[Prospects for use of short peptides in pharmacotherapeutic correction of Alzheimer's disease.]

Alzheimer's disease (AD) is the most common neurodegenerative disorder, characterized by progressive cognitive decline. This review discusses current therapeutic strategies for the treatment of Alzheimer's disease, their limitations, and potential prospects. The feasibility of comprehensive approach for AD therapy is considered in contrast to the classical method in the development of therapeutic strategy. Leu-Ile, Glu-Trp, Lys-Glu, Gly-Pro, Glu-Asp-Arg, Lys-Glu-Asp, Met-Glu-His-Phe-Pro-Gly-Pro short peptides are described as multitarget agents with a wide range of activity.

[Neuroprotective effects of peptides.]

Neurodegenerative diseases are a heterogeneous group of nervous system pathologies. They are found mainly in people of an older age group. The incidence of neurodegenerative diseases is continuously growing due to an increase in the average life expectancy of the population. At the moment, there are no effective and safe treatments for neurodegenerative diseases, which are most often diagnosed at the stage of decompensation, when therapy is ineffective and does not bring positive outcomes. Most of the currently used drugs act only symptomatically. The review provides analyzed data and information about the prospects of using peptide bioregulators as neuroprotectors with high physiological activity and low immunogenicity.

[Gender-specific effects of neonatal administration of melatonin on lifespan and age-associated patholgy in 129/Sv mice.]

Melatonin was administered at the dose of 1,2 mcg per capita (an equivalent to pediatric dosages) at days 1, 3 and 5 postpartum to 129/Sv mice, which were followed thereafter till their natural deaths. In adult males, findings included a decrease in body weight and an increase in the contribution of pulmonary lesions, which were revealed upon postmortem examinations, to the overall mortality. In adult females, no changes in body weight occurred, the proportion of middle- and late-age mice having irregular estrous cycles increased, and mortality associated with uterine hemangiomas was accelerated. Trends in malignant tumor yields were different: a decrease in males and an increase in females. Tends in survival patterns were expressed as significant increases or decreases in the lifespans of the last 25% and 10% of male or female survivors respectively. An analysis of the complete survivorships curves in terms of the Gompertz model showed that changes in the initial mortality and aging rate were within the limits determined by the artifactual component of the Strehler-Mildvan correlation between these parameters. On a whole, the trends found in the present work were opposite in males and females being mostly favorable for the former and adverse for the latter. Gender specificity should be kept in mind upon considering the use of melatonin by children and their mothers.

[Melatonin enhances antitumor effect of doxorubicin on a model of transplantable Ehrlich tumor in female sHR mice].

A combined antitumor effect of a single injection of doxorubicin and the indole hormone melatonin was investigated in the model of transplantable Ehrlich carcinoma in female SHR mice. Animals received melatonin either subcutaneous 10 mg/ kg in the evening or with water 10 mg/l at night (from 20 pm to 8 am) for 3 weeks. The results of an experiment showed that combined use of doxorubicin and melatonin both subcutaneous and with water leads to statistically significant inhibition of tumor growth compared with control and doxorubicin alone.

[Prospects of use of antidiabetic biguanides for cancer prevention and treatment: results of preclinical studies].

The critical analysis of preclinical testing of anticarcinogenic and antitumor activity of biguanides presented in this paper. Experiments have been conducted using in total more than 20 models of carcinogenesis including models of spontaneous , chemically- , radiation- and virus-induced carcinogenesis, as well as carcinoigenesis induced by special fat diets and by genetic modification in rodents. Cancer preventive effect of buiguanides has been studied in relation to total tumor incidence and to 17 target organs in animals of 3 species, including 25 various strains of mice, 4 strains of rats and 1 strain of hamsters using various routs of administration and doses. In the majority of cases (86%) the exposure to biguanides leads to inhibition of carcinogenesis. In 14% of the cases inhibitory effect of the drugs was not observed, however there was no any case of stimulation of carcinogenesis by antidiabetic biguanides., Metformin suppressed tumor growth in the majority of in vitro studies conducted in 46 different cell lines originated from malignant tumors of 15 localization as well as in athymic mice with xenografts of 31 tumor lines. It was concluded that there are sufficient experimental evidences of anticarcinogenic and antitumor effects of antidiabetic biguanides revealed in a number of models of induced and spontaneous carcinogenesis.

[Age dynamics of angiogenesis markers in transgenic HER-2/neu (FBV/N) mammary adenocarcinoma-prone mice].

Age-dependent angiogenesis intensity changes have been studied in transgenic HER-2/neu (FBV/N) mice characteristic of breast tumors' high incidence with hyperexpression of HER-2/neu. Concentration of vascular endothelial growth factor, insulin-dependent growth factor 1, nitrogen monoxide, tissue plasminogen activator and type 1 plasminogen activator inhibitor were assessed by means of immune-enzyme assay. The results testify to angiogenesis processes activation side by side with aging and growth of the tumors. Maximum manifestation of these disturbances (growth factors' blood concentrations increase and endotheliocytes' functional activity inhibition) has been revealed in 6-month-old mice during neoplasma maximum intensive and aggressive growth period.

