Teuxos 01.indd

ÖÁÑÌÁÊÅÕÔÉÊÇÔñéìçíéáßá Ýêäïóç ìå èÝìáôáÖáñìáêåõôéêþí ÅðéóôçìþíÔüìïò 24, Ôåý÷ïò É-II, ÉáíïõÜñéïò - Éïýíéïò 2012ÄÉÅÕÈÕÍÔÇÓ ÓÕÍÔÁÎÇÓ:Á. ÔóáíôßëçÊáèçãÞôñéá, ÐáíåðéóôÞìéï Áèçíþítsantili@pharm.uoa.grÁÑ×ÉÓÕÍÔÁÊÔÇÓ:Ã. Á. ÊáñßêáòÊáèçãçôÞò, Ôå÷íïëïãéêü Åêðáéäåõôéêü ºäñõìá Áèçíþíkarikasg@teiath.grPHARMAKEFTIKIA quarterly editionon pharmaceutical sciences’ topicsVolume 24, Issue É-II, January - June 2012EDITOR:A. TsantiliProfessor, University of Athenstsantili@pharm.uoa.grCO EDITOR:G.A. KarikasProfessor, Technological Educational Institute of Athenskarikasg@teiath.grÓÕÍÔÁÊÔÉÊÇ ÅÐÉÔÑÏÐÇÊ. ÄåìÝôæïò,ÊáèçãçôÞò, ÐáíåðéóôÞìéï ÁèçíþíÂ. Äçìüðïõëïò,ÊáèçãçôÞò, ÐáíåðéóôÞìéï ÈåóóáëïíßêçòÍ. Êüëìáí, Galenica SA×. Êïíôïãéþñãçò,PhD, ÐáíåðéóôÞìéï ÈåóóáëïíßêçòÐ. ÊïõñïõíÜêçò,Ïìïô. ÊáèçãçôÞò, ÐáíåðéóôÞìéï ÈåóóáëïíßêçòÐ. Ìá÷áßñáò,ÊáèçãçôÞò, ÐáíåðéóôÞìéï ÁèçíþíÓ. Íéêïëáñüðïõëïò,Áíáðë. ÊáèçãçôÞò, ÐáíåðéóôÞìéï ÐáôñþíÃ. ÐÜéñáò,Åðßê. ÊáèçãçôÞò, ÐáíåðéóôÞìéï ÐáôñþíÅ. ÐáíôåñÞ,Áíáðë. ÊáèçãÞôñéá ÐáíåðéóôÞìéï ÁèçíþíÄ. ÑÝêêáò,Áíáðë. ÊáèçãçôÞò, ÐáíåðéóôÞìéï ÁèçíþíEDITORIAL BOARDC. Demetzos,Professor, University of AthensV.J. Demopoulos,Professor, University of ThessalonikiN. Kolman, Galenica SACh. Kontogiorgis,PhD, University of ThessalonikiP. Kourounakis,Emeritus Professor, University of ThessalonikiP. Macheras,Professor, University of AthensS. Nikolaropoulos,Associate Professor, University of PatrasG. Pairas,Assistant Professor, University of PatrasI. Panderi,Associate Professor, University of AthensD. Rekkas,Associate Professor, University of AthensEMAIL ÃÉÁ ÊÁÔÁÈÅÓÇ ÅÑÃÁÓÉÙÍ:tsantili@pharm.uoa.grkarikasg@teiath.grEMAIL FOR ABSTRACT SUBMISSION:tsantili@pharm.uoa.grkarikasg@teiath.grÃéá ôçí çëåêôñïíéêÞ Ýêäïóç ôçò «ÖáñìáêåõôéêÞò»êáé ïäçãßåò ðñïò óõããñáöåßò åðéóêåöôåßôå ôçí äéåýèõíóçwww.hsmc.grÔá Üñèñá ðïõ äçìïóéåýïíôáé óôçí ÖáñìáêåõôéêÞêáôá÷ùñïýíôáé óôá Chemical Abstracts.For “Pharmakeftiki” electronic editionand instructions to authors please visitwww.hsmc.grArticles published in Pharmakeftikiare abstracted in Chemical Abstracts.

ÐÅÑÉÅ×ÏÌÅÍÁCONTENTSÖÁÑÌÁÊÅÕÔÉÊÇ 24, I-II, 2012 PHARMAKEFTIKI 24, I-II, 2012ÁÐÏ ÔÇ ÓÕÍÔÁÎÇ .....................................................................................1EDITORIAL ........................................................................................................ 1ÁÑÈÑÁ ÅÐÉÓÊÏÐÇÓÇÓÐñüóöáôåò ÅðéóôçìïíéêÝò Ðñüïäïéôçò Èåùñßáò ÅëåõèÝñùí Ñéæþíêáé Ïîåéäùôéêïý Stress ãéá ôçí ÃÞñáíóç.ÁíôéïîåéäùôéêÜ Óõìðëçñþìáôá ÄéáôñïöÞòÞ Èåñìéäéêüò Ðåñéïñéóìüò ãéá ôçí ÁíôéóôñïöÞôçò ÃÞñáíóçò;ÁèáíÜóéïò ÂáëáâáíßäçòÈþìç Âëá÷ïãéÜííçÊùíóôáíôßíïò ÖéùôÜêçò ........................................................................... 2-12Ïîåéäùôéêü Stressêáé Óáê÷áñþäçò ÄéáâÞôçòôýðïõ ÉÉÁíäñÝïõ Å. ÄÞìçôñáÁíäñåÜäïõ ÉùÜííá .....................................................................................13-33Óýíôïìç Áíáóêüðçóçôïõ Béïëïãéêïý Ñüëïõêáé ôùí Öáñìáêåõôéêþí ÉäéïôÞôùíôçò Ôáõñßíçò.×ñÞóåéò, åöáñìïãÝò êáé ðñïïðôéêÝò.Ó. ÊÝëëáÐ. ÐëáãåñÜòÁ. ÐáðáúùÜííïõÉ. ÁíáóôáóïðïýëïõÈ. Èåïöáíßäçò .............................................................................................. 34-39REVIEW ARTICLESRecent Scientific Advanceson the Free Radicaland Oxidative Stress Theory of Ageing.Dietary Supplements of Antioxidantsor Caloric Restrictionfor Reversing Ageing?Athanasios ValavanidisThomie VlachogianniKonstantinos Fiotakis .................................................................................. 2-12Oxidative Stressand type IIDiabetes MellitusDimitra AndreouIoanna Andreadou ....................................................................................... 13-33Brief Ïverviewof the Biological Roleand Pharmaceutical Propertiesof Taurine.Uses, applications and perspectives.S. KellaP. PlagerasA. PapaioannouI. AnastassopoulouTh.Theofanidis ............................................................................................... 34-39ÅÑÅÕÍÇÔÉÊÅÓ ÅÑÃÁÓÉÅÓÅðßäñáóç ôïõ õðåñéêïý ôïõ äéÜôñçôïõ(Hypericum perforatum L)óôçí åðïýëùóç ôñáýìáôïòäÝñìáôïò åðéìýùí.ÓáðïõíÜêçò Ê.×áôæçãéÜííç Å.Êþôóéïõ Á.ÔåóóåñïììÜôç ×. .........................................................................................40-41RESEARCH ARTICLESHypericum perforatumL Induced Accelerationon Wound HealingProcess in Rats.Sapounakis ConstantinChatzigianni EmmyKotsiou AntoniaTesseromatis Christine ................................................................................ 40-41Ãñáöåßï Äéïßêçóçò ÅëëçíéêÞò Åôáéñåßáò Öáñìáêï÷çìåßáòZITA ÓÕÍÅÄÑÉÁÊÅÓÊÁÉ ÔÏÕÑÉÓÔÉÊÅÓ ÅÐÉ×ÅÉÑÇÓÅÉÓ ÁÅ1o ÷ëì Ðáéáíßáò - Ìáñêïðïýëïõ19002, Ðáéáíßá, ÅëëÜäáÔçë: +30 211 100 1770-71E-mail: info@zita-congress.grHellenic Society of Medicinal Chemistry Management OfficeZITA CONGRESS SA1st klm Peanias-Markopoulou19002, Peania, GreeceTel: +30 211 100 1770-71Email: info@zita-congress.gr

ÁÐÏ ÔÇ ÓÕÍÔÁÎÇÅDITORIALÖÁÑÌÁÊÅÕÔÉÊÇ 24, I-II, 1, 2012 PHARMAKEFTIKI 24, I-II, 1, 2012Aãáðçôïß óõíÜäåëöïé,Aãáðçôïß áíáãíþóôåòÌåôÜ áðï äõï ðåñßðïõ ÷ñüíéá óéùðÞò ëüãù ïéêïíïìéêþíðñïâëçìÜôùí ôïõ åêäüôç, ç “ÖáñìáêåõôéêÞ” åßíáé êáé ðáëéóôá ÷Ýñéá óáò. Ôï íÝï îåêßíçìá ôïõ ðåñéïäéêïý, ôï ïðïßïáíÝëáâå íá åêäßäåé ç Åôáéñåßá Zita-Congress, áðïôåëåßìåãÜëç ÷áñÜ ãéá ìáò. Ìå íÝïõò, Üîéïõò óõíáäÝëöïõò íáðëáéóéþíïõí ôç ÓõíôáêôéêÞ ÅðéôñïðÞ ç “ÖáñìáêåõôéêÞ”èá äéáôçñÞóåé ôç öõóéïãíùìßá ôçò ùò ôñéìçíéáßï ðåñéïäéêüìå èÝìáôá Öáñìáêåõôéêþí Åðéóôçìþí, åíþ ðáñÜëëçëáåõåëðéóôïýìå üôé èá âåëôéùèåß êáé èá åêóõ÷ñïíéóôåßç ÝêäïóÞ ôçò, áîéïðïéþíôáò áðïôåëåóìáôéêüôåñá ôéòäõíáôüôçôåò ôçò ôå÷íïëïãßáò. Ôá Üñèñá ðïõ äçìïóéåýïíôáéóôç “ÖáñìáêåõôéêÞ” – óôçí áããëéêÞ Þ åëëçíéêÞ ãëþóóá ìåáããëéêÞ ðåñßëçøç- êáôá÷ùñïýíôáé óôá Chemical Abstractsåíþ ãßíïíôáé åíÝñãåéåò ãéá íá åíåñãïðïéçèïýí åê íÝïõ ïéêáôá÷ùñÞóåéò óôéò âÜóåéò äåäïìÝíùí EMÂASE êáé Scopus.Åëðßæïõìå ç “ÖáñìáêåõôéêÞ” ùò ôï ìüíï áìéãþòåðéóôçìïíéêü ðåñéïäéêü óôï ÷þñï ôùí ÖáñìáêåõôéêþíÅðéóôçìþí óôçí ÅëëÜäá, íá áðïôåëÝóåé êáé ðÜëé åíá âÞìáåíçìÝñùóçò êáé ðñïâïëÞò óýã÷ñïíùí åðéóôçìïíéêþí åîåëßîåùí,êáëýðôïíôáò ôï êåíü ðïõ åß÷å äçìéïõñãçèåß ìå ôçí áíáóôïëÞ ôçòÝêäïóÞò ôçò êáé ðáñáêáëïýìå ãéá ôçí åíåñãÞ õðïóôÞñéîÞ óáò.Ç ÓõíôáêôéêÞ ÅðéôñïðÞ1

