CNS distribution, signalling properties and central effects of G-protein coupled receptor 4.

Information on the distribution and biology of the G-protein coupled receptor 4 (GPR4) in the brain is limited. It is currently thought that GPR4 couples to Gs proteins and may mediate central respiratory sensitivity to CO2. Using a knock-in mouse model, abundant GPR4 expression was detected in the cerebrovascular endothelium and neurones of dorsal raphe, retro-trapezoidal nucleus locus coeruleus and lateral septum. A similar distribution was confirmed using RNAscope in situ hybridisation. In HEK293 cells, overexpressing GPR4, it was highly constitutively active at neutral pH with little further increase in cAMP towards acidic pH. The GPR4 antagonist NE 52-QQ57 effectively blocked GPR4-mediated cAMP accumulation (IC50 26.8 nM in HEK293 cells). In HUVEC which natively express GPR4, physiological acidification (pH 7.4-7.0) resulted in a cAMP increase by ∼55% which was completely prevented by 1 µM NE 52-QQ57. The main extracellular organic acid, l-lactic acid (LL; 1-10 mM), suppressed pH dependent activation of GPR4 in HEK293 and HUVEC cells, suggesting allosteric negative modulation. In unanaesthetised mice and rats, NE 52-QQ57 (20 mg kg-1) reduced ventilatory response to 5 and 10% CO2. In anaesthetised rats, systemic administration of NE 52-QQ57 (up to 20 mg kg-1) had no effect on hemodynamics, cerebral blood flow and blood oxygen level dependent responses. Central administration of NE 52-QQ57 (1 mM) in vagotomised anaesthetised rats did not affect CO2-induced respiratory responses. Our results indicate that GPR4 is expressed by multiple neuronal populations and endothelium and that its pH sensitivity is affected by level of expression and LL. NE 52-QQ57 blunts hypercapnic response to CO2 but this effect is absent under anaesthesia, possibly due to the inhibitory effect of LL on GPR4.

Exaggerated aggression and decreased anxiety in mice deficient in brain serotonin.

Serotonin is a major neurotransmitter in the central nervous system (CNS). Dysregulation of serotonin transmission in the CNS is reported to be related to different psychiatric disorders in humans including depression, impulsive aggression and anxiety disorders. The most frequently prescribed antidepressants and anxiolytics target the serotonergic system. However, these drugs are not effective in 20-30% of cases. The causes of this failure as well as the molecular mechanisms involved in the origin of psychological disorders are poorly understood. Biosynthesis of serotonin in the CNS is initiated by tryptophan hydroxylase 2 (TPH2). In this study, we used Tph2-deficient (Tph2(-/-)) mice to evaluate the impact of serotonin depletion in the brain on mouse behavior. Tph2(-/-) mice exhibited increased depression-like behavior in the forced swim test but not in the tail suspension test. In addition, they showed decreased anxiety-like behavior in three different paradigms: elevated plus maze, marble burying and novelty-suppressed feeding tests. These phenotypes were accompanied by strong aggressiveness observed in the resident-intruder paradigm. Despite carrying only one copy of the gene, heterozygous Tph2(+/-) mice showed only 10% reduction in brain serotonin, which was not sufficient to modulate behavior in the tested paradigms. Our findings provide unequivocal evidence on the pivotal role of central serotonin in anxiety and aggression.

[Genetic manipulation and studying of differentiation properties of rat induced pluripotent stem cells].

Induced pluripotent stem (iPS) cells are derived from somatic cells reprogrammed to the pluripotent state by the induced expression of defined transcription factors, achieved for the first time by the seminal work of Takahashi and Yamanaka. This new type of pluripotent cells has offered new exciting options in regenerative medicine allowing the replacement of cells and organs with the patient's own cells thereby avoiding immunological complications. In order to develop such technologies in approved animal models, iPS cells were also generated from rodents. Of course, the most important model for studying of different diseases is rat. In this study, we present a method suitable for rat iPS cells genetic modification by stable transfection and show necessary conditions for the first stages of direct differentiation.

Antimetastatic effect of thymus-dependent antigen (sheep erythrocytes) in C57BL/6 mice with Lewis carcinoma.

We revealed an antimetastatic effect of thymus-dependent corpuscular antigen (sheep erythrocytes) injected intravenously or intraperitoneally in sensitizing or high doses alone or in a complex with a course dose of cyclophosphamide to C57Bl/6 mice with Lewis carcinoma. Injection of the antigen appreciably reduced the number and volume of Lewis carcinoma metastases in the lungs, notably increased the therapeutic effect of cyclophosphamide, and restored hemopoiesis, particularly, the red blood stem suppressed by the tumor process and cytostatic treatment. The growth of primary tumors virtually did not change. High dose of sheep erythrocytes was more effective.

[The effect of the combined use of cryosurgery and hyperthermia on an experimental tumor process]. / Vliianie kombinirovannogo primeneniia kriokhirurgii i gipertermii na opukholevyi protsess v éksperimente.

The antitumour efficacy of a single cryosurgery use in combination with hyperthermia was studied in 165 mice with the Lewis carcinoma, sarcoma 180 and 169 rats with Guérin's carcinoma and sarcoma 45. A considerable decrease in the recurrence frequency was observed irrespective of the histological type of the primary tumour. The haemostasis-associated expressed hypoxia has been established to arise in tumour tissues after cryodestruction. A day after the cryodestruction a shift to alkaline pH in the tumour tissue has been observed along with hypoxia. The above conditions possibly specify the high antitumour efficacy of a combined use of the cryosurgery and hyperthermia.

