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Science, Technology and Medicine open access publisher.Publish, read and share novel research. The Diabetic Charcot Foot — New Insights on TreatmentFernando Grover Paez1, Sylvia Elena Totsuka Sutto1, Sara Pascoe Gonzalez1, Ernesto G. C Chipoy, M Berreur, S Couillaud, G Pradal, F Vallette, C Colombeix, Re?dini F, Heymann D, Blanchard F. Y Feng, Y Tang, J Guo, X Wang, Inhibition of LPS-induced TNF-_ production by calcitonin gene-related peptide (CGRP) in cultured mouse peritoneal macrophages. S Hopfner, C Krolak, S Kessler, R Tiling, Preoperative imaging of Charcot neuroarthropathy. Tyrosine kinases are important mediators of the signaling cascade, determining key roles in diverse biological processes like growth, differentiation, metabolism and apoptosis in response to external and internal stimuli. Multicellular organisms live in a complex milieu where signaling pathways contribute to critical links, for their existence. Tyrosine kinases are enzymes that selectively phosphorylates tyrosine residue in different substrates. Normally the level of cellular tyrosine kinase phosphorylation is tightly controlled by the antagonizing effect of tyrosine kinase and tyrosine phosphatases. The role of tyrosine kinases in cancer molecular pathogenesis is immense and recently kinases have come in vogue as potential anticancer drug targets, as a result a couple of anticancer drugs are in the market. Cancer arises by clonal proliferation from a cell, which builds up a series of mutations leading to abnormal signaling [68] . The role of tyrosine kinase in the control of cellular growth and differentiation is central to all organisms and has been found to participate in human neoplastic diseases.
Rusch V, Baselga J, Cardon-cardo C, Orazem J, Zaman M, Hoda S Mcintosh, J Kunie, J Dmitrovsky, E .
Fabbro D, Ruetz S, Buchdunger E, Cowan-Jacob SW, Fendrich G, Liebetanz J, Mestan J, O'Reilley T, Traxler P, Chaudhuri B, Fretz H, Zimmermann J, Meyer T, Caravatti G, Furet P, Manley PW.
Neshat MS, Mellinghoff IK, Tran C, Stiles B, Thomas G, Petersen R, Frost P, Gibbons JJ, Wu H, Sawyers CL. Grossbard ML, Freedman AS, Ritz J, Coral F, Goldmacher VS, Eliseo L, Spector N, Dear K, Lambert JM, Blattler WA.
Andrews DW, Resnicoff M, Flanders AE, Kenyon L, Curtis M, Merli G, Baserga R, Iliakis G, Aiken RD. Annie T, Fong T, Shawver LK, Sun L, Tang C, App H, Powell J, Kim YH, Schreck R, Wang X, Risan W, Ullrich Axel, Peter Hirth K, McMahon G. Mohammadi M, Frorum S, Hamby JM, Schroever MC, Panek RL, Lu GH, Eliseenkova AV, Green D, Schlessinger J, Hubbard SR. Stahel R, Rossi A, Petruzelka L, Kosimidis P, Braud F, Bernardo MM, Souquet P-J, Soto Parra H, Gridelli C. Drevs J, Hofmann I, Hugenschmidt H, Wittig C, Madjar H, Muller M, Wood J, Martiny-Baron G, Unger C, Marme D. Lockhart AC, Rudin C, Berlin J, Roth BJ, Hande KR, Martin RR, Sullivan TM, Grindel JM, Zhang R, Rothenberg RL.
The '''mitochondrion''' (plural '''mitochondria''') is a double membrane+-bound organelle+ found in all eukaryotic+ organisms, although some cells in some organisms may lack them (e.g. The first observations of intracellular structures that probably represented mitochondria were published in the 1840s. In 1939, experiments using minced muscle cells demonstrated that cellular respiration using one oxygen atom can form two adenosine triphosphate+ (ATP) molecules, and, in 1941, the concept of the phosphate bonds of ATP being a form of energy in cellular metabolism was developed by Fritz Albert Lipmann+. The first high-resolution electron micrographs+ appeared in 1952, replacing the Janus Green stains as the preferred way of visualising the mitochondria.
A mitochondrion contains DNA+, which is organized as several copies of a single, circular chromosome. A recent study by researchers of the University of Hawaii at Manoa+ and the Oregon State University+ indicates that the SAR11 clade+ of bacteria shares a relatively recent common ancestor with the mitochondria existing in most eukaryotic cells. The ribosomes coded for by the mitochondrial DNA are similar to those from bacteria in size and structure. The endosymbiotic+ relationship of mitochondria with their host cells was popularized by Lynn Margulis+.
A few groups of unicellular eukaryotes have only vestigial mitochondria or derived structures: the microsporidia+ns, metamonad+s, and archamoebae+.
A mitochondrion contains outer and inner membranes composed of phospholipid bilayer+s and protein+s.
The '''outer mitochondrial membrane''', which encloses the entire organelle, is 60 to 75 angstrom+s (A) thick.
Outside the outer membrane there are small (diameter: 60A) particles named sub-units of Parson.
The inner mitochondrial membrane is compartmentalized into numerous crista+e, which expand the surface area of the inner mitochondrial membrane, enhancing its ability to produce ATP. One recent mathematical modeling study has suggested that the optical properties of the cristae in filamentous mitochondria may affect the generation and propagation of light within the tissue. Mitochondria have their own genetic material, and the machinery to manufacture their own RNA+s and protein+s (''see: protein biosynthesis+''). The mitochondria-associated ER membrane (MAM) is another structural element that is increasingly recognized for its critical role in cellular physiology and homeostasis+. Purified MAM from subcellular fractionation has been shown to be enriched in enzymes involved in phospholipid exchange, in addition to channels associated with Ca2+ signaling. The MAM is enriched in enzymes involved in lipid biosynthesis, such as phosphatidylserine synthase on the ER face and phosphatidylserine decarboxylase on the mitochondrial face. Such trafficking capacity depends on the MAM, which has been shown to facilitate transfer of lipid intermediates between organelles. The MAM may also be part of the secretory pathway, in addition to its role in intracellular lipid trafficking.
A critical role for the ER in calcium signaling was acknowledged before such a role for the mitochondria was widely accepted, in part because the low affinity of Ca2+ channels localized to the outer mitochondrial membrane seemed to fly in the face of this organelle's purported responsiveness to changes in intracellular Ca2+ flux. The fate of these puffs—in particular, whether they remain restricted to isolated locales or integrated into Ca2+ waves for propagation throughout the cell—is determined in large part by MAM dynamics. Regulating ER release of Ca2+ at the MAM is especially critical because only a certain window of Ca2+ uptake sustains the mitochondria, and consequently the cell, at homeostasis. Recent advances in the identification of the tethers+ between the mitochondrial and ER membranes suggest that the scaffolding function of the molecular elements involved is secondary to other, non-structural functions. The MAM is a critical signaling, metabolic, and trafficking hub in the cell that allows for the integration of ER and mitochondrial physiology.
Mitochondria (and related structures) are found in all eukaryote+s (except one—the Oxymonad+ ''Monocercomonoides+'' sp.). A dominant role for the mitochondria is the production of ATP+, as reflected by the large number of proteins in the inner membrane for this task. Pyruvate+ molecules produced by glycolysis+ are actively transported+ across the inner mitochondrial membrane, and into the matrix where they can either be oxidized+ and combined with coenzyme A+ to form CO2, acetyl-CoA+, and NADH+, or they can be carboxylated+ (by pyruvate carboxylase+) to form oxaloacetate. Acetyl-CoA, on the other hand, derived from pyruvate oxidation, or from the beta-oxidation+ of fatty acids+, is the only fuel to enter the citric acid cycle.
The enzymes of the citric acid cycle are located in the mitochondrial matrix, with the exception of succinate dehydrogenase+, which is bound to the inner mitochondrial membrane as part of Complex II. The redox energy from NADH and FADH2 is transferred to oxygen (O2) in several steps via the electron transport chain. As the proton concentration increases in the intermembrane space, a strong electrochemical gradient+ is established across the inner membrane. Under certain conditions, protons can re-enter the mitochondrial matrix without contributing to ATP synthesis. The concentrations of free calcium in the cell can regulate an array of reactions and is important for signal transduction+ in the cell.
