Vitamin D Impact on the Liver and Kidney

Vitamin D Impact on the Liver and Kidney Revised vitamin D copy Sources and forms of vitamin D Vitamin D, also termed calciferol, is a fat-soluble secosteroid compound that is an essential regulatory factor for calcium and phosphate metabolism in humans and animals. Its biological functions involve a physiological action in bone formation and mineralization, muscle contraction, nerve signal modulation and transmission as well as many cellular metabolic effects in various organs. There are two forms of vitamin D that are metabolically important; vitamin D2 or ergocalciferol and vitamin D3 or cholecalciferol. The nutritional sources of both forms are limited to certain types of foods that naturally contain vitamin D and therefore it is added to some foods as a supplement. 1.1.1- Exogenous (Diet) Both forms of vitamin D (D2 and D3) are exogenously obtained in low quantities from some types of food in the diet. Vitamin D2 is rare as it is produced from fungal and plant sources such as mushrooms and cereals, as a result of irradiation, by ultraviolet photons, of the plant sterol ergosterol. When these foods are ingested, ergocalciferol is absorbed into the blood. Vitamin D3 , on the other hand, is available in very low amounts from animal sources including oily fish such as salmon and mackerel; other sources include meat, liver, cheese, cod liver oil, eggs and fortified foods such as margarine and milk (Holick, 2006; Engelsen et al., 2005; Nowson et al., 2004). Farmed salmon, for example, contains only 25% of the vitamin D levels present in wild salmon, however, the amount of vitamin D in canned food may affected by modern processing methods (Chen et al., 2007). 1.1.2- Endogenous In humans the principal precursor of vitamin D3 is cholesterol which is obtained from the diet. Cholesterol is initially converted to 7-dehydrocholesterol, provitamin D3, through the action of enzymes termed the mucosal dehydrogenase complex, present in the small intestine. Provitamin D3, is then incorporated within chylomicrons and transported to the skin where temperature dependent photoisomerisation processing of 7-dehydrocholesterol takes place in epidermal cells resulting in the production of D3. Within the epidermal cells, vitamin D3 undergoes photocoversion to its isomers 5,6-transvitamin D3 and suprasterol, a process which relies on the amount of ultraviolet radiation absorbed; inadequate sunlight exposure compromises this process (Holick, 2003; Iqbal, 1994). Sunlight exposure is therefore a crucial element in the regulation and enhancement of endogenous cholecalciferol production (Dusso, et al., 2005; Iqbal, 1994; Reichel, et al., 1989; Smith, 1988). Once photoconversion is completed, cholecalciferol binds to Vitamin D Binding Protein (VDBP) and transported to the liver for further metabolic processing. Vitamin D metabolism Both forms of vitamin D (D2 and D3) undergo similar metabolic activation in the liver and kidney respectively to produce the physiologically active form 1,25-dihydroxyvitamin D3. 1.2.1- Skin The skin is characterized by two layers, the outer epidermal region, consisting of several strata, and the inner dermal layer. Skin exposure to UVB rays in sunlight, characterized by a wavelength of 290 nm to 315 nm, allows the initial steps of vitamin D synthesis to occur using the substrate 7-dehydrocholesterol (7-DHC) as illustrated in step 1 of Figure 1. UVB absorption by 7-DHC is thought to occur actively in the stratum basale and stratum spinosum regions of the epidermal layer. The substrate 7-DHC is an important intermediate of cholesteryl ester biosynthesis from squalene. During the reaction, 7-DHC forms procholecalciferol through B ring opening of the steroid structure. This transition state is relatively unstable and can further undergo photocatalyzed reactions to form lumisterol and tachysterol (Wolpowitz and Gilchrest, 2006). Lumisterol and tachysterol have been shown to prevent vitamin D reaching intoxicating levels and do not have any direct vitamin D effects (Bouillon et al., 1998). In addition to this protective mechanism, previtamin D poisoning is also prevented because this is an equilibrium reaction that allows cholecalciferol to revert back to 7-DHC (Webb, 2006). Cholecalciferol (previtamin D3) is produced upon double bond rearrangement of procholecalciferol and remains in the extracellular space where it becomes bound to the ubiquitous VDBP (Holick, 2005). Figure1. Sources and steps of vitamin D synthesis in the three major sites: skin, liver and kidney (Figure obtained from Wolpowitz and Gilchrest, 2006). 1.2.2- Liver Cholecalciferol that has been transported to the liver undergoes the first step of its bioactivation, the hydroxylation of carbon 25 (Dusso, et al., 2005) by two hepatic enzymes; the microsomal and mitochomdrial 25-hydroxylases (Deluca et al., 1990). In hepatic cellular microsomes and mitochondria, vitamin D3 is hydroxylated at carbon 25 and transformed to 25-hydroxyvitamin D3 by both 25-hydroxylase enzymes. This enzyme complex requires the presence of essential catalytic cofactors including nicotinamide adenine dinucleotide phosphate (NAPDH), flavin adenine dinucleotide (FAD), ferredoxin and molecular oxygen for this reaction to proceed (Sahota and Hosking, 1999; Ohyama et al., 1997; Kumar, 1990). Recently, large numbers of hepatic cytochrome P-450 enzymes exhibiting 25-hydroxylase action have been identified in vitamin D activation pathways; these enzymes