Dehydroepiandrosterone and its sulfate are the most abundant steroids in humans. The metabolism of dehydroepiandrosterone can differ significantly depending on the organ or tissue and the subtype of steroid receptors expressed in it. For dehydroepiandrosterone, as a precursor of all steroid hormones, intracrine hormonal activity is inherent. This unique feature could be beneficial for the medicinal application, especially for the local treatment of various pathologies. At present, the clinical use of dehydroepiandrosterone is limited by its Intrarosa^® (Quebec city, QC, Canada) prasterone) 6.5 mg vaginal suppositories for the treatment of vaginal atrophy and dyspareunia, while the dehydroepiandrosterone synthetic derivatives Triplex, BNN 27, and Fluasterone have the investigational status for the treatment of various diseases. Here, we discuss the molecular targets of dehydroepiandrosterone, which open future prospects to expand its indications for use. Dehydroepiandrosterone, as an oral drug, is surmised to have promise in the treatment of osteoporosis, cachexia, and sarcopenia, as does 10% unguent for skin and muscle regeneration. Also, 5-androstenediol, a metabolite of dehydroepiandrosterone, is a promising candidate for the treatment of acute radiation syndrome and as an immunostimulating agent during radiopharmaceutical therapy. The design and synthesis of new 5-androstenediol derivatives with increased bioavailability may lead to the appearance of highly effective cytoprotectors on the pharmaceutical market. The argumentations for new clinical applications of these steroids and novel insights into their mechanisms of action are discussed.

A comparative analysis of the cytostatic effects of progestins (gestobutanoyl, megestrol acetate, amol, dienogest, and medroxyprogesterone acetate), glucocorticoids (hydrocortisone, dexamethasone), and diclofenac on tumor cells was carried out in order to confirm their in silico predicted probabilities experimentally. The results showed the different sensitivity of HeLa, MCF-7, Hep-2, K-562, and Wi-38 cell lines to progestins, glucocorticoids, and diclofenac. The minimum IC₅₀ was found for progestin gestobutanoyl (GB) as 18 µM for HeLa cells, and varied from 31 to 38 µM for MCF-7, Hep-2, and K-562. Glucocorticoids and diclofenac were much less cytotoxic in the HeLa, MCF-7, and Hep-2 cell lines than progestins, with IC₅₀ values in the range of 150–3000 μM. Myelogenous leukemia K-562 cells were the least sensitive to the action of progestins and glucocorticoids but the most sensitive to diclofenac, which showed a pronounced cytotoxic effect with an IC₅₀ of 31 μM. As we have shown earlier, progestins can uniquely modulate MPTP opening via the binding of adenine nucleotide translocase. On this basis, we evaluated the expression of adenylate nucleotide translocase ANT1 (SLC25 A4) as a possible participant in cytotoxic action in these cell lines after 48 h incubation with drugs. The results showed that progestins differently regulated ANT1 expression in different cell lines. Gestobutanoyl had the opposite effect on ANT1 expression in the HeLa, K562, and Wi-38 cells compared with the other progestins. It increased the ANT1 expression more than twofold in the HeLa and K562 cells but had no influence on the Wi-38 cells. Glucocorticoids and diclofenac increased ANT1 expression in the Wi-38 cells and decreased it in the K562, MCF-7, and Hep-2 cells. The modulation of ANT1 expression discovered in our study can be a new explanation of the cytotoxic and cytoprotective effects of hormones, which can vary depending on the cell type. ANT isoforms in normal and cancerous cells could be a new target for steroid hormone and anti-inflammatory drug action.

In order to evaluate the role of substituents at 3-C and 17-C in the cytotoxic and cytoprotective actions of DHEA and 5-AED molecules, their derivatives were synthesized by esterification using the corresponding acid anhydrides or acid chlorides. As a result, seven compounds were obtained: four DHEA derivatives (DHEA 3-propionate, DHEA 3-butanoate, DHEA 3-acetate, DHEA 3-methylsulfonate) and three 5-AED derivatives (5-AED 3-butanoate, 5-AED 3,17-dipropionate, 5-AED 3,17-dibutanoate). All of these compounds showed micromolar cytotoxic activity toward HeLa and K562 human cancer cells. The maximum cytostatic effect during long-term incubation for five days with HeLa and K562 cells was demonstrated by the propionic esters of the steroids: DHEA 3-propionate and 5-AED 3,17-dipropionate. These compounds stimulated the growth of normal Wi-38 cells by 30–50%, which indicates their cytoprotective properties toward noncancerous cells. The synthesized steroid derivatives exhibited antioxidant activity by reducing the production of reactive oxygen species (ROS) by peripheral blood mononuclear cells from healthy volunteers, as demonstrated in a luminol-stimulated chemiluminescence assay. The highest antioxidant effects were shown for the propionate ester of the steroid DHEA. DHEA 3-propionate inhibited luminol-stimulated chemiluminescence by 73% compared to the control, DHEA, which inhibited it only by 15%. These data show the promise of propionic substituents at 3-C and 17-C in steroid molecules for the creation of immunostimulatory and cytoprotective substances with antioxidant properties.

