Exosomal miRNA-146a is downregulated in clear cell renal cell carcinoma patients with severe immune-related adverse events.

Here we report the results of the pilot project of exosomal miRNA expression levels in clear cell renal cell carcinoma (ccRCC) patients with different clinical response to ICIs (nivolumab) and treatment related toxicity. Immune-related adverse events (irAEs) are a major cause of immune checkpoint inhibitors cancellation and therapy failure. Modern studies demonstrate evidence that exosomes are of great importance in the formation of tumor resistance to ICIs drugs and therapy. We performed exosomal miRNA-146a expression analysis using qPCR on 86 ccRCC patients and revealed a statistically significant (p = 0.01) decreased expression level in ccRCC patients with CTCAE grade 3-4 (M±SEM 1.71 ± 0.13) compared to CTCAE grade 0-2 group (M±SEM 2.30 ± 0.24). The expression levels of miRNA-126, miRNA-218 and miRNA-410 did not show statistically significant differences in the comparison groups (p > 0.05). Association analysis of rs2910164 in the miRNA-146a gene demonstrated that CC genotype and C allele carriers had higher risk of developing severe irAEs (p = 0.03, OR = 6.12; p = 0.01, OR = 2.42, respectively) compare with GG and GC carriers. That is the first attempt to identify biomarkers of ICIs treatment efficacy for ccRCC in the Volga-Ural region based on exosomal miRNAs analysis.

[Safety of tadalafil in patients with cardiovascular comorbidities].

Tadalafil is a drug from the phosphodiesterase-5 inhibitors (PDE-5) group, which is used to treat erectile dysfunction (ED), lower urinary tract symptoms (LUTS) caused by benign prostatic hyperplasia (BPH) and ED with LUTS in patients with BPH. The efficacy and safety of tadalafil were reviewed. The focus was on cardiovascular safety of tadalafil due to frequent cardiovascular comorbidities in patients with ED. We concluded that tadalafil is well tolerated and safe in patients with cardiovascular comorbidities and, in addition, has a beneficial effect on the cardiovascular system.

[Molecular aspects of the impact of the Speroton complex on the male fertility in idiopathic infertility].

AIM: To characterize the effect of the Speroton complex on the free radical homeostasis in the ejaculate of males of infertile couples and the likelihood of pregnancy in partners. MATERIALS AND METHODS: The study group comprised 30 men aged between 26 and 43 years (mean 33 +/- 4.8 years) with idiopathic infertility. All patients received Speroton one sachet once daily during meals for 3 months. The comparison group consisted of 29 men of fertile age having 1 to 3 healthy children. In infertile men, standard semen parameters including the ejaculate volume, sperm concentration, total count and proportion of abnormal forms were within the normal range. Markers of oxidative damage to ejaculate macromolecules were determined using standard diagnostic testing systems. RESULTS: The patients with idiopathic infertility were found to have statistically significant changes in the degree of chemical modification of ejaculate biopolymers. The level of lipid hydroperoxides in infertile men was significantly higher than in fertile participants. Taking Speroton resulted in the decrease of lipid hydroperoxides to the level that did not differ from that in the control group. Using Speroton was also accompanied by a decrease in the level of the oxidative damage DNA biomarker 8-oxodGu and a tendency toward normalization of the carbonyl modification of the ejaculate proteins. Five married couples in the treatment group reported achieving pregnancy. CONCLUSION: Taking Speroton was associated with the normalization of the balance of pro- and antioxidant processes in the ejaculate, as indicated by a decrease in the oxidative destruction of sperm biopolymers. The revealed molecular mechanism of the drug action is the basis for restoring the fertilizing ability and increasing the likelihood of pregnancy. The treatment effectiveness was 16.7%. Speroton is a promising drug that improves the functional sperm characteristics and contributes to achieving pregnancy in couples with a male infertility factor.

Dioxins in the semen of men with infertility.

The purpose of the present study was to assess ejaculate contamination by polychlorinated dibenzo-p-dioxins/furans in male infertility. The database of 168 infertile and 49 fertile men was included in the study. Dioxin content was determined using gas chromatography/high-resolution mass spectrometry (GC/HRMS). In the ejaculate of infertile men, the content of dioxins and furans was 2.2-2.3 times higher than in fertile donors. The maximum level of the most toxic dioxin congener was detected in pathospermia. Contamination of semen of infertile men by polychlorinated dibenzo-p-dioxins/furans supports the hypothesis about the relationship between environmental factors and reproductive health.

[Effects of L-carnitine on ejaculate parameters in males from infertile couples].

The aim of our investigation was detection of molecular mechanisms of an antioxidant action of L-carnitine (a transmembrane carrier of long-chain fatty acids) in idiopathic pathospermia. We treated 60 males from infertile couples with karniton (1 g/day). L-carnitine impact on ejaculate antioxidant status was assessed by registration of chemiluminescence and total antioxidant activity by colorimetric method according to changes in the color of ABTS chromogen. High dose-dependent antioxidant activity of the drug was found in testing on model systems in vitro. In vivo trials showed that patients given L-carnitine demonstrated a significant increase of the number of mobile spermatozoa of A category, positive changes in parameters of luminal-dependent and Fe2+ induced chemiluminescence of ejaculate in elevated antioxidant capacity of spermoplasma. After karniton treatment of the husbands 23% of their wives got pregnant. The treatment efficacy may be due to normalization of antioxidant status of ejaculate.

[Molecular markers of ejaculate fertility in officers of Internal Affairs Ministry Special Forces, if under battle stress].