Ca2+ influx to the mitochondrial matrix has recently been implicated as a mechanism to regulate respiratory bioenergetics+ by allowing the electrochemical potential across the membrane to transiently "pulse" from ??-dominated to pH-dominated, facilitating a reduction of oxidative stress+. The relationship between cellular proliferation and mitochondria has been investigated using cervical cancer+ HeLa+ cells. As in prokaryotes, there is a very high proportion of coding DNA and an absence of repeats.
In animals, the mitochondrial genome is typically a single circular chromosome that is approximately 16 kb long and has 37 genes.
While slight variations on the standard code had been predicted earlier, none was discovered until 1979, when researchers studying human mitochondrial genes+ determined that they used an alternative code. Some of these differences should be regarded as pseudo-changes in the genetic code due to the phenomenon of RNA editing+, which is common in mitochondria. Mitochondrial genomes have far fewer genes than the bacteria+ from which they are thought to be descended.
The right foot (plantar and lateral views) of a 59-year-old man with diabetic neuropathy showing collapse of the internal arch (arrow) and a large neuropathic ulcer on the midplantar surface. Cardona Munoz1 and Carlos Enrique Medina Garcia1[1] Department of Physiology, Cardiovascular Research Unit, University Center of Health Science, Universidad de Guadalajara, Mexico1.
B Jude, Intranasal calcitonin in the treatment of acute Charcot neuroosteoarthropathy: a randomized controlled trial. W Poll, Evaluation of the diabetic foot by MR imaging or plain radiography-an observational study. Downregulation of osteoblast markers and induction of the glial fibrillary acidic protein by oncostatin M in osteosarcoma cells require PKCdelta and STAT3. Interleukin 10 (IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Jeffcoate, Vascular calcification and osteolysis in diabetic neuropathy Is RANK-L the missing link? Levels of endothelial nitric oxide synthase and calcitonin gene-related peptide in the Charcot foot: a pilot study. M Collina, A Manto, et alSix-month treatment with alendronate in acute Charcot neuroarthropathy: a randomized controlled trial. Recent advances have implicated the role of tyrosine kinases in the pathophysiology of cancer. Tyrosine kinases are important mediators of this signal transduction process, leading to cell proliferation, differentiation, migration, metabolism and programmed cell death. There are several mechanisms by which tyrosine kinase might acquire transforming functions, but the ultimate result is the constitutive activation of normally controlled pathways leading to the activation of other signaling proteins and secondary messengers which serves to hamper the regulatory functions in cellular responses like cell division, growth and cell death [11] . Schematic view of different mechanisms leading to the constitutive activation of tyrosine kinase.
The complexity and the number of tyrosine kinases have greatly increased with the sequencing effort of the Human Genome Project, thus providing more opportunities for drug discovery. Tyrosine kinase inhibitors and their potential in clinical application are well documented by dramatic examples like, Gleevec, Iressa and Herceptin.
For instance, red blood cells+ have no mitochondria, whereas liver cells+ can have more than 2000.
Richard Altmann+, in 1894, established them as cell organelles and called them "bioblasts".
In the following years, the mechanism behind cellular respiration was further elaborated, although its link to the mitochondria was not known. This led to a more detailed analysis of the structure of the mitochondria, including confirmation that they were surrounded by a membrane.
In 1968, methods were developed for mapping the mitochondrial genes, with the genetic and physical map of yeast mitochondrial DNA being completed in 1976.
The endosymbiotic hypothesis suggests that mitochondria were originally prokaryotic+ cells, capable of implementing oxidative mechanisms that were not possible for eukaryotic cells; they became endosymbiont+s living inside the eukaryote.
This mitochondrial chromosome contains genes for redox+ proteins, such as those of the respiratory chain. They closely resemble the bacterial 70S+ ribosome and not the 80S+ cytoplasm+ic ribosomes, which are coded for by nuclear+ DNA. The endosymbiotic hypothesis+ suggests that mitochondria descended from bacteria that somehow survived endocytosis+ by another cell, and became incorporated into the cytoplasm+. These groups appear as the most primitive eukaryotes on phylogenetic trees+ constructed using rRNA+ information, which once suggested that they appeared before the origin of mitochondria. It has a protein-to-phospholipid ratio similar to that of the eukaryotic plasma membrane (about 1:1 by weight).
For typical liver mitochondria, the area of the inner membrane is about five times as large as the outer membrane.
Once considered a technical snag in cell fractionation techniques, the alleged ER vesicle contaminants that invariably appeared in the mitochondrial fraction have been re-identified as membranous structures derived from the MAM—the interface between mitochondria and the ER. These hints of a prominent role for the MAM in the regulation of cellular lipid stores and signal transduction have been borne out, with significant implications for mitochondrial-associated cellular phenomena, as discussed below. Because mitochondria are dynamic organelles constantly undergoing fission+ and fusion+ events, they require a constant and well-regulated supply of phospholipids for membrane integrity. In contrast to the standard vesicular mechanism of lipid transfer, evidence indicates that the physical proximity of the ER and mitochondrial membranes at the MAM allows for lipid flipping between opposed bilayers. In particular, the MAM appears to be an intermediate destination between the rough ER and the Golgi in the pathway that leads to very-low-density lipoprotein+, or VLDL, assembly and secretion. But the presence of the MAM resolves this apparent contradiction: the close physical association between the two organelles results in Ca2+ microdomains at contact points that facilitate efficient Ca2+ transmission from the ER to the mitochondria.
Although reuptake of Ca2+ by the ER (concomitant with its release) modulates the intensity of the puffs, thus insulating mitochondria to a certain degree from high Ca2+ exposure, the MAM often serves as a firewall that essentially buffers Ca2+ puffs by acting as a sink into which free ions released into the cytosol can be funneled.
The properties of the Ca2+ pump SERCA and the channel IP3R present on the ER membrane facilitate feedback regulation coordinated by MAM function. Sufficient intraorganelle Ca2+ signaling is required to stimulate metabolism by activating dehydrogenase enzymes critical to flux through the citric acid cycle.
In yeast, ERMES, a multiprotein complex of interacting ER- and mitochondrial-resident membrane proteins, is required for lipid transfer at the MAM and exemplifies this principle.
Coupling between these organelles is not simply structural but functional as well and critical for overall cellular physiology and homeostasis. Although commonly depicted as bean-like structures they form a highly dynamic network in the majority of cells where they constantly undergo fission+ and fusion+.
The central set of reactions involved in ATP production are collectively known as the citric acid cycle+, or the Krebs+ cycle.
This is done by oxidizing the major products of glucose+: pyruvate+, and NADH+, which are produced in the cytosol. This latter reaction ”fills up” the amount of oxaloacetate in the citric acid cycle, and is therefore an anaplerotic reaction+, increasing the cycle’s capacity to metabolize acetyl-CoA when the tissue's energy needs (e.g. With each turn of the cycle one molecule of acetyl-CoA is consumed for every molecule of oxaloacetate present in the mitochondrial matrix, and is never regenerated.
Here, the addition of oxaloacetate to the mitochondrion does not have a net anaplerotic effect, as another citric acid cycle intermediate (malate) is immediately removed from the mitochondrion to be converted into cytosolic oxaloacetate, which is ultimately converted into glucose, in a process that is almost the reverse of glycolysis+. The citric acid cycle oxidizes the acetyl-CoA to carbon dioxide, and, in the process, produces reduced cofactors (three molecules of NADH+ and one molecule of FADH2+) that are a source of electrons for the ''electron transport chain+'', and a molecule of GTP+ (that is readily converted to an ATP). These energy-rich molecules are produced within the matrix via the citric acid cycle but are also produced in the cytoplasm by glycolysis+. The protons can return to the matrix through the ATP synthase+ complex, and their potential energy is used to synthesize ATP+ from ADP and inorganic phosphate (Pi). This process is known as ''proton leak'' or ''mitochondrial uncoupling'' and is due to the facilitated diffusion+ of protons into the matrix. Mitochondria can transiently store calcium+, a contributing process for the cell's homeostasis of calcium. In neurons, concomitant increases in cytosolic and mitochondrial calcium act to synchronize neuronal activity with mitochondrial energy metabolism. For example, mitochondria in liver+ cells contain enzymes that allow them to detoxify ammonia+, a waste product of protein metabolism.
Tumor cells require an ample amount of ATP (Adenosine triphosphate+) in order to synthesize bioactive compounds such as lipid+s, protein+s, and nucleotide+s for rapid cell proliferation.
