Beauty Tips For Body Care
A rare genetic disease known as “Arterial Tortuosity Syndrome” (ATS) gets its name from the fact that these people have remarkably long and strangely curved and twisted major arteries. These malformations present a “tortuous” path for blood flow.ATS patients also suffer from other symptoms, including laxity of the skin, and joint hypermobility and instability. ATS is described as a “connective tissue disorder” and, relatively recently, the cause of this disease has been identified as mutations in the gene that encodes GLUT10. GLUT10 is one of the family of GLUT transporters that transport sugars and the oxidized form of vitamin C (DHAA) through various cell membranes. This disease is being studied intensively by researchers around the world, not so much I suppose in the search for a cure for this rare disease, but because this represents a rare human “gene knockout” model that enables researchers to examine the biochemical and physiological effects of a specific and known genetic flaw in human beings. Studies of diseases have resulted in much of what is known about normal human physiology today.For those familiar with vitamin C, and particularly with the symptoms and known etiology of scurvy, these studies are demonstrating some fascinating parallels. It is, in fact, difficult to not recognize these parallels when reading articles describing a “connective tissue disorder” characterized by “improperly formed collagen and elastin” resulting from the failure of “prolyl- and lysyl-hydroxylases to modify residues in collagens and elastin that stabilize the mature molecules,” and resulting in vascular, skin and joint problems. And, in fact, one paper published in 2010 very specifically hypothesizes that the impairment of the ability to transport DHAA into certain cell compartments is the primary defect in ATS:DHAA enters the endoplasmic reticulum (ER) using a hypothetical GLUT transporter. We hypothesize that GLUT10 is the uncharacterized transporter of DHAA. In the ER, DHAA is reduced to AA by the protein disulfide isomerase (PDI), a subunit of prolyl hydroxylases. Prolyl- and lysyl-hydroxylases modify residues in collagens and elastin that stabilize the mature molecules. In ATS, loss of GLUT10 would negatively affect the integrity of the deposited collagens and elastin, thus weakening the extracellular matrix of connective tissues… In the absence of GLUT10, reduction in the levels of AA/DHAA in the ER intracisternal compartment would be expected to lead to lowered prolyl- and lysyl-hydroxylase activities and, therefore, to a reduction in the number of hydroxyproline and hydroxylysine residues in collagens and elastin. We believe that in the vessel wall defective elastin is the likely cause of tortuosity whereas outside the cardiovascular system, like the joints and skin, the pathology probably reflects deposition of abnormal collagens.An interesting observation is that, if this hypothesis is correct, then it implies that it is the oxidized form of vitamin C (DHAA) that the cells must absorb for normal collagen and elastin formation.Of course, there are other studies and hypotheses, such as one published in 2012 that indicates mitochondrial dysfunction is involved in the pathogenesis of ATS. Nevertheless, impairment of DHAA transport remains the proposed causative factor at the core of this study:Mitochondrial dysfunction observed through altered transcriptional profiles in our study is consistent with the recent finding that GLUT10 is required for dehydroascorbic acid transport into the mitochondria…Glut10 is essential for cardiovascular development by facilitating both mitochondrial respiration and TGFb signaling.Most recently, in a study published just this month (September 2015), researchers examined skin fibroblasts from ATS patients and found a wide array of not only biochemical changes, but dysregulation of gene expression. While arguing neither for nor against the concept that bad collagen and elastin is the primary defect in ALS, they propose that the lack of vitamin C transport could also result in abnormal expression of other genes that could also explain part of the pathogenesis of ATS. Once again, however, abnormal transport of DHAA is at the core of their hypotheses, and once again this study implies that normal transport of DHAA is necessary for normal, healthy skin and arteries.In ATS, abnormal ascorbic acid nuclear homeostasis, due to the lack of GLUT10, should lead to altered gene expression. To discern the molecular mechanisms underlying the ATS aetiology, we performed gene expression profiling and biochemical studies on skin fibroblasts. Transcriptome analyses revealed the dysregulation of several genes involved in TGFβ signalling and extracellular matrix (ECM) homeostasis as well as the perturbation of specific pathways that control both the cell energy balance and the oxidative stress response. Biochemical and functional studies showed a marked increase in ROS-induced lipid peroxidation…which contributes to the redox imbalance and the compensatory antioxidant activity…GLUT10 deficiency results in severe cardiovascular and connective tissue manifestations in both humans and zebrafish… ATS is associated with abnormal collagens and elastin synthesis…None of this is inconsistent with the fact that human skin normally contains a very high ratio of DHAA to AA. It also supports the concept that DHAA is superior as a supplemental form of vitamin C for topical application, not only because DHAA is absorbed much better, but also because it appears to be the form that skin cells must absorb for proper collagen formation.Glucose transporter 10 and arterial tortuosity syndrome: The vitamin C connection. (July, 2010). FEBS Letters 584 2990–2994GLUT10 is required for the development of the cardiovascular system and the notochord and connects mitochondrial function to TGFβ signaling. (March, 2012). Human Molecular Genetics, Vol. 21, No. 6 1248–1259GLUT10 deficiency leads to oxidative stress and non-canonical alpha-v beta-3 integrin-mediated TGF-beta signaling associated with extracellular matrix disarray in arterial tortuosity syndrome skin fibroblasts. (September, 2015). Human Molecular Genetics doi: 10.1093/hmg/ddv382
Girls Blog 2015
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