23 research outputs found
The role of the S1P3 receptor in inflammation-associated proliferative disorders
No full textInflammation is involved in the pathogenesis of many different disorders,
including glomerulonephritis, fibrosis and cancer. Unraveling the regulatory
mechanisms underlying the molecular processes of inflammation remains
crucial for the development of novel therapeutics for future treatment of
inflammatory disorders.
Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid molecule,
which likely plays an important role in inflammation. However, the molecular
mechanisms involved in S1P-mediated inflammation are still not completely
understood. This work aimed to unravel the interconnection between S1P and
other molecular players implicated in inflammatory response, as well as to
indicate the S1P receptor subtype the activation of which contributes to
proliferation and migration of non-cancerous cells and to metastatic progression
of breast cancer. In addition, the therapeutic potential of drugs targeting early
steps of the inflammatory response was assessed.
As model systems for the non-cancerous studies we used renal mesangial
cells (rMC) and mouse embryonic fibroblasts (MEF), and for the cancer studies
the breast cancer cell line MDA-MB-231 and two metastatic sublines derived
from lung (4175) and bone (1833).
Our data demonstrate that the S1P3 receptor is strongly upregulated in
lung and bone metastatic cell lines compared to the parental MDA-MB-231
cells, and its activation by S1P has pro-inflammatory, pro-migratory and pro
invasive potential by inducing COX-2 expression and PGE2 signaling via EP2
and EP4. These data were confirmed in non-cancerous studies, where we found
that S1P3 receptor is upregulated in mMC and MEFs upon the loss of SphK2.
Our results show that the deficiency of SphK2 in these cells correlates with an
enhanced proliferative and migratory capacity, indicating that SphK2 exerts
suppressive effects on cell growth and migration. This finding is likely to be due
8
to the enhanced expression of S1P3, as its depletion in mesangial cells reduced
their proliferation and migration rate.
Our next study revealed that the novel cPLA2 inhibitors AVX001 and
AVX002 have an anti-inflammatory potential in cultures of rMC by reducing the pro-inflammatory mediator PGE2 through the inhibitory effect on NFκB
activation. Thus, they represent promising novel drugs for the treatment of
inflammatory disorders.
Altogether, our data demonstrate for the first time a critical role of the
S1P3 receptor in S1P-mediated proliferative and inflammatory responses, and
identify S1P3 as a potential target for therapeutic intervention to treat
inflammation-associated proliferative disorders
Down-regulation of serotonergic genes expression in the raphe nuclei of midbrain under chronic social defeat stress in male mice
No full textBackground: 
There is ample experimental evidence supporting the hypothesis that the brain serotonergic system is involved in the control of chronic social defeat stress (CSDS), depression and anxiety. The study aimed to analyze mRNA levels of the serotonergic genes in the raphe nuclei of the midbrain that may be associated with chronic social defeats consistently shown by male mice in special experimental settings. 

Methodology/Principal Findings: 
The serotonergic genes were the Tph2, Sert, Maoa and Htr1a. The Bdnf, Creb, Cphn, Gapdh, Hprt, B2M, 18S and Actb genes were also studied. The experimental groups were composed of male mice with experience of defeats in 21 daily encounters and male mice with the same track record of defeats followed by a no-defeat period without agonistic interactions (relative rest for 14 days). It has been shown that mRNA levels of the Tph2, Maoa, Sert, Htr1a, Bdnf and Creb genes in the raphe nuclei of defeated mice are decreased as compared with the controls. Under CSDS the Cphn, Gapdh, Hprt, B2M, 18S, Actb genes are also down-regulated. The expression of the serotonergic genes as well as the Cphn and Creb genes is not restored to the control level after the 2 weeks of relative rest. mRNA levels of other genes are not recovered to the control levels, although some up-regulation was observed in rested losers. Significant positive correlations were found between the total time of avoidance behavior demonstrated by the 21-day defeaters in agonistic interactions and Sert, Maoa, Bdnf, Gapdh and 18S mRNA levels. 