[Light-induced disruption of the circadian clock and risk of malignant tumors in laboratory animals: state of the problem].

There were obtained sufficient experimental evidence of the stimulating effect on the development of tumors (transplanted, spontaneous and induced by various carcinogenic agents), disorders of circadian function of the pineal gland (light-induced desynchronosis) caused by knockout or mutation of clock genes, pinealectomy, content in conditions of constant light or natural light regime of the North, as well as jetlag modeling in laboratory rodents. In experiments on various models of carcinogenesis it was found that sympathectomy (removal of the superior cervical ganglion), light deprivation, hibernation and application of melatonin, the natural hormone of the pineal gland, had an inhibitory effect on the development of transplanted, spontaneous and induced tumors of different histogenesis.

[Effect of epsilon-aminocaproic acid, cyclophosphamide and their combination on the growth of autochthonous sarcomas of mice induced by benzo(a)pyrene].

Antifibrinolytic drug epsilon-aminocaproic acid as a therapeutic form (5% solution in saline) was tested for antitumor activity in the autochthonous subcutaneous tumors of mice, induced by benzo (a) pyrene, in monotherapy mode (instead animals received drinking water) and in combination with cyclophosphamide, which was administered once intraperitoneally in the dose of 200 mg/kg. In the control groups, treated with drinking water and saline solution instead of water, there was no stabilization and reduction in tumor volume, while in the groups receiving epsilon-aminocaproic acid, cyclophosphamide and their combination statistically significantly in comparison with the control groups there was increased the proportion of tumors with not changed or reduced volume; epsilon-aminocaproic acid enhanced the antitumor effect of cyclophosphamide. The data obtained are for further study of the antitumor effect of epsilon-aminocaproic acid.

[The effect of sodium fluoroacetate and metformin on the antitumor activity of cyclophosphamide on the autochthonous mice sarcoma model].

Previously it was found that sodium fluoroacetate (SF) inhibited the growth of the Ehrlich cancer by means of monotherapy and enhanced the antitumor effect of cyclophosphamide (CP) in experiments with autochthonous subcutaneous tumors induced by benzo (a) pyrene. In this study a comparison of the antitumor activity of SF and metformin showed that both substances did not have significant effect in monotherapy but enhanced the effect of CP, increasing the percentage of tumors with the same or reduced volume. Besides, SF, unlike metformin increased the average duration of effect. The data obtained promoted further study of the mechanism of the antitumor effect of SF and the search effective combination with already known antitumor drugs.

[Effect of plastoquinone derivative SkQ1 on benzo(a)pyrene-induced soft tissue carcinogenesis].

Ninety female SHR mice were subcutaneously injected with a single dose of 2 mg benzo(a)pyrene (BaP) dissolved in 0.2 ml of vegetable oil. Since the next day after BaP injection mice were started to treat with mitochondria-targeted antioxidant SkQ1 at the doses of 5 and 50 nmol/kg/day in drinking water. Control animals received tap water. Study was finished by 358th day. Number of tumor-bearing mice increased in all groups exposed to BaP but retarded since 20th week in SkQ1-treated groups in comparison with control. Maximal tumor volume gain was observed in control mice resulting in premature death. By the 30th week of study only 20% of control animals survived, whereas SkQ1 treatment increased survival up to 30% at the dose of 5 nmol and 40% at the dose of 50 nmol. By the 40th week mean tumor volume in 5 and 50 nmol SkQ1-treated mice was 13 and 21 cm3 respectively, whereas in control--40 cm3. In SkQ1-treated mice pneumonia was observed rarely as compared with controls. It could be supposed, SkQ1 at the doses of 5 and 50 nmol/kg/day retarted BaP-induced soft tissue carcinogenesis in SHR mice.

[Effect of sodium fluoroacetate on Ehrlich solid tumor and autochthonous sarcoma growth in mice].

Due to biochemical characteristics of toxic action of fluoroacetate on energetics and metabolism of cells, including tumor cells, it was interesting to testify sodium fluoroacetate (SFA) for its antitumor activity in vivo. We have estimated that SFA significantly inhibits growth of Ehrlich tumor carcinoma. In experiments with autochthonous induced by benzo[a]pyrene subcutaneous tumors, SFA was not active in monotherapy regime, though potentiated antitumor effect of cyclophosphamide, significantly increasing the relative number of mice with stabilized or decreased tumor volume as well as the duration of this effect. The data obtained render basis for additional studies of mechanism of antitumor effect of SFA.

[Hyperplastic skin growth on the head of goldfish--comparative oncology aspects].

