Relevance: Mitochondrial dysfunction and systemic inflammation are believed to play pivotal role in the pathogenesis of polycystic ovary syndrome (PCOS) and related complications of metabolic disorders in adult patients. Though such researches are limited or almost absent in adolescents. The aim of the study is to evaluate the impact of mitochondrial dysfunction and systemic inflammation on PCOS pathogenesis during adolescence with regard to body mass index and insulin resistance. Design: a case-control study. Methods: The study included 95 adolescent girls (15 to 17 years old inclusive) diagnosed with PCOS based on the Rotterdam criteria. The control group consisted of 30 healthy girls of the same age with a regular menstrual cycle. All participants were subjected to a full clinical and instrumental examination, as well as an assessment of the levels of leptin, C-reactive protein (CRP), and malondialdehyde (MDA) as oxidative stress marker. Serum levels of IL-6, IL-10, IL-18, TNF-α, and plasma concentrations of macrophage migration inhibitory factor (MIF), sFas, and sFasL were determined. Patients with PCOS were divided into groups according to the presence of metabolic disorders (MD) (impaired glucose tolerance and/or over insulin resistance) and normal weight or excessive weight (NW or OW). Results: Patients with PCOS of NW in the absence of metabolic disorders (MD−/NW) had a lower concentration of MDA and a higher level of IL-10 compared to healthy girls (p < 0.05). The group (MD−/NW) was characterized with lower levels of CRP, leptin, MDA, and higher levels of sFasL, when compared to OW patients with PCOS in the absence of metabolic disorders (MD−/OW) (p < 0.05). Overweight adolescent girls with PCOS and metabolic disorders (MD+/OW) showed higher CRP, leptin, and a two-fold increase in IL-6 and IL-18 concentrations compared to the control group of healthy girls (p < 0.05 for all parameters). The group (MD+/OW) was also characterized with higher levels of CRP, leptin, MDA, IL-18, MIF (p < 0.05), when compared to overweight patients with PCOS in the absence of metabolic disorders (MD−/NW). In comparison with the MD−/OW group, the obese insulin resistant girls with PCOS (MD+/OW) had a highera level of IL-18 (p < 0.05). Moreover, the MD+/OW girls demonstrated a significant increase in CRP, MDA and IL-18 levels when compared to the MD+/NW group (p < 0.05). OW girls with PCOS without MD (MD−/OW) had lower concentrations of sFasL compared to healthy girls (p < 0.05), and higher levels of MDA compared to MD+/NW (p < 0.05). Adolescent girls of NW with PCOS and with MD (MD+/NW) had lower levels of MDA compared to the control group of healthy girls (p < 0.05). These data are confirmed by a correlation analysis and two-factor ANOVA test. Conclusions: Lean girls with PCOS demonstrate the protective mechanism of decrease in oxidative stress mediated by the activation of antioxidant defense, reduction of lipid peroxidation and systemic inflammation. Excessive weight and metabolic disorders in adolescents with PCOS are the most significant factors in reducing the capacity of antioxidant systems, activation of oxidative stress, mitochondrial dysfunction, and systemic inflammation.

