RESUMO

PURPOSE: Autoimmune diabetes (AD) in adults includes both the classical form of type 1 diabetes mellitus (T1DM) and latent autoimmune diabetes in adults (LADA). LADA shares clinical and metabolic features with type 1 and type 2 diabetes mellitus (T2DM). Ceramide (Cer) levels negatively correlate with insulin sensitivity in humans and animal models. However, only a few studies have focused on other sphingolipids, including sphingomyelin (SM). Therefore, we determined sphingolipids in patients with newly diagnosed diabetes as possible diagnostic biomarkers. MATERIALS AND METHODS: We evaluated sphingolipids in a cohort of 59 adults with newly diagnosed diabetes without prior hypoglycemic pharmacotherapy to distinguish diabetes mellitus types and for precise LADA definition. All patients with newly diagnosed diabetes were tested for the concentrations of individual Cer and SM species by gas-liquid chromatography. The study included healthy controls and patients with T1DM, T2DM and LADA. RESULTS: SM species were significantly altered in patients with newly diagnosed diabetes compared to healthy controls. SM-C16:0, C16:1, -C18:0, -C18:1, -C18:2, -C18:3, -C20:4, and -C22:6 species were found to be significantly elevated in LADA patients. In contrast, significant differences were observed for Cer species with saturated acyl chains, especially Cer-C14:0, -C16:0, -C18:0 (AD and T2DM), -C22:0, and -C24:0 (T1DM). Following ROC analysis, SM-C16:0, and particularly -C18:1, and -C20:4 may be supportive diagnostic markers for LADA. CONCLUSION: SM profiling in patients with newly diagnosed diabetes could be potentially helpful for differential diagnosis of LADA, T1DM, and T2DM in more challenging cases.


Assuntos
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Diabetes Autoimune Latente em Adultos , Adulto , Animais , Humanos , Esfingomielinas , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 2/diagnóstico , Projetos Piloto , Ceramidas/metabolismo , Esfingolipídeos , Biomarcadores , Hipoglicemiantes , Autoanticorpos
9.
Int J Mol Sci ; 23(6)2022 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-35328446

RESUMO

Here we report the reaction in the biphasic system of the in situ prepared selenols and thiols with 1,4-androstadiene-3,17-dione (1) or prednisone acetate (2) having α,ß-unsaturated ketone as an electrophilic functionalization. The Michael-type addition reaction resulted to be chemo- and stereoselective, affording a series of novel steroidal selenides and sulfides. This is an example of a one-step, eco-friendly process that bypasses some of the main concerns connected with the bad smell and the toxicity of these seleno- and thio-reagents. Furthermore, we demonstrated that the proposed methodology offers the possibility to prepare libraries of steroids variously and selectively decorated with different organochalcogen moieties at the C1 position starting from 1,4-androstadienic skeletons and leaving unaltered the C4-C5 unsaturation. Based on the data reported in the literature the introduction of an organoselenium or an organosulfur moiety in a steroid could provide new interesting pharmaceutically active entities exerting anticancer and antimicrobial activities. In this optic, new synthetic strategies to efficiently prepare this class of compounds could be strongly desirable.


Assuntos
Cetonas , Esteroides , Compostos de Sulfidrila , Sulfetos , Zinco
10.
Int J Mol Sci ; 23(4)2022 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-35216226

RESUMO

Conducted studies highlight that a mixture of genetic and environmental factors is responsible for rheumatoid arthritis (RA) development. This study aimed to analyze the available literature for the relationship between, on the one hand, single-nucleotide polymorphisms (SNPs) in the proinflammatory cytokines genes interleukin-1 (IL-1), -6, -8, -15, -17, -18, and -23, and tumor necrosis factor-alpha (TNF-α), and on the other hand, RA susceptibility, severity, and patients' response to applied treatment. The PubMed database was searched for sources. Preference was given to articles which were published within the past 20 years. Data indicate that the relationship between selected SNPs in proinflammatory cytokines genes and susceptibility to developing RA is inconclusive, and it depends on the ethnicity of the population. Although the allelic and genotypic frequencies of many SNPs in proinflammatory cytokines genes analyzed did not differ between RA patients and healthy controls, deeper analysis showed that these polymorphisms have a relationship with clinicopathological features of RA. SNPs in proinflammatory cytokines genes also "modify patients' response" to applied treatment. Further studies, on larger cohorts of subjects and in different populations, should be conducted to elucidate the role of SNPs in IL-1, -6, -8, -15, -17, -18, and -23, and TNF-α genes in RA patients.