Conclusions: 
CSDS experience inducing the development of mixed anxious/depression-like state in male mice down-regulates the serotonergic genes expression associated with the synthesis, inactivation and reception of serotonin. The Bdnf and Creb genes as well as the cell and metabolic Cphn, Gapdh, Hprt, B2M, Actb and 18S genes in the midbrain raphe nuclei are also down-regulated under CSDS. Period of relative rest is not enough for most genes to recover expression to the control levels
The ω3-polyunsaturated fatty acid derivatives AVX001 and AVX002 directly inhibit cytosolic phospholipase A(2) and suppress PGE(2) formation in mesangial cells
No full textω3-polyunsaturated fatty acids (ω3-PUFAs) are known to exert anti-inflammatory effects in various disease models although their direct targets are only poorly characterized
Sphingosine kinase 2 deficiency increases proliferation and migration of renal mouse mesangial cells and fibroblasts
No full textBoth of the sphingosine kinase (SK) subtypes SK-1 and SK-2 catalyze the production of the bioactive lipid molecule sphingosine 1-phosphate (S1P). However, the subtype-specific cellular functions are largely unknown. In this study, we investigated the cellular function of SK-2 in primary mouse renal mesangial cells (mMC) and embryonic fibroblasts (MEF) from wild-type C57BL/6 or SK-2 knockout (SK2ko) mice. We found that SK2ko cells displayed a significantly higher proliferative and migratory activity when compared to wild-type cells, with concomitant increased cellular activities of the classical extracellular signal regulated kinase (ERK) and PI3K/Akt cascades, and of the small G protein RhoA. Furthermore, we detected an upregulation of SK-1 protein and S1P3 receptor mRNA expression in SK-2ko cells. The MEK inhibitor U0126 and the S1P1/3 receptor antagonist VPC23019 blocked the increased migration of SK-2ko cells. Additionally, S1P3ko mesangial cells showed a reduced proliferative behavior and reduced migration rate upon S1P stimulation, suggesting a crucial involvement of the S1P3 receptor. In summary, our data demonstrate that SK-2 exerts suppressive effects on cell growth and migration in renal mesangial cells and fibroblasts, and that therapeutic targeting of SKs for treating proliferative diseases requires subtype-selective inhibitors
Upregulation of the S1P3 receptor in metastatic breast cancer cells increases migration and invasion by induction of PGE2 and EP2/EP4 activation.
No full textBreast cancer is one of the most common and devastating malignancies among women worldwide. Recent evidence suggests that malignant progression is also driven by processes involving the sphingolipid molecule sphingosine 1-phosphate (S1P) and its binding to cognate receptor subtypes on the cell surface. To investigate the effect of this interaction on the metastatic phenotype, we used the breast cancer cell line MDA-MB-231 and the sublines 4175 and 1833 derived from lung and bone metastases in nude mice, respectively. In both metastatic cell lines expression of the S1P3 receptor was strongly upregulated compared to the parental cells and correlated with higher S1P-induced intracellular calcium ([Ca(2+)]i), higher cyclooxygenase (COX)-2 and microsomal prostaglandin (PG) E2 synthase expression, and consequently with increased PGE2 synthesis. PGE2 synthesis was decreased by antagonists and siRNA against S1P3 and S1P2. Moreover, in parental MDA-MB-231 cells overexpression of S1P3 by cDNA transfection also increased PGE2 synthesis, but only after treatment with the DNA methyltransferase inhibitor 5-aza-2-deoxycytidine, indicating reversible silencing of the COX-2 promoter. Functionally, the metastatic sublines showed enhanced migration and Matrigel invasion in adapted Boyden chamber assays, which further increased by S1P stimulation. This response was abrogated by either S1P3 antagonism, COX-2 inhibition or PGE2 receptor 2 (EP2) and 4 (EP4) antagonism, but not by S1P2 antagonism. Our data demonstrate that in breast cancer cells overexpression of S1P3 and its activation by S1P has pro-inflammatory and pro-metastatic potential by inducing COX-2 expression and PGE2 signaling via EP2 and EP4
The deformity, moral depravity and the foolishness for Christ in the novel "Return to Ostrog" by Sasha Filipenko
No full textZa jeden z kluczowych w powieści Powrót do Ostroga należy uznać problem deformacji i brzydoty rozpatrywany przez Saszę Filipienkę na płaszczyźnie fizyczności / cielesności, jak i na płaszczyźnie metafizycznej – na przykładzie losów wychowanków sierocińca w Ostrogu, małego prowincjonalnego miasta na rosyjskiej Północy. W trawionej wszechogarniającą wyuczoną bezradnością rzeczywistości Ostroga rola „dziwaka - plugawcy - jurodziwego” przypada Piotrowi Pawłowowi, niegdysiejszemu wychowankowi sierocińca, człowiekowi o wielkiej wrażliwości, nadzwyczajnej moralności, twardo przekonanemu o konieczności działania na rzecz bliźniego i całego społeczeństwa. Obraz „saloity” Pawłowa pod wieloma względami stanowi aluzję do postaci Myszkina z powieści Idiota Fiodora Dostojewskiego.