Relevance: The clinical picture of polycystic ovary syndrome (PCOS) is extremely polymorphic, especially in adolescence. At the same time, the diagnostic criteria of PCOS in adolescence are still under discussion, and the hormonal parameters, including anti-Mullerian hormone range and hyperandrogenism, are not determined. The aim of the present study was to characterize the pivotal clinical and hormonal features of PCOS in adolescents and to establish the age-specific thresholds of the most essential hormonal parameters. Design: A case-control study. Methods: The study included 130 girls with PCOS according to the complete Rotterdam criteria, aged 15 to 17 years. The control group consisted of 30 healthy girls with a regular menstrual cycle of the same age. A complete clinical and laboratory examination, hormonal assays, and ultrasound of the pelvic organs were performed. The serums anti-Mullerian hormone (AMH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), LH/FSH, prolactin, estradiol, 17α-OH progesterone (17α-OHP), androstenedione, testosterone (T), dehydroepiandrosterone sulfate (DHEAS), sex hormone-binding globulin (SHBG), leptin, and free androgen index (FAI) were analyzed. The diagnostic accuracy of AMH, FAI, LH/FSH, T, and androstenedione levels in predicting PCOS in adolescents was established using a logistic regression model and calculating area under the receiver operator characteristic (ROC) curve (AUC). Results: The serum levels of LH (9.0 (5.4–13.8) vs. 3.7 (2.5–4.7) IU/L; p < 0.0001), LH/FSH (1.6 (1.0–2.3) vs. 0.7 (0.5–1.1); p < 0.0001), 17α–OHP (4.1 (3.2–5.1) vs. 3.4 (2.7–3.8) nmol/L; p = 0.0071), cortisol (464.0 ± 147.6 vs. 284.0 ± 129.7 nmol/L; p < 0.0001), prolactin (266.0 (175.0–405.0) vs. 189.0 (142.0–269.0) mIU/L; p = 0.0141), T (1.9 (1.2–2.5) vs. 0.8 (0.7–1.1) nmol/L; p < 0.0001), androstenedione (15.8 (11.6–23.2) vs. 8.3 (6.5–10.8) ng/mL; p < 0.0001), AMH (9.5 (7.5–14.9) vs. 5.8 (3.8–6.9) ng/mL; p < 0.0001), FAI (5.5 (2.8–7.0) vs. 1.6 (1.1–2.3); p < 0.0001), SHBG (37.0 (24.7–55.5) vs. 52.9 (39.0–67.6) nmol/L; p = 0.0136), DHEAS (6.8 ± 3.2 vs. 5.1 ± 1.5 μmol/L; p = 0.0039), and leptin (38.7 ± 27.1 vs. 23.7 ± 14.0 ng/mL; p = 0.0178) were significantly altered in the PCOS patients compared to the controls. Multivariate analysis of all studied hormonal and instrumental parameters of PCOS in adolescents revealed as the most essential: AMH level > 7.20 ng/mL, FAI > 2.75, androstenedione > 11.45 ng/mL, total T > 1.15 nmol/L, LH/FSH ratio > 1.23, and the volume of each ovary > 10.70 cm³ (for each criterion sensitivity ≥ 75.0–93.0%, specificity ≥ 83.0–93.0%). The diagnostic accuracy of PCOS determination was 90.2–91.6% with the combined use of either four detected indexes, which was significantly higher than the use of each index separately. The accuracy of PCOS diagnostics reached 92% using AMH and leptin concentrations when the value of the logistic regression function [85.73 − (1.73 × AMH) − (0.12 × Leptin)] was less than 70.72. Conclusions: The results of the study estimate the threshold for AMH, FAI, androstenedione, testosterone, LH/FSH, and ovarian volume, which could be suggested for use in the PCOS diagnostics in adolescents with a high sensitivity and specificity. Moreover, the combination of either four determined indexes improved the diagnostic accuracy for the PCOS detection in adolescents.

Arthritis is a widespread inflammatory disease associated with progressive articular surface degradation, ongoing pain, and hyperalgesia causing the development of functional limitations and disability. TRPV1 channel is one of the high-potential targets for the treatment of inflammatory diseases. Polypeptide APHC3 from sea anemone Heteractis crispa is a mode-selective TRPV1 antagonist that causes mild hypothermia and shows significant anti-inflammatory and analgesic activity in different models of pain. We evaluated the anti-inflammatory properties of APHC3 in models of monosodium iodoacetate (MIA)-induced osteoarthritis and complete Freund’s adjuvant (CFA)-induced rheumatoid monoarthritis in comparison with commonly used non-steroidal anti-inflammatory drugs (NSAIDs) such as diclofenac, ibuprofen, and meloxicam. Subcutaneous administration of APHC3 (0.1 mg/kg) significantly reversed joint swelling, disability, grip strength impairment, and thermal and mechanical hypersensitivity. The effect of APHC3 was equal to or better than that of reference NSAIDs. Protracted treatment with APHC3 decreased IL-1b concentration in synovial fluid, reduced inflammatory changes in joints, and prevented the progression of cartilage degradation. Therefore, polypeptide APHC3 has the potential to be an analgesic and anti-inflammatory substance for the alleviation of arthritis symptoms.