Dynamics of development and morphology of hyperplastic skin lesions ("hoods") on the head of goldfish, which were bred using artificial selection for more than thousand years, were studied. During monitoring of hundred fishes, at the age of 6 months "hoods" were found in 39.5%, among 14 months-old fishes in 60,7%. Morphologic examination of "hoods" on various stages of development revealed epithelial hyperplasia with increased clear mucous cells number, dermis thickening and oedema. On later stages developed papillomatous outgrowth and areas of epithelial intrusion. The comparative oncology analysis allow to hypothesize these skin growth to be a genetically determined benign neoplasm. This is the first example of artificially selected neoplasm described in the literature. It supports our hypothesis of the possible evolutionary role of tumors.

[The effect of SSH&H on the lifespan and spontaneous cancer development in transgenic mice with HER-2/neu mutation].

10 months old mice receiving SSH&H with daily food increased the lifespan in comparison to the control group. The maximal lifespan was increased by 1,6 months. For the long-living 10% group the mean lifespan increased by 8,7% compared to the control group (p<0,05). The mammary gland neoplasia rate was the same in both groups. The mean latent tumor development period duration, number and size of the tumors were also similar. There was a tendency to lower lung metastases rate in the experimental group. The cumulative neoplastic frequency curve for the experimental group was shifted to the right in comparison to the control group curve giving evidence to the inhibitory effect of SSH&H on the neoplastic rate in transgenic mice with HER-2/neu mutation.

[Metformin effect on urethane-induced tumorigenesis in mice].

Sixty one male 129/Sv mice were exposed to a single intraperitoneal injection of 1 g per kilo of urethane dissolved in 0.9% normal saline. Starting the next day from the injection the study group mice were given 1200 mg metformin per liter of drinking water 5 days a week for 26 weeks. The control group mice received pure drinking water. Six months after the urethane treatment the mice were killed and the morphology samples were taken. Twenty five of 31 (96.7%) control group mice developed tumors (lung adenomas and thymic lymphomas), while tumor development was observed in 25 of 31 (80.7%; p<0.05) mice exposed to metformin. Solid or trabecular lung adenomas developed in 90% of the control group mice and in 77% of the metformin group mice (p=0.119). Therefore, it is a first evidence of tumor-inhibitory effect of metformin in mice.

[Metformin slows down ageing processes at the cellular level in SHR mice].

It has been shown recently that metformin, the indirect mTOR-kinase inhibitor, significantly increases medium (by 37.8%) and maximum (by 10.3%) life span of SHR mice (Anisimov et al., 2008). We obtained fibroblasts from skin of 11-, 16-, 19- and 23-months-old SHR mice treated with metformin since the third and ninth day of life. We studied markers of cellular senescence in these fibroblasts. Significant differences were observed between the average number of senescence-associated heterochromatic foci (SAHF), the average of area nuclei and fluorescence intensity of nucleus after staining for gamma-H2AX in control and experimental animals. Also, we showed that metformin prevented the accumulation of fibroblasts with large area of nuclei; high activity of senescence-associated beta-galactosidase (SA-beta-gal), and high fluorescence intensity after staining for gamma-H2AX. It appears that accumulation of large quantity of senescence markers within a cell triggers it to enter the aging process. It appears that the increase of "old" cell population above the threshold disrupts the normal function of certain tissues, organs, and finally, the whole organism. It appears that metformin delays the "old" cells accumulation and prolongs the organism youth.

[The effect of mithochondria targeted antioxidant SkQ1 on aging, life span and spontaneous carcinogenesis in three mice strains].

Female outbred SHR mice, inbred 129/Sv mice and transgenic HER-2/neu mice were given mitochondria targeted antioxidant SkQ1 with drinking water in the various doses (0,5-2500 nmol/kg day) since the age of 2 months, whereas control animals received tap water. Age-related dynamics of the body weight and temperature, the amount of drinking water and consumed food, estrous function, as well as parameters of the life span and spontaneous carcinogenesis were estimated. As compared with controls, no difference in the parameters of body weight and temperature or amount of consumed food and water in the treated mice of all studied mice strains was revealed. In SkQ1-treated SHR mice, the tendencies of inhibition of the age-dependent disturbances of estrous function and aging appearance were observed. No effect of SkQ1 on estrous function and external view in inbred and transgenic mice was shown. SkQ1 treatment significantly decreased locomotor activity (in 12-15 months old SHR and 129/Sv mice) and exercise tolerance in old (20 months) SHR mice. The treatment with SkQ1 (0,5-50 nmol/kg day) increased parameters of the life span in SHR mice (mean life span, mean life span of the last 10% of survival, median and maximum life span) without significant effect on the life span in 129/Sv and HER-2/neu mice. There was no reliable difference in tumor development in all SkQ1-treated mice strains as compared with the control. The drug considerably inhibited the incidence of age-associated non-tumor pathology in SHR mice. Our data suggest geroprotective activity of SkQ1, and a lack of toxic or carcinogenic activities during long term use.