Modulation of signal transduction by vitamin E

The ability of vitamin E to modulate signal transduction and gene expression has been observed in numerous studies; however, the detailed molecular mechanisms involved are often not clear. The eight natural vitamin E analogues and synthetic derivatives affect signal transduction with different potency, possibly reflecting their different ability to interact with specific proteins. Vitamin E modulates the activity of several enzymes involved in signal transduction, such as protein kinase C, protein kinase B, protein tyrosine kinases, 5-, 12-, and 15-lipoxygenases, cyclooxygenase-2, phospholipase A2, protein phosphatase 2A, protein tyrosine phosphatase, and diacylglycerol kinase. Activation of some these enzymes after stimulation of cell surface receptors with growth factors or cytokines can be normalized by vitamin E. At the molecular level, the translocation of several of these enzymes to the plasma membrane is affected by vitamin E, suggesting that the modulation of protein-membrane interactions may be a common theme for vitamin E action. In this review the main effects of vitamin E on enzymes involved in signal transduction are summarized and the possible mechanisms leading to enzyme modulation evaluated. The elucidation of the molecular and cellular events affected by vitamin E could reveal novel strategies and molecular targets for developing similarly acting compounds.     

α-Tocopheryl succinate affects malignant cell viability,proliferation, and differentiation

The widespread occurrence of malignant tumors motivates great attention to finding and investigating effective new antitumor preparations. Such preparations include compounds of the vitamin E family. Among them, α-tocopheryl succinate (vitamin E succinate (VES)) has the most pronounced antitumor properties. In this review, various targets and mechanisms of the antitumor effect of vitamin E succinate are characterized. It has been shown that VES has multiple intracellular targets and effects, and as a result VES is able to induce apoptosis in tumor cells, inhibit their proliferation, induce differentiation, prevent metastasizing, and inhibit angiogenesis. However, VES has minimal effects on normal cells and tissues. Due to the variety of targets and selectivity of action, VES is a promising agent against malignant neoplasms. More detailed studies in this area can contribute to development of effective and safe chemotherapeutic preparations.     

Folate deficiency, mismatch repair-dependent apoptosis, and human disease

The vitamin that is most commonly deficient in the American diet is folate. Severe folate deficiency in humans is known to cause megaloblastic anemia and developmental defects, and is associated with an increased incidence of several forms of human cancer. Although the exact mechanisms by which this vitamin deficiency may cause these diseases are not known at the present time, recent work has shown that folate deficiency also causes genomic instability and programmed cell death (or apoptosis). Additionally, it is known that the DNA mismatch repair pathway mediates folate deficiency-induced apoptosis. This review will first describe work suggesting that folate deficiency causes genomic instability and apoptosis, then discuss possible mechanisms by which the mismatch repair pathway could trigger folate deficiency-induced apoptosis, which has either protective or destructive effects on tissue.     

Vitamin D3 induces autophagy of human myeloid leukemia cells

Vitamin D3 causes potent suppression of various cancer cells; however, significant supraphysiological concentrations of this compound are required for antineoplastic effects. Current combinatorial therapies with vitamin D3 are restricted to differentiation effects. It remains uncertain if autophagy is involved in vitamin D3 inhibition on leukemia cells. Here we show that besides triggering differentiation and inhibiting apoptosis, which was previously known, vitamin D3 triggers autophagic death in human myeloid leukemia cells. Inhibiting differentiation does not efficiently diminish vitamin D3 suppression on leukemia cells. Vitamin D3 up-regulates Beclin1, which binds to class III phosphatidylinositol 3-kinase to trigger autophagy. Vitamin D3 phosphorylates Bad in its BH3 domain, resulting in disassociation of the apoptotic Bad-Bcl-xL complex and association of Bcl-xL with Beclin1 and ultimate suppression of apoptotic signaling. Knockdown of Beclin1 eliminates vitamin D3-induced autophagy and inhibits differentiation but activates apoptosis, suggesting that Beclin1 is required for both autophagy and differentiation, and autophagy cooperates with differentiation but excludes apoptosis, in which Beclin1 acts as an interface for these three different cascades. Moreover, additional up-regulation of autophagy, but not apoptosis, dramatically improves vitamin D3 inhibition on leukemia cells. These findings extend our understanding of the action of vitamin D3 in antineoplastic effects and the role of Beclin1 in regulating multiple cellular cascades and suggest a potentially promising strategy with a significantly better antileukemia effect.     

