Delayed gonadotoxic effects were revealed in outbred male sexually mature rats (SD) after exposure to paclitaxel in the prepubertal period, and the possibility of their correction with p-tyrosol was shown. It was found, that administration of paclitaxel does not inhibit the ability of animals to conceive, but impairs the reserve capacity of the testicular tissue. In intact female rats crossed with male rats receiving paclitaxel, increased post-implantation fetal death was observed. Combined administration of paclitaxel and p-tyrosol alleviated the delayed effects of the cytostatic treatment on the prepubertal testis.

ЦЕЛЬ ИССЛЕДОВАНИЯ Оценить эффективность ректального введения исследуемого вещества цинка аргинил-глицината дигидрохлорид (ЦАГ) в дозе 16 мг на 1 кг массы тела в экспериментальной модели мужской инфертильности (патозооспермии) и сравнить полученные результаты с имеющимися в настоящее время данными клинических исследований. МАТЕРИАЛ И МЕТОДЫ В исследовании использованы 30 аутбредных крыс-самцов линии Wistar половозрелого возраста (11 нед), распределенных в три группы. В 1-ю группу (фон) включены интактные животные, во 2-ю группу (контроль) — крысы, получавшие свечи без действующего вещества (плацебо), в 3-ю группу (опытную) — животные, которым вводили ЦАГ в дозе 16 мг на 1 кг массы тела. Исследуемые вещества вводили ректально, в виде желатиновых свечей, один раз в день ежедневно в течение 5 дней до и 5 дней после введения этопозида (доза 30 мг на 1 кг массы тела), моделирующего патологию (для групп 2 и 3). Через сутки после последнего введения определяли показатели, характеризующие морфофункциональное состояние мужских половых клеток. РЕЗУЛЬТАТЫ Выявлена фармакологическая активность ЦАГ в эксперименте при олигозооспермии, астенозооспермии и тератозооспермии, которая характеризовалась высокой степенью выраженности; различия статистически значимы по сравнению с показателями в 1-й и 2-й группах. ВЫВОДЫ Полученные экспериментальные данные о действии цинка аргинил-глицината дигидрохлорид соответствуют результатам клинических исследований лекарственного препарата простатилен АЦ. Одним из действующих веществ этого препарата является исследуемый комплекс, эффективность его доказана в условиях реальной клинической практики при лечении больных с хроническим простатитом и нарушенной фертильностью, что позволяет рекомендовать использование данного вещества в андрологической практике в составе комбинированных лекарственных средств для лечения различных видов патоспермии.

The regenerative properties of p-tyrosol were investigated in a model of testicular insufficiency caused by a toxic effect on spermatogonial stem cells (single administration of paclitaxel in the maximum tolerable dose). Against the background of p-tyrosol administration, we observed an increase in the number of normal spermatogonia and Sertoli cells, stimulation of spermatogenesis, and renewal of the spermatogenic tissue. The treatment with p-tyrosol also led to a decrease in DNA damage in cells of the testicular tissue. These changes were accompanied by a decrease in the level of free radicals, an increase in antioxidant protection, and normalization of the redox potential.

Introduction. Benign prostatic hyperplasia (BPH) is a common urological disorder in older men. It is characterized by the development of glandularstromal hyperplasia of the prostate with the formation of new glandular structures and subsequent symptoms from the lower urinary tract. It has now been established that the pathogenesis of this disease is multifactorial and one of the possible mechanisms for the development of BPH is oxidative stress. Purpose. Study of the effect of phenols with a bulky isobornyl substituent (2,6-diisobornyl-4-methylphenol and 4-hydroxymethyl-2,6-diisobornylphenol)on the growth of experimental BPH and the antioxidant balance of prostate cells in comparison with Prostamol Uno. Materials and мethods. Experiments were carried out on 50 male Wistar rats. BPH was caused by daily administration of sulpiride (60 days) to male rats of late reproductive age. After 2 months, the animals were weighed and sacrificed in a CO2 chamber. The mass, mass coefficient, volume of the lateral lobe of the pancreas were determined, morphological analysis was performed. Investigated prooxidant and antioxidant activity. The results were processed by the method of variation statistics using the Mann-Whitney nonparametric U test. Results. The efficacy of the investigated drugs in BPH decreased in the following sequence: sulpiride + substance 4-hydroxymethyl-2,6-diisobornylphenol (HDB) → sulpiride + substance Dibornol (DB) → sulpiride + Prostamol Uno (PU). When comparing the results of evaluating the anti-prooxidant status with the therapeutic effect of the studied drugs, it was found that isobornylphenols, which are highly effective as prostatotropic drugs, did not show a more significant effect, compared to PU, on the redox potential of prostatic tissue cells. Conclusions. Drugs DB, HDB, PU have a normalizing effect on the level of severity of redox reactions in the sulpiride model of BPH.