ÁÑÈÑÏ ÅÐÉÓÊÏÐÇÓÇÓREVIEW ARTICLEÖÁÑÌÁÊÅÕÔÉÊÇ 24, I-II, 2-12, 2012 PHARMAKEFTIKI 24, I-II, 2-12, 2012Recent Scientific Advances on the Free Radicaland Oxidative Stress Theory of Ageing.Dietary Supplements of Antioxidants or Caloric Restriction for Reversing Ageing?Athanasios Valavanidis, Thomie Vlachogianni and Konstantinos FiotakisDepartment of Chemistry, University of Athens,University Campus Zografou, 15784 Athens, GreeceSummaryTheories were proposed through the years for the reasonsof ageing in aerobic biological systems. Some of thesetheories lost favor because of lack of scientific support butother remained as potential avenues of biogerontologicalresearch. In the 1950s Denham Harman announcedhis seminal proposal that reactive oxygen species (ROS)are an important cause of ageing. He proposed that freeradicals formed endogenously as by-products from normalmetabolism played an important role in ageing, as well asthe mitochondria because these organelles proved to bea major site of ROS production. Aerobic organisms undernormal conditions accumulate oxidative damage tocellular macromolecules (imbalance of pro-oxidants andantioxidants agents) that increases during ageing, contributingprogressively to increased oxidative stress and to thedecline of cellular processes. In the last decades new clueshave been discovered about the role of oxidative stress inthe mammalian ageing and a deeper understanding hasbeen developed of age-related diseases in humans. Thecurrent research tested the direct involvement of oxidativestress in ageing in mice and other organisms and thedata support the oxidative theory of ageing. Supplementswith antioxidant vitamins/minerals during randomizedclinical trials showed conflicting efficacy data on improvingvarious oxidative stress diseases. Caloric (or calorie)restriction (CR) in the other hand proved to be beneficialin metabolic, hormonal and functional changes in adultmen and women. This review presents the most importantadvances in scientific research and experiments in vivo forthe oxidative theory of ageing.IntroductionThe origins of the free radical theory of ageing (or aging)go back to the 1950s when it was discovered that oxygenfree radicals formed in situ in the cellular compartments ofthe aerobic organisms in response to radiation and oxygenmetabolism are responsible for various oxidative damage. 1,2Denham Harman, noting that radiation and oxygenpoisoning “induces mutations, cancer and ageing”, proposedthat oxygen free radicals that are formed endogenouslyfrom normal oxygen-utilizing metabolic processes(specifically hydroxyl, HO . , and hydroperoxyl radicals,HO 2 . ) play an essential role in the ageing process. 3 Traditionally,chemists thought that free radicals are very limitedin biological systems, because of their reactivity andshort half-life, despite the reports to the contrary and theirdetection by various scientists in biological materials. 4,5Then, a very important discovery of superoxide dismutase(SOD) by McCord and Fridovich in 1969 and the demonstrationof the existence of hydrogen peroxide (H 2O 2) invivo in 1979, gave credibility to the theory of free radicals. 6,7In 1972, Harman added a modification to his theory, givinga central role to the mitochondria of the aerobic organisms,because these organelles generate a large amount of reactiveoxygen species (ROS, the term has been establishedas meaning oxygen free radicals and highly oxidant oxygenchemicals, such as H 2O 2) in cells. 8 In the following years, thetheory was supported by new experimental evidence, namelythat oxidative cellular damage, through oxidative stressin aerobic organisms, increases during ageing and that mitochondriaare central to ageing. Studies showed that mitochondriaDNA deletions and point mutations (mtDNA)are induced by oxidative stress and accumulate with age inaerobic organisms from worms to humans. 9-12The hypothesis of free radicals of ageing has been refinedin the last decades encompassing also other forms ofreactive oxygen substances, such as peroxides, aldehydes,nitrogen oxides and other compounds which contributeto oxidative damage in cells. A chronic state of oxidativestress exists in cells of aerobic organisms even undernormal physiological conditions because of an imbalanceof prooxidant and antioxidant substances and enzymes. 13This imbalance leads to a steady-state accumulation ofoxidative damage for a variety of important macromolecules(proteins, enzymes, lipids, DNA, etc) that increasesduring ageing. Progressively, these damages lead to lossof functional efficiency of cellular metabolic processes. A“strong” version of oxidative stress determines life span,while a “weaker” version of oxidative stress is associatedmainly with age-related diseases. 14Reactive oxygen species (ROS) are from one hand veryimportant for the physiological metabolic processes ofaerobic organisms, including humans, but at the same timegenerate oxidative stress which changes dramatically withage. Also, there is mounting genetic evidence that linksoxidants and oxidative stress responsiveness to ageing. In2

Figure 3. ROS and free radicals such as HO .can causeoxidative damage to mitochondrial proteins, mutations inmtDNA or decrease the DNA repair mechanisms. Also, ROScan escape the mitochondrial membrane causing nuclearDNA damage in cells, or apoptosis because of DNA mutations.These oxidative damages advance ageing of organisms.Oxidative stress, biology of ageing,diseases and cancerAlthough maximum life span (longevity) is the mostrelevant and defined endpoint of with regard to ageing,in large multicellular organisms ageing does not proceeduniformly. This concept of focal ageing or segmented progeria,is particularly important in a variety of age-relatedhuman diseases. The two most important age-related diseasesare cardiovascular and neurodegenerative disordersthat increase exponentially with age. Also, in the last decadesthere is a growing convergence between the our understandingof the biology of ageing and the basic mechanismsthat underlie cancer. 22The maintenance of DNA represents a fundamentaland continuous problem to every cell. DNA repair and genomicstability in aerobic organisms have been explainedin recent years and there are multiple pathways to senseand repair damaged DNA in cells, depending on the natureof damage and on the phase of the cell cycle. Genomicinstability is a hallmark of most cancers but also the hallmarkof ageing. Age-dependent increase in chromosomalinstability has been known for some time to occur in simpleorganisms (such as yeast) but also in mammals. 