Signaling pathways and their miRNA regulators involved in the etiopathology of idiopathic pulmonary fibrosis (IPF) and hypersensitivity pneumonitis (HP)

  Idiopathic pulmonary fibrosis (IPF) and hypersensitivity pneumonitis (HP) belong to heterogenic group of interstitial lung diseases (ILD). For the reason that this group of diseases present with complex clinical non-specific features, they represent a diagnostic and therapeutic challenge. In this review we focus on several crucial signaling pathways participating in inflammation, fibrosis and EMT processes, so important in the course of ILD: TNF-α/NFκβ, TGF-β/SMAD, Wnt-β-catenin and PI3K-Akt signaling. Moreover, this review summarizes the role of selected signaling pathways and some miRNAs which are their regulators during development and progression of IPF and HP. Recent advances indicate the potential role of miRNAs as a molecular markers differentiating clinical course of ILD.

Proteomic biomarkers of non-small cell lung cancer patients

Lung cancer is a disease with a very low 5-year survival rate (6–13%) worldwide. The most frequently diagnosed histological type of this cancer is non-small cell lung cancer (NSCLC). Poor prognosis for lung cancer — including NSCLC — is mainly related to the fact that patients are diagnosed in the advanced stages of the disease. The aim of this study is to summarize data that concerns new directions of research regarding diagnostic biomarkers that could be used to support the routine diagnosis of this cancer. In recent years, proteomic analysis has become an important tool for cancer biology research, complementing genetic analysis. Among the numerous methods of proteomic analysis, mass spectrometry techniques enable the extremely accurate qualitative and quantitative identification of hundreds of proteins in small volumes of various biological samples. Such analyses may soon become the basis of improvement in lung cancer diagnostic procedures. This study presents the latest reports in proteomic research concerning the diagnosis of NSCLC. New potential proteomic biomarkers, whose presence indicates the development of a neoplastic process at an early stage, are presented. We describe biomarkers whose altered expression levels correlate with different stages of cancer. We also present protein biomarkers that help differentiate NSCLC subtypes. In the clinical workup of NSCLC patients, it is important not only to make an early diagnosis, but also to monitor the development of the neoplastic disease. Considering this fact, we also present examples of biomarkers whose abnormal expression may indicate a high risk of metastasis to the lymph nodes. This paper also emphasizes the need to conduct further research that would confirm the usefulness of the described biomarkers in clinical practice

Selected molecular events in the pathogenesis of sarcoidosis — recent advances

Sarcoidosis is an orphan inflammatory disorder that can virtually affect any organ or system in the body, although the lungs and lymph nodes are most frequently involved. Sarcoidosis is believed to derive from an interaction between environmental and genetic agents. Many studies emphasize a strong association between certain human leukocyte antigen (HLA) alleles and sarcoidosis susceptibility. Several new insights have allowed the further evaluation of other candidate genes with a potential function in the immunopathogenesis of sarcoidosis. This review summarizes recent advances in the identification of novel molecular markers that may play a role in different stages of disease, such as the acute phase of inflammation, granuloma formation and fibrosis. Furthermore, this article elucidates the role of both TGF-b/Smad and (HIF)-1a-VEGF-ING-4 signaling pathways in the development of sarcoidosis. The potential epigenetic regulation of the processes occurring in sarcoidosis by miRNA is also discussed.Sarcoidosis is an orphan inflammatory disorder that can virtually affect any organ or system in the body, although the lungs and lymph nodes are most frequently involved. Sarcoidosis is believed to derive from an interaction between environmental and genetic agents. Many studies emphasize a strong association between certain human leukocyte antigen (HLA) alleles and sarcoidosis susceptibility. Several new insights have allowed the further evaluation of other candidate genes with a potential function in the immunopathogenesis of sarcoidosis. This review summarizes recent advances in the identification of novel molecular markers that may play a role in different stages of disease, such as the acute phase of inflammation, granuloma formation and fibrosis. Furthermore, this article elucidates the role of both TGF-b/Smad and (HIF)-1a-VEGF-ING-4 signaling pathways in the development of sarcoidosis. The potential epigenetic regulation of the processes occurring in sarcoidosis by miRNA is also discussed

An Analysis of IL-10, IL-17A, IL-17RA, IL-23A and IL-23R Expression and Their Correlation with Clinical Course in Patients with Psoriasis.