include CYP27A1, CYP3A4, CYP2D25 and CYP2R1 (Dusso, et al., 2005; Cheng et al., 2003; Sawada et al., 2000). However, CYP2R1 is b elieved to be the principal enzyme in the hepatic pathway and the presence of a genetic mutation in its gene may compromise the outcome of this process; both CYP27A1 and CYP2D25 demonstrate high capacity and low affinity features, therefore, their activity is considered insignificant in this pathway (Dusso, et al., 2005; Cheng et al., 2003; Sawada et al., 2000). This metabolic step is inefficiently regulated, i.e. the levels of 25-hydroxy vitamin D are elevated as dietary intake of vitamin D increases. Consequently, over 95% of 25-hydroxyvitamin D in serum circulates as 25-hydroxyvitamin D3 which has a half-life of approximately three weeks, and is therefore used in the assessment of vitamin D status (Dusso, et al., 2005; Reichel et al., 1989). The metabolically inert 25-hydroxyvitamin D3 is then transported to the kidney for the second step of its bioactivation. 1.2.3- Kidney The second step of vitamin D3 bioactivation takes place at the proximal convoluted tubule of the kidney. Hydroxylation occurs at C-1 of 25-hydroxyvitamin D3 whereby the highly active 25-hydroxyvitamin D3 1-ÃŽ ±-hydroxylase (CYP27B1) incorporates a hydroxyl group to Carbon-1 of the first ring to form the biologically active metabolite 1,25-dihydroxyvitamin D3 (Holick,2006; Dusso, et al., 2005; Deluca et al, 1990; Reichel, et al., 1989). The high activity of 1-ÃŽ ±-hydroxylase (CYP27B1) present in kidney is not unique to this organ and can also be found in some other organs (Bouillon, 1998). The renal hydroxylation of 25-hydroxyvitamin D3 is the rate-limiting step in the production of 1,25-dihydroxyvitamin D3 and is well regulated. An alternative pathway of hydroxylation of 25-hydroxyvitamin D3 within renal mitochondria takes place at Carbon-24 to form 24,25-dihydroxyvitamin D3 which is metabolically inert. This process is catalyzed by renal 24-ÃŽ ±-hydroxylase in response to 1-ÃŽ ±-hy droxylase suppression. However, 24-ÃŽ ±-hydroxylase not only initiates the attachment of the hydroxyl group at Carbon-24 but also enhances the dehydrogenation of 24,25-dihydroxyvitamin D3 and hydroxylation at Carbon 23 and 26 (Sahota and Hosking, 1999; Bouillon, 1998; Reichel, et al., 1989). Renal hydroxylases require the presence of catalytic cofactors that enhance their synthetic activities during this process. Figure 2 shows the details of vitamin synthesis including the enzymes and cofactors required for each step. Figure2. Enzymes, cofactor and intermediates compounds of vitamin D metabolism (Bouillon et al. 1998) 1.2.4- Regulation of vitamin D metabolism Numbers of factors have been demonstrated to be important in the regulation of vitamin D metabolism; particularly significant its regulation through renal production. The factors involved in this regulation comprise parathyroid hormone (PTH), calcitonin, dietary calcium and phosphate, insulin and insulin-like growth factor and 1,25-dihydroxyvitamin D3 itself (Holick,2006; Deluca, 2004; Sahota and Hosking, 1999). Key interactions of vitamin D with its receptor are known to initiate gene regulation. These mechanisms have been studied using vitamin D analogues which have revealed the mechanism of assembly of transcriptions factors and promotion of gene regulation by this molecule (Cheng et al., 2004; Wu et al., 2002). Figure 3 shows the effect of various regulators on vitamin D metabolism. Figure 3: Alternate pathway for vitamin D3 under different metabolic conditions of low mineral Ca and P levels, PTH concentration and secretion of GH / IGH (Figure obtained from Gomez, 2006). 1.2.4.1- Parathyroid Hormone Parathyroid hormone (PTH) is the primary regulator of renal 1,25-dihydroxyvitamin D3 formation (Holick, 2006; Dusso et al., 2005; Bouillon et al., 1998; Issa et al., 1998). PTH regulates 1,25-dihydroxyvitamin D3 production directly through enhancing 1-ÃŽ ±-hydroxylase activity within kidney cells and increasing the genetic transcription rate of renal proximal tubular 1-ÃŽ ±-hydroxylase both of which result in an increase in the renal 1,25-dihydroxyvitamin D3 production rate. High levels of 1,25-dihydroxyvitamin D3 suppress the enzyme transcription activity and PTH concentration. Thus, renal 1,25-dihydroxyvitamin D3 has a negative feedback response on PTH secretion, providing an efficient regulatory control of renal 1,25-dihydroxyvitamin D3 homeostasis (Dusso, et al., 2005; Holick,2003; Sahota and Hosking, 1999; Reichel, et al., 1989; Iqbal, 1994). 1.2.4.2- Calcium Dietary calcium exhibits a direct regulatory influence on renal 1-ÃŽ ±-hydroxylase activity via fluctuating serum calcium concentration and indirectly via its effect on serum PTH concentration. Calcium exerts its effect through calcium-sensing receptor (CaR) activation within the parathyroid gland and renal proximal tubules cells in response to low calcium concentration. Thus, the low intracellular calcium levels lead to increased production of 1,25-dihydroxyvitamin D3 within renal cells (Ramasamy, 2006; Bland et al., 1999; Chattopadhyay et al., 1996). On the other hand, it has been shown that high calcium concentrations markedly impair renal 1,25-dihydroxyvitamin D3 formation in human nephrotic cell cultures and in parathyroidectomised animals (Bland et al., 1999; Chattopadhyay et al., 1996). An increase in extracellular calcium indirectly suppresses 1,25-dihydroxyvitamin D3 production at the proximal convoluted tubule by inhibiting PTH release (Deluca, 2004; Carpenter, 1990). Howev er, the detailed mechanism of calcium-sensing receptors (CaR) activation is not yet fully understood (Dusso, et al., 2005; Hewison, et al., 2000). 