23,24Increasing evidence from laboratory, animal and clinicalstudies indicate that ROS may participate in the pathogenesisof these diseases. Experiments showed that thevessel wall of patients with atheroscrerotic risk factors, butno overt disease, is characterized by significant increasein vascular ROS production. 25 Mutations in genes thatregulate antioxidant enzymes (such as SOD, glutathione,etc) and deficiencies in antioxidant vitamins E or A havebeen found by in vivo experiments to increase the risk foratherosclerosis, retinal degeneration and familial amylotropiclateral sclerosis. 26.-28The common feature to many of these diseases of ageingis the recruitment of inflammatory cells. These cellscontribute to oxidative stress in large part because theycontain the potent NADPH oxidase system. The NADPH(nicotinamide adenine dinucleotide phosphate-oxidase)is a membrane-bound enzyme complex which is presentin neutrophils, macrophages, microglia and vascular cells.Once activated, the NADPH oxidase produces largeamounts of superoxide anion (O 2. −). Although superoxidecan be reduced to H 2O 2by SOD, small amounts escape theenzymatic dismutation and react with nitric oxide (NO . )producing endogenously the oxidant peroxynitrite (NO . +O 2. − → ONOO− ) and other highly damaging radical species.The link between inflammation and ROS seems toprovide a useful framework for understanding oxidativestress and disease progression. 29-31The role of micronutrients (vitamins, minerals,biochemicals), oxidative stress and longevityFor most of human evolution, caloric shortage probablylimited population growth. The advent of agriculturemade diets rich in calories and nutrients. The introductionof potato in Europe and rice varieties in Asia were majorfactors enabling high population growth and density. Althoughcaloric shortage is a thing of the past for most ofthe countries on the global scale, the abundance of carbohydrates,meat, fat-rich foods, inexpensive processed foodsand sugary drinks generated a new epidemic of obesity associatedwith micronutrient malnutrition. 32,33Numerous epidemiological and clinical studies in thepast decades have demonstrated that regular fruit and vegetableconsumption (rich in polyphenols, flavonoids andother antioxidants) reduces cellular oxidative damage, increasesplasma antioxidants and reduces the risk for variousage-related diseases and mortality. 34-37Dietary research and nutritional supplementation withantioxidants advanced in response to these studies. Theclinical use of antioxidant vitamins, minerals and biochemicalshas gained considerable interest during the lastdecade. 39-41Based on these promising data, supplements of vitamins(E, C, A, D , B 6, B 12), minerals (Zn, Ca, Mg, etc)and biochemicals (á-lipoic acid, curcumin, melatonin, resveratrol,isoflavones, etc) were applied through protocolsaimed to prevent age-related diseases. Prevention of cardiovasculardiseases was an obvious subject (atherosclerosis,hypertension, coronary vasculature, etc) with antioxidants,but the results were conflicting for the efficacy ofantioxidants. 42-46Chronic Obstructive Pulmonary Diseases (COPD) isconnected with oxidative stress. Targeting oxidative stresswith antioxidants is obviously a likely goal for beneficialtreatment of COPD, but results were very limited. 47 Treat-4

ment of amylotropic lateral sclerosis and multiple sclerosiswith antioxidants showed conflicting evidence for theefficacy of antioxidants. 48,49 The majority of clinical trialsidentified positive effects for supplementation with antioxidantsfor the type 2 diabetes. 50 Ambiguous clinical resultshave been found in the treatment of cognitive impairmentand neurodegenerative diseases (e.g. Alzheimer’sdisease) with antioxidants. 51,52 Oxidative DNA damage(as measured with the biomarker of the mutagenic adduct8-OHdG) decreases substantially with supplementation ofvitamin D and calcium. 53Are concentrations of plasma antioxidants and longevityin centenarians connected? The question was answeredby scientists with the measurements of plasma levels of vitaminC, uric acid, vitamin E and A, carotenoids, activityof SOD and GPx in healthy centenarians, elderly aged 80-99 years and over 60 years of age. From the results it is evidentthat healthy centenarians show a particular profile inwhich high levels of vitamins seem to be important in guaranteeingtheir extreme longevity. 54 Antioxidant status inelderly persons is a predictor for health and longevity. 55,56Daily human diet intake needs around 40 essentialmicronutrients. The optimum amount of micronutrientsis essential to maximize the protection of important biologicalmacromolecules from oxidative damage and keepthe metabolic network. Dietary intake of micronutrientschanges with age 57 (Table 1).The age when calorie restriction is started, the severityof diet restriction and the genetic background of theanimal determine the extend of life extension. In rodents(rats or mice) a 30% to 60% reduction in calorie intakebelow the usual ad libitum intake of food (in accordancewith desire) caused a proportionate 30% to 60% increasein maximum life span. The experiments showed slow primaryageing and extend of maximum life span for rats andmice. 61,62 Also, experiments with rodents with intermittentfasting (or alternate-day feeding) increases resistance tostress and prolongs maximum life span. 63Studies of calorie restriction with rodents found that delayedthe occurrence of chronic diseases, including diabetes,atherosclerosis, cardiomyopathy, autoimmune diseases,kidney and respiratory diseases and various cancers. 64-66In addition, calorie restriction has been proved to decreaseneurodegeneration in the brain and enhance neurogenesisin animal models of Alzheimer’s and Parkinson diseases,Huntington disease and stroke. 