The tripeptide glutathione (GSH) is the most abundant cellular non-enzymatic antioxidant. The GSH system plays a crucial role in antioxidant defense against oxidative stress and in supporting cellular redox homeostasis, regulating the reduction of lipid peroxides, and protecting cells from ferroptosis depending on the GSH level, which is maintained in a state of dynamic equilibrium not only by the activities of GSH synthesis enzymes, transporters of GSH precursor amino acids, and GSH transporters, but also by the actions of GSH-related enzymes. Some GSH-related enzymes are key enzymes with antioxidant functions such as glutathione peroxidases (GPxs), especially GPx4, and glutathione S-transferases (GSTs), which use GSH as a co-substrate for the reduction of hydroperoxides to alcohols, whereas glutathione-specific gamma-glutamyl cyclotransferase 1 (ChaC1) degrades intracellular GSH, so they can correspondingly lead to suppression or induction of ferroptosis. Ferroptosis is characterized by a buildup of lipid peroxides due to excessive lipid peroxidation and iron accumulation, which results from redox imbalance between ferroptosis's drivers and defense systems, including impaired cellular antioxidant systems, particularly disruptions of GSH metabolism. It appears pertinent to assess the influence on ferroptosis regulation by GSH-dependent enzymes that utilize the GSH pool in diverse ways. This review offers an updated exploration of the roles of GPx4, ChaC1, and GSTs in redox regulation of ferroptosis in cancer cells, with a focus on both the regulation of each enzyme's activity and their possible interactions, considering the impact on the risk of ferroptosis induction.

A major challenging problem facing effective ovarian cancer therapy is cisplatin resistance. Re-sensitization of cisplatin-resistant ovarian cancer cells to cisplatin (CDDP) has become a critical issue. Curcumin (CUR), the most abundant dietary polyphenolic curcuminoids derived from turmeric (Curcuma longa), has achieved previously significant anti-cancer effects against human ovarian adenocarcinoma SKOV-3/CDDP cisplatin-resistant cells by inhibition the gene expression of the antioxidant enzymes (SOD1, SOD2, GPX1, CAT and HO1), transcription factor NFE2L2 and signaling pathway (PIK3CA/AKT1/MTOR). However, the detailed mechanisms of curcumin-mediated re-sensitization to cisplatin in SKOV-3/CDDP cells still need further exploration. Here, a suggested curcumin pre-treatment therapeutic strategy has been evaluated to effectively overcome cisplatin-resistant ovarian cancer SKOV-3/CDDP and to improve our understanding of the mechanisms behind cisplatin resistance. The findings of the present study suggest that the curcumin pre-treatment significantly exhibited cytotoxic effects and inhibited the proliferation of the SKOV-3/CDDP cell line compared to the simultaneous addition of drugs. Precisely, apoptosis induced by curcumin pre-treatment in SKOV-3/CDDP cells is mediated by mitochondrial apoptotic pathway (cleaved caspases 9, 3 and cleaved PARP) activation as well as by inhibition of thioredoxin reductase (TRXR1) and mTOR/STAT3 signaling pathway. This current study could deepen our understanding of the anticancer mechanism of CUR pre-treatment, which not only facilitates the re-sensitization of ovarian cancer cells to cisplatin but may lead to the development of targeted and effective therapeutics to eradicate SKOV-3/CDDP cancer cells.

The article presents the data of current publications on the problem of respiratory lesions in immune-mediated inflammatory rheumatic diseases and the results of our own studies on the frequency and spectrum of bronchopulmonary pathology in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), systemic connective tissue diseases, and ANCA vasculitis. Respiratory system lesions are detected in 24.5–70.2 % of patients with inflammatory RD according to different authors. Interstitial lung diseases, pulmonary fibrosis, and bronchial obstruction prevail in the structure of respiratory disorders. Polymorphism of pulmonary manifestations of RD includes pulmonary hypertension, which is recorded in more than a third of patients with systemic connective tissue diseases. As our own clinical data showed, respiratory lesions occurred in 33 people (27.5 %) out of 120 patients with immune-mediated inflammatory RD. The leading form of damage was interstitial pneumonia and interstitial pulmonary fibrosis. Among the patients with determined lung involvement were individuals with RA, SSc, ANCA vasculitis, AS and Sjogren's disease. The article presents a clinical case of the interstitial pneumonia in a patient with RA. The contribution of uncontrolled rheumatoid inflammation and disease-modifying therapy to the manifestation of pulmonary involvement is discussed. The positive effect of IL-6 inhibitor in abolishing RA activity and pulmonary lesion is shown.