It encodes 37 genes: 13 for subunits+ of respiratory complexes I, III, IV and V, 22 for mitochondrial tRNA+ (for the 20 standard amino acids, plus an extra gene for leucine and serine), and 2 for rRNA+.
Mitochondrial genes are transcribed+ as multigenic transcripts, which are cleaved and polyadenylated+ to yield mature mRNA+s.
Although, the mitochondria of many other eukaryotes, including most plants, use the standard code. In higher plants, it was thought that CGG encoded for tryptophan+ and not arginine+; however, the codon in the processed RNA was discovered to be the UGG codon, consistent with the standard genetic code+ for tryptophan. Although some have been lost altogether, many have been transferred to the nucleus+, such as the respiratory complex II protein subunits.
On the one hand, RANK-L (receptor activator of nuclear factor-_B ligand), a surface-bound molecule found on osteoblasts and bone-marrow stromal cells, binds to its specific membrane-bound receptor RANK (receptor activator of nuclear factor-_B) at the surface of preosteoclasts and other cells of this lineage. IntroductionThe association between Charcot neuroarthropathy (CN) and diabetes mellitus was first described by Jordan in 1936 (Jordan WR, 1936).
PathogenesisThe Charcot foot has been documented to occur as a consequence of various peripheral neuropathies; however, diabetic neuropathy has become the most common etiology.
F Gramm, M Legg, T Flood, Diabetic osteoarthropathy: clinical and roentgenographic observations in 90 cases.
E Heufelder, The role of receptor activator of nuclear factor- ligand and osteoprotegerin in the pathogenesis and treatment of metabolic bone diseases. E Edmonds, A Sabokbar, Increased osteoclastic activity in acute Charcot’s osteoarthropathy: the role of receptor activator of nuclear factor-ligand.
H Mehta, M Patel, et alMarrow versus infection in the Charcot joint: indium-111 leukocyte and technetium-99m sulfur colloid scintigraphy.
H Lerner, IL-6, leukemia inhibitory factor, and oncostatinMstimulate bone resorption and regulate the expression of receptor activator of NF-ligand, osteoprotegerin, and receptor activator of NF- in mouse calvariae. Though their activity is tightly regulated in normal cells, they may acquire transforming functions due to mutation(s), overexpression and autocrine paracrine stimulation, leading to malignancy. Tyrosine kinases are a family of enzymes, which catalyzes phosphorylation of select tyrosine residues in target proteins, using ATP. Activation by mutationAn important mechanism leading to tyrosine kinase deregulation is mutation. BCR-ABL and human leukemiaCML is a chronic myelodysplastic hematopoietic stem cell disorder syndrome (95% of the CML) resulting from a reciprocal translocation between chromosome-9 and chromosome-22, the Philadelphia chromosome.
TEL-ABL and human leukemiaTEL-ABL tyrosine kinase like ABL-BCR is constitutively phosphorylated due to reciprocal translocation t(9,12) in case of ALL and with a complex karyotype t(9,12,14) in patients with CML. Autocrine-Paracrine loopsAutocrine-paracrine stimulation serves as an important mechanism for the constitutive activation of tyrosine kinase specially receptor tyrosine kinases.
EGFR in autocrine paracrine loopsStrong associations have been studied among the expression of EGFR and it's primary ligand EGF and TGFα in many human cancers including non small cell lung cancer [22] , bladder cancer, breast cancer and glioblastoma multiforme.
PDGFR in Autocrine paracrine LoopConcurrent expression of PDGFR and it's cognate ligand PDGF-A and PDGF-B has been observed in most astrocytic brain tumors and gliomas [26] . Insulin like growth factor receptors in Autocrine growth loopCoexpression of IGFR and its ligand IGF I and IGF II is reported in the pathogenesis of breast cancer, prostrate cancer and small cell lung cancer [27] .
Recent understanding of the molecular pathophysiology of cancer have highlighted that many tyrosine kinases are found upstream or downstream of epidemiologically relevant oncogenes or tumor suppressor, in particular the receptor tyrosine kinases [30] . Site of targetingCancer research got a boom with the declaration by the US president Richard Nixon in The National Cancer Act (1971). The ATP binding siteATP binds within a deep cleft formed between the two lobes of the tyrosine kinase domain. ATP is depicted in red, Sug1, Hyp1 & Hyc1 are residues lining the sugar region, hydrophobic pocket (Hyp), hydrophobic channel (Huc) and hinge region (Hin) respectively (redrawn) [34].
Small molecule inhibitorTyrosine kinase forms a significant share of all oncoproteins thus they take centre stage as possible targets for cancer therapy. Monoclonal antibodyThe extracellular domain of the receptor tyrosine kinase provides an excellent target for monoclonal antibodies.
Hsp 90 and other novel strategiesHeat shock proteins (Hsp-s) are ubiquitous proteins known for the maintenance of cellular homeostasis and are inducible under variety of stresses.
Antibody drug conjugateFrontline therapy being scarcely full proof, hence there is a resurgent trend towards immunotherapy. Antisense strategies and peptide drugsAntisense are small pieces of synthetic oligonucleotides that are designed to interact with the mRNA by Watson-Crick base pairing to block the transcription and thus translation of target proteins. With over 500 kinases in the human kinome and as many as 200-300 protein kinases mediating a large number of pathways in a cell at a particular time, selectivity becomes very important considering the cost of drug development. Several tyrosine kinase inhibitors are undergoing human trials and several are in the pipeline of drug discovery. Mukhopadhyay is an Associate Professor of the Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Punjab, India-160062.
The introduction of tissue fractionation+ by Albert Claude+ allowed mitochondria to be isolated from other cell fractions and biochemical analysis to be conducted on them alone. It also showed a second membrane inside the mitochondria that folded up in ridges dividing up the inner chamber and that the size and shape of the mitochondria varied from cell to cell. In the autogenous hypothesis, mitochondria were born by splitting off a portion of DNA from the nucleus of the eukaryotic cell at the time of divergence with the prokaryotes; this DNA portion would have been enclosed by membranes, which could not be crossed by proteins. The ability of these bacteria to conduct respiration+ in host cells that had relied on glycolysis+ and fermentation+ would have provided a considerable evolutionary advantage. Because of this double-membraned organization, there are five distinct parts to a mitochondrion. Because the outer membrane is freely permeable to small molecules, the concentrations of small molecules, such as ions and sugars, in the intermembrane space is the same as in the cytosol+.

This ratio is variable and mitochondria from cells that have a greater demand for ATP, such as muscle cells, contain even more cristae.
The matrix is important in the production of ATP with the aid of the ATP synthase contained in the inner membrane. The 13 mitochondrial peptides+ in humans are integrated into the inner mitochondrial membrane, along with protein+s encoded by gene+s that reside in the host cell's nucleus+.
Physical coupling between these two organelles had previously been observed in electron micrographs and has more recently been probed with fluorescence microscopy+. Not only has the MAM provided insight into the mechanistic basis underlying such physiological processes as intrinsic apoptosis and the propagation of calcium signaling, but it also favors a more refined view of the mitochondria. But mitochondria are not only a destination for the phospholipids they finish synthesis of; rather, this organelle also plays a role in inter-organelle trafficking of the intermediates and products of phospholipid biosynthetic pathways, ceramide and cholesterol metabolism, and glycosphingolipid anabolism.
Despite this unusual and seemingly energetically unfavorable mechanism, such transport does not require ATP. Transmission occurs in response to so-called "Ca2+ puffs" generated by spontaneous clustering and activation of IP3R+, a canonical ER membrane Ca2+ channel.
This Ca2+ tunneling occurs through the low-affinity Ca2+ receptor VDAC1, which recently has been shown to be physically tethered+ to the IP3R clusters on the ER membrane and enriched at the MAM.
In particular, the clearance of Ca2+ by the MAM allows for spatio-temporal pattern+ing of Ca2+ signaling because Ca2+ alters IP3R activity in a biphasic manner. However, once Ca2+ signaling in the mitochondria passes a certain threshold, it stimulates the intrinsic pathway of apoptosis in part by collapsing the mitochondrial membrane potential required for metabolism. One of its components, for example, is also a constituent of the protein complex required for insertion of transmembrane beta-barrel proteins into the lipid bilayer. The MAM thus offers a perspective on mitochondria that diverges from the traditional view of this organelle as a static, isolated unit appropriated for its metabolic capacity by the cell. This type of cellular respiration+ known as aerobic respiration+, is dependent on the presence of oxygen+. Adding more of any of these intermediates to the mitochondrion therefore means that the additional amount is retained within the cycle, increasing all the other intermediates as one is converted into the other.