Assuntos
Artrite Reumatoide/genética , Citocinas/genética , Predisposição Genética para Doença/genética , Inflamação/genética , Polimorfismo de Nucleotídeo Único/genética , Humanos
11.
Front Neurol ; 12: 631134, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33889124

RESUMO

Fc receptors have been shown to play a role in several autoimmune diseases. We aimed to test, for the first time, whether some of the single nucleotide variants in the FCRL5 gene were associated with multiple sclerosis (MS) susceptibility and clinical manifestations in the Polish population. The case-control study included 94 individuals with MS and 160 healthy subjects. We genotyped two single nucleotide variants of the FCRL5 gene: rs2012199 and rs6679793. The age of onset, disease duration, and clinical condition of the MS subjects were analyzed. For statistical analysis, we used the chi-squared test confirmed with Fisher's exact test. We observed the significant differences in the distribution of investigated FCRL5 genotypes between MS subjects and healthy controls. The CC and CT genotypes, as well as the C allele of rs2012199, were significantly more common in the MS subjects, as were genotypes AA and AG, and allele A of rs6679793. We noted that decreased MS susceptibility was associated with the T allele rs2012199 (OR = 0.37, p = 0.0002) and G allele rs6679793 (OR = 0.6, p = 0.02). Our results support the role of the FCRL5 locus in MS predisposition and extend the evidence of its influence on autoimmunity.

12.
J Pediatr Gastroenterol Nutr ; 73(2): 203-209, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33756508

RESUMO

OBJECTIVES: The aim of this study was to examine the role of ghrelin, obestatin, and glutamate and their receptors in the pathogenesis of children functional constipation. METHODS: Children ages 4-17 were the subject of the study: 121 children with constipation (55 boys and 66 girls), 36 patients of the same age (26 boys and 10 girls) were the controls. Expression of ghrelin, obestatin, and glutamate receptors on gastric and colon specimens taken by endoscopy were assessed. The concentration of the above agents was estimated in serum by the enzyme-linked immunosorbent assay test. RESULTS: The lower median serum concentrations of ghrelin, in the constipated children than in controls were confirmed (1.9 ng/mL vs 2.6 ng/mL, P < 0.05). The expression of the metabotropic receptor 7 for glutamate (mGlu7) RNA was higher in the stomach (32.49 vs 31.47, P < 0.05), and was lower in the rectum in constipated patients compared to the control group (31.76 vs 32.62, P < 0.05). A negative correlation between the concentration of ghrelin in serum and colonic transient time (P = 0.01, rho = -0.23) was shown in the study group.Higher median expression of obestatin receptor G protein-coupled receptor39 in rectal mucosae was found in a constipated group than in the controls (29.9 vs 26.9, P < 0.05). CONCLUSION: Ghrelin, and receptors for ghrelin, obestatin, and glutamate in gastrointestinal mucosa play a role in the pathogenesis of functional constipation in children.


Assuntos
Grelina , Receptores de Glutamato Metabotrópico , Adolescente , Criança , Pré-Escolar , Constipação Intestinal , Feminino , Humanos , Masculino
13.
Int J Mol Sci ; 22(4)2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33670244

RESUMO

The paired sialic acid-binding immunoglobulin like lectins (Siglecs) are characterized by similar cellular distribution and ligand recognition but opposing signalling functions attributed to different intracellular sequences. Since sialic acid-Siglec axis are known to control immune homeostasis, the imbalance between activatory and inhibitory mechanisms of glycan-dependent immune control is considered to promote pathology. The role of sialylation in cancer is described, however, its importance in immune regulation in gliomas is not fully understood. The experimental and clinical observation suggest that dexamethasone (Dex) and temozolomide (TMZ), used in the glioma management, alter the immunity within the tumour microenvironment. Using glioma-microglia/monocytes transwell co-cultures, we investigated modulatory action of Dex/TMZ on paired Siglecs. Based on real-time PCR and flow cytometry, we found changes in SIGLEC genes and their products. These effects were accompanied by altered cytokine profile and immune cells phenotype switching measured by arginases expression. Additionally, the exposure to Dex or TMZ increased the binding of inhibitory Siglec-5 and Siglec-11 fusion proteins to glioma cells. Our study suggests that the therapy-induced modulation of the interplay between sialoglycans and paired Siglecs, dependently on patient's phenotype, is of particular signification in the immune surveillance in the glioma management and may be useful in glioma patient's therapy plan verification.