1.2.4.3- Phosphate Dietary phosphate intake and serum phosphate concentrations exhibit regulatory effects on 1,25-dihydroxyvitamin D3 production in proximal renal tubules. This effect has been demonstrated in several studies which showed that a decrease in dietary phosphate accelerated renal formation of 1,25-dihydroxyvitamin D3, but did not directly affect 1, 25-dihydroxyvitamin D3 catabolism. Conversely, elevated serum phosphate and increased phosphate intake led to decreased production of 1, 25-dihydroxyvitamin D3 (Carpenter, 1989; Reichel et al., 1989). Several studies have shown that inorganic phosphate levels have no significant direct effect on mitochondrial 1-ÃŽ ±-hydroxylase activity in cultured renal cells in the short term, suggesting that the action of inorganic phosphate is not mediated via changes in PTH and Calcium concentrations and is possibly inducted by other hormones such as growth hormone, insulin and insulin-like growth factor (Khanal et al., 2006; Dusso et al., 2005; Carpenter, 1 989). In recent studies, fibroblast growth factor 23 (FGF-23), frizzled-related protein 4 (FRP-4) and matrix extracellular phosphoglycoprotein (MEPE) have all been identified as potent and key regulatory factors of 1-ÃŽ ±-hydroxylase activity in renal cells. These factors act through a biphasic mechanism on renal phosphate homeostasis and modulate the circulating levels of 1, 25-dihydroxyvitamin D3 produced by proximal renal tubules (Dusso et al., 2005; Inoue et al., 2005; Mirams et al., 2004). 1.2.4.4- Calcitonin Calcitonin belongs to a family of calcium regulating hormones that is produced in the parafollicular cells of the thyroid gland, also known as C cells. It is a short and linear polypeptide with a molecular weight of only 3.7 kD. It is characterized by 32 amino acids and a disulfide bridge in the N terminal portion of the peptide. Calcitonin is secreted in response to increased free Ca2+ in blood and acts on osteoclasts, the bone resorbing cells, as a suppressor of bone dissolution. Although calcitonin decreases Ca+2 and inorganic phosphate in blood, it also has the ability to recruit phosphorus into other cells. In addition to these metabolic functions, it is also involved in the upregualtion of CYP27B hydroxylase through the protein kinase C pathway (Yoshida et al., 1999) via a phosphorylation cascade that activates cAMP and induces the expression of hydroxylase thereby activating the transformation of 25(OH) D3 to 1,25(OH)2 D3. In addition to the significant role as a calcium regulating hormone, calcitonin is also known to stimulate the production of vitamin D in tandem with PTH (Yoshida et al., 1999; Wongsurawat and Armbrecht, 1991). Previous studies revealed that 1-ÃŽ ±-hydroxylase mRNA expression, 1-ÃŽ ±-hydroxylase activity and the production of 25(OH)D and 1,25(OH)2D3 all increased in rat kidney cells following the administration of calcitonin (Yoshida et al., 1999; Galante et al., 1972; Rasmussent et al., 1972). However, in cases of diabetes, it is postulated that the kidney becomes immune to the effect of this hormone in diabetic rats which lead to increase vitamin D production (Wongsurawat and Ambrecht, 1991). 1.2.4.5- Growth hormone, Insulin and Insulin-like growth factor-1 Growth hormone (GH) has many regulatory actions in various metabolic processes in humans and mammals and its effect on mineral homeostasis in target organs such as bone and renal cells is well documented. While the regulatory effects of GH on dietary calcium and phosphate metabolism in different tissues have been established, its effect on vitamin D metabolism remains controversial. However, many studies have shown that GH increases the expression of 1-ÃŽ ±-hydroxylase and 1, 25-dihydroxyvitamin D3 in cultured cells and experimental animals (Gomez, 2006). Wu and colleagues reported that serum1, 25-dihydroxyvitamin D3 increases after GH administration in hypophysectomized rats fed with a phosphate depleted diet. Short-term studies in healthy humans have shown that GH raises 1-ÃŽ ±-hydroxylase enzyme activity and promotes 1, 25-dihydroxyvitamin D3 synthesis without changes in PTH, calcium and phosphate concentrations, suggesting that the increasing circulating levels of 1, 25-dihydroxy vitamin D3 following GH administration is not mediated by PTH action (Wu et al., 1997; Bianda et al., 1997; Wright et al., 1996). GH has also been shown to lead to increased production and serum concentration of 1, 25-dihydroxyvitamin D3 in pigs and in renal impaired prepubescent children. These are thought to be a result of the direct and indirect effects of GH on 1-ÃŽ ±-hydroxylase expression, and on calcium and inorganic phosphate homeostasis in renal tubules cells (Strife and Hug, 1996; Denis et al., 1995). However, the action of GH on vitamin D metabolism in vitro remains uncertain and may involve other regulatory factors such as PTH and Insulin-like growth factor-1 (IGF-1). It has been shown that GH does not raise 1, 25-dihydroxyvitamin D3 levels directly in cultured cells obtained from aged-rats; yet it stimulates calcium absorption and the expression of calcium binding proteins in vitro indicating that the effect of GH is mediated through the action of other factors such as IGF-1 (Fleet et al., 1991). Insulin is another key factor with a role in vitamin