It is the oxidation of the acetate portion of acetyl-CoA that produces CO2 and water, with the energy thus released captured in the form of ATP. Reducing equivalent+s from the cytoplasm can be imported via the malate-aspartate shuttle+ system of antiporter+ proteins or feed into the electron transport chain using a glycerol phosphate shuttle+. This process is called chemiosmosis+, and was first described by Peter Mitchell+ who was awarded the 1978 Nobel Prize in Chemistry+ for his work. The process results in the unharnessed potential energy of the proton electrochemical gradient being released as heat.
In fact, their ability to rapidly take in calcium for later release makes them very good "cytosolic buffers" for calcium. Mitochondrial matrix calcium levels can reach the tens of micromolar levels, which is necessary for the activation of isocitrate dehydrogenase+, one of the key regulatory enzymes of the Kreb's cycle+.
A mutation in the genes regulating any of these functions can result in mitochondrial disease+s. The majority of ATP in tumor cells is generated via the oxidative phosphorylation+ pathway (OxPhos). Not all proteins necessary for mitochondrial function are encoded by the mitochondrial genome; most are coded by genes in the cell nucleus+ and the corresponding proteins are imported into the mitochondrion.
Many slight variants have been discovered since, including various alternative mitochondrial codes.
Of note, the arthropod mitochondrial genetic code has undergone parallel evolution within a phylum, with some organisms uniquely translating AGG to lysine. The binding subsequently triggers a kinase cascade that promotes osteoclast differentiation, activation and survival. Since that time numerous treatment protocols have been proposed for this potentially devastating condition.
A Elias, The earliest magnetic resonance imaging sign of mid-foot charcot osteoarthropathy is oedema of subchondral (subarticular) bone marrow which needs prompt therapeutic offloading. A Hamilton, Anti-inflammatory action of IL-4: negative regulation of contact sensitivity to trinitrochlorobenzene. R Cavanagh, The role of proinflammatory cytokines in the cause of neuropathic osteoarthropathy (acute Charcot foot) in diabetes. F Wahl, A Aruffo, D Hollenbaugh, Stimulation of CD40 with purified soluble gp39 induces proinflammatory responses in human monocytes. Constitutive oncogenic activation in cancer cells can be blocked by selective tyrosine kinase inhibitors and thus considered as a promising approach for innovative genome based therapeutics.
This covalent post-translational modification is a pivotal component of normal cellular communication and maintenance of homeostasis [1,2] . The receptor tyrosine kinases are not only cell surface transmembrane receptors, but are also enzymes having kinase activity.
Break point cluster region (BCR) sequences of chromosome-22 on translocation juxtaposes with the c-ABL tyrosine kinase of chromosome-9. TEL which is a putative transcription factor is fused in-frame with exon-2 of the ABL proto-oncogene, producing a fusion protein product with elevated tyrosine kinase activity [14,19] .
This activation loop is stimulated when a receptor tyrosine kinase is abnormally expressed or overexpressed in presence of it's associated ligand or when there is an overexpression of the ligand in presence of it's cognate receptor. Increased expression of EGFR is reported in 40-80% of non small cell lung cancer and is also overexpressed in 50% of primary lung cancer [15] . Elevated IGF-I R autophosphorylation and kinase activity has been reported in breast cancer [28] . Hence low molecular weight tyrosine phosphorylation inhibitors (tyrphostins) have been proposed to be prospective anti-proliferating agents. With the advancement of genomics, design, selection and production of therapeutic monoclonal antibodies has become much more easier. Hsp-s are mainly involved in the proper folding of other proteins and hence referred to as molecular chaperons [48,49] .
The efficacy of the antibodies that targets specific molecules expressed by tumor cells can be increased by attaching toxins to them [53] . An insitu tumor after a period of time abruptly sparks the formation of new blood vessels from the preexisting vasculature a process termed as angiogenesis or neovascularization. Hence strategies to move kinase drug discovery in a more rapid, comprehensive and efficient manner, including tyrosine kinase target validation, selectivity and drugability are the demand of time [71] . The activities of these drugs are restricted to cancers with alterations in kinase targets, hence broad application of this treatment strategy are challenging.
His research interest is in the area of mitochondrial bioenergetics of cancer cell of haemato-oncologic diseases. Mitochondria have been implicated in several human diseases, including mitochondrial disorders+, cardiac+ dysfunction, and heart failure.
These compartments or regions include the outer membrane, the intermembrane space+, the inner membrane+, and the cristae+ and matrix+. Leonor Michaelis+ discovered that Janus green+ can be used as a supravital stain+ for mitochondria in 1900.
In 1946, he concluded that cytochrome oxidase+ and other enzymes responsible for the respiratory chain were isolated to the mitchondria. Since mitochondria have many features in common with bacteria+, the most accredited theory at present is endosymbiosis+. The mitochondrial genome codes for some RNAs of ribosome+s, and the 22 tRNA+s necessary for the translation of messenger RNA+s into protein.
These porins form channels that allow molecules of 5000 daltons+ or less in molecular weight to freely diffuse+ from one side of the membrane to the other. However, large proteins must have a specific signaling sequence to be transported across the outer membrane, so the protein composition of this space is different from the protein composition of the cytosol+.
This phospholipid was originally discovered in cow+ hearts in 1942, and is usually characteristic of mitochondrial and bacterial plasma membranes.
The matrix contains a highly concentrated mixture of hundreds of enzymes, special mitochondrial ribosomes+, tRNA+, and several copies of the mitochondrial DNA+ genome+.
Such studies estimate that at the MAM, which may comprise up to 20% of the mitochondrial outer membrane, the ER and mitochondria are separated by a mere 10–25 nm and held together by protein tethering complexes. Though often seen as static, isolated 'powerhouses' hijacked for cellular metabolism through an ancient endosymbiotic event, the evolution of the MAM underscores the extent to which mitochondria have been integrated into overall cellular physiology, with intimate physical and functional coupling to the endomembrane system.
Instead, in yeast, it has been shown to be dependent on a multiprotein tethering structure termed the ER-mitochondria encounter structure, or ERMES, although it remains unclear whether this structure directly mediates lipid transfer or is required to keep the membranes in sufficiently close proximity to lower the energy barrier for lipid flipping. The ability of mitochondria to serve as a Ca2+ sink is a result of the electrochemical gradient generated during oxidative phosphorylation, which makes tunneling of the cation an exergonic process.
SERCA+ is likewise affected by mitochondrial feedback: uptake of Ca2+ by the MAM stimulates ATP production, thus providing energy that enables SERCA to reload the ER with Ca2+ for continued Ca2+ efflux at the MAM.
Studies examining the role of pro- and anti-apoptotic factors support this model; for example, the anti-apoptotic factor Bcl-2 has been shown to interact with IP3Rs to reduce Ca2+ filling of the ER, leading to reduced efflux at the MAM and preventing collapse of the mitochondrial membrane potential post-apoptotic stimuli.
Instead, this mitochondrial-ER interface emphasizes the integration of the mitochondria, the product of an endosymbiotic event, into diverse cellular processes.
When oxygen is limited, the glycolytic products will be metabolized by anaerobic fermentation+, a process that is independent of the mitochondria. Hence, the addition of any one of them to the cycle has an anaplerotic effect, and its removal has a cataplerotic effect. Protein complexes+ in the inner membrane (NADH dehydrogenase (ubiquinone)+, cytochrome c reductase+, and cytochrome c oxidase+) perform the transfer and the incremental release of energy is used to pump protons+ (H+) into the intermembrane space. The endoplasmic reticulum (ER) is the most significant storage site of calcium, and there is a significant interplay between the mitochondrion and ER with regard to calcium. Interference with OxPhos have shown to cause cell cycle arrest suggesting that mitochondria play a role in cell proliferation. The exact number of genes encoded by the nucleus and the mitochondrial genome+ differs between species. Instead, this mitochondrial genome is arranged in 18 minicircular chromosomes, each of which is 3–4 kb long and has one to three genes. A few organisms, such as the ''Cryptosporidium+'', actually have mitochondria that lack any DNA, presumably because all their genes have been lost or transferred. On the other hand, OPG (osteoprotegerin), which is also expressed by osteoblasts, acts as a decoy receptor to bind and effectively neutralize RANK-L which, in turn, limits excess osteoclastogenesis and osteolysis.