Background— Notch1 regulates binary cell fate determination and is critical for angiogenesis and cardiovascular development. However, the pathophysiological role of Notch1 in the postnatal period is not known. We hypothesize that Notch1 signaling in vascular smooth muscle cells (SMCs) may contribute to neointimal formation after vascular injury. Methods and Results— We performed carotid artery ligation in wild-type, control (SMC-specific Cre recombinase transgenic [smCre-Tg]), general Notch1 heterozygous deficient (N1 +/− ), SMC-specific Notch1 heterozygous deficient (smN1 +/− ), and general Notch3 homozygous deficient (N3 −/− ) mice. Compared with wild-type or control mice, N1 +/− and smN1 +/− mice showed a 70% decrease in neointimal formation after carotid artery ligation. However, neointimal formation was similar between wild-type and N3 −/− mice. Indeed, SMCs derived from explanted aortas of either N1 +/− - or smN1 +/− mice showed decreased chemotaxis and proliferation and increased apoptosis compared with control or N3 −/− mice. This correlated with decreased staining of proliferating cell nuclear antigen–positive cells and increased staining of cleaved caspase-3 in the intima of N1 +/− - or smN1 +/− mice. In SMCs derived from CHF1/Hey2 −/− mice, activation of Notch signaling did not lead to increased SMC proliferation or migration. Conclusions— These findings indicate that Notch1, rather than Notch3, mediates SMC proliferation and neointimal formation after vascular injury through CHF1/Hey2 and suggest that therapies that target Notch1/CHF1/Hey2 in SMCs may be beneficial in preventing vascular proliferative diseases.

Изучено влияние мексидола, дигидрокверцитина, диборнола и пара-тирозола на количество ДНК-повреждений и редокс-потенциал в клетках тестикулярной ткани крыс. Установлено, что в условиях ДНК-повреждений клеток сперматогенной ткани все исследуемые соединения, кроме мексидола, снижали в клетках число разрывов ДНК и оказывали нормализующее действие на их редокс-потенциал. Наибольшая терапевтическая активность выявлялась у дигидрокверцетина. The effect of mexidol, dihydroquercetin, dibornol and paratyrosol on the amount of DNA damage and the redox potential in rat testicular tissue cells was studied. It was established, that all studied compounds, except mexidol, reduced the number of DNA breaks in the cells and had a normalizing effect on their redox potential under the conditions of DNA damage to spermatogenic tissue cells. The highest therapeutic activity was detected in dihydroquercetin.

The effect of mexidol, dihydroquercetin, dibornol and paratyrosol on the amount of DNA damage and the redox potential in rat testicular tissue cells was studied. It was established, that all studied compounds, except mexidol, reduced the number of DNA breaks in the cells and had a normalizing effect on their redox potential under the conditions of DNA damage to spermatogenic tissue cells. The highest therapeutic activity was detected in dihydroquercetin.

The purpose of the study was a comparative assessment of long-term toxic effects of cytotoxic drugs (anthracycline antibiotics, topoisomerase activity inhibitors, platinum and taxane complex compounds) on male reproductive function. Material and methods. 2.5-month-old male Wistar rats were used in the experiment. The following cytotoxic drugs were administered to animals in the maximum tolerated dose: Vepesid (etoposide, Teva, Israel), Irinotecan (Campto, Rhone-Poulens, Great Britain), Carboplatin (kemokarb, Dabur India Ltd., India), Paclitaxel (mitotax, Dr. Reddy`s, India), Platidiam (Lachema, Czech Republic), Pharmorubicin (Farmitalia, Carlo Erba). The reproductive status was assessed 90 and 180 days after administration of cytotoxic drugs. The fertilizing ability, productivity of spermatogenesis and the viability of a fertilized egg were evaluated. To determine the sensitivity of different types of spermatogonia to the drugs, we studied the dynamics of the number of their cell populations 2, 5, 10, 15, 30, 90 and 180 days after starting the experiment. Results. In long-term follow-up following administration of farmorubicin and paclitaxel to male rats, a complete (pharmacorubicin) or partial (paclitaxel) decrease in the fertilizing ability due to oligospermia was detected. The decrease in spermatogenesis productivitywas reversible. In rats treated with topoisomerase activity inhibitors, the fertilizing ability was preserved, however spermatogenic failure was also seen, as judged by the total sperm number. In the long term after the administration of platinum complexes, no decline in the reproductive function was observed, and the spermatogenesis productivity corresponded to the control values. The severity of toxic effects on gonads was determined by the sensitivity of different types of spermatogonia to the action of drugs. Pharmorubicin and paclitaxel exerted a pronounced toxic effect on stem spermatogonial cells. Paclitaxel and carboplatin induced dominant lethal mutations in spermatogonia, but the likelihood of gametes bearing genetic damage incompatible with life decreased over time.