67-69Scientists suggest that the mechanisms responsible forcalorie restriction-mediated beneficial effects on primaryageing (in rodents) probably involve the metabolic adaptationto restriction itself, including:(a) calorie restriction (CR) decreased production ofreactive oxygen species (ROS) and modulation of the endogenousantioxidant systems, which decrease oxidativestress that induce damages to tissues. 70,71Table 1: RECOMMENDED DIETARY ALLOWANCE OF MICRONUTRIENTSMicronutrientMineralsIron (Fe)Zinc (Zn)Selenium (Se)VitaminsVitamin E (a-tocopherol)Vitamin C (ascorbic acid)Folic acidB 6B 12BiochemicalsRDA (recommended dietary allowance)18,000 (women 20-30 years) ìg8,000 (women 50+ years) ìg8,000-11,000 (women/men 50+ years) ìg20-65 ìg6-10 mg40-60 mg150-200, 400 (pregnant women) ìg0,3-2,0 mg0,3-2,0 ìgFlavonoids, polyphenols, á-lopoic acid,isoflavones, caretonoids, gloutathione, niacin,Caloric restriction can be beneficial forchronic diseases, cancer and ageingThe first research on caloric (or calorie) restriction inexperimental animals was contacted in 1935. Calorie restrictionin rats (implemented after puberty), extendedmedian and maximum life span and prevented the severityof chronic diseases. 58 Subsequent experiments in differentspecies (rodents, flies, fish, yeast) have shown that calorierestriction, defined as a reduction of food (diet, calories)without malnutrition, slows ageing, increase maximum lifespan and reduces the extend of diseases and cancer. 59,60(b) decreased circulating triiodothyronine (T 3) (serumthyroid hormone) levels and sympathetic nervous systemactivity, which cause a decrease in body temperature andwhole-body resting energy expenditure from baseline. 72-74(c) decrease plasma concentrations of inflammatorycytokines and a mild increase of cortisol, which reducessystemic inflammation. 75,76(d) protection of the immune system, which with ageingis becoming weaker. 77(e) increased expression of protein chaperons, such asheat shock protein 70, and neurotrophic factors. 785

(e) CR decreased plasma concentrations of anabolichormones and growth factors, which are involved in ageingand tumorigenesis. 79,80(f) CR enhanced DNA repair processes, 81 increasedremoval of damaged cellular proteins and oxidized lipids,and decreased glycation end products. 82Experimental data suggest that many of the cellular effectsof CR are mediated by regulating gene expression,through up-regulation of genes involved in repair and survivalmechanism (by protecting against oxidative damage),down-regulation of genes involved in mediating inflammationand prevention of changes in gene expression that occurwith ageing. 83,84Caloric restriction and ageingin experimental animalsAnimal models for studies of calorie restriction formany years included yeast, worms, flies and laboratory rodents(mice and rats) and in the last decade nonhumanprimates. 85,86Experiments of dietary restriction (calorie restriction),i.e. a reduction of food intake by 40-60% without malnutrition,has been proved to have remarkable benefits forhealth and lifespan in diverse species, as yeast, roundworms,flies and rodents. The roundworm Caenorhabditiselegans (C. elegans) has been used in a great variety ofcaloric restriction experiments. 87,88 As in yeast and flies,over-expression of the Caenorhabditis elegans sirtuin genesir-2.1 leads to extension of lifespan and deletion of thegene shortens lifespan. 89Figure 4. Model organisms of ageing studies: yeast (Saccharomycescerevisiae), roundworms (Caenorhabditis elegans),fruit flies (Drosophila melanogaster) and mice. Caloricrestriction studies with these model organisms decreasedoxidative stress biomarkers and increased substantially theirlife span.Scientists were studying for years the budding yeast Saccharomycescerevisiae and its replicative ageing. A screenfor genes that determine yeast replicative lifespan identifiedthe SIR complex (including the Sir2 histone deacetylase).Yeast Sir2 is a nicotinamide adenine dinucleotide(NAD + ) –dependent histone (protein) deacetylase thathas been proposed to mediate effects of life extension undercaloric restriction. 90,91 Sir proteins were already knownto be involved in gene silencing (SIR stands for Silent InformationRegulator). Sir2 is one of several enzymes thatremove acetyl tags from the histones, but requires thesmall molecule of NAD (known as a conduit of many metabolicreactions in cells). This association between Sir2and NAD is very important because it links Sir2 activity tometabolism and thus potentially to the relation betweendiet and ageing observed in caloric restriction. 92-94Another experimental animal for studying mechanismsof ageing is the fruit fly Drosophila melanogaster. The lifespan of Drosophila melanogaster, under experimental conditionsof caloric or dietary restriction, was extended. 95-98Rodents (mice and rats) and primates were used inexperiments for the study of caloric restriction on ageingand longevity. It is not yet known whether caloric restrictionaffects primary ageing and extends maximum lifespan on long lived mammals. There are ongoing studiesthat evaluating the effect of such restriction on ageingin mice and rats with positive outcome. 99-101 Experimentswith rhesus monkeys will probably take another 10 to 15years before adequate data are available for reliable results.Nonetheless, the data currently available from thesestudies have shown that many of the metabolic, hormonal,anti-inflammatory, and body compositional changes thatoccur in caloric-restricted rodents also occur under similarconditions in caloric-restricted monkeys. 102-105Experiments of caloric restrictionand ageing in humansStudies of caloric restriction and the effects on longevityin humans are very difficult to come to a definiteconclusion because there are no validated biomarkers thatcan serve as surrogate markers of ageing. Also, there arepractical difficulties to conduct randomized, diet-controlled,long-term survival studies in humans. 106,107There are data from epidemiological studies whichsuggest that diet restriction can have beneficial effectson the factors involved in the pathogenesis of primaryand secondary ageing and life expectancy in humans.During the World War I and II there were food shortagesin many European countries that were associatedwith sharp decrease in coronary heart disease mortality.After the end of the war the cardiovascular diseasesincreased again. 108,109 In another study it was foundthat the Japanese in the Okinawa island are consuming30% less calories than the average Japanese populationand had ~35% lower rates of cardiovascular disease and6