Early diagnosis and swift care are the keys to reducing amputation risk in this patient population. When a bone is fractured, the release of proinflammatory cytokines including tumor necrosis factor- ? and interleukin-1? leads to increased expression of the polypeptide receptor activator of nuclear factor-Kb ligand (RANKL) from any of a number of local cell types. S Cytokine-induced, osteoclastic bone resorption in Charcot arthropathy: an immunohistochemical study.
R Page, et alBisphosphonates in the treatment of Charcot neuroarthropathy: a double-blind randomised controlled trial. L Teitelbaum, Tumor necrosis factor superfamily cytokines and the pathogenesis of inflammatory osteolisis. The modes of oncogenic activation and the different approaches for tyrosine kinase inhibition, like small molecule inhibitors, monoclonal antibodies, heat shock proteins, immunoconjugates, antisense and peptide drugs are reviewed in light of the important molecules.
Tyrosine kinases are implicated in several steps of neoplastic development and progression. Different ligands employ different strategies by which they achieve the stable dimeric conformation. The structural organization of the receptor tyrosine kinase exhibits a multidomain extracellular ligand for conveying ligand specificity, a single pass transmembrane hydrophobic helix and a cytoplasmic portion containing a tyrosine kinase domain. EGFRv III mutant lacks amino acid 6-273 which gives rise to receptor tyrosine kinase constitutive activity, that leads to cell proliferation in the absence of ligand in glioblastomas, ovarian tumors and non small cell lung carcinoma [12] . The fusion gene produces a 210 KDa mutant protein in which the first exon of c-ABL has been replaced by BCR sequences, encoding either 927 or 902 amino acid.
TGFα another ligand of EGFR is also involved in autocrine paracrine growth loops in 20-40% of lung cancer [23] . Inhibiting the activity of tyrosine kinases by low molecular weight compounds capable of interfering with either ligand binding (in the case of receptor tyrosine kinases) [31] or with protein substrate (in case of non receptor tyrosine kinase) has proved to be difficult [32] . By late 1980s it was proved that low molecular weight EGFR inhibitors could block EGF dependent cell proliferation [35] . The revolution in antibody technology now allows us to produce humanized, human chimeric or bispecific antibody for targeted cancer therapy [31,42] . Existing immunotoxins are based on bacterial toxins like pseudomonas exotoxin, plant exotoxin like ricin or radio-nucleotides. Biochemical, cell based assay and screening methods for the through profiling of the kinase inhibitors using monoclonal antibody based multi-immunoblotting, fluorescent polarization assays, nonradioactive high throughput assays, 2-D NMR approaches should be exploited.
The quick selection of epidemiologically relevant, drugable tyrosine kinase targets coupled to efficient lead finding and optimization needs more intervention in the area of highthroughput cancer genome based molecular therapeutics. His research interest also includes kinetics of electron transfer enzyme and reactive oxygen species.
In 2014, a study including ten children diagnosed with severe autism suggests that autism+ may be correlated with mitochondrial defects.. In 1904, Friedrich Meves+, made the first recorded observation of mitochondria in plants in cells of the white waterlily, ''Nymphaea alba+'' and in 1908, along with Claudius Regaud+, suggested that they contain proteins and lipids.
Eugene Kennedy+ and Albert Lehninger+ discovered in 1948 that mitochondria are the site of oxidative phosphorylation+ in eukaryotes.
Larger proteins can enter the mitochondrion if a signaling sequence at their N-terminus+ binds to a large multisubunit protein+ called translocase+ of the outer membrane, which then actively moves+ them across the membrane. Cardiolipin contains four fatty acids rather than two, and may help to make the inner membrane impermeable.
These are not simple random folds but rather invaginations of the inner membrane, which can affect overall chemiosmotic+ function. Of the enzymes, the major functions include oxidation of pyruvate+ and fatty acids+, and the citric acid cycle+. Normally, mild calcium influx from cytosol into the mitochondrial matrix causes transient depolarization that is corrected by pumping out protons.
Thus, the MAM is not a passive buffer for Ca2+ puffs; rather it helps modulate further Ca2+ signaling through feedback loops that affect ER dynamics.
Given the need for such fine regulation of Ca2+ signaling, it is perhaps unsurprising that dysregulated mitochondrial Ca2+ has been implicated in several neurodegenerative diseases, while the catalogue of tumor suppressors includes a few that are enriched at the MAM.
Other proteins implicated in scaffolding likewise have functions independent of structural tethering at the MAM; for example, ER-resident and mitochondrial-resident mitofusins form heterocomplexes that regulate the number of inter-organelle contact sites, although mitofusins were first identified for their role in fission+ and fusion+ events between individual mitochondria. The production of ATP from glucose has an approximately 13-times higher yield during aerobic respiration compared to fermentation.
These anaplerotic and cataplerotic reactions will, during the course of the cycle, increase or decrease the amount of oxaloacetate available to combine with acetyl-CoA to form citric acid.
This process is efficient, but a small percentage of electrons may prematurely reduce oxygen, forming reactive oxygen species+ such as superoxide+. The calcium is taken up into the matrix+ by the mitochondrial calcium uniporter+ on the inner mitochondrial membrane+. Mitochondrial ATP production is also vital for cell division+ in addition to other basic functions in the cell including the regulation of cell volume, solute concentration+, and cellular architecture.
In ''Cryptosporidium'', the mitochondria have an altered ATP+ generation system that renders the parasite resistant to many classical mitochondrial inhibitors+ such as cyanide+, azide+, and atovaquone+. This division and segregation process must be tightly controlled so that each daughter cell receives at least one mitochondrion. RANKL triggers the synthesis of the nuclear transcription factor nuclear factor-kb (NF-kb), and this in turn stimulates the maturation of osteoclasts from osteoclast precursor cells. R Bushman, The natural history of acute Charcot’s arthropathy in a diabetic foot specialty clinic.
As angiogenesis is a major event in cancer growth and proliferation, tyrosine kinase inhibitors as a target for anti-angiogenesis can be aptly applied as a new mode of cancer therapy. Tyrosine kinase signaling pathways normally prevent deregulated proliferation or contribute to sensitivity towards apoptotic stimuli. The kinase domain has regulatory sequence both on the N and C terminal end [2,8] .NRTK are cytoplasmic proteins, exhibiting considerable structural variability.
Point mutations either in the extracellular domain of the FGFR 3 results in an unpaired cysteine residue allowing abnormal receptor dimerization through intermolecular disulfide bonding, or in the activation loop of kinase domain were identified in multiple myeloma. Another BCR-ABL fusion protein of 185 KDa containing BCR sequences from exon 1fused to exon 2-11 of c-ABL, is found in 10% of adult ALL patients. The helix-loop-helix motif of TEL is believed to induce homodimerization and kinase activation of the TEL-ABL and TEL-PDGFRβ fusion proteins.
Burning examples are being provided by EGFR, PDGFR and IGF receptors and their associated ligands [22] . EGFR overexpression of wild type or mutated forms is documented in 40% of cases of glioblastoma multiforme [24] and 40%-50 % of bladder cancer patient [25] .
Hence a strong association of autocrine paracrine loops has been implicated in the pathogenesis of several cancers. Although the bisubstrate inhibitor approach offered promise, but with very little practical progress.
Within a short time reports concerning effective tyrosine kinase inhibitors was the key promising development in anticancer development. Most kinases require molecular chaperons to maintain their activation competent conformation.
The toxins are chemically conjugated to a specific ligand such as the variable domain of the heavy or light chain of the monoclonal antibody.
Grb2 is an essential component in the Ras signaling pathway and it's interaction with Sos is responsible for the down stream signaling process.
This process though occurs normally during embryonic development, female reproductive cycle or wound healing is found as a crucial step in tumor transition from benign to malignant form, capable of spreading throughout the body [61, 62, 63] .VEGF (Flt-1) receptor tyrosine kinase mediated mitogenesis of human endothelial cells and growth of multiple tumor types is inhibited by SU5416 [64] . Structure based drug design (SBDD) strategies depending on bioinformatics, computational approaches, mathematical models of tumor and normal tissue response, highthroughput X-ray crystallography and chemo-genomic approaches can be used to advance molecules through the routine drug discovery process. All these concerted effort may pave the silverlining to tailor made personalised cancer therapeutics. Insulin also helps move glucose (blood sugar) into cells, where it can be stored and used for energy.