Preferential involvement of both ROS and ceramide in fenretinide-induced apoptosis of HL60 rather than NB4 and U937 cells

Leukemic cells responding to apoptosis-inducing drugs can be varied in terms of the mechanisms of action. Fenretinide, a synthetic retinoid, is worth of study as a promising candidate for apoptosis-based therapy of leukemia. Yet, it remains unclear whether this drug exerts the similar mechanisms on different leukemic cells. Here, we report a comparative analysis of fenretinide-induced apoptosis in three acute myeloid leukemic (AML) cell lines including HL60, NB4 and U937. Through a series of antagonist assays, we revealed similarities and differences of mechanisms involved in these three cell lines. Antioxidant vitamin C completely abrogated fenretinide-induced apoptosis in all cell lines, demonstrating that ROS is an essential and common mediator. However, the apoptotic effects of fenretinide could be blocked by ceramide synthase inhibitor fumonisin B₁ only in HL60 rather than the other two. Moreover, fumonisin B₁ was unable to inhibit the generation of ROS in fenretinide-treated HL60 cells, indicating that ROS may function as upstream stimulus of ceramide-mediated apoptosis. These comparative results strongly suggest that the apoptotic response induced by fenretinide in HL60 involves both ROS and ceramide, whereas drug-induced apoptosis in NB4 and U937 requires ROS but is independent of ceramide. Differentiated modes of action exerting on AML may guide the use of this apoptosis-inducing drug, and hence advance our knowledge about the nature of cancer-specific responses to this drug.     

Erythropoietin as an antiapoptotic, tissue-protective cytokine

Erythropoietin (EPO) increases the number of circulating erythrocytes primarily by preventing apoptosis of erythroid progenitors. In addition to this proerythroid action, results of recent studies show that systemically administered EPO is protective in vivo, in several animal models of neuronal injury. In vitro, EPO prevents neuronal apoptosis induced by a variety of stimuli. This review summarizes the neuroprotective actions of EPO and discusses the underlying mechanisms in terms of signal transduction pathways involved. The understanding of these mechanisms will help differentiate the neuroprotective actions of EPO from its role in the bone marrow.     

Interaction of the nitric oxide signaling system with the Sphingomyelin cycle and Peroxidation on transmission of toxic signal of tumor necrosis factor-α in ischemia-reperfusion

This review discusses the functional role of nitric oxide in ischemia-reperfusion injury and mechanisms of signal transduction of apoptosis, which accompanies ischemic damage to organs and tissues. On induction of apoptosis an interaction is observed of the nitric oxide signaling system with the sphingomyelin cycle, which is a source of a proapoptotic agent ceramide. Evidence is presented of an interaction of the sphingomyelin cycle enzymes and ceramide with nitric oxide and enzymes synthesizing nitric oxide. The role of a proinflammatory cytokine TNF-α in apoptosis and ischemia-reperfusion and mechanisms of its cytotoxic action, which involve nitric oxide, the sphingomyelin cycle, and lipid peroxidation are discussed. A comprehensive study of these signaling systems provides insight into the molecular mechanism of apoptosis during ischemia and allows us to consider new approaches for treatment of diseases associated with the activation of apoptosis.     

Vitamin D and prostate cancer.

Classically, the actions of vitamin D have been associated with bone and mineral metabolism. More recent studies have shown that vitamin D metabolites induce differentiation and/or inhibit cell proliferation of a number of malignant and nonmalignant cell types including prostate cancer cells. Epidemiological studies show correlations between the risk factors for prostate cancer and conditions that can result in decreased vitamin D levels. The active metabolite of vitamin D, 1,25-dihydroxyvitamin D3 (calcitriol), inhibits growth of both primary cultures of human prostate cancer cells and cancer cell lines, but the mechanism by which the cells are growth-inhibited has not been clearly defined. Initial studies suggest that calcitriol alters cell cycle progression and may also initiate apoptosis. One of the disadvantages of using vitamin D in vivo is side-effects such as hypercalcemia at doses above physiological levels. Analogs of calcitriol have been developed that have comparable or more potent antiproliferative effects but are less calcemic. Further research into the mechanisms of vitamin D action in prostate and identification of suitable analogs for use in vivo may lead to its use in the treatment or prevention of prostate cancer.     