The most abundant tripeptide—glutathione (GSH)—and the major GSH-related enzymes—glutathione peroxidases (GPxs) and glutathione S-transferases (GSTs)—are highly significant in the regulation of tumor cell viability, initiation of tumor development, its progression, and drug resistance. The high level of GSH synthesis in different cancer types depends not only on the increasing expression of the key enzymes of the γ-glutamyl cycle but also on the changes in transport velocity of its precursor amino acids. The ability of GPxs to reduce hydroperoxides is used for cellular viability, and each member of the GPx family has a different mechanism of action and site for maintaining redox balance. GSTs not only catalyze the conjugation of GSH to electrophilic substances and the reduction of organic hydroperoxides but also take part in the regulation of cellular signaling pathways. By catalyzing the S-glutathionylation of key target proteins, GSTs are involved in the regulation of major cellular processes, including metabolism (e.g., glycolysis and the PPP), signal transduction, transcription regulation, and the development of resistance to anticancer drugs. In this review, recent findings in GSH synthesis, the roles and functions of GPxs, and GST isoforms in cancer development are discussed, along with the search for GST and GPx inhibitors for cancer treatment.

This paper discusses psoriatic arthritis (PsA) in view of clinically relevant innovative aspects. It was demonstrated that the current paradigm of PsA regards this disease as a multidisciplinary entity due to its systemic manifestations and high rate of comorbidity. The development of joint lesions in psoriasis includes preclinical, subclinical, and prodromal phases, which are considered as pre-PsA and an indication for escalating therapy. Inhibitors of the proinflammatory interleukin (IL) 17/IL-23 axis have been demonstrated to prevent the progression of arthritis in patients with early or very early PsA. Consequently, the "treatment to intercept PsA" strategy has been proposed as a means of managing joint damage at the subclinical stage. A substantial body of evidence has been amassed to demonstrate the efficacy and safety of guselkumab, a selective IL-23 inhibitor, for the treatment of PsA. The drug has demonstrated its efficacy not only in PsA, but also in patients who have failed to respond to biologic agents and targeting drugs. The authors present a case report illustrating the high therapeutic effect of guselkumab in a patient with severe psoriasis and PsA, comorbidities, and resistance to methotrexate and IL-17 inhibitors. Thus, advances in studying the immunopathogenesis of PsA and psoriasis have led to the identification of new therapeutic targets, which are being exploited in clinical practice through the use of modern selective immunosuppressants. KEYWORDS: psoriatic arthritis, psoriasis, therapy resistance, interleukin 23, guselkumab. FOR CITATION: Babaeva A.R., Kalinina E.V., Zvonorenko M.S., Solodenkova K.S., Osadchuk M.A. Current strategy for the management of comorbid patients with psoriatic arthritis: focus on interleukin 23 inhibition. Russian Medical Inquiry. 2024;8(2):73–83 (in Russ.). DOI: 10.32364/2587-6821-2024-8-2-4.

Systemic lupus erythematosus (SLE) is characterized by a variety of clinical manifestations, which are defined as separate phenotypes of the disease. Despite the universality of immunopathological reactions, which are based on the formation of anti-nuclear antibodies and antibodies to native DNA, the spectrum and severity of immunological disorders in individual phenotypes are different. The role of type I interferons (IFN) in the SLE pathogenesis has now been proven. Hypersecretion of IFN-α and IFN-β leads to the production of antibodies against the components of the cell nucleus through activation of the native and adaptive immunity system. The current treatment strategy provides for achieving remission or low activity with immunosuppressants, including selective ones, such as biological agents. According to the updated international recommendations, anifrolumab, monoclonal antibodies against type I IFN, which has demonstrated high efficacy in the treatment of SLE with skin-mucous and joint lesions., can be used for the treatment of SLE along with rituximab and belimumab. The article presents our own clinical observation on the analysis of the effecacy and safety of anifrolumab in the treatment of a young patient with high-activity SLE and pronounced skin manifestations. It was shown that after the first injections of the drug, there was a rapid dynamics of skin and joint syndrome, the activity of SLE decreased from maximum to minimum according to the SELENA-SLEDAI index. The results obtained confirm the rationale of including anifrolumab in the treatment regimen in cases of insufficient previous therapy.