In humans, 615 distinct types of protein have been identified from cardiac+ mitochondria, whereas in rats+, 940 proteins have been reported. Over time, the fractionation method was further developed, improving the quality of the mitochondria isolated, and other elements of cell respiration were determined to occur in the mitochondria. Unlike the outer membrane, the inner membrane doesn't contain porins, and is highly impermeable to all molecules. The mitochondrial content of otherwise similar cells can vary substantially in size and membrane potential, with differences arising from sources including uneven partitioning at cell divisions, leading to extrinsic differences+ in ATP levels and downstream cellular processes.
Recently it has been shown that plant mitochondria can produce a limited amount of ATP without oxygen by using the alternate substrate nitrite+. This in turn increases or decreases the rate of ATP+ production by the mitochondrion, and thus the availability of ATP to the cell. This can cause oxidative stress+ in the mitochondria and may contribute to the decline in mitochondrial function associated with the aging process.
Thermogenin is primarily found in brown adipose tissue+, or brown fat, and is responsible for non-shivering thermogenesis. ATP levels differ at various stages of the cell cycle suggesting that there is a relationship between the abundance of ATP and the cell's ability to enter a new cell cycle.
In general, mitochondrial DNA lacks intron+s, as is the case in the human mitochondrial genome; however, introns have been observed in some eukaryotic mitochondrial DNA, such as that of yeast+ and protist+s, including ''Dictyostelium+ discoideum''.
In other eukaryotes (in mammals for example), mitochondria may replicate their DNA and divide mainly in response to the energy needs of the cell, rather than in phase with the cell cycle. Treatment of the patient should take into account the stage of CN, site(s) of involvement, presence or absence of ulceration, presence or absence of infection, overall medical status, and level of compliance. At the same time, NF-kb stimulates the production of the glycopeptide osteoprotegerin (OPG) from osteoblasts. The review concludes with a discussion on the application of modern techniques and knowledge of the kinome as means to gear up the tyrosine kinase drug discovery process. These signaling pathways are often genetically or epigenetically altered in cancer cells to impart a selection advantage to the cancer cells. The NRTK have a kinase domain and often possess several additional signaling or protein-protein interacting domains such as SH2, SH3 and the PH domain [9] . Somatic mutations in the EGFR 2 and 3 have been associated with human bladder and cervical carcinomas. The BCR-ABL chimeric gene product has a tyrosine kinase activity several fold higher than it's normal counterpart and correlates with the disease phenotype [14,15,16,17,18] . NPM-ALK fusion products t(2,5) is constitutively activated in Anaplastic large cell lymphoma [20,21] .
With further research in the following years it was quite clear that neglected kinase targets against the biases have come into vogue [36] .
Members of the EGFR family are involved in some complex biological signal transduction network. Normal cells lacking the cancer specific antigens are not targeted by the targeted antibody [54] . The use of recent strides in RNA interferance (RNAi) appears to be a promising approach for silencing gene expression, thus elucidating genetics of human disease with emphasis into the biological role of the kinase signaling pathways [72,73] . Kingsbury, in 1912, first related them with cell respiration, but almost exclusively based on morphological observations.

However, the exact relationship of the ancestor of mitochondria to the alphaproteobacteria+ and whether the mitochondrion was formed at the same time or after the nucleus, remains controversial. This is important in the ER-mitochondria calcium signaling and is involved in the transfer of lipids between the ER and mitochondria.
Almost all ions and molecules require special membrane transporters to enter or exit the matrix.
In addition to the matrix pool of grp75, a portion serves as a chaperone that physically links the mitochondrial and ER Ca2+ channels VDAC and IP3R for efficient Ca2+ transmission at the MAM. The mitochondria can be found nestled between myofibril+s of muscle+ or wrapped around the sperm+ flagellum+. Brown adipose tissue is found in mammals, and is at its highest levels in early life and in hibernating animals. Release of this calcium back into the cell's interior can occur via a sodium-calcium exchange protein or via "calcium-induced-calcium-release" pathways.
ATP's role in the basic functions of the cell make the cell cycle+ sensitive to changes in the availability of mitochondrial derived ATP.
The most commonly used classification is the three-staged system described by Eichenholtz: Stage I is the developmental or acute phase, Stage II is the coalescent or quiescent phase, and Stage III is the consolidation or reconstruction and reconstitution phase (Eichenoltz SN, 1966). Thus, it is no wonder that aberrant enhanced signaling emanating from tyrosine kinase endows these enzymes a dominating oncoprotein status, resulting in the malfunctioning of signaling network [3] .
Breakpoints of abnormal chromosomal translocation are also an important source of mutation [13] .
Chaperon based inhibitors other than interacting with protein kinases, prevent the associated chaperon(s) from maintaining the activation competent conformation of the kinase. The most promising immunotoxin is the EGF fusion protein DAB389EGF, which is a fused EGF specific sequence and diphtheria toxin and have been found to be effective in EGFR over expressing breast tumor and non small cell lung cancer. PD98059 is an important inhibitor of MAPK cascade that lies downstream of Ras pathway and thus is effective in many tumors [66] .
Paul is a PhD student of the Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Punjab, India-160062. Although most of a cell's DNA+ is contained in the cell nucleus+, the mitochondrion has its own independent genome+ that shows substantial similarity to bacteria+l genome+s.
In 1913, particles from extracts of guinea-pig liver were linked to respiration by Otto Heinrich Warburg+, which he called "grana". Proteins are ferried into the matrix via the translocase of the inner membrane+ (TIM) complex or via Oxa1. Another potential tether is Sigma-1R, a non-opioid receptor whose stabilization of ER-resident IP3R may preserve communication at the MAM during the metabolic stress response. This can initiate calcium spikes or calcium waves with large changes in the membrane potential+. The variation in ATP levels at different stages of the cell cycle support the hypothesis that mitochondria play an important role in cell cycle regulation. During transcription, the tRNAs acquire their characteristic L-shape that gets recognized and cleaved by specific enzymes. Involvement of the midfoot is most common in the diabetic population and this site tends to be more amenable to conservative options versus hindfoot or ankle CN.
It has been suggested that this results in continual production of proinflammatory cytokines, RANKL, NF-kb, and osteoclasts, which in turn leads to continuing local osteolysis (La Fontaine J et al., 2008). The discovery that SRC oncogene having a transforming non receptor tyrosine kinase activity [4] , and the finding of EGFR, the first receptor tyrosine kinase paved the way to the understanding of the role and significance of tyrosine kinase in cancer [5] . ATP binds in the cleft in between the two lobes and the tyrosine containing sequence of the protein substrate interacts with the residues of the C terminal lobe.
Their overexpression leads to elevated MAP kinase and PI3 kinase recruitment and subsequent suppression of apoptosis, deregulation of cell cycle and proliferation.Based on the discovery of the importance of HER-2 gene amplification in breast cancer Herceptin (Transtuzumab) was developed by Genetech in 1988 and is one of the best examples of targetted next generation anticancer therapeutic for cancer.
The result being the proteosomal degradation of the misfolded kinases, thus diminishing the level of many kinases. The use of therapeutic antibody for the development of antibody-drug conjugate has been tried to improve the therapeutic potential e.g. Antiangiogenic drugs stops new vessels from forming around a tumor and break up the existing network of abnormal capillaries that feeds the cancerous mass, thus shrinks the tumor by limiting blood supply.
Warburg and Heinrich Otto Wieland+, who had also postulated a similar particle mechanism, disagreed on the chemical nature of the respiration.
In addition, there is a membrane potential across the inner membrane, formed by the action of the enzymes of the electron transport chain+. The association with the cytoskeleton determines mitochondrial shape, which can affect the function as well: different structures of the mitochondrial network may afford the population a variety of physical, chemical, and signalling advantages or disadvantages. These can activate a series of second messenger system+ proteins that can coordinate processes such as neurotransmitter release+ in nerve cells and release of hormone+s in endocrine cells. Although the specific mechanisms between mitochondria and the cell cycle regulation is not well understood, studies have shown that low energy cell cycle checkpoints monitor the energy capability before committing to another round of cell division. Generally, conservative care for the CN foot and ankle has been recommended for the following scenarios: joints in the acute phase, deformities that are clinically stable and that do not compromise the soft tissue envelope, stable deformities without soft tissue or bone infection, patients who do not have adequate arterial perfusion to support surgical reconstruction, and those patients who are extremely high risk for anesthesia and surgical intervention due to the presence of multiple severe comorbid conditions. Osteoclasts generated in vitro in the presence of macrophage colony-stimulating factor and RANKL from patients with active CN have been shown to be more aggressive and exhibit an increase in their resorptive activity that peptides normally secreted from nerve terminals are also important in the underlying pathophysiology.
