Can vitamin D be an adjuvant therapy for juvenile rheumatic diseases?

Vitamin D, known for its essential role in calcium and bone homeostasis, has multiple effects beyond the skeleton, including regulation of immunity and modulation of autoimmune processes. Several reports have shown suboptimal serum 25 hydroxyvitamin D [25(OH)D] levels in people with different inflammatory and autoimmune rheumatic conditions, and an association between 25(OH)D levels, disease activity and outcomes. Although most available data pertain to adults, insights often are extended to children. Juvenile rheumatic diseases (JRDs) are a significant health problem during growth because of their complex pathogenesis, chronic nature, multisystemic involvement, and long-term consequences. So far, there is no definitive or clear evidence to confirm the preventive or therapeutic effect of vitamin D supplementation in JRDs, because results from randomized controlled trials (RCTs) have produced inconsistent outcomes. This review aims to explore and discuss the potential role of vitamin D in treating selected JRDs. Medline/PubMed, EMBASE, and Scopus were comprehensively searched in June 2023 for any study on vitamin D supplementary role in treating the most common JRDs. We used the following keywords: "vitamin D" combined with the terms "juvenile idiopathic arthritis", "juvenile systemic scleroderma", "juvenile systemic lupus erythematosus", "juvenile inflammatory myopathies", "Behcet disease", "periodic fever syndromes" and "juvenile rheumatic diseases". Observational studies have found that serum 25(OH)D concentrations are lower in juvenile idiopathic arthritis, juvenile systemic lupus erythematosus, juvenile systemic scleroderma, Behcet disease and proinflammatory cytokine concentrations are higher. This suggests that vitamin D supplementation might be beneficial, however, current data are insufficient to confirm definitively the complementary role of vitamin D in the treatment of JRDs. Considering the high prevalence of vitamin D deficiency worldwide, children and adolescents should be encouraged to supplement vitamin D according to current recommendations. More interventional studies, especially well-designed RCTs, assessing the dose-response effect and adjuvant effect in specific diseases, are needed to determine the potential significance of vitamin D in JRDs treatment.

Selected Fungicides as Potential EDC Estrogenic Micropollutants in the Environment.

An increasing level of pesticide exposition is being observed as a result of the consumption of large amounts of fruits, vegetables and grain products, which are key components of the vegetarian diet. Fungicides have been classified as endocrine-disrupting compounds, but their mechanisms of action have not yet been clarified. The effect of boscalid (B), cyprodinil (C) and iprodione (I) combined with Tamoxifen (T) and 17ß-estradiol (E2) on cell viability, cell proliferation, reporter gene expression, ROS content, the cell membrane's function, cell morphology and antioxidant enzymes gene expression in MCF-7 and T47D-KBluc cell lines were investigated. The cell lines were chosen due to their response to 17ß -estradiol. The selected fungicides are commonly used in Poland to protect crops against fungi. Our results revealed that the studied fungicides caused significant increases in cell viability and proliferation, and estrogenic activity was present in all studied compounds depending on their concentrations. Oxidative stress activated uncontrolled cancer cell proliferation by inducing ROS production and by inhibiting antioxidant defense. Our findings verify that the studied fungicides could possibly exhibit endocrine-disrupting properties and exposure should be avoided.

Clustered microRNAs: The molecular mechanism supporting the maintenance of luteal function during early pregnancy.

MicroRNAs (miRNAs) are recognized as the important regulators of ovarian function. However, little is known about the hormonal regulation of miRNA expression and the role of the specific miRNA-mRNA interactions in corpus luteum. Therefore, the present study was undertaken to determine: (a) the expression of miRNAs in the corpus luteum in early pregnancy vs regression; (b) the effect of conceptus and uterine signals in the expression of selected miRNAs; and (c) the role of specific miRNA-mRNA interactions in the molecular changes and secretory function of the corpus luteum in the pig. The results showed that the majority of miRNAs differentially expressed in the corpus luteum in early pregnancy vs regression belong to independent clusters (eg, miR-99b, miR-532), which are highly conserved among different animal species. The main conceptus signal in the pig (17ß-estradiol) elevated the luteal expression of the miR-99b cluster and lowered the expression of NR4A1 and AKR1C1, the genes involved in corpus luteum regression. Furthermore, the delivery of miR-99b cluster mimics to luteal tissue concomitantly decreased NR4A1 and AKR1C1 expression and enhanced progesterone secretion. The present study demonstrated that conceptus signals can support the maintenance of luteal function during pregnancy by clustered miRNA-stimulated pathways, governing the expression of genes involved in luteal regression.

Pannexins and Connexins: Their Relevance for Oocyte Developmental Competence.