The article is devoted to the analysis of the current state of the problem of the most common autoinflammatory disease – familial Mediterranean fever (FMF). The authors provide data on the prevalence of FMF, the genetic mechanisms of its development, the influence of MEFV gene mutations on the manifestation of FMF and its clinical phenotypes. The polymorphism of the mutated MEFV gene in various ethnic populations is discussed. Particular attention is paid to the combination of FMF with other rheumatic processes, primarily with spondyloarthritis. It has been shown that immunoinflammatory comorbidity is characteristic of the early onset of FMF, a more severe course of this disease, and is determined by the specific genotype of the patient. In this regard, the importance of genetic analysis is emphasized not only for the timely verification of FMF, but also for determining the prognosis in terms of the risk of developing spondyloarthritis and amyloidosis. An analysis of works on the pharmacotherapy of FMF showed that although colchicine remains the first-line drug, interleukin-1 inhibitors are actively used in the treatment of patients with FMF. The results of multicenter studies demonstrate the high efficacy and safety of the intelekin-1 inhibitor canakinumab in the treatment of FMF and other autoinflammatory diseases in children and adults. In this regard, with the development of colchicine resistance or poor tolerability of colchicine, interleukin-1 inhibitors are considered as the optimal therapeutic option.

The article discusses the effect of the plant polyphenol curcumin on the resistance of SKOV-3 ovar-ian adenocarcinoma cells to the antitumor drug cisplatin. Data are presented showing that the ac-tion of curcumin causes a “reversal” of drug resistance in tumor cells, which is associated with suppression of the cellular antioxidant system and the PI3K/Akt/mTOR signaling pathway.

Cardiovascular and metabolic comorbidities in patients with rheumatic diseases (RD) determine the risk of adverse outcomes. Gout is one of the diseases which significantly increase the cardiovascular risk (CVR). The authors present a literature review elucidating the prevalence and spectrum of cardiovascular (CVD) and metabolic diseases, as well as the proven CVR factors in persons with RDs, including gout. As demonstrated, the increased CVR amid RDs is caused not only by a higher prevalence of the traditional CVR factors but is also related to multiple specific disease-associated risk factors. Chronic systemic inflammation, the development of internal organ lesions and the long-term use of anti-inflammatory therapy contribute negatively to the overall CVR. Thus, RDs are considered as important CVR re-classifiers and require a compulsory revision of the risk factors. Currently, the national and international guidelines for the CVR prevention in persons with RD have been developed and used in practice. Among RDs, a special place is held by gout which is characterized by common cardiovascular comorbidities and reduced glomerular filtration rate. The recent studies have demonstrated that in the management of patients with hyperuricemia (HU) and gout it is necessary to achieve a sustained target level of uric acid for preventing adverse effects on the organ systems and reducing CVR. Among the recommended therapeutic options for patients with cardiovascular and renal comorbidities, the preference is given to febuxostat, a urate-lowering drug with high activity and proven safety. KEYWORDS: comorbidities, rheumatic diseases, gout, cardiovascular risk, febuxostat. FOR CITATION: Babaeva A.R., Kalinina E.V., Zvonorenko M.S. et al. Cardiovascular and metabolic comorbidities associated with rheumatic diseases: focus on hyperuricemia and gout. Russian Medical Inquiry. 2023;7(3):150–159 (in Russ.). DOI: 10.32364/2587- 6821-2023-7-3-150-159.

Introduction. Used tire rubber cracking with organic solvents leads to rubber devulcanization and dispersion of the material to nanosized particles. The process can be carried out in a flow reactor. The obtained nanomodifiers are compatible with bitumen and predictably change the bituminous binder technical characteristics. Various practical solutions have been proposed for the use of the resulting modified bituminous binders in the road construction and strengthening soil foundations. Methods and materials. It has been proposed to use a method of joint cracking of rubber with organic solvents to obtain a nanostructured modifier of bitumen. The obtained nanostructural modifier has been studied by the methods of analyzing the sizes of nanoparticles and solubility in toluene. For the bituminous binders obtained with the use of nanomodifiers, standard characteristics for bitumen, such as needle penetration depth, softening temperature, brittleness temperature and extensibility have been determined. Results and discussion. It is established that during the proposed process, a nanostructural modifier compatible with bitumen is formed. It is shown that the addition of a nanomodifier to bitumen makes it possible to purposefully change the properties of the resulting bitumen binder, improve the consumer properties of the bitumen binder and expand its application areas. It is proposed to use the obtained product as a component of waterproofing mastics for waterproofing the underground parts of buildings and structures. Conclusion. Joint cracking of rubber with organic solvents in a flow reactor allows obtaining a nanostructural modifier compatible with bitumen. The resulting product has improved properties compared to the original bitumen, which expands its scope of application. It is proposed to use the resulting product for the manufacture of waterproofing mastics. The proposed technical solutions make it possible to reduce the environmental load of automobile tires wastes.