Assuntos
Antígenos CD/farmacologia , Antígenos de Diferenciação Mielomonocítica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Encefálicas , Glioma , Lectinas/farmacologia , Proteínas de Membrana/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Dexametasona/farmacologia , Glioma/tratamento farmacológico , Glioma/imunologia , Glioma/patologia , Humanos , Fatores Imunológicos/farmacologia , Células THP-1 , Temozolomida/farmacologia
14.
J Clin Med ; 10(2)2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33561079

RESUMO

Follicle-stimulating hormone receptor (FSHR) plays an essential role as one of the most important molecules in response to some of infertility related medications. Impaired ovarian reserve and poor response to such treatments are partially dependent on the FSHR molecule itself. However, the function and drug sensitivity for this receptor may change due to various allele and polymorphisms in the FSHR gene. Studies indicated some of the FSHR-mediated treatments utilized in clinical centers display different outcomes in specific populations, which may arise from FSHR altered genotypes in certain patients. To support the increased demands for reaching the personalized drug and hormone therapy in clinics, focusing on actionable variants through Pharmacogenomic analysis of this receptor may be necessary. The current study tries to display a perspective view on genetic assessments for Pharmacogenomic profiling of the FSHR gene via providing a systematic and critical overview on the genetics of FSHR and its diverse responses to ligands for infertility treatment in females with impaired ovarian responses and show the potential effects of the patient genetic make-up on related binding substances efficacy. All identified functional drug-related alleles were selected through a comprehensive literature search and analyzed. Advanced technologies for the genetic evaluation of them are also discussed properly.

15.
J Clin Med ; 10(1)2020 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-33374421

RESUMO

Pharmacogenomics (PGx) is the knowledge of diverse drug responses and effects in people, based on their genomic profiles. Such information is considered as one of the main directions to reach personalized medicine in future clinical practices. Since the start of applying next generation sequencing (NGS) methods in drug related clinical investigations, many common medicines found their genetic data for the related metabolizing/shipping proteins in the human body. Yet, the employing of technology is accompanied by big obtained data, which most of them have no clear guidelines for consideration in routine treatment decisions for patients. This review article talks about different types of NGS derived PGx variants in clinical studies and try to display the current and newly developed approaches to deal with pharmacogenetic data with/without clear guidelines for considering in clinical settings.

16.
Front Endocrinol (Lausanne) ; 11: 544658, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33193078

RESUMO

Introduction: The pathogenesis of autoimmune thyroid diseases is complicated and not completely known. Among the causes of thyroid autoimmunity, we distinguish genetic predisposition and environmental factors. Graves' disease and Hashimoto's thyroiditis are associated with a disturbance of immune tolerance of thyroid antigen molecules. The IL2RA gene is located on chromosome 10 and encodes the interleukin 2 receptor (IL2RA), which is expressed by the regulatory T-cells (Tregs) responsible for suppression. It has been shown that this gene and its polymorphism occur in people with various autoimmune diseases (e.g. type 1 diabetes mellitus, rheumatoid arthritis, Graves' disease, or multiple sclerosis). The FAIM2 gene is located on chromosome 12 and encodes the molecule involved in the apoptosis inhibition process. The PADI4 gene is located on chromosome 1, and its expression is associated with activation of T-cells, differentiation of macrophages, which leads to increased inflammation. Aim: The aim of the study was to analyze the polymorphisms of the IL-2RA (rs7093069), FAIM2 (rs7138803) and PADI4 (rs1748033) genes and their correlation to thyroid hormones and anti-thyroid antibodies in pediatric patients with Graves' disease and Hashimoto's thyroiditis compared to the control group. Material and Methods: The study was performed in 180 patients with GD (mean age 16.5 ± 2), 80 with HT (mean age, 15.2 ± 2.2), and 114 children without any autoimmune diseases (mean age 16.3 ± 3) recruited from the endocrinology outpatient clinic. Three single nucleotide polymorphisms (SNPs): rs7138803-FAIM2, rs7093069-IL-2RA, and rs1748033 PADI4 were determined by TaqMan SNP QuanStudio 12K Flex-OpenArray genotyping with PCR and correlated to thyroid hormones and anti-thyroid antibodies. Results: Rs7090369-IL-2RA allele T was more frequent in patients with AITDs (33.7% in GD vs 28.7% in HT, p = 0.077, OR = 1.52) compared with healthy children (25%). Allele T of that gene predisposes to the occurrence of autoimmune thyroid diseases, especially GD and TT genotype gives a statistically significant 5.2 times higher risk of GD (p = 0.03, OR = 5.26) and increased risk of HT (p = 0.109, OR = 4.46). Allele A rs7138803-FAIM2 is more frequent in patients with GD (p = 0.071, OR = 1.45) and HT (p = 0.028, OR = 1.8). In our data the presence of GG genotype of that gene significantly reduces the risk of autoimmune thyroid diseases (p = 0.05, OR = 0.42). Allele C rs1748033PADI4 and its CC genotype were more frequent in patients with autoimmune thyroid diseases, but it was not statistically significant. The occurrence of CT genotype significantly reduces the risk of HT (p = 0.03, OR = 0.4). Conclusions: 1). Polymorphisms rs7138803-FAIM2 and rs1748033-PADI4 are more frequent in patients with autoimmune thyroid diseases, more frequent in patients with Hashimoto' thyroiditis, but the occurrence of GG rs7138803-FAIM2 genotype could reduce the risk of thyrocyte apoptosis inhibition. 2). The TT rs7093069-IL2RA genotype may increase the risk of autoimmune thyroid diseases. 3). Analysis of polymorphisms of given genes in clinical practice will allow to determine predisposition to autoimmune thyroid disease development, to find symptoms of thyroid gland dysfunction earlier and to use appropriate treatment.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Doenças Autoimunes/genética , Subunidade alfa de Receptor de Interleucina-2/genética , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único , Proteína-Arginina Desiminase do Tipo 4/genética , Doenças da Glândula Tireoide/genética , Adolescente , Doenças Autoimunes/complicações , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Masculino , Doenças da Glândula Tireoide/complicações
17.
J Immunol Res ; 2020: 8838014, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33224992