The oocyte is the major determinant of embryo developmental competence in all mammalian species. Although fundamental advances have been generated in the field of reproductive medicine and assisted reproductive technologies in the past three decades, researchers and clinicians are still trying to elucidate molecular factors and pathways, which could be pivotal for the oocyte's developmental competence. The cell-to-cell and cell-to-matrix communications are crucial not only for oocytes but also for multicellular organisms in general. This latter mentioned communication is among others possibly due to the Connexin and Pannexin families of large-pore forming channels. Pannexins belong to a protein group of ATP-release channels, therefore of high importance for the oocyte due to its requirements of high energy supply. An increasing body of studies on Pannexins provided evidence that these channels not only play a role during physiological processes of an oocyte but also during pathological circumstances which could lead to the development of diseases or infertility. Connexins are proteins that form membrane channels and gap-junctions, and more precisely, these proteins enable the exchange of some ions and molecules, and therefore they do play a fundamental role in the communication between the oocyte and accompanying cells. Herein, the role of Pannexins and Connexins for the processes of oogenesis, folliculogenesis, oocyte maturation and fertilization will be discussed and, at the end of this review, Pannexin and Connexin related pathologies and their impact on the developmental competence of oocytes will be provided.

Oxytocin antagonism reverses the effects of high oestrogen levels and oxytocin on decidualization and cyclooxygenase activity in endometrial tissues.

RESEARCH QUESTION: What is the in-vitro effect of oxytocin receptor (OTR) antagonism on parameters of receptivity in human endometrial explants and endometrial stromal cell lines cultured in oestradiol-rich conditions mimicking ovarian stimulation? DESIGN: Experimental in-vitro study on endometrial tissue explants collected by aspiration biopsy from 30 women undergoing fertility treatment and cultured endometrial tHESC cell line. The study examined the effects of high oestradiol, oxytocin and OTR antagonist on parameters of decidualization (cell viability and prolactin secretion) as well as cyclooxygenase-1/2 (COX-1/2) activity and prostaglandin F2α (PGF2α) secretion. Changes in expression of OXTR and COX-2 genes were examined using quantitative polymerase chain reaction (qPCR). RESULTS: In experiments on cultured endometrial cell line, high oestradiol and oxytocin similarly limited the viability of cells. In cultured endometrial explants both also decreased the secretion of prolactin (a marker of decidualization) and augmented endometrial COX-2 activity and formation of PGF2α. Oxytocin antagonist atosiban was confirmed to reverse the above effects, both in the endometrial line and endometrial explants. Addition of atosiban to cultures acted analogously in experiments employing both oxytocin and high oestradiol. CONCLUSIONS: Oxytocin antagonist reversed the effects of high oestradiol and oxytocin on parameters related to endometrial receptivity in conditions mimicking ovarian stimulation. This might point to a novel, endometrium-related mechanism to support embryo implantation achieved by the application of oxytocin antagonist prior to embryo transfer.

Circulating serum miR-362-3p and miR-6721-5p as potential biomarkers for classification patients with adult-type diffuse glioma.

According to the fifth edition of the WHO Classification of Tumours of the Central Nervous System (CNS) published in 2021, grade 4 gliomas classification includes IDH-mutant astrocytomas and wild-type IDH glioblastomas. Unfortunately, despite precision oncology development, the prognosis for patients with grade 4 glioma remains poor, indicating an urgent need for better diagnostic and therapeutic strategies. Circulating miRNAs besides being important regulators of cancer development could serve as promising diagnostic biomarkers for patients with grade 4 glioma. Here, we propose a two-miRNA miR-362-3p and miR-6721-5p screening signature for serum for non-invasive classification of identified glioma cases into the highest-grade 4 and lower-grade gliomas. A total of 102 samples were included in this study, comprising 78 grade 4 glioma cases and 24 grade 2-3 glioma subjects. Using the NanoString platform, seven miRNAs were identified as differentially expressed (DE), which was subsequently confirmed via RT-qPCR analysis. Next, numerous combinations of DE miRNAs were employed to develop classification models. The dual panel of miR-362-3p and miR-6721-5p displayed the highest diagnostic value to differentiate grade 4 patients and lower grade cases with an AUC of 0.867. Additionally, this signature also had a high AUC = 0.854 in the verification cohorts by RT-qPCR and an AUC = 0.842 using external data from the GEO public database. The functional annotation analyses of predicted DE miRNA target genes showed their primary involvement in the STAT3 and HIF-1 signalling pathways and the signalling pathway of pluripotency of stem cells and glioblastoma-related pathways. For additional exploration of miRNA expression patterns correlated with glioma, we performed the Weighted Gene-Co Expression Network Analysis (WGCNA). We showed that the modules most associated with glioma grade contained as many as six DE miRNAs. In conclusion, this study presents the first evidence of serum miRNA expression profiling in adult-type diffuse glioma using a classification based on the WHO 2021 guidelines. We expect that the discovered dual miR-362-3p and miR-6721-5p signatures have the potential to be utilised for grading gliomas in clinical applications.