lower cancer mortality than the average Japanese. Also,they had one of the highest number of centenarians inthe world. 110However, these associations are not enough indicatorsthat can prove a relationship between decreased caloricrestriction and improved effects in longevity and decreasein ageing diseases.There are more than ten recent human studies withvoluntary self imposed caloric restriction or accidental inducedcaloric restriction for short-term randomized controlledtrials (6-12 months). These studies examined theconnection between caloric restriction and biological adaptationsthat might be responsible for the slowed ageingprocess. Findings from these studies were very promising.The caloric restriction group of men and women, comparedto the control group, showed decreased body fat andbody mass index (BMI), blood pressure, marked reductionin metabolic risk factors for coronary heart disease,decrease levels of insulin, decreased T 3levels, improvedlipid profile, decreased TNF-á/adiponectin ratio and levelsof insulin and glucose, lower plasma concentrations ofinflammatory markers, and other beneficial markers of reducedoxidative stress and ageing. 111-120Some studies found also that CR decreased bonemass as well lower extremity muscle mass and strength.Despite many similarities in the metabolic adaptationto CR observed in rodents and humans, it is not knownif such restriction affects maximum lifespan in humans.Obesity is associated with serious medical diseases andpremature mortality. Weight loss induced by CR (negativeenergy balance) simultaneously improves multiplemetabolic risk factors for cardiovascular disease andother medical abnormalities associated with obesity. Inthe other hand, it must be emphasized that excessive caloricrestriction (defined as a decrease in calorie intakethat can be dangerous on organ functions and health)that is more than 45% of the energy requirements cancause anemia, muscle wasting, neurologic deficits, lowerextremity edema, weakness, dizziness, lethargy anddepression. 66,68Genetics, dietary restriction and mechanismsof ageing in small organismsMolecular biologists discovered in recent years thatthe ageing process is subject to regulation by classicalsignaling pathways and transcription factors in biologicalsystems. Many of these pathways were discovered for thefirst time in small, short-lived organisms such as yeast,worms, flies and rodents. It was found that many mutationsthat extend lifespan affect stress-response genes ornutrient sensors. When food is plentiful and stress levelsare low, these genes support growth and reproduction,but under harsh conditions their activities change (someup and others are turned down) and as consequence theanimal undergoes a global physiological shift towardscell protection and maintenance. These shifts protectthe animal from environmental stresses and it also extendslifespan. 121Nutrient and stress sensors mediate lifespan extensionsthat occur in response to many different environmentaland physiological signals. The best known of these signalsis dietary (or caloric) restriction, which extends lifespan inmany species, from yeast to primates. 122In worms, flies and mice (as well as yeast), geneticand/or phenotypic analysis suggests that chronic dietaryrestriction increases lifespan by downregulating TORactivity. The TOR pathway (kinase Target Of Rapamycin,a protein) is known to regulate autophagy and translation(see Figure 5). The small arrows indicate upregulationor downregulation. In worms and flies, lifespanextension by means of TOR inhibition has been shownto require autophagy, and in all three species, inhibitingtranslation by inactivating the TOR target ribosomalS6 kinase increases lifespan. PHA-4 is requiredfor autophagy in Caenorhabditis elegans TOR mutants.PHA-4 also affects expression of stress-response genesin response to dietary restriction; its effect on translationhas not been examined. In flies, components of therespiratory electron transport chain escape translationalinhibition when TOR activity is reduced, resulting in increasedrespiration. 121Figure 5. Mechanisms of chronic dietary restriction inexperimental animals such as C. elegans, Drosophila melanogasterand mouse, with beneficial effects on oxidativestress and prolonged lifespan. 121Chronic dietary restriction also increases respiration inworms, in response to activity of the SKN-1 transcriptionfactor in neurons (green). In worms and flies, this increasein respiration has been shown to contribute to lifespanextension. Whether TOR affects respiration in worms, orSKN-1 affects respiration in flies, is not known. In flies andmice, chronic dietary restriction may increase lifespan, at7

least in part, by downregulating insulin/IGF-1 signaling(IIS, red). Sirtuins are required for chronic dietary restrictionto extend lifespan in flies and mice, but whetherthey act in the insulin/IGF-1 and/or TOR pathways is notknown. 123-126ConclusionsOne of the most widely accepted theories of ageing isthe free radical or oxidative stress theory. Reactive oxygenspecies (ROS) are byproducts of energy metabolismand oxygen consumption in aerobic organisms, resultingin the slow but steady damage, which accelerates withageing, of membrane lipids, proteins-enzymes and DNA.These damages progressively lead to degenerative diseases,organ dysfunction, cancer and death. Caloric intakeis an important determinant of health. Inadequate or excessiveenergy intake can have detrimental effects in thebody composition, organ functions and ageing. Experimentswith animal models showed that caloric restriction(CR) decreased ageing processes, restricted degenerativediseases and prolong maximum lifespan. Experiment withhumans showed that caloric restriction although does notprolong lifespan, decreases degenerative diseases, andhase a beneficial effect on the quality of late life by reducingthe burden of chronic diseases. Additional studies areneeded to identify the molecular and cellular