Experimental model of sulpiride-provoked benign prostatic hyperplasia was employed to comparatively assess the effect of phenolic antioxidants (dihydroquercetin, p-thyrozol, dibornol, and prostagenin) on prostate morphology. All examined agents decreased the degree of hyperplasia in acinar epithelium; the greatest efficacy was demonstrated by prostagenin. Moreover, dihydroquercetin and p-thyrozol increased the cross-section area of acinar lumina and prostate volume, which is inadmissible in this pathology. These results suggest that the use of phenolic antioxidants in the therapy of benign prostatic hyperplasia should be strictly controlled.

Antiviral drug Kagocel in concentrations of 0.0008, 0.004, 0.02, 0.1, 0.5, and 2.5 mg/ml with or without metabolic activation does not induce gene mutations in S. typhimurium strains ТА98, ТА100, ТА1535, and ТА1537 and in a combination of E. coli strains pKM101 and uvrA. A single intragastric administration of Kagocel in a daily therapeutic dose and a 10-fold daily therapeutic dose to male mice or multiple administrations in daily therapeutic dose to male and female mice did not led to a significant increase in the percentage of chromosomal aberrations in the bone marrow cells. DNA comet assay revealed no significant increase in the incidence of DNA breaks in cells of mouse testes after single or multiple administration of Kagocel at daily therapeutic and 10-fold daily therapeutic doses. Our results indicate that Kagocel exhibits no genotoxic activity in the studied dose range.

The effect of phenolic antioxidants (dihydroquercetin, p-tyrosol, dibornol) on the morphology, functions, and redox processes in the reproductive cells of male rats was studied on the model of experimental pathospermia. All antioxidants reduced the percentage of degenerative forms of spermatozoa. Dibornol was most effective. Dihydroquercetin and p-tyrosol did not increase the total number of spermatozoa and the percentage of their mobile forms. These indicators were improved only by dibornol. After administration of all test drugs, the antioxidant potential of spermatozoa increased and did not significantly differ from the baseline values.

We studied the efficiency of dihydroquercetin on the model of chronic nonbacterial inflammation of the prostatic gland in rats. It was found that administration of dihydroquercetin was followed by a significant decrease in the area of the connective tissue in the prostatic gland to initial levels, which attested to antifibrotic properties of this oxidant. Additionally, the substance prevented the development of atrophy of acinus epithelium. After administration of reference drug Prostamol Uno, only moderate antifibrotic effects were observed.

Effectiveness of the granulocyte colony-stimulating factor immobilized by using electronbeam synthesis nanotechnology was investigated on the model of experimental testicular failure caused by the toxic effect on stem spermatogonia. Administration of the drug to experimental paclitaxel-treated animals increased the number of sources of the proliferative pool of spermatogenesis and its productivity. The effectiveness of immobilized granulocyte colony-stimulating factor was based on its ability to stimulate reparative regeneration of the spermatogenic tissue, which manifested in a decrease in spermatogenic layer maturity and increase in the number of microenvironment cells. Effectiveness of the immobilized form of the drug was superior to that of non-immobilized form.

A course of dihydroquercetin (antioxidant) injections to 5-month-old Wistar rats with sulpiride-induced benign prostatic hyperplasia led to reduction of proliferative activity in the glandular structures and to attenuation of the inflammatory reaction in the tissue. Prostatic antioxidant/prooxidant balance returned to normal after the treatment.

Blood flow arrest in the inferior vena cava at the level of the inferior pole of the kidney led to the development of epithelial degeneration and stromal sclerosis after 1.5 months, dilatation of the veins, and congestion of secretion in rats. These signs corresponded to the morphological picture of category IIIB prostatitis or to signs of noninflammatory chronic prostatitis (hemodynamic disorders, sclerosis, degeneration). On the other hand, there was no cellular infiltration of the glandular tissue associated with infection and inflammation.

The aim of the research was to study the influence of p-thyrozol on the morphology and antioxidant-prooxidant balance in prostate of rats at sulpiride-induced benign prostatic hyperplasia. It was found that introduction of p-thyrozol promoted thwarting progress of pathological process that was proved by less degree of manifestation of proliferative processes in epithelium and of cellular infiltration of stroma. In addition, increase of antioxidant reserve of gland was registered.