Vitamin C suppresses proliferation of the human melanoma cell SK-MEL-2 through the inhibition of cyclooxygenase-2 (COX-2) expression and the modulation of insulin-like growth factor II (IGF-II) production

Vitamin C plays a crucial role in the suppression of proliferation of several types of cancer. Over-expression of cyclooxygenase (COX)-2 and type I insulin-like growth factor (IGF) receptor are important for proliferation and protection from apoptosis in malignancies. However, its specific mechanisms, especially the interaction between COX-2 expression and IGF-I axis mediated by vitamin C, remain yet to be clarified. Therefore, we investigated the effects of vitamin C on the proliferation of melanoma cells via the modulation of COX-2 expression and IGF-I axis. As a result, we found that 1.0 mM vitamin C inhibits the proliferation of SK-MEL-2 without induction of apoptosis. At that moment, IGF-II production was decreased, followed by the inhibition of COX-2 activity. IGF-IR expression was also down-regulated by vitamin C treatment. It coincided with the result from the inhibition of COX-2 by NS-398 and COX-2 siRNA. In addition, the decreased IGF-IR expression by vitamin C was restored by the treatment of recombinant prostaglandin E2. Finally, we determined whether the signal pathway would be involved in vitamin C-induced IGF-II and IGF-IR down-regulation. When the cells were exposed to SB203580, a specific inhibitor of p38 MAPK, COX-2 expression was dramatically recovered. In addition, phosphorylated p38 MAPK was increased after vitamin C treatment. Taken together, vitamin C suppresses proliferation of the human melanoma cell line SK-MEL2 via the down-regulation of IGF-II production and IGF-IR expression, which is followed by the activation of p38 MAPK and the inhibition of COX-2 expression.     

Dual role of vitamin C in an oxygen-sensitive system: discrepancy between DNA damage and cell death

Although vitamin C is considered to act both as pro-oxidant and antioxidant, the mechanisms underlying these actions are still unclear. Using the oxygen-sensitive system of a strict anaerobe, Prevotella melaninogenica, we investigated both the pro-oxidant and antioxidant mechanisms of vitamin C. In the presence of vitamin C, the 8-hydroxydeoxyguanosine (8OHdG) formation induced by oxygen exposure was enhanced, probably due to the action of vitamin C on hydrogen peroxide generated during oxygen exposure: while catalase almost completely suppressed the enhancing effect of vitamin C, 8OHdG formation induced by hydrogen peroxide was enhanced by vitamin C. By contrast, the presence of vitamin C inhibited bacterial cell death, membrane damage, and lipid peroxidation induced by oxygen exposure. Sodium azide showed similar effects to vitamin C, thus the antioxidant action of vitamin C may be due to its quenching of the singlet oxygen generated in this system. Both the pro-oxidant and antioxidant effects of vitamin C were observed only in acidic conditions.     

Role of Ca ions and protein kinase C in the action of vitamin E on respiratory burst of neutrophils and blast transformation of lymphocytes]

It was shown that vitamin E decreased the stimulating role of oxidative burst activators which influenced on Ca(2+)-dependent mechanisms (A23187, verapamil, FMLP). Jointly addition of this vitamin and blood plasma contained tocopherol-binding proteins influenced on mechanisms associated with protein kinase C. It was shown that Ca ions can also take part in tocopherol's action on blast transformation of lymphocytes.     

Molecular mechanisms of leptin and pro-apoptotic signals induced by menadione in HepG2 cells

Apoptosis is a significant physiological function in the cell. P⁵³ is known as tumor suppressor cellular factor, executive caspases are also the most involved pathway for apoptosis. Menadione (VK3) has apoptotic action on many harmful cells, but the molecular role of adipokines is not studied enough in this regard, so the ability of menadione to modify the adipokine (leptin hormone), caspase-3 and P⁵³ signals to induce its apoptotic action on HepG2 cells was studied. The study revealed that menadione has anti-viability and apoptotic effect at sub-G1 phase of HepG2 cell cycle. Its cytotoxic effect is mediated by molecular mechanisms included: inhibiting leptin expression and level, activating caspase-3 pathway and up-regulating the expression of P⁵³. Menadione exerts its apoptotic mechanisms in a concentration and time dependent way through ROS generation. In addition to the known apoptotic pathways, the results indicate that suppressing leptin pathway is a significant mechanism for menadione apoptotic effect which made it as a potential therapeutic vitamin in preventing hepatocyte survival and proliferation.     