mechanismsresponsible for the CR effects and to discover reliable andsensitive biomarkers of ageing.References1. Gilbert DL, Colton CA. Reactive Oxygen Species inBiological Systems: An Interdisciplinary Approach.Kluwer Academic, New York, 1999.2. Gerschman R, Gilbert DL, Nye SW, Fenn WO. Influenceof x-irradiation on oxygen poisoning in mice.Proc Soc Exp Biol Med 86:27-29, 1954.3. Harman D. Aging: a theory based on free radical andradiation chemistry. J Gerontol 11:298-300, 1956.4. Gerschman R, Gilbert DL, Nye, Dwyer P, Fenn WO.Oxygen poisoning and x-irradiation; a mechanism incommon. Science 119:623-626, 1954.5. Commoner B, Townsend J, Pake GE. Free radicals inbiological materials. Nature 174:689-691, 1954.6. McCord JM, Fridovich I. Superoxide dismutase: Anenzymic fuction for erythrocuprein (hemocuprein). JBiol Chem 244:6049-6055, 1969.7. Chance B, Sies H, Boveris A. Hydroperoxide metabolismin mammalian organs. Physiol Rev 59:527-605,1979.8. Harman D. The biologic clock: the mitochondria? JAm Geriatr Soc 20:145-147, 1972.9. Fraga CG, Shigenaga MK, Park JW, Degan P, AmesBN. Oxidative damage to DNA during aging: 8-hydroxy-2-deoxyguanosinein rat organ DNA and urine.Proc Natl Acad Sci USA 87:4533-4537, 1990.Ðñüóöáôåò ÅðéóôçìïíéêÝò Ðñüïäïéôçò Èåùñßáò ÅëåõèÝñùí Ñéæþí êáéÏîåéäùôéêïý Stress ãéá ôçí ÃÞñáíóç.ÁíôéïîåéäùôéêÜ Óõìðëçñþìáôá ÄéáôñïöÞò Þ ÈåñìéäéêüòÐåñéïñéóìüò ãéá ôçí ÁíôéóôñïöÞ ôçò ÃÞñáíóçò;ÁèáíÜóéïò Âáëáâáíßäçò, Èþìç Âëá÷ïãéÜííç êáéÊùíóôáíôßíïò ÖéùôÜêçòÔìÞìá ×çìåßáò, ÐáíåðéóôÞìéï Áèçíþí,Ðáíåðéóôçìéïýðïëç ÆùãñÜöïõ, 15784 ÁèÞíáÐåñßëçøçÔéò ôåëåõôáßåò äåêáåôßåò Ý÷ïõí ðñïôáèåß áñêåôÝòåðéóôçìïíéêÝò èåùñßåò ãéá ôçí ãÞñáíóç ôùí áåñüâéùíâéïëïãéêþí óõóôçìÜôùí. ÌåñéêÝò áðü ôéò èåùñßåò äåíåðéâåâáéþèçêáí áðü ôéò åðéóôçìïíéêÝò Ýñåõíåò åíþ ÜëëåòðáñÝìåéíáí ãéáôß áðïôÝëåóáí ðñüóöïñåò äéüäïõòãéá ôçí ãåñïíôïëïãéêÞ Ýñåõíá. Óôç äåêáåôßá ôïõ 1950 ïáìåñéêáíüò åðéóôÞìïíáò Denham Harman áíáêïßíùóåôçí äçìéïõñãéêÞ ðñüôáóç üôé äñáóôéêÝò ïîõãïíïý÷åòåíþóåéò (ROS) ðáßæïõí óçìáíôéêü ñüëï óôç ãÞñáíóç.Ðñüôåéíå üôé åëåýèåñåò ñßæåò ðïõ ó÷çìáôßæïíôáé åíäïãåíþòùò ðáñáðñïúüíôá ôïõ öõóéïëïãéêïý ìåôáâïëéóìïýðáßæïõí óçìáíôéêü ñüëï óôç ãÞñáíóç, êáèþò êáéôá ìéôï÷üíäñéá ðïõ åßíáé ôá êõôôáñéêÜ ïñãáíßäéá üðïõðáñÜãïíôáé ôá ROS. Ïé áåñüâéïé ïñãáíéóìïß êÜôùáðü öõóéïëïãéêÝò óõíèÞêåò óõóóùñåýïõí äéÜöïñåòïîåéäùôéêÝò âëÜâåò óå êõôôáñéêÜ ìáêñïìüñéá (ëüãùáíéóïññïðßáò ïîåéäùôéêþí êáé áíôéïîåéäùôéêþí ðáñáãüíôùí)ðïõ áõîÜíåôáé ìå ôç ãÞñáíóç, óõìâÜëëïíôáòðñïïäåõôéêÜ óå áõîçìÝíï ïîåéäùôéêü stress êáé ìåßùóçôùí êõôôáñéêþí ëåéôïõñãéþí. Ôéò ôåëåõôáßåò äåêáåôßåòíÝåò áíáêáëýøåéò êáé åðéóôçìïíéêÜ äåäïìÝíá åðéâåâáéþíïõíôï ñüëï ôïõ ïîåéäùôéêïý stress óôçí ãÞñáíóçôùí èçëáóôéêþí, åíþ Ý÷åé åðéôåõ÷èåß âáèýôåñç êáôáíüçóçôùí åêöõëéóôéêþí áóèåíåéþí ôçò ãÞñáíóçò óôïõòáíèñþðïõò. Ïé ðñüóöáôåò Ýñåõíåò Ý÷ïõí ìåëåôÞóåéôçí Üìåóç óõììåôï÷Þ ôïõ ïîåéäùôéêïý stress óôç ãÞñáíóçôùí ìõþí (ðïíôéêþí) êáé Üëëùí ðåéñáìáôïæþùíêáé ïé ðåéñáìáôéêÝò åíäåßîåéò õðïóôçñßæïõí ôç èåùñßáôïõ ïîåéäùôéêïý stress ãéá ôç ãÞñáíóç. ÐåéñÜìáôá ìåáíôéïîåéäùôéêÜ óõìðëçñþìáôá äéáôñïöÞò, âéôáìßíåò/ìåôáëëéêÜ é÷íïóôïé÷åßá, Ý÷ïõí äåßîåé áìöéóâçôïýìåíáêáé óõãêñïõüìåíá áðïôåëÝóìáôá óå ôõ÷áéïðïéçìÝíåòêëéíéêÝò ìåëÝôåò óå üôé áöïñÜ óôç âåëôßùóç áóèåíåéþíðïõ ïöåßëïíôáé óôï ïîåéäùôéêü stress. Áíôßèåôá,ðåéñÜìáôá èåñìéäéêïý ðåñéïñéóìïý Ýäåéîáí üôé äßíïõíèåôéêÝò áðïäåßîåéò ãéá åõåñãåôéêÜ áðïôåëÝóìáôá óå ìåôáâïëéêÝò,ïñìïíéêÝò êáé ëåéôïõñãéêÝò áëëáãÝò óå çëéêéùìÝíïõòÜíäñåò êáé ãõíáßêåò. Ç áíáóêüðçóç áõôÞðáñïõóéÜæåé ôéò ðëÝïí ðñüóöáôåò êáé óçìáíôéêÝò Ýñåõíåòêáé ðåéñÜìáôá in vivo ãéá ôï ñüëï ôïõ ïîåéäùôéêïýstress óôç ãÞñáíóç.Áëëçëïãñáößá: Áè. Âáëáâáíßäçò,E-mail : valavanidis@chem.uoa.gr8

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108. Strom A, Jensen RA. Mortality from circulatorydiseases in Norway 1940-1945. Lancet 258:126-129,1951.109. Hindhede M. The effects of food restriction duringwar on mortality in Copenhagen JAMA 74:381-382,1920.110. Kagawa Y. Impact of Westernization on the nutritionof Japanese: changes in physique, cancer, longevityand centenarians. Prev Med 7:205-217, 1978.111. Keys A, Brozek J, Henschels A, Mickelsen O, TaylorH. The Biology of Human Starvation, Vol. 2. Universityof Minnesota Press, Minneapolis, 1950.112. Walford RL, Mock D, Verdery R, MacCallum T.Calorie restriction in biosphere 2: alterationas inphysiologic, hematologic, hormonal, and biochemicalparameters in human restricted for a 2-year period. JGerontol A Biol Sci Med Sci 57:B211-B224, 2002.113. Fontana L, Meyer TE, Klein S, Holloszy JP. Longtermcalorie restriction is highly effective in reducingthe risk for atherosclerosis in humans. Proc Natl AcadSci USA 101:6659-6663, 2004.114. Fontana L, Klein S, Holloszy JO, Premachandra BN.Effect of long-term calorie restriction with adequateprotein and mictronutrients on thyroid hormones. JClin Endocrinol Metab 91:3232-3235, 2006.115. Mayer TE, Kovacs SJ, Ehsani AA, Klein S, HolloszyJO, Fontana L. Long-term calorie restricition amelioratesthe decline in diastolic function in humans. JAm Coll Cardiol 47:398-402, 2006.116. Heilbronn LK, de Jonge L, Frisard MI, DeLany JP,Larso-Meyer DE, et al. Effect of 6-month calorie restrictionon biomarkers of longevity, metabolic adaptation,and oxidative stress in overweight individuals:a randomized controlled trial. Pennington CALERIETeam. JAMA 295:1539-1548, 2006.117. Larson-Meyer DE, Hellbronn LK, Redman LM, etal. Effect of calorie restriction with or without exerciseon insulin sensitivity, beta-cell function, fat cellsize, and ectopic lipid overweight subjects. DiabetesCare 29:1337-1344, 2006118. Racette SB, Weiss EP, Villareal DT, et al. One yearof calorie restriction in humans: feasibility and effectson body composition and abdominal adipose tissue. JGerontol A Biol Sci Med Sci 61:943-950, 2006119. Weiss EP, Racette SB, Villareal DT, et al. Improvementsin glucose tolerance and insulin action inducedby increasing energy expenditure or decreasing energyintake: a randomized controlled trial. Am J ClinNutr 84:1033-1042, 2006120. Villareal DT, Fontana L, Weiss EP, et al. Bone mineraldensity response to calorie restriction-inducedweight loss or exercise-induced weight-loss: a randomizedcontrolled trial. Arch Intern Med 166:2502-2510, 2006.121. Kenyon CJ. The genetics of ageing. Nature 464:504-512, 2010.122. Colman RJ, et al. Dietary restriction delays diseaseonset and mortality in rhesus monkeys. Science325:201-204, 2009.123. Kapahi EL, et al. Regulation of lifespan in Drosophilaby modulation of genes by TOR and Sch9 in responseto nutrients. Curr Biol 14:885-890, 2004.124. Rogina B, Helfand SL. Sir2 nedateds longevity in threfly through a pathway related to calorie restriction.Proc Natl Acad Sci USA 101: 15998-16003, 2004.125. Honjoh S, Yamamoto T, Uno M, Nishida E. Signalingthrough RHEB-1 mediates intermittent fasting-inducedlongevity in C. elegans. Nature 457:726-730, 2009.126. Greer EL, Brunet A. Different dietary restrictionregiments extend lifespan by both independent andoverlapping genetic pathways in C. elegans. Aging Cell8:113-127, 2009.12