Calcium ions (Ca²⁺) influx to mitochondrial matrix is crucial for the life of a cell. Mitochondrial calcium uniporter (mtCU) is a protein complex which consists of the pore-forming subunit (MCU) and several regulatory subunits. MtCU is the main contributor to inward Ca²⁺ currents through the inner mitochondrial membrane. Extensive investigations of mtCU involvement into normal and pathological molecular pathways started from the moment of discovery of its molecular components. A crucial role of mtCU in the control of these pathways is now recognized in both health and disease. In particular, impairments of mtCU function have been demonstrated for cardiovascular and skeletal muscle-associated pathologies. This review summarizes the current state of knowledge on mtCU structure, regulation, and function in different types of muscle tissues in health and disease.

Progressive articular surface degradation during arthritis causes ongoing pain and hyperalgesia that lead to the development of functional disability. TRPA1 channel significantly contributes to the activation of sensory neurons that initiate neurogenic inflammation and mediates pain signal transduction to the central nervous system. Peptide Ms 9a-1 from the sea anemone Metridium senile is a positive allosteric modulator of TRPA1 and shows significant anti-inflammatory and analgesic activity in different models of pain. We used a model of monosodium iodoacetate (MIA)-induced osteoarthritis to evaluate the anti-inflammatory properties of Ms 9a-1 in comparison with APHC3 (a polypeptide modulator of TRPV1 channel) and non-steroidal anti-inflammatory drugs (NSAIDs) such as meloxicam and ibuprofen. Administration of Ms 9a-1 (0.1 mg/kg, subcutaneously) significantly reversed joint swelling, disability, thermal and mechanical hypersensitivity, and grip strength impairment. The effect of Ms 9a-1 was equal to or better than that of reference drugs. Post-treatment histological analysis revealed that long-term administration of Ms9a-1 could reduce inflammatory changes in joints and prevent the progression of cartilage and bone destruction at the same level as meloxicam. Peptide Ms 9a-1 showed significant analgesic and anti-inflammatory effects in the model of MIA-induced OA, and therefore positive allosteric modulators could be considered for the alleviation of OA symptoms.

The neuropeptide nocistatin (NS) is expressed by the nervous system cells and neutrophils as a part of a precursor protein and can undergo stepwise limited proteolysis. Previously, it was shown that rat NS (rNS) is able to activate acid-sensing ion channels (ASICs) and that this effect correlates with the acidic nature of NS. Here, we investigated changes in the properties of rNS in the course of its proteolytic degradation by comparing the effects of the full-size rNS and its two cleavage fragments on the rat isoform 3 ASICs (ASIC3) expressed in X. laevis oocytes and pain perception in mice. The rNS acted as both positive and negative modulator by lowering the steady-state desensitization of ASIC3 at pH 6.8-7.0 and reducing the channel’s response to stimuli at pH 6.0-6.9, respectively. The truncated rNSΔ21 peptide lacking 21 amino acid residues from the N-terminus retained the positive modulatory activity, while the C-terminal pentapeptide (rNSΔ30) acted only as a negative ASIC3 modulator. The effects of the studied peptides were confirmed in animal tests: rNS and rNSΔ21 induced a pain-related behavior, whereas rNSΔ30 showed the analgesic effect. Therefore, we have shown that the mode of rNS action changes during its stepwise degradation, from an algesic molecule through a pain enhancer to a pain reliever (rNSΔ30 pentapeptide), which can be considered as a promising drug candidate.