Being one of the most common dermatological inflammatory disorders, psoriasis is a frequent subject of research. It is considered to be a T cell-dependent immune disease whose pathogenesis is influenced by cytokines, such as IL-10, IL-17A, IL-17RA, IL-23A and IL-23R. The present study examines whether the expression of selected genes is correlated with the clinical course of psoriasis, assessed by the PASI, BSA and DLQI scales. Skin biopsies and blood from 60 patients with psoriasis and 24 healthy controls were obtained for RNA isolation. These were subjected to RT-PCR for IL-10, IL-17A, IL-17RA, IL-23A and IL-23R genes. The results were presented as an RQ value. IL-17A and IL-23R expression levels were higher in psoriatic skin compared to controls, while IL-10 expression was lower. A positive correlation was also found between RQ for IL-23A and PASI index. Psoriatic skin is characterised by elevated expression of IL-17A and IL-23R and decreased expression of IL-10. This indicates that the selected cytokines may be one of the factors involved in the pathogenesis and pathomechanism of psoriasis, but more studies need to be made before we can elucidate the exact reason for the unbalance in cytokine expression levels

Proteomic Biomarkers of Non-Small Cell Lung Cancer Patients

Lung cancer is a disease with a very low 5-year survival rate (6–13%) worldwide. The most frequently diagnosed histological type of this cancer is non-small cell lung cancer (NSCLC). Poor prognosis for lung cancer—including NSCLC—is mainly related to the fact that patients are diagnosed in the advanced stages of the disease. The aim of this study is to summarize data that concerns new directions of research regarding diagnostic biomarkers that could be used to support the routine diagnosis of this cancer. In recent years, proteomic analysis has become an important tool for cancer biology research, complementing genetic analysis. Among the numerous methods of proteomic analysis, mass spectrometry techniques enable the extremely accurate qualitative and quantitative identification of hundreds of proteins in small volumes of various biological samples. Such analyses may soon become the basis of improvement in lung cancer diagnostic procedures. This study presents the latest reports in proteomic research concerning the diagnosis of NSCLC. New potential proteomic biomarkers, whose presence indicates the development of a neoplastic process at an early stage, are presented. We describe biomarkers whose altered expression levels correlate with different stages of cancer. We also present protein biomarkers that help differentiate NSCLC subtypes. In the clinical workup of NSCLC patients, it is important not only to make an early diagnosis, but also to monitor the development of the neoplastic disease. Considering this fact, we also present examples of biomarkers whose abnormal expression may indicate a high risk of metastasis to the lymph nodes. This paper also emphasizes the need to conduct further research that would confirm the usefulness of the described biomarkers in clinical practice

A role of vitamin D in athletes

Witamina D jest prohormonem, który jest wytwarzany w ludzkiej skórze pod wpływem promieni słonecznych oraz może zostać dostarczona egzogennie, poprzez dietę i/lub rekomendowaną suplementację. Utrzymanie prawidłowego poziomu witaminy D w surowicy jest istotne, ze względu na zachowanie dobrego stanu zdrowia populacji, jak również prewencję wielu chorób, np. takich jak cukrzyca, nowotwory czy schorzenia autoimmunologiczne. Większość populacji krajów na całym Świecie ma problem z utrzymaniem odpowiedniego poziomu witaminy D w populacji. Interesujące jest to, że prewencja jej niedoboru jest dużo skuteczniejsza w Europie niż w Azji, Australii czy USA, szczególnie w grupach podwyższonego ryzyka: u osób starszych, niemowląt i kobiet ciężarnych. Jak dotąd, niewiele uwagi poświęcono badaniom populacji sportowców profesjonalnych, jako grupie wysokiego ryzyka niedoboru witaminy D. Obserwowane jej niedobory u sportowców, wiążą się przede wszystkim ze wzmożonym obrotem tkanki kostnej, mikrouszkodzeniami układu ruchu, indukowanym intensywnymi ćwiczeniami. Kolejną przyczyną niedoboru witaminy D w tej grupie jest niedostateczna jej synteza spowodowana ograniczonym dostępem promieni słonecznych, występującym w zamkniętych ośrodkach sportowych. Z dotychczas przeprowadzonych badań wynika, że prawidłowy poziom witaminy D w istotny sposób poprawia wydajność fizyczną, poprzez swoje pozytywne działanie na system szkieletowo-mięśniowy. Odpowiedni poziom witaminy D u sportowców determinuje zwiększoną kurczliwość mięśni, ich siłę i moc, a także poprawę wydolności tlenowej, co pozwala na osiągnięcie lepszych rezultatów sportowych. Suplementacja witaminą D wpływa również na poprawę zdolności regeneracyjnych mikrourazów tkanki mięśniowej czy tkanki łącznej oraz powoduje zmniejszenie bólu w przypadku wystąpienia pourazowego stanu zapalnego. Wykazano, że niedobór witaminy D zwiększa podatność sportowców na sezonowe zachorowania wirusowe i bakteryjne, co znacząco ogranicza ich możliwości treningowe. Powyżej opisane fakty, świadczą o potrzebie monitorowania poziomu witaminy D w surowicy w całej populacji, a w szczególności w grupach ryzyka, w tym u zawodowych sportowców. Działanie takie pozwoli na uzupełnienie opracowanych rekomendacji dotyczących schematów suplementacji witaminy D o grupę sportowców jako potencjalną grupę jej niedoborów.Vitamin D is a prohormone which is produced in the human skin upon exposure to the sunlight and delivered exogenously from the diet and/or a recommended dose of supplementation. Maintaining the adequate vitamin D serum status is of great importance in establishing good health in the population. It is also pivotal in prevention of high burden diseases e.g. like diabetes, cancer, cardiovascular diseases and autoimmune disorders. Most of the countries in the world have a problem with maintaining an adequate level of vitamin D in society. It is interesting that prevention its deficiency is much more effective in Europe than in Asia, Australia or the USA, especially in high-risk groups: the elderly, infants and pregnant women. So far, little attention has been focused on the population of professional athletes, as a high risk group of vitamin D deficiencies. Observed vitamin D deficits in athletes, are associated with increased bone turnover, musculoskeletal exercise induced damage and limited access to sunlight, occurring in closed sports centres. In light of published studies appears that, vitamin D significantly improves physical performance through its helpful action on the skeletal and muscular system. In addition, its appropriate level in athletes is associated with increased muscle contractility, strength and power, as well as improved aerobic capacity, which allows them to achieve better sports results during the competition. Moreover, vitamin D supplementation improves the regenerative capacity of microinjuries in the muscle tissue or tendons and reduces the pain if inflammation occurs. In turn, its deficiency reduces the susceptibility of athletes to seasonal viral and bacterial diseases. The above-described facts testify to the need to monitor the level of vitamin D in the serum in the whole population, and in particular in the risk group of professional athletes. This action will allow to consistently introduce recommendations regarding vitamin D supplementation schemes to prevent its deficiency