ÁÑÈÑÏ ÅÐÉÓÊÏÐÇÓÇÓREVIEW ARTICLEÖÁÑÌÁÊÅÕÔÉÊÇ 24, I-II, 13-33, 2012 PHARMAKEFTIKI 24, I-II, 13-33, 2012Ïîåéäùôéêü stress êáé óáê÷áñþäçò äéáâÞôçò ôýðïõ ÉÉÁíäñÝïõ Å. ÄÞìçôñá , ÁíäñåÜäïõ ÉùÜííáÔïìÝáò ÖáñìáêåõôéêÞò ×çìåßáò, ÔìÞìá ÖáñìáêåõôéêÞò,ÐáíåðéóôÞìéï Áèçíþí, Ðáíåðéóôçìéïýðïëç, 157 71 ÆùãñÜöïõ, ÁèÞíáÐåñßëçøçÇ äéáâçôéêÞ áããåéïðÜèåéá êáé íåöñïðÜèåéá åßíáé ïéêýñéåò áéôßåò èíçóéìüôçôáò êáé èíçôüôçôáò óôïõò áóèåíåßòìå äéáâÞôç ôýðïõ É êáé ÉÉ. ÓçìáíôéêÝò êëéíéêÝò ìåëÝôåòüðùò ïé Diabetes Control and Complications Trial(DCCT) êáé United Kingdom Prospective Diabetes Study(UKPDS) áðïäåéêíýïõí ôç óõó÷Ýôéóç áõôþí ôùí åðéðëïêþíìå ôçí õðåñãëõêáéìßá êáé ôá õøçëÜ åðßðåäá åëåýèåñùíëéðáñþí ïîÝùí óôç ãåíéêÞ êõêëïöïñßá (áíåîÜñôçôááðü ôçí äéáöïñÜ óôçí ðáèïöõóéïëïãßá ôïõ äéáâÞôç ôýðïõÉ êáé ÉÉ) 1 .Ç õðåñãëõêáéìßá êáé ôá áõîçìÝíá åëåýèåñá ëéðáñÜïîÝá åõèýíïíôáé ãéá ôç äçìéïõñãßá äñáóôéêþí ìïñöþíïîõãüíïõ (ROS) ìå óõíÝðåéá ôçí åìöÜíéóç ïîåéäùôéêïýstress óå ìéá ðïéêéëßá éóôþí. Áðïõóßá áíôéóôáèìéóôéêþíáðïêñßóåùí áðü ôïí åíäïãåíÞ áíôéïîåéäùôéêü ìç÷áíéóìü,ôï éóïæýãéï áíÜìåóá óôç äçìéïõñãßá êáé áðïäüìçóçôùí äñáóôéêþí ìïñöþí ïîõãüíïõ (ROS) äéáôáñÜóóåôáé,ìå áðïôÝëåóìá ôçí åíåñãïðïßçóç åðáãüìåíùí-áðü ôïïîåéäùôéêü-stressäéáêõôôáñéêþí óçìáôïäïôéêþí ïäþí.Ç åíåñãïðïßçóç ôùí óçìáôïäïôéêþí áõôþí ïäþí äéáäñáìáôßæåéóçìáíôéêü ñüëï óôçí áíÜðôõîç áíôßóôáóçòôùí éóôþí-óôü÷ùí óôç äñÜóç ôçò éíóïõëßíçò, óôç ìåßùóçôçò ÝêêñéóÞò ôçò (ìÝóù äõóëåéôïõñãßáò ôùí â- êõôôÜñùíôïõ ðáãêñÝáôïò) êáé óôçí áíÜðôõîç ôùí äéáâçôéêþí åðéðëïêþí.Ç éäéüôçôá ôùí áíôéïîåéäùôéêþí íá ðñïóôáôåýïõíáðü ôéò åðéðëïêÝò ôçò õðåñãëõêáéìßáò êáé ôùí áõîçìÝíùíåëåýèåñùí ëéðáñþí ïîÝùí in vitro, óå óõíäõáóìüìå ôá êëéíéêþò áðïäåäåéãìÝíá ïöÝëç ôçò èåñáðåßáò ìåáíôéïîåéäùôéêÜ åðéâåâáéþíïõí ôïí áéôéïëïãéêü ñüëï ôïõïîåéäùôéêïý stress óôçí åêêßíçóç Þ/êáé ôçí åðéäåßíùóçáõôþí ôùí áíùìáëéþí. Óôçí ðáñïýóá åðéóêüðçóç ðáñáôßèåíôáéïé âéï÷çìéêÝò äéáäéêáóßåò âÜóåé ôùí ïðïßùí ôïåðáãüìåíï áðü ôçí õðåñãëõêáéìßá êáé ôá åëåýèåñá ëéðáñÜïîÝá ïîåéäùôéêü stress, ðñïêáëåß éíóïõëéíïáíôßóôáóç,äõóëåéôïõñãßá â-êõôôÜñùí ôïõ ðáãêñÝáôïò (áäõíáìßáÝêêñéóçò éíóïõëßíçò) êáé äéáâçôéêÝò åðéðëïêÝò.1. ÅéóáãùãÞÏ äéáâÞôçò ôýðïõ ÉÉ (Þ ìç éíóïõëéíïåîáñôþìåíïò äéáâÞôçò,ÍÉDDM) åßíáé ìßá ÷ñüíéá ìåôáâïëéêÞ äéáôáñá-÷Þ êáé ïñèüôåñá ìßá åôåñïãåíÞò ïìÜäá óõíäñüìùí ðïõ÷áñáêôçñßæåôáé áðü åëáôôùìÝíç åõáéóèçóßá ôùí êõôôÜñùíóôç äñÜóç ôçò éíóïõëßíçò (öáéíüìåíï ðïõ ïíïìÜæåôáééíóïõëéíïáíôï÷Þ Þ éíóïõëéíïáíôßóôáóç), áõîçìÝíççðáôéêÞ ðáñáãùãÞ ãëõêüæçò êáé åëáôôùìÝíç Ýêêñéóçéíóïõëßíçò 2,3,4,5,6 . H åëáôôùìÝíç åõáéóèçóßá óôçí éíóïõëßíç,ç ïðïßá åíôïðßæåôáé óõíÞèùò óôá ðñþôá óôÜäéá ôïõìåôáâïëéêïý áõôïý óõíäñüìïõ, ïäçãåß óå áýîçóç ôçòðáñáãüìåíçò éíóïõëßíçò êáé ôåëéêÜ óå åîÜíôëçóç êáé äõóëåéôïõñãßáôùí â êõôôÜñùí ôïõ ðáãêñÝáôïò.Ï äéáâÞôçò ôýðïõ ÉÉ åßíáé áðïôÝëåóìá áëëçëåðßäñáóçòìåôáîý ãåíåôéêÞò ðñïäéÜèåóçò 7,8,9,10 , ðåñéâáëëïíôéêþíêáé óõìðåñéöïñéóôéêþí ðáñáãüíôùí êéíäýíïõ. Åêôüò áðüôç ãåíåôéêÞ âÜóç ôïõ äéáâÞôç ôýðïõ ÉÉ, õðÜñ÷ïõí éó÷õñÝòåíäåßîåéò üôé ðáñÜãïíôåò üðùò ç ðá÷õóáñêßá, ç õøçëÞðñüóëçøç èåñìßäùí êáé ç Ýëëåéøç óùìáôéêÞò äñáóôçñéüôçôáòáðïôåëïýí âáóéêïýò ìç-ãåíåôéêïýò, ôñïðïðïéÞóéìïõòðáñÜãïíôåò êéíäýíïõ åìöÜíéóçò ôçò íüóïõ. ÐáñÜëëçëáõðÜñ÷ïõí êáé ìç ôñïðïðïéÞóéìïé ðáñÜãïíôåò üðùòç êëçñïíïìéêüôçôá, ç åèíéêüôçôá, ç çëéêßá êáé ôï ÷áìçëüóùìáôéêü âÜñïò êáôÜ ôç ãÝííçóç ïé ïðïßïé åðßóçò óõìâÜëëïõíóôçí ðáèïãÝíåéá ôïõ äéáâÞôç ôýðïõ ÉÉ.Óýìöùíá ìå ôïí Ðáãêüóìéï Ïñãáíéóìü Õãåßáò, ìÝ÷ñéôï 2030 ðåñéóóüôåñá áðü 300 åêáôïììýñéá Üíèñùðïé èáÝ÷ïõí åêäçëþóåé óáê÷áñþäç äéáâÞôç ôýðïõ ÉÉ. Óôç ÷þñáìáò, ôï 6% ôïõ ãåíéêïý ðëçèõóìïý ðÜó÷åé áðü óáê÷áñþäçäéáâÞôç. Ç íüóïò Ý÷åé õøçëüôåñï åðéðïëáóìü (óõ÷íüôçôáåìöÜíéóçò) óôï äõôéêü êüóìï (éäéáßôåñá ï äéáâÞôçòôýðïõ ÉÉ) êáé áõôü áðïôåëåß ìéá áêüìç óáöÞ Ýíäåéîç ãéáôç óõó÷Ýôéóç ôçò íüóïõ ìå ôï óýã÷ñïíï ôñüðï æùÞò, ôéò äéáôñïöéêÝòóõíÞèåéåò êáé ôçí Ýëëåéøç óùìáôéêÞò Üóêçóçò.Ï óáê÷áñþäçò äéáâÞôçò ôýðïõ ÉÉ áðïôåëåß ìéá áðü ôéò êýñéåòáéôßåò èáíÜôïõ ðáãêïóìßùò êáèþò áðïôåëåß ðáñÜãïíôáêéíäýíïõ óôçí áíÜðôõîç êáñäéáããåéáêþí íïóçìÜôùí.2. ÅðéðëïêÝò ôïõ äéáâÞôç ôýðïõ ÉÉÏé åðéðëïêÝò ôïõ äéáâÞôç ìðïñïýí íá ôáîéíïìçèïýíóå ôñåßò êáôçãïñßåò: ìõïêáñäéïðÜèåéåò, ìÜêñï-áããåéáêÝòêáé ìßêñï-áããåéáêÝò åðéðëïêÝò 1 .Ç äéáâçôéêÞ ìõïêáñäéïðÜèåéá åðéöÝñåé ðáèïëïãéêÝòêáé ëåéôïõñãéêÝò áëëáãÝò óôá êáñäéïìõïêýôôáñá ðñïêáëþíôáòäéáóôïëéêÞ äõóëåéôïõñãßá ôùí êïéëéþí, åíäéÜìåóçßíùóç, äéáäï÷éêÞ åëÜôôùóç ôïõ ðëçèõóìïý ôùí êáñäéïìõïêõôôÜñùíêáé ìåßùóç ôçò óõóôáëôéêüôçôáò.Ïé ìáêñïáããåéáêÝò åðéðëïêÝò ôïõ äéáâÞôç ðåñéëáìâÜíïõíôç óôåöáíéáßá íüóï, ôçí áèçñùìÜôùóç êáé ôçíðåñéöåñéêÞ áããåéïðÜèåéá.Óôéò ìéêñïáããåéáêÝò åðéðëïêÝò, ïé ðáèïëïãéêÝò ìåôáâïëÝòôùí ìéêñïáããåßùí åðçñåÜæïõí ôç ëåéôïõñãéêüôçôáôïõ áìöéâëçóôñïåéäïýò ÷éôþíá (äéáâçôéêÞ áìöéâëçóôñïåéäïðÜèåéá)ôùí íåöñþí (äéáâçôéêÞ íåöñïðÜèåéá) êáé ôùííåýñùí (äéáâçôéêÞ íåõñïðÜèåéá). Åðßóçò, ðåñéïñßæïõí ôçíáããåßùóç ôïõ ìõïêáñäßïõ êáé ôçí éêáíüôçôá åðïýëùóçòôùí åëêþí. Ç åîÝëéîç áõôþí ôùí êáñäéáããåéáêþí åðéðëïêþíó÷åôßæåôáé Üìåóá ìå ôçí õðåñãëõêáéìßá êáé ôá åëåýèåñáëéðáñÜ ïîÝá. Óõíåðþò, ï áõóôçñüò êáé ìáêñï÷ñüíéïòãëõêáéìéêüò Ýëåã÷ïò åßíáé ç ðéï áðïôåëåóìáôéêÞ ðñïóÝããéóçóôçí ðñüëçøç ôùí äéáâçôéêþí åðéðëïêþí.13