Development of oxidative/nitrosative stress associated with the activation of oncogenic pathways results from the increase in the generation of reactive oxygen and nitrogen species (ROS/RNS) in tumor cells, where they can have a dual effect. At high concentrations, ROS/RNS cause cell death and limit tumor growth at certain phases of its development, while their low amounts promote oxidative/nitrosative modifications of key redox-dependent residues in regulatory proteins. The reversibility of such modifications as S-glutathionylation and S-nitrosylation that proceed through the electrophilic attack of ROS/RNS on nucleophilic Cys residues ensures the redox-dependent switch in the activity of signaling proteins, as well as the ability of these compounds to control cell proliferation and programmed cell death. The content of S-glutathionylated and S-nitrosylated proteins is controlled by the balance between S-glutathionylation/deglutathionylation and S-nitrosylation/denitrosylation, respectively, and depends on the cellular redox status. The extent of S-glutathionylation and S-nitrosylation of protein targets and their ratio largely determine the status and direction of signaling pathways in cancer cells. The review discusses the features of S-glutathionylation and S-nitrosylation reactions and systems that control them in cancer cells, as well as their relationship with redox-dependent processes and tumor growth.

Previously, we demonstrated that the overexpression of antioxidant enzymes (SOD-1, SOD-2, Gpx-1, CAT, and HO-1), transcription factor NFE2L2, and the signaling pathway (PI3K/Akt/mTOR) contribute to the cisplatin resistance of SKOV-3/CDDP ovarian cells, and treatment with quercetin (QU) alone has been shown to inhibit the expression of these genes. The aim of this study was to expand the previous data by examining the efficiency of reversing cisplatin resistance and investigating the underlying mechanism of pre-treatment with QU followed by cisplatin in the same ovarian cancer cells. The pre-incubation of SKOV-3/CDDP cells with quercetin at an optimum dose prior to treatment with cisplatin exhibited a significant cytotoxic effect. Furthermore, a long incubation with only QU for 48 h caused cell cycle arrest at the G1/S phase, while a QU pre-treatment induced sub-G1 phase cell accumulation (apoptosis) in a time-dependent manner. An in-depth study of the mechanism of the actions revealed that QU pre-treatment acted as a pro-oxidant that induced ROS production by inhibiting the thioredoxin antioxidant system Trx/TrxR. Moreover, QU pre-treatment showed activation of the mitochondrial apoptotic pathway (cleaved caspases 9, 7, and 3 and cleaved PARP) through downregulation of the signaling pathway (mTOR/STAT3) in SKOV-3/CDDP cells. This study provides further new data for the mechanism by which the QU pre-treatment re-sensitizes SKOV-3/CDDP cells to cisplatin.

This brief report provides an overview of pharmacovigilance information on adverse reactions during post-registration use of medicines recommended for the treatment of mental and behavioral disorders caused by alcohol consumption in the Russian Federation, and its reports were included in the database of the World Health Organizations international drug monitoring program as of January 1, 2023. The safety indicators of benzodiazepines, phenobarbital, butyrophenones, anticonvulsants, thiamine, and magnesium preparations were analyzed. The article may be of interest to pharmacovigilance specialists, doctors, researchers, developers and health regulators, pharmacologists, and clinical pharmacologists.

The problem of the appearance of odors in drinking water associated with the development of algae and cyanobacteria in reservoirs of drinking water sources is considered. The results of the analysis of information on the main types of organisms that are sources of odorants in drinking water, chemicals produced by them and a description of odors are presented. Most often, the causes of odors in drinking water are the massive development of Aphanizomenon flos-aquae and Oscillatoria agardhii , which are producers of geosmin and 2-methylisoborneol. The classification of hazard levels for water pollution by cyanobacteria and recommended measures, including the frequency of monitoring and sampling, are given. The measures implemented with a decrease in the number of cyanobacteria in reservoirs of drinking water supply sources by physical, chemical and biological methods are presented. Methods of removal of intracellular and extracellular cyanotoxins from drinking water are described. The analysis of the efficiency of removal of various substances with odorizing effect from drinking water is presented.

The article presents an analysis of the current view of comorbidity problem in rheumatology from the perspective of inflammatory disorders of the joints and spine combination with the most common diseases of the internal organs and endocrine system. The data gained from recent sources regarding the frequency and structure of concomitant disorders in patients with rheumatoid arthritis (RA) and spondylarthritis (ankylosing spondylitis [AS] and psoriatic arthritis [PsA]) are presented. It has been shown that the most common comorbidity in patients with RA, AS, PsA are diseases of the gastrointestinal tract and cardiovascular diseases. The authors present the results of their own research on the study of comorbidity in RA, AS and PsA, which are consistent with modern literature data. It is noted that there are specific disease-associated factors, as well as the negative effect of anti-inflammatory drugs in the development and manifestation of comorbid pathology.