D homeostasis. Insulin significantly decreases renal hydroxylase activity and renal synthetic capacity of 1, 25-dihydroxyvitamin D3 in insulin deficient patients or those receiving insulin therapy (Armbrecht et al., 1996). However, a study of different routes of therapeutic insulin administration in human diabetic subjects concluded that insulin induces the hepatic hydroxylation of 25-hydroxyvitamin D3. This effect is related to the fact that insulin is a potent inducer of the vast majority of liver hydroxylases enzymes (Colette et al., 1989). This study also showed that there was no significant difference in circulating levels of 1,25-dihydroxyvitamin D3 between different methods of insulin administration. Serum 1,25-dihydroxyvitamin D3 is maintained at normal concentrations in those subjects on long term insulin therapy; however, continuous intraperitioneal infusion procedure (CPII) may augment hepatic 25-hydroxlase activity (Col ette et al., 1989). Similarly insulin has shown a significant effect on stimulating 1,25-dihydroxyvitamin D3 production through 1,25-dihydroxyvitamin D3 and PTH stimulation with no concomitant action on 24-hydroxylase expression in rat osteoblast cells when these cells were cultured with known concentrations of 1,25-dihydroxyvitamin D3 and PTH (Armbrecht et al., 1996). Insulin-like growth factor-1 (IGF-1) is a relatively small peptide that is primarily expressed in hepatic cells and to a lesser extent in some other cells and tissues. It has been identified as one of the potent regulatory components of mineral metabolism in humans and mammals. Recent studies on the metabolic effect of IGF-1 revealed that the administration of IGF-1 to aged laboratory animals, fed on a calcium- and phosphate- deficient diet, can restore 1-ÃŽ ±-hydroxylase activity and enhance the production of 1,25-dihydroxyvitamin D3. In contrast, there was no significant effect of IGF-1 on enzyme activity and 1,25-dihydroxyvitamin D3 levels in adolescent or elderly rats fed on a calcium and phosphate fortified diet concluding that the expression of IGF-1 is not age related but related to the dietary calcium and phosphorus status. (Gomez, 2006; Wong et al., 1997; Wu et al., 1997). In healthy human subjects, a significant effect of IGF-1 on renal 1,25-dihydroxyvitamin D3 synthesis wa s observed after short term infusion with IGF-1. There was no noticeable alteration of the levels of circulating calcium, phosphate and PTH highlighting the role of IGF-1 in stimulating renal expression of 1-ÃŽ ±-hydroxylase and 1,25-dihydroxyvitamin D3 formation in conjunction with GH, independently from PTH (Bianda et al., 1997). In vitro studies have shown that IGF-1 influences the expression of 1-ÃŽ ±-hydroxylase and 1,25-dihydroxyvitamin D3 synthesis in cells cultured from non renal human tissues. Halhali and colleagues demonstrated that IGF-1 noticeably elevates both the enzyme activity and 1,25-dihydroxyvitamin D3 levels when added into cultured syncytiotrophoblast cells obtained from human placental sources. This study demonstrated that IGF-1 strongly enhances the ability of non renal cells to produce 1,25-dihydroxyvitamin D3 without involvement of GH and PTH (Halhali et al., 1997). 1.2.4.6- 1, 25-dihyroxy vitamin D3 The circulating levels of 1,25-dihydroxyvitamin D3 modulate its production by renal cells through an indirect negative feedback mechanism. This mechanism appears to reduce the likelihood of vitamin D toxicity by inhibiting 1,25-dihydroxyvitamin D3 synthesis by an indirect mechanism that controls the 1-ÃŽ ±-hydroxylase gene expression at the molecular level rather than inhibiting 1,25-dihydroxyvitamin D3 synthesis directly. However, the exact mechanism is not yet fully understood (Dusso et al., 2005; Deluca et al., 1990). A recent study examined the effect of 1,25-dihydroxyvitamin D3 on 1-ÃŽ ±-hydroxylase production by cultured human keratinocytes. Keratinocytes were cultured with labeled 25-hydroxyvitamin D3 and different concentrations of 1-ÃŽ ±-hydroxylase mRNA and 24-hydroxylase- suppressed proteins. The 1,25-dihydroxyvitamin D3 did not suppress either the 1-ÃŽ ±-hydroxylase activity or the rate of gene transcription. The study implied that metabolic regulation of 1,25-dihydroxyvi tamin D3 is related to the molecules biodegradation in response to augmented 24-hydroxylase activity rather than 1,25-dihydroxyvitamin D3 formation by 1-ÃŽ ±-hydroxylase (Xie et al., 2002). In addition, Wu and colleagues demonstrated a possible alternative mechanism of 1,25-dihydroxyvitamin D3 synthesis linked to the fact that both 24-hydroxylase and 1-ÃŽ ±-hydroxylase enzymes share equivalent metabolic capability and they proposed the possibility of protein- protein interaction between intracellular vitamin D binding protein and 1-ÃŽ ±-hydroxylase (Wu et al., 2002). 