Thyroxine signal transduction in liver cells involves phospholipase C and phospholipase D activation. Genomic independent action of thyroid hormone

BACKGROUND: Numerous investigations demonstrate a novel role of thyroid hormone as a modulator of signal transduction. Protein kinase C (PKC) is critical to the mechanism by which thyroid hormones potentiate both the antiviral and immunomodulatory actions of IFNγ in different cells and regulate the exchange of signalling phospholipids in hepatocytes. Because nothing is known about accumulation of PKC modulator - diacylglycerol in cells treated with T(4), we examined the nongenomic effect of thyroid hormones on DAG formation and phospholipase activation in liver cells. RESULTS: The results obtained provide the first demonstration of phospholipase C, phospholipase D and protein kinase C nongenomic activation and diacylglycerol (DAG) accumulation by L-T(4) in liver cells. The experiments were performed in either the [(14)C]CH(3)COOH-labeled rat liver slices or isolated hepatocytes pre-labeled by [(14)C]oleic acid. L-T(4) activates the DAG production in a concentration- and time-dependent manner. DAG formation in stimulated cells is biphasic and short-lived event: there is an initial, rapid rise in DAG concentration and then a slower accumulation that can be sustained for a few minutes. The early phase of L-T(4) generated DAG only is accompanied by phosphatidylinositol 4,5-bisphosphate level decrease and inositol 1,4,5-trisphosphate formation while the second phase is abolished by PKC inhibitor l,(5-isoquinolinesulphonyl)2methylpiperasine dihydrochloride (H7) and propranolol. The second phase of DAG production is accompanied by free choline release, phosphatidylcholine content drop and phosphatidylethanol (Peth) formation. Inhibitor of phospholipase-C-dependent phosphoinositide hydrolysis, neomycin sulfate, reduced the Peth as well as the DAG response to L-T(4). CONCLUSIONS: The present data have indicated the DAG signaling in thyroid hormone-stimulated liver cells. L-thyroxine activates a dual phospholipase pathway in a sequential and synchronized manner: phospholipase C initiates the DAG formation, and PKC mediates the integration of phospholipase D into the signaling response during the sustained phase of agonist stimulation

Effects of thyroxine and 1-methyl, 2-mercaptoimidazol on phosphoinositides synthesis in rat liver

BACKGROUND: Phosphoinositides mediate one of the intracellular signal transduction pathways and produce a class of second messengers that are involved in the action of hormones and neurotransmitters on target cells. Thyroid hormones are well known regulators of lipid metabolism and modulators of signal transduction in cells. However, little is known about phosphoinositides cycle regulation by thyroid hormones. The present paper deals with phosphoinositides synthesis de novo and acylation in liver at different thyroid status of rats. RESULTS: The experiments were performed in either the rat liver or hepatocytes of 90- and 720-day-old rats. Myo-[(3)H]inositol, [(14)C]CH(3)COONa, [(14)C]oleic and [(3)H]arachidonic acids were used to investigate the phosphatidylinositol (PtdIns), phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate (PtdInsP(2)) synthesis. 1-methyl, 2-mercaptoimidazol-induced hypothyroidism was associated with the decrease of myo-[(3)H]inositol and [(3)H]arachidonic acids incorporation into liver phosphoinositides and total phospholipids, respectively. The thyroxine (L-T(4)) injection to hypothyroid animals increased the hormones contents in blood serum and PtdInsP(2 )synthesis de novo as well as [(3)H]arachidonic acids incorporation into the PtdIns and PtdInsP(2). Under the hormone action, the [(14)C]oleic acid incorporation into PtdIns reduced in the liver of hypothyroid animals. A single injection of L-T(4 )to the euthyroid [(14)C]CH(3)COONa-pre-treated animals or addition of the hormone to a culture medium of hepatocytes was accompanied by the rapid prominent increase in the levels of the newly synthesized PtdIns and PtdInsP(2 )and in the mass of phosphatidic acid in the liver or the cells. CONCLUSIONS: The data obtained have demonstrated that thyroid hormones are of vital importance in the regulation of arachidonate-containing phosphoinositides metabolism in the liver. The drug-induced malfunction of thyroid gland noticeably changed the phosphoinositides synthesis de novo. The L-T(4 )injection to the animals was followed by the time-dependent increase of polyphosphoinositide synthesis in the liver. The both long-term and short-term hormone effects on the newly synthesized PtdInsP(2 )have been determined

Effects of flavonoids on sphingolipid turnover in the toxin-damaged liver and liver cells

<p>Abstract</p> <p>Background</p> <p>The ceramide generation is an early event in the apoptotic response to numerous stimuli including the oxidative stress and ceramide analogs mimic the stress effect and induce apoptosis. Flavonoids of German chamomile are reported to exhibit the hepatoprotective effect. Flavonoids affect sphingolipid metabolism and reduce the elevated ceramide level in the aged liver. In the present paper, the ceramide content and production in the CCl₄- and ethanol-treated liver and hepatocytes as well as the correction of sphingolipid metabolism in the damaged liver using the mixture of German chamomile flavonoids (chamiloflan) or apigenin-7-glucoside (AP7Glu) have been investigated.</p> <p>Results</p> <p>The experiments were performed in either the rat liver or hepatocytes of normal, CCl₄- and ethanol-treated or flavonoid- and toxin plus flavonoid-treated animals. [¹⁴C]palmitic acid and [methyl-¹⁴C-phosphorylcholine]sphingomyelin were used to investigate the sphingolipid turnover. Addition of the CCl₄or ethanol to isolated hepatocyte suspensions caused loss of cell viability and increased the lactate dehydrogenase release from the cells into supernatant and ceramide level in the cells. CCl₄administration to the rats enlarged ceramide mass as well as neutral sphingomyelinase (SMase) activity and reduced ceramide degradation by the neutral ceramidase. Pretreatment of isolated hepatocytes with flavonoids abrogated the CCl₄effects on the cell membrane integrity and normalized the ceramide content. Flavonoid administration to the rats normalized the elevated ceramide content in the damaged liver via neutral SMase inhibition and ceramidase activation.</p> <p>Conclusion</p> <p>The data obtained have demonstrated that flavonoids affect sphingolipid metabolism in the CCl₄- and ethanol-damaged liver and liver cells. Flavonoids normalized activities of key enzymes of sphingolipid turnover (neutral SMase and ceramidase) and ceramide contents in the damaged liver and liver cells, and stabilized the hepatocyte membranes.</p