Analizując przedstawioną w powieści Filipienki problematykę deformującego, destrukcyjnego wpływu systemu państwa autorytarno-totalitarnego na dzieci i ich dalsze losy, można dojść do wniosku o zawarciu w utworze aluzji do fragmentów powieści Człowiek śmiechu Wiktora Hugo, w których pisarz pochyla się nad kwestią celowego oszpecania i okaleczania dziecka. Obaj prozaicy zgodni co do społecznego zdiagnozowania problemu: dziecko jest zabawką w rękach systemu, poniżanie go i pozbawienie podstawowych praw i wolności prowadzi do utraty przezeń podmiotowości, obdarcia z człowieczeństwa, powstawania trwałego kalectwa – emocjonalnego, mentalnego i duchowego. Dotyczy to nie tylko jednostki, ale i całego społeczeństwa, czyli w przypadku Powrotu do Ostroga – społeczeństwa postsowieckiej autorytarno-totalitarnej Rosji.The problem of deformity and moral depravity is one of the key issues in the novel Return to Ostrog. The author of the novel analyzes this issue on the physical and metaphysical plane by considering the fate of the inhabitants and, specifically, orphanage children in Ostrog, a small provincial town in the Russian North. In Ostrog, which is suffering of the all-encompassing learned helplessness, the role of the "freak – fool for Christ" falls to Pyotr Pavlov, an orphan, a man of great sensitivity and extraordinary morality, who is firmly convinced of the necessity to act for one's neighbor’s and the common good. In many ways, Pavlov's "foolishness for Christ" is an allusion to Prince Myshkin, the character from the novel The Idiot by Fyodor Dostoyevsky.
The analysis of the issue of the deforming and destructive influence of the authoritarian-totalitarian state on children and their future, which is presented in Filipenko's novel, leads to the conclusion about the allusion to fragments of the novel The Man Who Laughs by Victor Hugo. In this novel, the author examines the issue of deliberate disfigurement and mutilation of children. Both, Hugo and Filipenko, agree on the social diagnosis of the issue: children are mere toys in the hands of the system, which humiliates and deprives them of basic rights and freedoms. As the result, children loose their social subjectivity and suffer permanent disability at emotional, mental and spiritual planes by being stripped of their humanity. Such outcome befalls both the individual and the entire society – in the case of Return to Ostrog, the society of post-Soviet authoritarian-totalitarian Russia
Запрет конкуренции в отношениях между работником и юридическим лицом
No full textВыпускная квалификационная работа представляет собой исследование природы запрета конкуренции через призму правового положения лиц, осуществляющих функции органов юридического лица (должностных лиц), как вопроса теоретически и практически значимого. Природа запрета конкуренции рассмотрена в аспекте как общей обязанности лица, осуществляющего функцию органа юридического лица (должностного лица), воздерживаться от конкуренции, так и обязательства физического лица (бывшего руководителя) воздерживаться от конкуренции в рамках договорных отношений с бывшим работодателем. В работе произведен анализ зарубежного законодательного регулирования запрета конкуренции. Автор делает вывод, что отсутствие в законодательстве Российской Федерации прямого указания на запрет конкуренции между руководителем (работником) и юридическим лицом не является препятствием использования данной конструкции на практике. Отечественная судебная практика в состоянии самостоятельно выработать позицию, позволяющую внедрить указанную конструкцию в гражданско-правовой оборот, опираясь на саму природу запрета конкуренции.Graduation qualification work is a study of the nature of the non-competition through the prism of the legal status of persons performing the functions of the bodies of a legal entity (officials) as a matter of theory and practice. The nature of the non-competition is considered in the aspect of both the general duty of the person exercising the function of the body of a legal entity (official), to refrain from competition, and the obligation of an individual (former leader) to refrain from competition within the framework of contractual relations with the former employer. The work analyzes the foreign legislative regulation of the non-competition. The author concludes that the absence in the legislation of the Russian Federation of a direct indication of the non-competition between a manager (employee) and a legal entity is not an obstacle to the use of this design in practice. Domestic judicial practice is able to independently develop a position that allows the introduction of this design in the civil legal turnover, relying on the very nature of the ban on competition
Экономическое обоснование формирования региональных технико-внедренческих зон.