1.2.5- Vitamin D Transport, receptors and mechanism of action Vitamin D receptor (VDR), also known as calcitriol receptor, is a member of the steroid family and belongs to the nuclear receptor superfamily (NHR). Human VDR until recently was thought to comprises four functional units with a total of 427 amino acids residues with an estimated molecular weight of about 48 kDa. These units are the DNA binding domain (DBD) or C domain, the D domain and the ligand binding domain (LBD) or E domain. More recently, a carboxy-group with undefined function, known as the F region has been identified (Christakos et al., 2003; Aranda and Pascual, 2001; Rastinejad et al., 2000). These units as, shown in figure 4, are also known as A/B domain. The A/B region of VDR contains a low number of amino acids that participates in essential ligand-independent receptor stimulation (Aranda and Pascual, 2001; Issa et al., 1998). It is not yet clear if the deletion of A/B domain from VDR will compromise ligand binding, DNA binding or its transactivation features (Issa et a l., 1998). In contrast, the structure of the DNA binding domain or C region among NHRs comprises 40% unique amino acids sequences and a domain of more than 67 resemble amino acids residues (Rastinejad et al., 2000). Moreover, the core structure of DBD comprises between 22 and 114 amino acid residues, nine of them are cysteines. Eight of cysteine residues orchestrate with zinc atoms in tetrahedral fashion to form a dual â€Å"zinc-like finger† DNA binding configurations containing approximately 70 amino acids with a carboxy-terminal extension (CTE). This encloses T and A boxes in a dual helix molecule in which one helix is essential for definitive interaction with the main domain on DNA while the second helix takes a part in receptors structural properties (i.e. receptor dimerization) (Aranda and Pascual, 2001; Issa et al., 1998). However, the integration of the structural amino acids of the DBD ÃŽ ±-helix one, at the site of the first zinc atom, determines the selectivity and specificity of recognition of DBD and forms an area known as the â€Å"P Box†. Similarly; the integration of amino acids at the position of the second zinc atom modulates the formation of a configuration termed the â€Å"D Box† which forms a dimerization interface zone (Aranda and Pascual, 2001; Rastinejad et al., 2000; Issa et al., 1998). Furthermore the vast majority of DBD amino acid units are basic amino acids which enhance the non-covalent binding of the DNA helix at the negatively charged phosphate group (Issa et al., 1998). The ligand binding domain (LBD) or E domain has a spherical configuration with many functional regions composed of 12 cohered helix anchors defined as H1 to H12. LBD itself comprises a net of 427 amino acids which contribute to homodimerization and heterodimerization and the interaction of hormones and costimulaotors by a crucial transactivational mechanism (Aranda and Pascual, 2001; Weatherman et al., 2000; Issa et al., 1998). Crystallograp hic studies show that LBD have two cohered and integrated domains, the Ti or â€Å"signature motif† and the carboxy or C terminal AF-2 providing the self-ligand transcriptional properties; hence a higher degree of attraction of 1,25 dihydroxyvitamin D3 binding is observed at 382 to 402 of LBD amino acid sequence and any genetic aberration at this particular amino acids sequence will diminish the interaction capability of LBD (Aranda and Pascual, 2001; Issa et al., 1998). Figure 4: The primary structure of the vitamin D receptor (VDR) and the binding of retinoid X receptor (RXR)-VDR heterodimers to vitamin D response elements (VDREs) in the form of DR3 and ER6 motifs. (Figure from Lin and White, 2003) 1,25-dihydroxyvitamin D3, has been identified as steroid hormone with a mechanism of action similar to other steroid hormones, causing new protein expression in various target organs. Based on the nuclear receptors structural studies, calcitriol is known to exert its biological action through binding with VDR in the cell nucleus to mediate a cascade of transcriptional and translational processes resulting in either the regulation or inhibition of new protein expression in target tissues or the binding to plasma membrane receptors without stimulating new protein synthesis (Nezbedova and Brtko, 2004; Reichel and Norman, 1989). Two different receptors for 1,25-dihydroxyvitamin D3 have been recognized in different target cells; identified as genomic VDRnuc and typical VDRmem .These receptors provide the best dynamical conformational forms for calcitriol interaction and to evoke its genomic and non-genomic effects (Norman et al., 2002). The binding of 1,25-dihydroxyvitamin D3 to VDRnuc e nhances the interaction with an undistinguished protein known as the nuclear accessory factor (NAF) and to the caroxy-terminal of VDR. This interaction leads to a structural conversion pattern of the C-terminal of VDR allowing the AF-2 domain to attach with other transcriptional elements such as SCR-1, calcium binding protein (CBP) and P300. This promotes the binding of the heterodimer molecule with DNA at the vitamin D response sites (VDRE) and directs its transcriptional gene activity (Jones et al., 1998; Iqbal, 1994). In addition, these coactivators play a role in DNA configurational changes through histone acetyl transferase activation pathway of the core components of histones. This results in mechanical instability of the DNA structure and enhances the net binding capacity of the coactivators with their corresponding receptors at nucleosomal histone level and leads to the upregulation of these transcriptional coactivators which in trun, accelerate the net gene transcriptional rate to promote the synthesis of the analogous protein (Lipkin and Lamprech, 2006; Jones et al., 1998). Conversely, the non-genomic or classical effect of 1,25-dihydroxyvitamin D3 is modulated through its binding with the surface cellular membrane receptor known as mVDR which initiates an immediate response in various target tissues with no genomic transcriptional activity. Many studies demonstrate the rapid effect of calcitriol in rapidly increasing both the level of circulating calcium