[Effectiveness of combined action of vitamins A, E and C and cyclophosphane or adriamycin on growth of transplanted tumors in mice]. / Effektivnost' kompleksnogo deistviia vitaminov A, E, C s tsiklofosfanom ili adriamitsinom na rost perevivnykh opukholei u myshei.

The antitumour, antimetastatic and antileukemic effect of cyclophosphane and adriamycin in combination with vitamins A. E. C was studied according to the scheme developed by the authors. The preliminary administration of vitamins was established to intensify the effect of cytostatics and to lower considerably their toxic action. Cyclophosphane proved to be more effective relative to the Lewis lung carcinoma than adriamycin.

[The combined use of cryosurgery and solcoseryl in treating malignant neoplasms]. / Kombinirovannoe ispol'zovanie kriokhirurgii i solkoserila pri lechenii zlokachestvennykh novoobrazovanii.

Antitumour efficacy of a combined use of cryosurgery and solcoseryl in mice with Lewis carcinoma was studied. Solcoseryl improves results of cryosurgery. An increase in antitumour effect with a combined use of cryodestruction and solcoseryl is supposed to be followed by the rise of oxygen tension in tissues. Solcoseryl injection followed by cryosurgery of cancer of mouth cavity mucosa in patients considerably accelerates the wound surface regeneration. Thus solcoseryl increases the treatment efficacy of the cryosurgical method.

[A comparative study of the efficacy of cryosurgical and operative treatments in transplanted tumors]. / Sravnitel'noe izuchenie éffektivnosti kriokhirurgicheskogo i operativnogo lecheniia perevivnykh opukholei.

Antitumor efficacy of cryosurgery and standard surgical procedures for Lewis carcinoma, melanoma B16, Guerin's carcinoma and Walker's carcinosarcoma was compared in the treatment of 846 experimental animals. The study established the superiority or, at least, similar efficacy of cryosurgery in terms of cure, survival and radicality of primary tumor treatment. Unlike standard surgery, cryosurgery was followed by distant metastases being inhibited in mice. Although there was no significant difference in the incidence of metastases to regional lymph nodes in rats, it was higher than in untreated animals in both treatment groups. Cryonecrosis of tumor tissue is a factor of distant and regional metastases development following cryosurgery.

[Effect of solcoseryl on oxygen metabolism and growth of experimental tumors]. / Vliianie solkoserila na kislorodnyi obmen i techenie opukholevogo protsessa v éksperimente.

Antihypoxant and antitumour properties of solcoseryl were studied on intact and tumour-bearing rats and mice. By the polarographic method it is found that solcoseryl increases the oxygen metabolism only in animal hypoxic tissues and improves, probably, energy production of their mitochondria. On many tumour strains it is shown that the injections of solcoseryl decelerate the growth of some tumours, inhibit the metastatic process and produce no toxic effect on the animals.

[Oxygen metabolic characteristics in the tumor process]. / Osobennosti kislorodnogo obmena pri opukholevom protsesse.

The data available in literature and results of the authors, own investigations on the oxygen metabolism during the appearance and development of the tumour process are presented. The important role of biological oxidation disorders in cell malignancy is discussed. The appearance and development of malignant tumours occur against a background of tissues hypoxia. Severe hypoxia and anoxia are observed constantly in the tumour tissue. Some mechanisms of hypoxia development and cell respiration reduction in malignant tumours are considered. Necessity of methods and drugs searching (antihypoxic agents and antioxidants) for correction of oxygen homeostasis disturbances and increase of antitumour resistance of the organism is substantiated.

[Effect of the cryodestruction and surgical removal of Guérin's carcinoma on metastasis into the regional lymph nodes]. / Vliianie kriodestruktsii i khirurgicheskogo udaleniia kartsinomy Gerena na metastazirovanie v regionarnye limfaticheskie uzly.

The influence of cryodestruction and surgical treatment of the primary tumour in rats with the transplanted Guerin's carcinoma was studied including their effect on the degree of metastatic spreading to the regional lymph nodes. The rate of regional metastases under the cryotherapy influence is shown to be somewhat higher than resulting from surgical removal of a tumor and is positively lower than in the case of amputation of tumor affected extremity.

[Effect of cryodestruction of Lewis lung carcinoma in mice on the development of metastases]. / Vliianie kriodestruktsii kartsinomy legkikh L'iuis na razvitie metastazov.

The effect of the primary tumour cryodestruction on a degree of metastatic spreading in the lungs was investigated in experiments with C57B1/6 mice with Lewis carcinoma of the lungs. It is found that after the tumour cryosurgery there was a less quantity of metastases as compared with operated animals (surgical removal of the tumour or amputation of the limb with the tumour) or with untreated animals. A regular correlation is observed between the degree of metastatic spreading and the efficiency of the primary tumour treatment. The relapse after cryosurgery or surgical removal of the tumour led to an increase in the quantity of pulmonary metastases.

[Oxygen tension in the tissues of animals during the process of malignant tumor growth]. / Napriazhenie kisloroda v tkaniakh zhivotnykh v protsesse rosta zlokachestvennykh opukholei

It has been shown polarographically that the oxygen supply and consumption in transplantable Heren carcinoma and normal tissues of the tumor organism are reduced as compared with such indices in intact animals. As the tumor grows, oxygen tension in normal tissues is gradually lowered both under normal conditions and oxygen ventilation, while the time of its consumption by tissues is longer. Such changes in tissues pO2 are not observed in subcutaneous transplantation of muscle tissue suspension in animals and also in transplantable tumor resorption.