RESUMO

PURPOSE: Multiple sclerosis (MS) is an autoimmune disease, and genetic factors play an important role in its pathogenesis and progression. The aim of our study was to evaluate the frequencies of alleles and genetic variants of the T-cell homeostasis-related genes, in subjects with MS, as well as to investigate the association with MS clinical manifestations and disability. METHODS: 94 subjects with MS and 160 healthy individuals have been genotyped for seven common single-nucleotide variants in IL-2RA, CTLA4, CD40, and PADI4 genes. The ages of onset, duration of the disease, and clinical condition of the MS subjects were analysed. We used the Chi2 test confirmed with Fisher's exact test for statistical analysis. RESULTS: The frequency of allele T and CT/TT genotypes (rs7093069) in the IL2RA gene, as well as the T allele and CT/TT genotypes in rs12722598, were significantly higher in the control group. The significant differences between studied groups we also found for the G allele and GG/GA genotypes of rs3087243 in CTLA4 gene, which were more common among the control group. The heterozygous genotype TC (rs1883832) of CD40 gene was more common in the control subjects, and the frequency of the alleles and genotypes in the rs1748033 of the PADI4 gene did not differ between the studied groups. Between the studied genotypes, we did not observe any significant differences in the age of onset and duration of disease, including sex stratification. CONCLUSION: Our results highlight the protective role of some of the T-cell homeostasis-related genetic variants in MS development, but not in its clinical manifestation.


Assuntos
Suscetibilidade a Doenças , Esclerose Múltipla/epidemiologia , Esclerose Múltipla/etiologia , Polimorfismo de Nucleotídeo Único , Linfócitos T/imunologia , Linfócitos T/metabolismo , Adulto , Alelos , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Homeostase/genética , Homeostase/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico , Fenótipo , Polônia/epidemiologia , Vigilância da População
18.
Arch Immunol Ther Exp (Warsz) ; 68(6): 32, 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33125603

RESUMO

A proliferation-inducing ligand (APRIL) is a member of the tumor necrosis factor superfamily that was first identified as a factor favoring tumorigenesis. APRIL is important fitness and survival factors for B cells and plasma cells in the periphery. Considering this, as well as the quantitative predominance of neutrophils among the peripheral blood leukocytes, we carried out the first study assessing the influence of the transforming growth factor (TGF)-ß signaling pathway on APRIL expression in these cells. Furthermore, as the Rb1 ginsenoside is known to exhibit multiple pharmacological activities, we verified if the saponin is capable of modulating the process. The present study shows that TGF-ß increased the expression of APRIL and the level of phospho-p38, phospho-Akt(T308), and phospho-Akt(S473) in the cytoplasmic fraction, as well as the expression of Fra1, c-Fos, and c-Jun in the nuclear fraction, of neutrophils. However, exposure of these cells to Rb1 reduced the expression and level of the investigated proteins. No changes were found in the expression of APRIL and the level of p-p38 in the cytoplasmic fraction of neutrophils following the application of Rb1 alone, as well as in the neutrophils incubated first with Rb1 and then with TGF-ß, whereas a higher level of phosphorylation was observed for Akt and PI3 kinases in the cells. Moreover, a higher expression of all the studied transcription factors was observed in the nuclear fraction of neutrophils. Based on the observed changes, it may be assumed that the expression of APRIL molecule in TGF-ß-induced neutrophils and its regulation by Rb1 are associated with PI3K/AKT signaling pathways and transcription factors Fra-1, Fra-2, c-Jun, and c-Fos. Rb1 appears to be a favorable factor that may be potentially used in the modulation of tumor-promoting APRIL expression.