No full textВ условиях перехода к рыночной экономике целью каждого региона становится максимальная реализация экономической активности. Одним из инновационных направлений развития регионов является создание технико-внедренческих зон, которые меняют расклад сил, влияющих на пространственное развитие, многосторонне трансформируя побудительные мотивы движения материальных, трудовых и финансовых ресурсов. Для обоснования формирования региональных технико-внедренческих зон Брестской области проведена оценка социально-экономического потенциала, конкурентоспособности и инновационной активности отраслей и регионов, что позволило комплексно обосновать уровень развития регионов, сформировать зоны и определить для них полюсы экономического роста. = In conditions of market-transition economy the goal ofeach region is to maximize economic activity. One of the innovative directions in the development ofregions is the creation of techno zones which influence regional progress by radically changing the motives determining the movement of manpower and material and financial resources. To justify the creation of local techno zones in Brest region the author has estimated the socio-economic potential, competitiveness and innovative activity of particular industries and regions, thus making it possible to estimate the level of development of particular regions, to create zones and to determine the poles of their economic growth
Economic substantiation of formation regional technical and introduced zones
No full textВ условиях перехода к рыночной экономике целью каждого региона становится максимальная реализация экономической активности. Одним из инновационных направлений развития регионов является создание технико-внедренческих зон, которые меняют расклад сил, влияющих на пространственное развитие, многосторонне трансформируя побудительные мотивы движения материальных, трудовых и финансовых ресурсов. Для обоснования формирования региональных технико-внедренческих зон Брестской области проведена оценка социально-экономического потенциала, конкурентоспособности и инновационной активности отраслей и регионов, что позволило комплексно обосновать уровень развития регионов, сформировать зоны и определить для них полюсы экономического роста.In conditions of market-transition economy the goal ofeach region is to maximize economic activity. One of the innovative directions in the development ofregions is the creation of techno zones which influence regional progress by radically changing the motives determining the movement of manpower and material and financial resources. To justify the creation of local techno zones in Brest region the author has estimated the socio-economic potential, competitiveness and innovative activity of particular industries and regions, thus making it possible to estimate the level of development of particular regions, to create zones and to determine the poles of their economic growth
Духовні і моральні ціннісні орієнтації як гарантія особистісно значущих якостей студентської молоді
No full textIn the article it is studied out that the spiritual and moral value orientations education of students is becoming increasingly important. It is determined that the need to establish in education approaches that ensure a harmonious balance of moral and professional qualities of graduates of higher education institutions is emphasized in the strategic documents of education of Ukraine. The research emphasizes that the effectiveness of spiritual and moral education of future engineers is realized due to students' awareness of the essence of spiritual and moral value orientations, as well as stimulating the need for professional self-development of future professionals. The article describes the implementation of the author's special course “Spiritual and moral value orientations: ways of education” in the educational process of Kharkiv National Automobile and Road University.В статті з’ясовано, що виховання духовних моральних ціннісних орієнтацій у студентів набуває актуальності. Визначено, що потреба утвердження в освіті підходів, які забезпечують гармонійний баланс моральних і професійних якостей випускників закладів вищої освіти, акцентується у стратегічних документах освіти України щодо ціннісних орієнтирів сучасної школи та національно-патріотичного
виховання в закладах освіти. В дослідженні підкреслено, що ефективність виховання духовності та моральності у майбутніх інженерів відбувається за рахунок усвідомлення студентами сутності духовних моральних ціннісних орієнтацій, а також стимулювання потреби професійного саморозвитку у майбутніх фахівців. У статті описано реалізацію авторського спецкурсу “Духовні і моральні ціннісні орієнтації: шляхи виховання” в освітньому процесі Харківського національного автомобільно-дорожнього університету