Radiation-Induced Cerebro-Ophthalmic Effectsin Humans

: Exposure to ionizing radiation (IR) could affect the human brain and eyes leading to both cognitive and visual impairments. The aim of this paper was to review and analyze the current literature, and to comment on the ensuing findings in the light of our personal contributions in this field. The review was carried out according to the PRISMA guidelines by searching PubMed, Scopus, Embase, PsycINFO and Google Scholar English papers published from January 2000 to January 2020. The results showed that prenatally or childhood-exposed individuals are a particular target group with a higher risk for possible radiation effects and neurodegenerative diseases. In adulthood and medical/interventional radiologists, the most frequent IR-induced ophthalmic effects include cataracts, glaucoma, optic neuropathy, retinopathy and angiopathy, sometimes associated with specific neurocognitive deficits. According to available information that eye alterations may induce or may be associated with brain dysfunctions and vice versa, we propose to label this relationship “eye-brain axis”, as well as to deepen the diagnosis of eye pathologies as early and easily obtainable markers of possible low dose IR-induced brain damage

Vitamin E Prevents Lipogenesis Dysregulation in the Liver Cells at Old Age Vitamin E Prevents Lipogenesis Dysregulation in the Liver Cells at Old Age

Abstract Thyroid hormones play critical roles in lipogenesis regulation. Genomic dependent and genomic independent effects of triiodothyronine on free fatty acids (FFA) synthesis have been determined. The lipogenesis regulation with L-thyroxine (T4) in the liver cells of 3-and 24-month-old rats and effects of vitamin E (?-tocopherol acetate) or N-acetylcistein (NAC) on old liver response to hormone action have been investigated. T4 in both experiments in vivo and in vitro increased lipogenesis in liver cells of young rats, while old hepatocytes were resistant to the hormone action. Vitamin E as well as N-acetylcistein (NAC) increased significantly the liver and hepatocytes sensitivity to the T4 action at old age. However, the vitamin E-dependent induction of FFA synthesis with T4 was not followed by FFA accumulation. The newly synthesized FFA were used for cholesterol and neutral lipids synthesis in old liver cells treated with T4 plus vitamin E or NAC. The data obtained have demonstrated for the first time that the age-dependent lipogenesis dysregulation depends on redox state changes in liver. Vitamin E improved both the long-term and the short-term genomic independent thyroid hormone lipogenesis regulation at old age

Modulation of Insulin Sensitivity of Hepatocytes by the Pharmacological Downregulation of Phospholipase D

Background. The role of phospholipase D (PLD) as a positive modulator of glucose uptake activation by insulin in muscle and adipose cells has been demonstrated. The role of PLD in the regulation of glucose metabolism by insulin in the primary hepatocytes has been determined in this study. Methods. For this purpose, we studied effects of inhibitors of PLD on glucose uptake and glycogen synthesis stimulation by insulin. To determine the PLD activity, the method based on determination of products of transphosphatidylation reaction, phosphatidylethanol or phosphatidylbutanol, was used. Results. Inhibition of PLD by a general antagonist (1-butanol) or specific inhibitor, halopemide, or N-hexanoylsphingosine, or by cellular ceramides accumulated in doxorubicin-treated hepatocytes decreased insulin-stimulated glucose metabolism. Doxorubicin-induced hepatocytes resistance to insulin action could be abolished by inhibition of ceramide production. Halopemide could nullify this effect. Addition of propranolol, as well as inhibitors of phosphatidylinositol 3-kinase (PI3-kinase) (wortmannin, LY294002) or suppressors of Akt phosphorylation/activity, luteolin-7-O-glucoside or apigenin-7-O-glucoside, to the culture media could block cell response to insulin action. Conclusion. PLD plays an important role in the insulin signaling in the hepatocytes. PLD is activated downstream of PI3-kinase and Akt and is highly sensitive to ceramide content in the liver cells

Formation of Marketing Strategies and Programs in the Context of Global Change Формирование маркетинговых стратегий и программ в условиях глобальных изменений

This article gived an analysis of modern trends in globalization processes and their connection with the formation of a global business strategy. It was substantiated the topicality of forming a new conceptual approach to strategy development in a «stable instability». It was proposed a model of development strategy, which involves the formation of interconnected network of alternative strategies, and allows flexible to adapt to changing conditions.<br>В статье выполнен анализ современных тенденций глобализационных процессов и их связи с формированием глобальной стратегии предприятия. Обоснована актуальность формирования нового концептуального подхода к разработке стратегии в условиях «стабильной неустойчивости». Предложена модель разработки стратегии, которая предусматривает формирование сети взаимосвязанных альтернативных стратегий и позволяет гибко адаптироваться к изменяющимся условиям