Detection of cross-resistance between methotrexate and azoles in Candida albicans and Meyerozyma guilliermondii: an in vitro study

In recent years, there has been a rapid increase in the incidence of Candida infections. The different species of the genus Candida vary in their virulence abilities and susceptibility to antifungal agents, depending on several external factors. The result of such modifications may be cross-resistance, which is understood as an acquired resistance to a certain antimicrobial agent after exposure to another drug. The aim of this study was to determine the possibility of cross-resistance between fluconazole, voriconazole, itraconazole, and methotrexate in Candida albicans and Meyerozyma guilliermondii (syn. Candida guilliermondii). Fifteen strains of M. guilliermondii and eight strains of C. albicans, including the standard strains, were tested. For all strains, the minimum inhibitory concentrations (MICs) for fluconazole, voriconazole, and itraconazole were determined before and after stimulation with methotrexate. The median MICs in M. guilliermondii before and after stimulation were 9.333 and 64 mg/L (p = 0.005) for fluconazole; 0.917 and 1.667 mg/L (p = 0.001) for itraconazole, respectively. No significant change in MIC was observed for voriconazole. For C. albicans strains, the median MICs before and after stimulation were 0.917 and 64 mg/L (p = 0.012) for fluconazole; 0.344 and 1.135 mg/L (p = 0.018) for voriconazole, respectively. There was no significant change in MIC values for itraconazole. Thus, this study demonstrates the presence of cross-resistance between voriconazole, itraconazole, fluconazole, and methotrexate for the selected strains. Methotrexate exposure induces different responses when certain drugs are used for various species. Therefore, if a patient was previously exposed to methotrexate, there may be a higher risk of treatment failure with fluconazole than with other azoles such as voriconazole for fungemia caused by M. guilliermondii or itraconazole for C. albicans infection

The Significance of the Alter miR let-7a and miR-335 Expression Level Regulating the CCR7/CCL19 Axis as Potential Biomarkers of Tumor Progression in NSCLC

The chemokine receptor 7/C-C ligand 19 chemokine (CCR7/CCL19) has been implicated in the development and progression of NSCLC. Its expression is regulated by various epigenetic factors including miRNAs. The aim of this study was to assess the expression of CCR7/CCL19 in cancer tissue in relation to that of miRNAs (miR-let-7a, miR-335) as transcriptional regulators. The expression of the tested miRNAs was also evaluated in serum exosomes. Sixty patients (n = 60) were enrolled in the study. The total expression of the studied mRNA and miRNAs were evaluated using qPCR. Tumor tissue fragments, macroscopically unchanged adjacent tissue, and serum were used as controls. Higher CCR7 and CCL19 mRNA expression levels were observed in tumor tissue compared to control. According to stages of the disease (AJCC tumor staging), the greatest expression level of the studied genes’ mRNA was observed in patients with stage III. In NSCLC patients, lower miR let-7a expression level was observed in tumor tissue compared to serum; however, miR-335 expression level was higher (p p > 0.05) with liquid biopsy. Significantly greater miR-335 expression level and lower miR let-7a expression level in serum were observed in patients with metastases to lymph nodes. Our findings reveal a significant correlation between the expression levels of the mRNA of the studied genes and miRNAs. Changes in miR-335 and miR let-7a expression levels in the serum exosomes of NSCLC patients in relation to lymph node metastases and tumor stage may serve as a non-invasive molecular biomarker of tumor progression