Basis for the historical stages for studying the biochemistry of vitamins. Noncoenzymatic mechanisms of vitamin B1

Biochemistry of vitamins is one of the leading trends in the fundamental researches of A. V. Palladin Institute of Biochemistry from the moment of its foundation in 1925. The Laboratory of Vitamins Biochemistry was organised in 1994, it was reorganized into the Department of Vitamins Biochemistry in 1966, and later it was renamed as the Department of Coenzymes Biochemistry. Now the investigations at the Coenzymes Biochemistry Department headed (from 1986) by G. V. Donchenko, Corr.-Member of the National Academy of Sciences of Ukraine, are directed to estimation of vitamins A, E, B1 and PP action molecular mechanisms. Investigation of specific protein-acceptors of vitamins and their biologically active derivatives is a contemporary and effective methodological approach to the estimation of some molecular mechanisms of vitamins action on cellular metabolism. Considering the challenging theoretical and practical aspects of the further fundamental investigation development in the molecular vitaminology the following items are currently being worked in the Department last time: 1. Study of some molecular mechanisms of thiamine and vitamin PP neurotropic action. These investigations are oriented to clearing some new aspects of noncoenzymic mechanism of its influence on the nervous cell functioning both in the norm and at some nervous diseases. 2. Study of some molecular mechanisms of regulation by means of fat-soluble vitamins A, E and their specific proteins-acceptors of DNA, RNA and protein biosynthesis in the nuclei and mitochondria of actively proliferous cells. These investigations are aimed to the estimation of molecular mechanisms of fat-soluble vitamins participation in the regulation of DNA-dependent synthesis of RNA, RNA-polymerase activity, mechanism of their anticancerogenous effect, vitamin E participation in the realisation of nuclear genetic information. 3. Study of intracellular protein-receptors, which take part in realisation of vitamins and their biologically active derivatives functions in the human and animals' organism. The investigations, directed to study of a role of retinol-binding proteins in exchange of the vitamin A and in biosynthesis of DNA, RNA and proteins, the role of tocopherol-binding proteins in realisation of biological action of vitamin E in cells and thiamine-binding proteins in realisation of neurotropic action of vitamin B1 are actively developed. 4. Investigation of mechanisms of antioxidizing and antiradical biological action of vitamin D3, ecdisterone and related biologically active compounds. Basing on the fundamental researches some vitamins preparations have been created, such as "Carotin-M", "Cardiovit", "Evit-1", "Soevit", "Metovit", "Caratel'ka" and others. The results of fundamental investigation of noncoenzymic thiamine function led us to elaboration of a new hypothesis about molecular mechanism of vitamin B1 neurotropic action. According to the hypothesis the thiamine high neuroactivity is a result of existence in the nervous ending a specific mobile thiamine pool and connection thiamine metabolism with nervous cell membrane potential and acetylcholine metabolism.     

Stabilization of rat liver tyrosine aminotransferase in vivo by pyridoxine administration.

Administration of pyridoxine stabilizes rat liver tyrosine aminotransferase in vivo, whereas administration of cortisol, cyclic AMP, glucagon, insulin, tryptophan or tyrosine does not. The results of these and other experiments with pyridoxine are discussed in relation to the mechanisms of action of this vitamin on the activity of the enzyme.     

Cell-adhesion and morphological changes are not sufficient to support anchorage-dependent cell growth via non-integrin-mediated attachment

Cell-adhesion and spread are important for cell survival. Although extensive studies have suggested several potential mechanisms of action, it is not yet clear how important cell-morphological change per se contributes to the cell-surviving signal. We employed a non-integrin-mediated cell-adhesion system to explore this question. BHK-Japanese encephalitis virus (JEV) cells (BHK21 cells that are persistently infected with JEV) express a large amount of JEV-envelope protein (JEV E) on their surfaces, and can attach and form pseudopodia on the anti-JEV E antibody-coated substrates. However, cells that adhered on the antibody substrate underwent a caspase-3-mediated apoptosis together with a down-regulation of mitogen-activated protein kinase activity within 20 h after adhesion, which indicates that viral-protein-mediated cell-adhesion and cell-spread are not sufficient for supporting cell survival. This provides a different perspective for the study of the relationships between the cell-morphological change and the cell-survival signal.     

TNF-α信号传导通路的分子机理

肿瘤坏死因子α（tumor necrosis factor-alpha,TNF-α）是一种具有多效生物学效应的细胞因子.TNF的生物学效应都是通过细胞表面的2种TNF受体（TNFR）引发,其信号传导通路主要包括caspase家族介导的细胞凋亡、衔接蛋白TRAF介导的转录因子NF-κB和JNK蛋白激酶的活化.TNFR1和TNFR2的生物学功能不是独立的,许多生物学活性由二者共同完成.3条信号传导通路之间及各通路内部含有各种调节机制,使TNF的各种生物学功能协调发挥出来.本文评述了3条信号传导通路最新进展、关键激酶的研究状况及其在整个信号网络中的作用机理,如IKK的激活以及重要的信号转导分子RIP、TRAF2、TRUSS的结构、相互作用的方式等