Assuntos
Ginsenosídeos/farmacologia , Leucócitos Mononucleares/imunologia , Neutrófilos/imunologia , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Células Cultivadas , Regulação da Expressão Gênica , Voluntários Saudáveis , Humanos , Masculino , Neutrófilos/efeitos dos fármacos , Panax/imunologia , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
19.
BMC Med Genet ; 21(1): 198, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-33036569

RESUMO

BACKGROUND: Thrombophilia is a hypercoagulable state that may have a genetic basis (inherited) or can be acquired. It is a multifactorial condition and only the mutual interactions between the environment and genes may lead to the development of clinical manifestation. This state is the main factor promoting venous (rarely arterial) thromboembolism (VTE). Inherited thrombophilia is mainly associated with two pathogenic variants in the V coagulation factor (FV) and the prothrombin (FII) genes. The aim of our study was to evaluate the frequency of two pathogenic variants in FII and FV genes as inherited thrombophilia factors in a group within the Polish population in comparison with other described populations. METHODS: All studied groups consisted of 633 unrelated patients aged between 18 and 70. Individuals in the research group come from the Podlasie region of Poland. Genotyping of FII and FV variants was performed using the 7900HT Fast Real-Time PCR System and were genotyped by TaqMan assay. RESULTS: The pathogenic allele frequency for A allele was 0.03 (3%) and 0.07 (7%) for FII and FV genes, respectively. The GA/AA genotypes (c.*97G > A variant) were observed in only 33 (5.03%) individuals in the studied group. Additionally, the frequency of GA/AA genotypes was over 17.4% in the coagulation factor V. Co-incidence of heterozygous genotype GA of variants FII and FV genes was observed in only 4 subjects. CONCLUSION: The FII gene variant shown in our study is less frequent than in other European countries (about 6%). In contrast, the A allele of the FV gene occurs with a frequency similar to that of Northern, Central and South Central Europe (about 5%).


Assuntos
Fator V/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , Protrombina/genética , Trombofilia/genética , Adolescente , Adulto , Idoso , Alelos , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Trombofilia/diagnóstico , Adulto Jovem
20.
Front Pediatr ; 8: 481, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32974248

RESUMO

Autoimmune thyroid diseases (AITDs) which include Graves' disease (GD) and Hashimoto's thyroiditis (HT) as well as type 1 diabetes (T1D) are common autoimmune disorders in children. Many genes are involved in the modulation of the immune system and their polymorphisms might predispose to autoimmune diseases development. According to the literature genes encoding IL2RA (alpha subunit of Interleukin 2 receptor), IFIH1 (Interferon induced with helicase C domain 1) and CTLA-4 (cytotoxic T cell antigen 4) might be associated with autoimmune diseases pathogenesis. The aim of the study was to assess the association of chosen single nucleotide polymorphisms (SNPs) of IL2RA, IFIH1, and CTLA-4 genes in the group of Polish children with AITDs and in children with T1D. We analyzed single nucleotide polymorphisms (SNPs) in the IL2RA region (rs7093069), IFIH1 region (rs1990760) and CTLA-4 region (rs231775) in group of Polish children and adolescents with type 1 diabetes (n = 194) and autoimmune thyroid diseases (GD n = 170, HT n = 81) and healthy age and sex matched controls for comparison (n = 110). There were significant differences observed between T1D patients and control group in alleles of IL2RA (rs7093069 T > C) and CTLA-4 (rs231775 G > A). In addition, the study revealed T/T genotype at the IL2RA locus (rs7093069) and G/G genotype at the CTLA-4 locus (rs231775) to be statistically significant more frequent in children with T1D. Moreover, genotypes C/T and T/T at the IFIH1 locus (rs1990760) were significantly more frequent in patients with T1D than in controls. We observed no significant differences between AITD patients and a control group in analyzed SNPs. In conclusion, we detected that each allele T of rs7093069 SNP at the IL2RA locus and G allele of rs231775 SNP at the CTLA-4 locus as well as C/T and T/T genotypes of rs1990760 SNP at the IFIH1 locus are predisposing in terms of T1D development. Thereby, we confirmed that IL2RA, IFIH1, and CTLA-4 gene locus have a role in T1D susceptibility. The analysis of selected SNPs revealed no association with AITDs in a group of Polish children and adolescents.

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