and its absorption rate in animal intestines, evoking phosphoinoisitide bioactivation, cyclic guanosine monophosphate (cGMP) elevation, activation of protein kinase C and triggering the mitogen activated protein kinase pathways and involving the chloride gates action potential in different organs (Dusso et al., 2005; Nezbedova and Brtko, 2004; Boyan and Schwartz, 2004; Norman et al., 2002). The entire mechanism, as shown in figure 5, for the rapid effect of calcitriol remains doubtful, however; the proposed mechanism is mediated through the interaction with mVDR leading to a series of intracellular sig naling events. Signaling is orchestrated by the activation of various metabolic pathways involving different transportation mechanisms of certain mineral components of target organs. (Pedrozo et al., 1999; Norman et al., 1999; Revelli et al., 1998). However, other studies reveal that the genomic effect of 1,25-dihydroxyvitamin D3 is independent of its non-genomic mechanism (Dusso et al., 2005). Figure 5: Cellular mechanism of action of 1,25(OH)2D3 (Figure from Horst et al., 1997) 1.3- Biological actions of Vitamin D on target tissues and Systems The active form of vitamin D, 1,25-dihydroxyvitamin D3 is well recognized as a member of steroid hormones that mediates several metabolic and non-metabolic processes in various organs in human and animals as shown in figure 6. 1.3.1- Intestine Mineral absorption in the intestines is increased in the presence of the hormone 1,25(OH) vitamin D. However without this, only 10 to 15% of dietary calcium and 60% of phosphorus is absorbed from the diet (De Luca, 2004). Ca2+ and HPO42- are also absorbed when intestinal cells interact with the vitamin D- VDR- RXR complex. The latter enhances the expression of the epithelial calcium channel and calcium-binding protein which recruits calcium and phosphorus (Holick, 2007). Knock out mice experiments studying the effect of VDR gene deletions also show that the size of the small intestines is related to the levels of calcitriol and dietary calcium availability. Vitamin D deficient mice fed with diets low in calcium exhibited the largest small intestine to large intestine ratio (Cantorna et al., 2004). VDR knock-out mice experiments also aid in the discovery of calcium channels, the route for Ca absorption, in the intestine (Peng et al., 1999). Calbindin is a potent calcium transporter in mammals which characterized by a high affinity for calcium ions. Therefore, the binding of vitamin D to VDR and RXR signals an increased production of calbindin which facilitates systemic Ca2+ ions transportation and prevent the occurrence of calcium toxicity in the intestines. Figure 6: Schematic diagram of the effects of Vitamin D on different tissues and organs (Figure from Holick, 2007). 1.3.2- Bone Takeda et al. (1999) studied the role of vitamin D and VDR in bone cells using knock out mice experiments. Their results showed that bone cells formation triggering mechanisms such as cell to cell interaction between osteoblast and osteoclast progenitors and stromal cells induced by 1,25(OH)2 vitamin D3 and provoke the formation of osteoclasts. In their capacity as bone resorbing cells, osteoclasts can be triggered by low serum calcium levels, to break down bone and free calcium back in to the blood thus redistributing calcium throughout the body. However, this does not occur without the expression of VDR and without vitamin D complexing with its receptor. This study emphasizes the important role of recognition sites on the VDR and the structural implications that the receptor-ligand binding has on VDREs and transcription initiation. Although the effects of PTH

An Analysis of In Cold Blood by Truman Capote Essay

Without giving away any of the forthcoming plot, Truman Capote presents us with a deep sense of negativity throughout the first few paragraphs as he sets the scene for novel. Every mention of a location is swiftly followed by a feeling of emptiness: â€Å"Holcomb, too, can be seen from great distances. Not that there is much to see†¦Ã¢â‚¬  This automatically presents the reader with an air of negativity, almost pre-empting what is going to occur later on in the thrilling novel. Later in the paragraph, Capote presents us with the sentence â€Å"the streets, unnamed, unshaded, unpaved†. This emphasises the feeling that something bad is going to happen by suggesting that because the area/location is completely un-protected, any life that enters the boundaries of Holcomb is also un-protected from what will turn out to be a true contradiction of humanity. The fact that the houses are described as â€Å"one-storey frame affairs† further emphasises the idea that it is completely un-protected. Capote presents us with the idea of a forgotten town, or even a ghost town in a manner of speaking. As Capote details the different establishments in Holcomb, he soon causes juxtaposition of mood: â€Å"Holcomb Bank. The bank failed in 1933†. Capote does not present any form of positivity in the first couple of paragraphs, and the detailing of a bank that had been abandoned for many years adds to the ghostly atmosphere. This ghostly atmosphere is directly linked to a feeling of death and decay. Perhaps these themes will be investigated as the novel progresses. I feel Capote cleverly presents us with a subtle plot overview without actually telling us what is going to happen. He simply presents us with an atmosphere; an atmosphere that is sure to stick in our minds as we read the novel.