The Expression of TGF-β1, SMAD3, ILK and miRNA-21 in the Ectopic and Eutopic Endometrium of Women with Endometriosis

The molecular pathogenesis of endometriosis has been associated with pathological alterations of protein expression via disturbances in homeostatic genes, miRNA expression profiles, and signaling pathways that play an essential role in the epithelial-mesenchymal transition (EMT) process. TGF-β1 has been hypothesized to play a key role in the development and progression of endometriosis, but the activation of a specific mechanism via the TGF-β-SMAD-ILK axis in the formation of endometriotic lesions is poorly understood. The aim of this study was to assess the expression of EMT markers (TGF-β1, SMAD3, ILK) and miR-21 in ectopic endometrium (ECE), in its eutopic (EUE) counterpart, and in the endometrium of healthy women. The expression level of the tested genes and miRNA was also evaluated in peripheral blood mononuclear cells (PBMC) in women with and without endometriosis. Fifty-four patients (n = 54; with endometriosis, n = 29, and without endometriosis, n = 25) were enrolled in the study. The expression levels (RQ) of the studied genes and miRNA were evaluated using qPCR. Endometriosis patients manifested higher TGF-β1, SMAD3, and ILK expression levels in the eutopic endometrium and a decreased expression level in the ectopic lesions in relation to control tissue. Compared to the endometrium of healthy participants, miR-21 expression levels did not change in the eutopic endometrium of women with endometriosis, but the RQ was higher in their endometrial implants. In PBMC, negative correlations were found between the expression level of miR-21 and the studied genes, with the strongest statistically significant correlation observed between miR-21 and TGF-β1. Our results suggest the loss of the endometrial epithelial phenotype defined by the differential expression of the TGF-β1, SMAD3 and ILK genes in the eutopic and ectopic endometrium. We concluded that the TGF-β1-SMAD3-ILK signaling pathway, probably via a mechanism related to the EMT, may be important in the pathogenesis of endometriosis. We also identified miR-21 as a possible inhibitor of this TGF-β1-SMAD3-ILK axis

Assessment of <i>BMP7</i>, <i>SMAD4</i>, and <i>CDH1</i> Expression Profile and Regulatory miRNA-542-3p in Eutopic and Ectopic Endometrium of Women with Endometriosis

Alterations in the expression of numerous genes and the miRNAs that are recognized as their regulators in the endometrial cells of women with endometriosis may disrupt the intracellular signaling pathways associated with epithelial–mesenchymal transition (EMT). So far, the functional role of BMP7 in endometrial physiology has been confirmed, especially in the context of fertility, but the role of the activation of a specific mechanism operating through the BMP–SMAD–CDH1 axis in the formation of endometrial lesions remains unexplored. The aim of this study was to evaluate the expression profile of miR-542-3p and the EMT markers (BMP7, SMAD4, CDH1) in matched eutopic endometrium (EUE) and ectopic endometrium (ECE) samples from women with endometriosis in relation to healthy women. The levels of expression of the studied genes and miRNA in peripheral blood mononuclear cells (PBMCs) obtained from women diagnosed with endometriosis and those without the disease were also evaluated. Fifty-four patients (n = 54: with endometriosis—n = 29 and without endometriosis—n = 25) were included in the study. A comparative analysis of the relative mean expression values (RQ) of the studied mRNA and miRNA assessed by RT-qPCR demonstrated downregulation of BMP7, SMAD4, and CDH1 expression in ectopic lesions and upregulation in the eutopic endometrium compared with the control group. In the eutopic tissue of women with endometriosis, miR-542-3p expression was similar to that of the control but significantly lower than in endometrial lesions. We also confirmed a trend towards a negative correlation between miR-542-3p and BMP7 in ectopic tissue, and in PBMC, a significant negative correlation of miR-542-3p with further BMP signaling genes, i.e., SMAD4 and CDH1, was observed. These results indicate that the miRNA selected by us may be a potential negative regulator of BMP7-SMAD4-CDH1 signaling associated with EMT. The different patterns of BMP7, SMAD4, and CDH1 gene expression in ECE, EUE, and the control endometrium observed by us suggests the loss of the endometrial epithelium phenotype in women with endometriosis and demonstrates their involvement in the pathogenesis and pathomechanism of this disease