With the deciphering of the Human Genome Project more than 90 tyrosine kinases have been found out.
Some ligand receptor is not sufficient for some complex and is stabilized by accessory molecules e.g. RTK are activated by ligand binding to the extracellular domain followed by dimerization of receptors, facilitating trans-phosphorylation in the cytoplasmic domain whereas the activation mechanism of NRTK is more complex, involving heterologous protein-protein interaction to enable transphosphorylation [10] .
These substrate mimics can be interestingly converted into ATP mimics once the nitrogen of the characteristic benzene malonitrile is incorporated into the second ring. Tyrosine kinases are key regulators of cell survival and proliferation in breast cancer [42,43] . The Hsp-s has an unique ATP binding site, including a Bergerat fold characteristic of bacterial gyrase, topoisomerases and histidine kinases. Tositumomab by GlaxoSmithcline [55] , Anti-Tac(Fv)-PE38(LMB-2) against CD25, in B, T cell lymphoma and anti-B4-bR against CD19 in B-Non Hodgkins lymphoma [56] . Treatment of cancer faces the main fear of acquired drug resistance but antiangiogenic therapy does not induce acquired drug resistance and hence can prove valuable for long-term maintenance therapy [67] .
It was not until 1925, when David Keilin+ discovered cytochromes+, that the respiratory chain+ was described.
Mitochondria in cells are always distributed along microtubules and the distribution of these organelles is also correlated with the endoplasmic reticulum. In this chapter we present an overview of evidence-based non-operative treatment for CN with an emphasis on the most recent developments in therapy.2. The more science entangles the intricacies of cellular signaling the more we find the involvement of tyrosine kinase in cellular signaling circuits that are implicated in cancer development. FGFs are unable to activate FGFR complex and is stabilized by heparin sulfate proteoglycans (HSPG). The orphan receptor tyrosine kinase HER2 gene is amplified in breast cancer and acts as a major signaling partner for other EGFR family members leading to proliferation, differentiation, antiapoptosis [44] and tumor progression [45] . Thus the ATP binding site serves as a robust antitumor target for kinase related chaperone machinery. As molecular studies of cancer have started revealing an increased epitope repertoire due to great strides in genomics and proteomics, the search for more effective Antibody-drug conjugate has got a spur in recent times [57] . Recent evidence suggests that vimentin+, one of the components of the cytoskeleton, is also critical to the association with the cytoskeleton. Tyrosine kinases represent a major portion of all oncoprotein that play a transforming role in a plethora of cancers.
Ligand binding to the extracellular domain stabilizes the formation of active dimmers and consequently protein tyrosine kinase activation.Structural studies of the catalytic core of several RTKs, supported by biochemical and kinetic studies of receptor phosphorylation have provided proof that receptor oligomerization increases the local concentration of the RTKs, leading to efficient transphosphorylation of tyrosine residues in the activation loop of the catalytic domain.
The ATP binding site though evolutionarily conserved can be selectively targeted by taking advantage of the minor difference in the kinase domain. Herceptin was the first genome based targeted anticancer therapeutic, approved by FDA in 1998. Important examples are Geldanamycin, Cisplatin, Novobiocin, Radicol and other purine based inhibitors. A type 1 diabetes diet is designed to provide maximum nutrition, while limiting sugar, carbohydrates, and sodium. The process begins with a hyperemia usually following trauma to the foot or ankle (Yu GV & Hudson JR, 2002). Patients with acute Charcot, in both the active and recovered phase, peripheral monocytes acquire a proinflammatory immune phenotype characterized by increased production of proinflammatory cytokines, reduced secretion of anti-inflammatory cytokines, increased expression of co-stimulatory surface molecules, and increased resistance to apoptosis. Hence the identification and development of therapeutic agents for disease states that are linked to abnormal activation of tyrosine kinases due to enhanced expression, mutation or autocrine stimulation leading to abnormal downstream oncogenic signaling have taken a centre stage as a potent target for cancer therapy [6,7] . Upon tyrosine phosphorylation the activation loop adopts an open conformation that gives access to ATP and substrates and makes ATP transfer from Mg-ATP to tyrosine residue on the receptor itself and on cellular proteins involved in signal transduction.The ATP binding intracellular catalytic domain that catalyzes receptor autophosphorylation displays the highest level of conservation between the RTKs.
The minor difference leads to changes in hydrogen bonding and hydrophobic interactions resulting in differences of affinity [38] . Binding of Herceptin to HER receptor leads to receptor internalization, inhibition of cell cycle progression and antibody dependent cellular toxicity or eliciting the immune response.
Monocytes play a pivotal role in the development and maintenance of the inflammatory response.
The ATP binding site serves as a docking site for specific binding of cytoplasmic signaling proteins containing Src homology-2 (SH2) and protein tyrosine binding (PTB) domains. Herceptin induces normalization and regression of angiogenesis in HER-2 overexpressing breast cancer [46] and even blocks cleavage of HER2, which generates a membrane-bound constitutively active truncated receptor.
These proteins in turn recruit additional effector molecules having SH2, SH3, PTB and Pleckstrin homology (PH) domain. Rituximab is an anti CD20 antibody, effective against Non Hodkins Lymphoma [47] .EFGR is also overexpresed in many cancers especially in breast cancer. The normal architecture of the foot may be disturbed and plantar ulceration at the site of deformity may be present. Thus, the activation of inflammatory and suppression of anti-inflammatory cytokines that we have found in patients with acute Charcot is consistent with the abnormally intense and prolonged inflammatory response that characterizes the acute phase of this disease.
This results in the assembly of signaling complexes to the activated receptor and the membrane and subsequent activation of a cascade of intracellular biochemical signals, which leads to the activation or repression of various subsets of genes and thus defines the biological response to signals. Gleevec selectively and effectively inhibits the kinase activity of BCR-ABL fusion protein, which is responsible for the constitutive proliferative signaling. A growing body of evidence is now supporting the possibility that this inflammatory response plays a pivotal pathogenetic role in the changes in bone and joints that develop in this disorder (Jeffcoate WJ et al., 2005).
During these processes, receptors migrate within the plasma membrane and are internalized through clathrin-coated invagination, which eventually seal off and forms an endocytic vesicle. Without proper diet, exercise, and insulin therapy, a person with type 1 diabetes could suffer adverse health effects. The endocytic vesicles fuse with the lysosomes and in the process the receptor and ligand may be degraded by the lysosomal enzymes. STI571 remains bound to the ATP binding cleft of the unphospholrylated (activation loop) Abl, thus establishing extensive contacts with residues lining the cleft and with peptide segments just outside the cleft. Important anti-EGFR monoclonal antibodies are C225 by Imclone and 2C4 by Genetech and Osidem by Mederex. Health complications associated with this type of diabetes include: vision problems high blood pressure, which increases risk for heart attack, stroke, and poor circulation kidney damage nerve damage skin sores and infections, which can cause pain and may lead to tissue death Following proper dietary guidelines can help mitigate the difficulties of type 1 diabetes, keep your health free from complications, and make your life better overall. Most patients are in the mid-fifties, but neuroarthropathy can occur at any age (Sanders LJ & Frykberg RG, 1993).
A large change in conformation of the nucleotide binding domain is accompanied with the binding of the drug.
Indeed, several reports support the possibility that IL-6 could in fact induce an osteocytic phenotype (Chipoy C et al., 2004). During the whole process of receptor internalization the ligand receptor complex is dissociated and this results in the termination of the signaling reaction. The binding of STI571 prevents ATP to access the ATP binding cleft and thus inhibits subsequent tyrosine phosphorylation of the substrate [34,36,39] . Angiogenesis, the formation of new blood vessels to the tumor site is mainly induced and regulated by VEGF.