Policemen of the World - 947 Words

Policemen of the World Final Paper Courtney N Carpenter Strayer University Contemporary US History Professor Tonya Simmons March 13, 2015 Policemen of the World Thesis and Outline Most people would agree that if the U.S. were to launch missiles to attack Syria in vengeance for their alleged use of the nerve agent sarin against anti- government rebels, it would be another addition to the long list of U.S. foreign military operations. Prior presidents have resulted to war after the country was directly attacked, such as by Japan at the start of WII. But more frequently, American presidents have moved forward without consulting congress, using their authority as the country’s leader or commander in chief. With that leverage, they†¦show more content†¦Lastly, the U.S. and Great Britain invade Iraq and topple the government of Dictator Saddam Hussein. The U.S. invasion in Iraq lasts for the next several years during that time it escalates the violence and fragile political stability of the U.S. In 2008, more people we fueled to remove Bush from office and we in the hopes of change that was promised by newly elected President Obama. References Adelman, J. (2013, November 24). Why the u.s. remains the worlds unchallenged superpower. Retrieved from http://www.forbes.com/sites/realspin/2013/11/24/why-the-u-s-remains-the-worlds-unchallenged-superpower/ Roy, A. (2014, June 19). The us invasion of iraq: The most cowardly war ever fought in history. Retrieved from http://www.globalresearch.ca/the-us-invasion-of-iraq-the-most-cowardly-war-ever-fought-in-history/5387751 ‘unintended consequences’: Obama traces origin of isis to bush-era iraq invasion. (2015, March 17). Retrieved from http://rt.com/usa/241325-obama-isis-iraq-bush/ Walsh, K. (2013, March 19). 10 years ago, the u.s. invaded iraq. Retrieved from http://www.usnews.com/news/blogs/press-past/2013/03/19/10-years-ago-the-us-invaded-iraq Yew, L. (2007, January). The united states, iraq, and the war on terror. Retrieved fromShow MoreRelatedPolicemen Of The World Thesis And Outline Final 2 2307 Words   |  10 Pages Assignment 2.1: Policemen of the World Thesis and Outline Stephanie Clay Strayer University 24 May 2014 Introduction Over the last seventy years, the U.S. Military has developed into one of the main tools used by our International Partners to manage complex crisis that pose a serious threat to international peace and security past the United States borders. The number of military personnel that are being deployed to investigate, assist when peacekeeping is greatly needed hasRead MoreSurvivors of Natural Causes and the Media600 Words   |  3 PagesSurvivors of Natural Causes and the Media All around the world, natural disasters are occurring. 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Dulce Et Decorum Est - 2365 Words

â€Å"Anyone, who truly wants to go to war, has never really been there before† Kosovar. This not so famous quote, tells about how blind people were to the horrors and tribulations of war due to a force we call propaganda. â€Å"Dulce et Decorum est pro patria mori† is a controversial phrase used to describe the benefits of going to war. It has different translations but it basically states â€Å"it is sweet and fitting to die for one’s country†, this is just one of the many techniques a nation could use to shade the soldiers to the harsh reality of war. In this essay I will be evaluating two poems Dulce et Decorum est and The Charge of the Light Brigade. â€Å"Dulce et Decorum† est is a poem about war written by Wilfred Owen during World War 1 in 1917-1918.†¦show more content†¦My point is also exercised within the gerunds by continuing the gerunds it suggest that after everyone he still couldn’t do anything to help the soldier. Owen uses inclusive language to make the reader feel sympathy for soldiers blinded by war. â€Å"My friend, you would not tell with such high zest† The use of the words â€Å"My friend† and â€Å"you† already tells us that we are the audience of this quote. The phrase means that we will not talk about war/death enthusiastically because nothing good comes out of it. My point is also expressed somewhere else in the fourth stanza; the poet describes war as â€Å"obscene as cancer†. The incentive behind the poem at this point in time is to enlighten readers to the effects of propaganda on soldiers during World War 1. But during Owens time, this poem was a warning to any soldier or soldier to be, to not experience warfare. Owen also wrote this poem to mock the phrase â€Å"Dulce et Decorum est pro patria mori† he does this in many lines of his poem. I saved this phrase for last because it is the most influential is â€Å"Behind the wagon that i flung him in† This phrase is powerful because many of the translation tell us that â€Å"it is sweet and proper†Ã¢â‚¬ it is pleasing and beauteous†and â€Å"it is sweet and honourable†; as human beings there is no logic behind saying flinging a man behind a wagon is honourable. Gathering all of Owens firsthand experience of war his preparation of war is that it is a negative unethical way of settlingShow MoreRelated Dulce et Decorum Est Essay1618 Words   |  7 PagesDulce et Decorum Est In Wilfred Owen’s poem â€Å"Dulce et Decorum Est† the speaker’s argument against whether there is true honor in dieing for ones country in World War I contradicts the old Latin