BACKGROUND: Pemphigus is a group of potentially fatal chronic cutaneous diseases in which blisters appear on the skin and mucous membranes as a result of IgG autoantibodies binding to desmosomes in the epidermis, leading to keratinocytes acantholysis. Currently, methods to monitor disease activity and therapy efficiency using various biomarkers are being investigated. MicroRNA expression, in particular miR-338-3p, has been one of these biomarkers, as changes in miR-338-3p expression may trigger the Th1/Th2 cell imbalance and possibly be involved in the pathogenesis of the disease. AIM: This study aimed to design a protocol to evaluate the level of miR-338-3p expression in peripheral blood mononuclear cells and verify the diagnostic value of miR-338-3p expression in pemphigus. MATERIALS AND METHODS: Experimental prospective comparative study was conducted from February 2023 to February 2024 at the Dermatology Department of Sechenov University. The study included 10 patients with pemphigus in the active stage of the disease, 3 patients in remission, and 9 participants of the control group. The expression of miRNA-338-3p was analyzed by real-time polymerase chain reaction, cDNA was obtained using StemLoop method. The evaluation of miRNA-338-3p expression level was based on its comparison with the expression of U6 gene using 2-ΔΔСt method. RESULTS: The expression level of miR-338-3p was analyzed in 10 patients in the active stage of the disease (5 men, 50%; 5 women, 50%; mean age 46±10.7 years), 3 patients in remission (2 women, 66.7%; 1 man, 33.3%; mean age 57±8 years), 9 control group (8 women, 88.9%; 1 man, 11.1%; mean age 36±16.8 years). The mean expression level of miR-338-3p was 8.64 (SD±5.72) in patients with active disease, 3.38 (SD±1.44) in patients in remission, and 1.48 (SD±1.12) in controls. A statistically significant increase in the expression level of miR-338-3p was found in patients in the active disease stage compared to the control group (p=0.002). A statistically significant correlation was found between the level of miR-338-3p expression and the PDAI index score (p 0.001). CONCLUSION: Based on the data obtained in this study, it can be assumed that microRNAs are important in pemphigus, and miR-338-3p expression in particular may serve as a key element in pemphigus pathogenesis. More detailed study of microRNAs and analysis of expression variability according to clinical data may provide the basis for developing new diagnostic methods and severity scoring, allowing more accurate and less invasive diagnostic methods, as well as monitoring and predicting disease progression.

BACKGROUND: Pemphigus is a group of life-threatening, chronic, progressive skin disease. To implement timely and adequate therapy aimed at preserving life and improving its quality, it is necessary to provide a diagnostic test confirming the diagnosis. AIM: This study aimed to compare the expression levels of miR-338-3p and miR-424-5p in patients with pemphigus during therapy and remission, as well as in control groups of patients with other bullous skin diseases and healthy controls, and to evaluate the diagnostic value of miR-338-3p and miR-424-5p expression. MATERIALS AND METHODS: Prospective comparative study was conducted. The study included 20 patients with active pemphigus, 15 patients in remission, 15 healthy control group participants, and 6 patients with other bullous diseases in the active stage. The expression of miRNA-338-3p and miR-424-5p was evaluated by qRT-PCR, cDNA was obtained using StemLoop technology. MicroRNA relative expression levels were analyzed based on its comparison with the expression of U6 gene using 2-ΔΔСT method. RESULTS: The expression levels of miR-338-3p and miR-424-5p were significantly higher in patients with pemphigus active stage compared to all other groups (p 0.001). There was a statistically significant relationship between miR-338-3p expression level and disease severity according to the PDAI index (p 0.001), for miR-424-5p there was also a positive correlation with severity, but with a weaker relationship. ROC analysis showed high diagnostic accuracy of miR-338-3p (AUC 0.94) and miR-424-5p (AUC 0.93) for differentiating between patients with active pemphigus and healthy controls, with sensitivity and specificity of 95.0% and 75.0%, 95.0% and 73.3%, respectively. At week 3 from the start of glucocorticosteroid therapy, miR-338-3p levels were significantly decreased in patients in the active pemphigus (p=0.035), whereas no statistically significant decrease in miR-424-5p was observed. CONCLUSION: miR-338-3p and miR-424-5p are significant in pemphigus as potential biomarkers for diagnosis and severity grade, and the expression level of miR-338-3p can be used to determine the efficacy of pathogenetic therapy.

Pemphigus is a life-threatening autoimmune blistering disease that presents diagnostic challenges due to its variable clinical manifestations. In this study, we evaluated the potential of miR-338-3p and miR-424-5p as biomarkers in the peripheral blood mononuclear cells (PBMCs) of patients with pemphigus vulgaris and foliaceus. Expression levels were analyzed in 37 active pemphigus patients, 20 in remission, 20 healthy controls, and 10 patients with other bullous dermatoses. Both microRNAs were significantly elevated in active disease (p < 0.0001). After three weeks of systemic glucocorticoid therapy, miR-338-3p expression decreased 1.36-fold (p = 0.0001). miR-338-3p expression strongly correlated with Pemphigus Disease Area Index scores (r = 0.828, p < 0.0001), whereas miR-424-5p expression showed no significant correlation (p = 0.198). ROC analysis demonstrated high diagnostic accuracy (area under the curve [AUC]: 0.9711 for miR-338-3p and 0.9581 for miR-424-5p), with sensitivities and specificities exceeding 90%. These findings indicate that miR-338-3p and miR-424-5p are promising diagnostic and monitoring biomarkers in pemphigus, with miR-338-3p reflecting treatment response.