Iressa is a selective inhibitor of EGF receptor tyrosine kinase in non small cell lung cancer and squamous cell carcinoma [40] .The downstream target of PI3K pathway, mTOR (non receptor tyrosine kinase) responsible for abnormal cellular growth and proliferation in glioblastoma and renal cancer is inhibited by rapamycin and CCI779. Blocking angiogenesis is now considered to be a promising approach for anticancer therapy and the use of anti-VEGF MAb has demonstrated tumor suppression.Certain antigens are overexpressed in cancers. A nutritionist or dietitian can help you come up with meal plans, and create a diet that works for you in the long term. The main problem is that, at this stage of the disease, not only is the clinical diagnosis not easy to make, but standard radiography often cannot distinguish acute CN from other conditions. Indeed, both the phenotype of monocytes from diabetic patients with uncomplicated neuropathy and that of monocytes from diabetic patients with neuropathy and osteomyelitis-associated foot inflammation was not different from that of cells from healthy control subjects. P12 antigen overexpression is associated with a wide range of cancer cell lines and tissues and antibody directed towards these antigens may serve as important contributors to cancer therapeutics as exemplified by the results of priliminary trials. This indicates that neither diabetes nor neuropathy or inflammation, per se, is associated with any modulation of the inflammatory response of monocytes.
MAb P12 reacts with the carbohydrate sequence present on high molecular weight glycoproteins. Radioisotope technetium (Tc-99m) bone scintigraphy has good sensitivity, but poor specificity, for osseous pathology and only shows increased focal uptake during the bony phase. Interestingly, we found that all the modification of the immune phenotype of monocytes disappeared after recovery in patients with acute Charcot.
Oncologists are now interested in newer MAbs as promising agents for the treatment of cancer. This suggests that the initiating cause that triggers the inflammatory response in patients with acute Charcot acts in an environment where mechanisms that physiologically control the intensity and duration of inflammation are lacking. Two theories, initially thought to be competing concepts, are now considered to be overlapping to varying degrees.
Having a well-stocked kitchen or carrying healthy snacks with you can cut down on unnecessary sugar, carbohydrates, sodium, and fat that can spike blood sugar. On the one hand, the neurotraumatic theory proposes that, in the presence of sensorimotor neuropathy, abnormal plantar pressure occurs. This is supported by the amyotrophy of intrinsic muscles, and the imbalance between the extensor and flexor muscles. To maintain blood sugar levels, dont skip meals, and try to eat around the same time each day.
In addition, the bones and joints lose their protective sensory capacity, allowing repetitive trauma that, in turn, leads to excessive extension of the ligaments, and microfractures and more joint dislocation. On the other hand, the neurovascular theory suggests that the autonomic neuropathy leads to a hyperaemic state, with an increase in blood flow to the lower limbs due to the development of arteriovenous shunts. The current belief is that once the disease is triggered in a susceptible individual, it is mediated through a process of uncontrolled inflammation in the foot. This inflammation leads to osteolysis and is indirectly responsible for the progressive fracture and dislocation that characterizes its presentation (Jeffcoate WJ et al, 2005).However, as mentioned before, the common link is the local inflammation (Baumhauer et al, 2006) that is associated with the release of proinflammatory cytokines such as interleukin (IL)-1? and tumour necrosis factor (TNF)-?, which are known mediators of bone resorption via excess osteoclactic activity (Petrova et al, 2007).
Fruits Fruits are natural sources of sugar and should be counted as carbohydrates if youre using a diet plan. Interestingly, a dissociation between the local inflammatory response related to the increased proinflammatory cytokine secretion and lack of systemic inflammatory response has been found in patients with CN (Jeffcoate WJ, 2004). At the same time, NF-кB induces the increased expression of the glycoprotein osteoprotegerin (OPG), which acts as a decoy receptor for RANK-L to effectively neutralize its effect and so avoid excess osteolysis (Fig.
These include: most green leafy vegetables asparagus beets carrots celery cucumber onions peppers sprouts tomatoes Always choose fresh or frozen vegetables without added salt or sauces.
Physiologically, this process is limited by immobilization in response to the pain caused by local inflammation. However, when pain perception is reduced due to sensory neuropathy, there is no protective suppression, thereby allowing the inflammatory process to continue which, in turn, ultimately leads to osteolysis and bone breakdown.
Diferential diagnosisWhile cellulitis may seem to be the likely diagnosis, if a patient with long-standing diabetes, a history of poor glycemic control, and peripheral neuropathy presents with a red, hot, swollen foot with no history of open ulceration, then Charcot neuroarthropathy should be at the top of the list in the differential diagnosis.
Other possibilities include osteomyelitis, acute gout, cellulitis, abscess, neuropathic fracture, and deep venous thrombosis.
However, if the patient has no open ulceration or history of an open wound, infection is probably not the culprit. Carbohydrates can come in the form of beans, starchy vegetables, fruit juices, pasta, or bread.
Laboratory tests There are no laboratory criteria for the diagnosis of Charcot neuroarthropathy and no hematologic markers, but laboratory testing can help narrow the differential diagnosis. Leukocytosis, an elevated C-reactive protein and erythrocyte sedimentation rate, and recent unexplained hyperglycemia suggest infection. Imaging studiesRadiographs are the primary initial imaging method for evaluation of the foot in diabetic patients. Easily available and inexpensive, they provide information on bone structure, alignment, and mineralization. MRI primarily images protons in fat and water and can depict anatomy and pathology in both soft tissue and bone in great detail. Three-phase bone scans, based on technetium-99m (99mTc), are highly sensitive for active bone pathology. However, diminished circulation can result in false-negative exams and, perhaps more importantly, uptake is not specific for osteoarthropathy. Evaluation of bone mineral density (BMD) may be useful in those with diabetes to assess onset of CN as well as fracture risk. Fruits, vegetables, nuts, and other foods travel easily and are great to have on hand when you need them.
However, a negative result obviously should not offer any confidence regarding lack of disease. If the patient has anulceration with a high likelihood of deep infection, MRI is the best diagnostic modality. The decision of nuclear imaging versus MRI is largely based on personal preference, availability, and local experience. In general, if metal is present in the foot, nuclear medicine exams are preferred, whereas diffuse or regional ischemia makes MRI the preferred exam.The diagnosis of active Charcot foot is primarily based on history and clinical findings but should be confirmed by imaging. Inflammation plays a key role in the pathophysiology of the Charcot foot and is the earliest clinical finding.
The X-rays should be the initial imaging performed, and one should look for subtle fractures or subluxations if no obvious pathology is visible.
MRI or nuclear imaging can confirm clinical suspicions in the presence of normal-appearing radiographs. In the other hand, Positron emission tomography (PET) with fluorine-18 fluorodeoxyglucose is also gaining support, especially when combined with computed tomography (CT). This PET-CT hybrid has better anatomic localization than PET alone.PET-CT is very reliable for differentiating Charcot neuroarthropathy from osteomyelitis, a distinction that can be difficult to make when Charcot neuroarthropathy is complicated by adjacent loss of skin integrity. Many physicians also recommend elastic stockings (eg, Stockinette) or an elastic tubular bandage (eg, Tubigrip) to reduce edema under the cast.
Drug therapyDue to bone mineral density alterations in CN patients manifested by localized osteopenic changes, bisphosphonates have been tested for their benefit with off-loading in Stage I. Bisphosphonates are pyrophosphate analogs that inhibit osteoclastic bone resorption and are commonly used in treatment of conditions characterized by abnormal bone turnover. Pamidronate is the most commonly used and acts by attaching onto hydroxyapatite crystals in newly synthesized bone matrix, blocking access of osteoclast precursors to this matrix. There was a statistically significant reduction in bone turnover, symptoms, and disease activity. Similarly, (Pitocco et al., 2005) showed significant reduction in bone resorption markers with the use of another bisphosphonate alendronate and noted clinical improvements in the CN foot at 6 months. Some clinicians also prescribe bisphosphonates in the early stages of treatment, as the bone mineral density of the affected foot is low. New insights on treatmentSimilarly, use of calcitonin and non-steroidal anti-inflammatory drugs has been reported as adjunct treatment to conventional therapy. After oral administration, it is rapidly broken down and deacetylated into its active metabolite, rhein, (Spencer CM., 1997). The expression of NF-kB is induced by the cytokine RANK-L, which is accompanied by increased production of osteoprotegerin (OPG). A randomized controlled trial by (Bem et al., 2006) was performed on 32 acute CN patients administered 200 IU daily, showing reduction in markers of bone turnover as well as a decreased time to healing.
ConclusionConservative options continue to evolve in their indications for the treatment of the CN foot and ankle.
The modalities discussed within this chaspter provide a wide variety of options; yet, a further higher level of evidence studies is warranted.
There is no doubt that there are specific indications for conservative management versus surgical.

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