The article presents results of studies in males participated in anti-terrorist military operations in local conflict areas. Findings are intact general spermogram parameters with lower serum and/or ejaculate levels of glycodeline and inhibin B--that is a precondition for high risk reproductive disorders under battle stress.

[Oxidative stress of spermatozoa in pathogenesis of male infertility].

Oxidative stress is a common pathology seen in approximately half of all infertile men. Peroxides causing infertility are generated by sperm and seminal leukocytes. Oxidative stress occurs when production of potentially destructive reactive oxygen species exceeds natural antioxidant defenses resulting in cellular damage. The causes of the oxidative stress include environmental factors (phthalates et al.), chronic inflammation of the prostate, varicocele, autoimmune response to seminal antigens.

[Spermicidal properties of major environmental pollutants assigned to polychlorbiphenyls class].

The authors considered accumulation of environmental pollutants assigned to polychlorbiphenyls class in fat tissue and reproductive organs of male rats, discovered major accumulation of the pollutants in epididymis, demonstrated significant changes in cellular contents and functional properties of sperm.

[Effect of propolis bioflavonoids on lipoperoxidation processes in the gonads of rats intoxicated by polychlorinated biphenyls].

The check of a hypothesis about possible participation oxidative stress to infringement of fertility is spent at a poisoning polychlorbefeniles. Increased ability to generation of reactive oxygen species by morphologically defective spermatozoa has been revealed. There is a decrease of total antioxidizing activity of testis. Is shown antioxidant activity bioflavonoids of propolis.

Gonadotoxic effect of polychlorobiphenyls.

The distribution of polychlorobiphenyls (environmental pollutants) in the reproductive organs and fatty tissues of rats was analyzed and selective accumulation of the toxicants in the epididymis, but not in the ovaries, was demonstrated. Reduction of the fertilizing activity of the ejaculate after chronic exposure to polychlorobiphenyls was detected. Mechanisms of spermatogenic dysfunction under conditions of high technogenic load are discussed.

[Spermatogenesis impairment by polychlorbiphenyls: endocrine and paracrine mechanisms of the damage]. / Narushenie spermatogeneza polokhlorbifenilami: éndokrinnye i parakrinnye mekhanizmy povrezhdeniia.

Possible role of changed contents of certain cytokines in the genesis of reproductive disorders was studied in an experiment with rats intoxicated chronically by polychlorbiphenyl (PCB) ecopollutants at the total doses of 0.3 g/kg of the body weight (0.05 LD50 and 3 g/kg of the body weight (0.5 LD50). The enzyme immunodetection was used to analyze blood serum, testicle tissues and sperm for interleukin-1beta, interleukin-6, interleukin-4, tumor necrosis factor alpha, and testosterone and estradiol. The experiment showed that chronic PCB intoxication significantly increases the production of pro-inflammatory cytokines and decreases the production of anti-inflammatory cytokines on a background of a sharp testosterone reduction and inversion of the androgen-estrogen profile. Implications of these shifts to steroido- and spermatogenesis are discussed along with cell and molecular mechanisms of cytokine-mediate PCB intoxication.

[Effect of 2,4-D ecotoxicants on spermatogenesis and fertility of albino rats]. / Vliianie ékotoksikantov gruppy 2,4-D na spermatogenez i plodovitost' belykh krys.

Characteristics of spermatogenesis, morphometric changes in the Leydig's and Sertoli's cells, and fertility of albino rats exposed to various doses of 2.4-D were investigated. Chronic injection of the herbicide led to transitional sterility against pronounced disorders of spermatogenesis, hyperplasia of sertolicytes and predominance of low-active forms of the Leydig's cells. An assumption concerning possible role of altered gonadostat in genesis of the reproductive disorders is offered.

[Morphofunctional characteristics of the testis of albino rats exposed to dioxin-containing herbicide 2,4-D]. / Morfofunktsional'naia kharakteristika semennikov belykh krys pri vozdeistvii dioksinsoderzhashchego gerbitsida 2,4-D.

Endocrine system of the gonads of white rats after subacute poisoning with 2,4-D was studied. Signs of increased steroidogenesis in Leydig cells, a decrease of plasma testosterone concentration and decrease of the gonad sensitivity to chorionic gonadotropin were observed.

[The effect of the dioxin-containing herbicide 2,4-D on the hormonal status of experimental animals]. / Vliianie dioksinsoderzhashchego gerbitsida 2,4-D na gormonal'nyi status éksperimental'nykh zhivotnykh.

The article presents studies of hormonal state in rats under daily or 20-day peroral administration of variable doses of 2,4-D herbicide containing dioxine. Changed levels of thyroid hormones, insulin, cortisol, testosterone and estradiol appeared to be divergent and dose-dependent, proving direct toxic effects of the herbicide in endocrine organs, altered hormonal effects in target organs and disorders of peripheral hormonal metabolism.

[The nicotinamide coenzyme system in experimental burn disease during prepubescence]. / O sostoianii sistemy nikotinamidnykh kofermentov pri éksperimental'noi ozhogovoi bplezni v dopubertatnom vozraste.

Distinct impairments were observed in metabolism of nicotinamide coenzymes in liver tissue of preadolescent rats with severe thermic burns: a decrease in total content of the coenzymes, a decrease in content of oxidized forms and elevation of reduced derivatives, inhibition of biosynthesis and stimulation of the nicotinamide coenzymes catabolism, especially high during acute period of burns. Nicotinamide, administered at a dose of 50 mg/kg into animals, was shown to correct the coenzymes content and activity of glyceraldehydephosphate dehydrogenase in liver tissue of rats with burns.