saying, Dulce et Decorum Est, which translated means, â€Å"it is sweet and honorable to die for the fatherland†; which is exemplified through Owen’s use of title, diction, metaphor and simile, imagery, and structure throughout the entirety of the poem. The first device used by Owen in the poem is withoutRead MoreDulce Et Decorum Est2255 Words   |  10 Pages «Dulce et decorum est », Wilfred Owen (1917, 1920)  «Dulce et decorum est » is a poem written by British poet Wilfred Owen, during World War one, in 1917. The translation of the Latin title is:  «It is sweet and proper ». The completed sentence is as follows:  «It is sweet and proper to die for ones country ». This forms, what the writer refers to as,  «The old Lie ». The poem holds a strong criticism towards the conventional view of war at that written time. I shall now comment briefly on that timesRead MoreDulce Et Decorum Est by Wilfred Owen774 Words   |  3 PagesThe poem â€Å"Dulce Et Decorum Est† certainly describes a memorable and thought-provoking scene of World War I. The title of the poem translates to â€Å"It is sweet and meet to die for one’s country.† Throughout the rest of the work, Wilfred Owen indirectly addresses the claim made in the title. He accomplishes this by utilizing the power of the pen to produce startling imagery of the war time and experiences that may actually be personal for him. However, in the last few lines, he makes a more direct statementRead More Dulce et Decorum Est Essay1748 Words   |  7 PagesWilfred Owen’s â€Å"Dulce et Decorum Est† and E. E Cummings’, â€Å"next to of course god america i† are poems that critique patriotic propaganda. Both poems use words and images to effectively depict the influence that patriotic propaganda has on war. â€Å"Dulce et Decorum Est† uses descriptive words to create realistic images of the horrors soldiers are faced with during combat, whereas â€Å"next to of course god america i† uses sarcasm to inform readers that the abuse of propaganda can be used to manipulate othersRead More Dulce et decorum est Essay703 Words   |  3 PagesDulce et decorum est is a well known battlefield poem written by Wilfred Owen. Critical Analysis Dulce et decorum est is a well known battlefield poem written by Wilfred Owen. It has been written in the first person and the present tense to make the reader feel as if they are actually there. It is in three clear sections, which are eight-line stanzas, rhyming ABABCDCD. It has an extra four lines in the last stanza to incorporate the main message of the poem. It uses many similes andRead MoreDulce Et Decorum Est Analysis Essays1122 Words   |  5 Pages‘Dulce Et Decorum Est’ Essay For years, war and the honour of war has been built up and glorified unfairly by the media in cartoons, movies, games, news and even songs as well as warmongers trying to cash in on unsuspecting and gullible young men who want to be recognized as heroes. Wilfred Owen, who had served in World War 1 and died while defending his country age 25, wrote the poem ‘Dulce Et Decorum Est’ as an attempt to dismantle the unrealistic expectations about war that boys who are ‘ardentRead MoreDulce Et Decorum Est by Wilfred Owen Essays1369 Words   |  6 PagesDulce Et Decorum Est by Wilfred Owen In the poem, Dulce Et Decorum Est by Wilfred Owen, the social climate of the World War I era is reflected through the poets use of vivid imagery and poetic techniques. The poem itself presents an a blunt impression of the world through its linking of ideas and language in its text. The poem addresses the falsehood that war is glorious, that it is noble, it describes the true horror and waste that is war, with the aim of changingRead MoreWilfred Owen s Dulce Et Decorum Est1880 Words   |  8 PagesThroughout the ages, poetry has played--and continues to play--a significant part in the shaping of a generation. It ranges from passionate sonnets of love to the gruesome realities of life. One such example of harsh realism is Wilfred Owen s Dulce et Decorum Est. Owen s piece breaks the conventions of early 20th Century modernism and idealistic war poetry, vividly depicts the traumatizing experiences of World War I, and employs various poetic devices to further his haunted tone and overall messageRead MoreDulce Et Decorum Est And The Charge Of The Light Brigade740 Words   |  3 PagesExperience of Battle In this essay, I will be analyzing the two different poems â€Å"Dulce Et Decorum Est† and â€Å"The charge of the Light Brigade†. While reading and analyzing these poems I will be comparing and contrasting the difference between the two poems and also determining the poet’s literary devices to make the point of both authors. War is a sorted out exertion by a legislature or other vast association to stop or annihilation something that is seen as perilous or awful. It is for the mostRead MoreIs Vitai Lampada Similar to Dulce Et Decorum Est1634 Words   |  7 PagesI am going to compare and contrast the way in which different attitudes to war are presented in the poems ‘Dulce et Decorum est’. And ‘Vitai Lampada’. Both poem are a bout war but they are wrote in completely different ways. Firstly, Wilfred Owen wrote a poem named Dulce et Decorum. Wilfred Owen was born in 1893 in Owestry, Shropshire and he died in 1918. Dulce et Decorum was written in 1917. Wilfred Owen enlisted for the war in 1915 and trained in England until the end of 1916