3. Ïîåéäùôéêü stressÙò ïîåéäùôéêü stress ïñßæåôáé ç äéáôáñá÷Þ ôçò éóïññïðßáòìåôáîý ôùí ïîåéäùôéêþí êáé áíôéïîåéäùôéêþí ïõóéþíôïõ êõôôÜñïõ êáé ïöåßëåôáé åßôå óå áõîçìÝíç ðáñáãùãÞäñáóôéêþí ìïñöþí ïîõãüíïõ (ROS: Reactive OxygenSpecies) åßôå óå áíåðÜñêåéá ôùí êõôôáñéêþí áíôéïîåéäùôéêþíìç÷áíéóìþí 11 . Óå ÷áìçëÝò óõãêåíôñþóåéò ïéROS ðáñïõóéÜæïõí åõåñãåôéêÝò äñÜóåéò óõììåôÝ÷ïíôáòóå äéáäéêáóßåò üðùò ç êõôôáñéêÞ áðüêñéóç óôï stress,ç ìåôáãùãÞ óÞìáôïò, ç êõôôáñéêÞ äéáöïñïðïßçóç, ç ìåôáãñáöÞôùí ãïíéäßùí, ï êõôôáñéêüò ðïëëáðëáóéáóìüò,ç öëåãìïíÞ êáé ç áðüðôùóç 12,13,14 . Áíôßèåôá, ðåñßóóåéáROS ðñïêáëåß âëÜâåò óôá êõôôáñéêÜ ëéðßäéá, ôéò ðñùôåÀíåòêáé ôï DNA áíáóôÝëëïíôáò ôç ëåéôïõñãßá ôïõò.ÊáôÜ óõíÝðåéá ôï ïîåéäùôéêü stress åíï÷ïðïéåßôáé ãéáôçí ðáèïöõóéïëïãßá ðïëëþí íïóçìÜôùí (ð.÷. åðéðëïêÝòêáé éíóïõëéíïáíôßóôáóç óôï óáê÷áñþäç äéáâÞôç ôýðïõÉÉ) êáèþò êáé ãéá ôç äéáäéêáóßá ôçò ãÞñáíóçò. Ç éóïññïðßááíÜìåóá óôéò åõåñãåôéêÝò êáé åðéâëáâåßò äñÜóåéòôùí ñéæþí åßíáé æùôéêÞò óçìáóßáò ãéá ôïõò ïñãáíéóìïýòêáé äéáöõëÜóóåôáé ìå Ýíá óýíïëï ìç÷áíéóìþí ãíùóôüùò «ïîåéäïáíáãùãéêÞ ñýèìéóç» (redox regulation). ÇïîåéäïáíáãùãéêÞ ñýèìéóç äéáôçñåß ôçí ïîåéäïáíáãùãéêÞïìïéüóôáóç êáé ðñïóôáôåýåé ôïõò æþíôåò ïñãáíéóìïýòáðü ôï ïîåéäùôéêü stress 15 . ÓõìðåñáóìáôéêÜ, ôïïîåéäùôéêü stress ìðïñåß íá ÷áñáêôçñéóôåß ùò äéáôáñá-÷Þ ôçò ïîåéäïáíáãùãéêÞò ñýèìéóçò 16 .4. ÄñáóôéêÝò ìïñöÝò ïîõãüíïõ(reactive oxygen species, ROS)ÓÞìåñá åßíáé ãíùóôü üôé üëåò ó÷åäüí ïé åðéâëáâåßòåðéäñÜóåéò ôïõ ïîõãüíïõ ïöåßëïíôáé óôï ó÷çìáôéóìüåëåýèåñùí ñéæþí (free radicals) êáé Üëëùí äñáóôéêþíìïñöþí ïîõãüíïõ (reactive oxygen species, ROS), óôáïðïßá ðåñéëáìâÜíïíôáé ôá ðñùôïãåíÞ äñáóôéêÜ ðáñÜãùãáôïõ ïîõãüíïõ áëëÜ êáé üëá åêåßíá (ñßæåò Þ ìç), ôáïðïßá ðñïêýðôïõí äåõôåñïãåíþò êáôÜ ôéò äéÜöïñåò ÷çìéêÝòáëëçëåðéäñÜóåéò ìå ôá óôïé÷åßá ôïõ êõôôáñéêïý ðåñéâÜëëïíôïò(ð.÷. åëåýèåñåò õðåñïîõë-ñßæåò R-C-O-O . êáéáëêïîõë-ñßæåò R-C-O . , åíäéÜìåóá ðñïúüíôá ôçò õðåñïîåßäùóçòëéðéäßùí) 17 . Ïé ROS ó÷çìáôßæïíôáé áíáðüöåõêôáóôïí áåñüâéï ìåôáâïëéóìü êáé åßíáé ç êýñéá áéôßá åêäÞëùóçòôïõ öáéíïìÝíïõ ôïõ ïîåéäùôéêïý stress óôá êýôôáñá.Ìéá åëåýèåñç ñßæá ó÷çìáôßæåôáé áðü ìßá ìç-ñßæá ç ïðïßá(á) ÷Üíåé Ýíá çëåêôñüíéï, (â) äÝ÷åôáé Ýíá çëåêôñüíéï Þ(ã) õößóôáôáé ïìïëõôéêÞ äéÜóðáóç (homolytic fission)åíüò ïìïéïðïëéêïý äåóìïý:á) × → e- + X .â) Y + e- → Y . -ã) × : Y→ X . +Y .Áíôßóôñïöá áðü ôçí ïìïëõôéêÞ äéÜóðáóç, äýï åëåýèåñåòñßæåò ìðïñïýí íá áíôéäñÜóïõí ìåôáîý ôïõò êáé íáóõíäåèïýí ïìïéïðïëéêÜ, ïðüôå ðñïêýðôåé ìéá ìç-ñßæá(X . + Y . → Y−X), ãåãïíüò ðïõ åßíáé ðïëý óðÜíéï, áöïý çóõãêÝíôñùóç ôùí åëåõèÝñùí ñéæþí äéáôçñåßôáé óå ðïëý÷áìçëÜ åðßðåäá áêüìç êáé óå êáôáóôÜóåéò Ýíôïíïõ ïîåéäùôéêïýstress. Áíôßèåôá, ìéá åëåýèåñç ñßæá óõíÞèùòáíôéäñÜ ìå ìéá ìç-ñßæá (ôá ðåñéóóüôåñá âéïëïãéêÜ ìüñéáäåí åßíáé åëåýèåñåò ñßæåò) ìå ôïõò åîÞò ôñüðïõò:á) ðñïóèåôéêÜ, üôáí ç åëåýèåñç ñßæá óõíäÝåôáé ìå ôç ìçñßæá(ð.÷. ðñïóèÞêç ôïõ ÏÇ . óôçí ãïõáíßíç ôïõ DNA:× . + Õ → [×-Õ] . )â) áíáãùãéêÜ, üôáí ç åëåýèåñç ñßæá äñá ùò áíáãùãéêüòðáñÜãïíôáò, ðáñá÷ùñþíôáò ôï áóýæåõêôü ôçò çëåêôñüíéïóôç ìç-ñßæá: × . + Õ → × + + Õ . -ã) ïîåéäùôéêÜ, üôáí ç åëåýèåñç ñßæá äñá ùò ïîåéäùôéêüòðáñÜãïíôáò, äå÷üìåíç Ýíá çëåêôñüíéï áðü ôç ìç-ñßæá:X . + Y → X - + Y . +ä) áöáéñåôéêÜ, üôáí ç åëåýèåñç ñßæá áðïóðÜ Ýíá Üôïìïõäñïãüíïõ áðü ôïí áíèñáêéêü óêåëåôü ìéáò ïñãáíéêÞòÝíùóçò. ×áñáêôçñéóôéêü ðáñÜäåéãìá ôÝôïéáò áíôßäñáóçòåßíáé ç ðñïóâïëÞ ôùí ðëåõñéêþí áëõóßäùí ëéðáñþíïîÝùí áðü ôçí åëåýèåñç ñßæá õäñïîõëßïõ, ìå ôçí ïðïßááñ÷ßæïõí ïé áëõóùôÝò áíôéäñÜóåéò ôçò õðåñïîåßäùóçòôùí ëéðéäßùí:¸ôóé ó÷çìáôßæåôáé ìéá íÝá åëåýèåñç ñßæá, ç ïðïßááí åßíáé åðßóçò äñáóôéêÞ ìðïñåß íá áíôéäñÜóåé åê íÝïõìå Ýíá Üëëï ìüñéï ê.ï.ê. ÐáñÜäåéãìá ôÝôïéùí áëõóéäùôþíáíôéäñÜóåùí åëåõèÝñùí ñéæþí åßíáé ç õðåñïîåßäùóçôùí ëéðéäßùí ðïõ áðïôåëåß ôïí êýñéï ìç÷áíéóìü ðñüêëçóçòïîåéäùôéêÞò âëÜâçò óå âéïëïãéêÝò ìåìâñÜíåò.Åêôüò áðü ôéò ROS ðïëý óçìáíôéêÝò óôï ïîåéäùôéêü stressåßíáé êáé ïé äñáóôéêÝò ìïñöÝò (ñßæåò Þ ìç) Üëëùí ÷çìéêþíóôïé÷åßùí êáé ìïñßùí, ðïõ äéáêñßíïíôáé áíÜëïãá ìå ôçíðñïÝëåõóÞ ôïõò óå åêåßíåò ðïõ õðÜñ÷ïõí óôï ðåñéâÜëëïíôùí êõôôÜñùí êáé óå åêåßíåò ðïõ ó÷çìáôßæïíôáé áðü ôçäñÜóç ôùí ROS åðß ôùí äéáöüñùí êõôôáñéêþí óõóôáôéêþí.Óôçí ðñþôç êáôçãïñßá áíÞêïõí ôá éüíôá óéäÞñïõ,÷áëêïý êáé Üëëùí ìåôÜëëùí ìåôÜðôùóçò (ðïõ êáôáëýïõíáíôéäñÜóåéò ôïõ ïîåéäùôéêïý stress êáé ðñïÜãïõíïîåéäùôéêÝò âëÜâåò óôï êýôôáñï), ôá éüíôá ÷ëùñßïõ êáéôï ÍÏ . (ðïõ ðáñÜãåôáé áðü ôçí L-áñãéíßíç ìå ôç äñÜóçôïõ åíæýìïõ óõíèåôÜóç ôïõ ÍÏ (ÍÏS) êáé Ý÷åé ïîåéäùôéêÞêáé áíôéïîåéäùôéêÞ äñÜóç). Óôç äåýôåñç êáôçãïñßááíÞêïõí ïé åëåýèåñåò ñßæåò èåßïõ RS . (ðñïúüíôá ôçò ïîåéäùôéêÞòâëÜâçò Þ áíôéïîåéäùôéêÞò äñÜóçò äéáöüñùí èåéïëþí),åëåýèåñåò ñßæåò Üíèñáêá R-C . (åíäéÜìåóá ðñïúüíôáôçò õðåñïîåßäùóçò ëéðéäßùí), ôï õðåñïîõíéôñþäåòáíéüí ÏÍÏÏ- (ðñïúüí ôçò áíôßäñáóçò Ï 2 .- êáé ÍÏ . ), ôïõðï÷ëùñéþäåò ïîý HOCl (ðñïúüí ôçò áíôßäñáóçò Ç 2Ï 2êáé Cl-) ê.á.5. Äçìéïõñãßá äñáóôéêþí ìïñöþí ïîõãüíïõ (ROS)5.1 Ìéôï÷ïíäñéáêÞ ðáñáãùãÞ ROSÊáôÜ ôç äéÜñêåéá ôçò ìéôï÷ïíäñéáêÞò áíáðíïÞò (êýêëïòôïõ Krebs,áëõóßäá ìåôáöïñÜò çëåêôñïíßùí) ôïìïñéáêü ïîõãüíï åßíáé áðáñáßôçôï ãéá ôï ìåôáâïëéóìüôçò ãëõêüæçò êáé Üëëùí õðïóôñùìÜôùí. Óôïí êýêëï ôïõKrebs ç ÷çìéêÞ åíÝñãåéá áðü äéáöïñåôéêÜ õðïóôñþìáôá÷ñçóéìïðïéåßôáé ãéá ôç ìåôáôñïðÞ ôïõ ADP óå ATP (öùóöïñõëßùóçåðéðÝäïõ õðïóôñþìáôïò) (Ó÷Þìá 1) 18 .14

Ó÷Þìá 1: Öùóöïñõëßùóç åðéðÝäïõ õðïóôñþìáôïòÓôçí áëõóßäá ìåôáöïñÜò çëåêôñïíßùí, ç åíÝñãåéá ãéáôç öùóöïñõëßùóç ôïõ ADP ðñïÝñ÷åôáé áðü ìéá óåéñÜïîåéäïáíáãùãéêþí áíôéäñÜóåùí (ïîåéäùôéêÞ öùóöïñõëßùóç).Õðü öõóéïëïãéêÝò óõíèÞêåò, Ýíá ðïóïóôüìåôáîý 0,4 êáé 4% ôïõ êáôáíáëéóêüìåíïõ áðü ôçí ïîåéäùôéêÞöùóöïñõëßùóç ïîõãüíïõ ìåôáôñÝðåôáé óå ñßæåòõðåñïîåéäéêïý áíéüíôïò (O .- 2) 19,20,21,22,23,24 . Óôç óõíÝ÷åéá,.-ôï O 2ìðïñåß íá ìåôáôñáðåß óå Üëëåò äñáóôéêÝò ìïñöÝòïîõãüíïõ (ROS) êáé áæþôïõ (RÍS). Ïé åëåýèåñåòñßæåò óõíÞèùò åîïõäåôåñþíïíôáé áðü ôïõò åíäïãåíåßòáíôéïîåéäùôéêïýò ìç÷áíéóìïýò ðïõ èá áíáöåñèïýí óôçóõíÝ÷åéá. ×áñáêôçñéóôéêÜ ôï O .- 2åîïõäåôåñþíåôáé ðñïòÇ 2Ï 2áðü ôçí õðåñïîåéäéêÞ äéóìïõôÜóç 2 (SOD2) 19,20(Ó÷Þìá 2) 18 . Ôï Ç 2Ï 2áíÜãåôáé áðü ôçí õðåñïîåéäÜóç ôçòãëïõôáèåéüíçò ðñïò Ï 2êáé Ç 2Ï óôá ìéôï÷üíäñéá Þ äéá-÷Ýåôáé óôï êõôôáñüðëáóìá êáé áíÜãåôáé áðü ôï ÝíæõìïêáôáëÜóç óôá õðåñïîõóþìáôá. Ðáñïõóßá ìåôÜëëùí ìåôÜðôùóçòüðùò ï Fe êáé ï Cu ôï Ç 2Ï 2ìåôáôñÝðåôáé óôçíéó÷õñÜ äñáóôéêÞ õäñïîõëéêÞ ñßæá ÏÇ . .ôÜñùí áõôþí ðñïêáëåß ìåôáêßíçóç ôùí êõôôáñïðëáóìáôéêþíõðïìïíÜäùí óôçí êõôôáñéêÞ ìåìâñÜíç ìå áðïôÝëåóìáôï ó÷çìáôéóìïý ðïëõìåñéêþí óõìðëüêùí ìå äñÜóçïîåéäÜóçò. Ïé NAD(P)H ïîåéäÜóåò êáôáëýïõí ôçí áíáãùãÞôïõ Ï 2÷ñçóéìïðïéþíôáò ôï NADH (íéêïôéíáìéäïáäåíéíïíïõêëåïôßäéï)Þ ôï NADPH (öùóöïñéêü íéêïôéíáìéäï-áäåíéíïíïõêëåïôßäéï)óáí äüôç çëåêôñïíßùí.NAD(P)H +2O 2→ NAD(P) + + H + .-+ Ï 2H NAD(P)H ïîåéäÜóç åßíáé ç êýñéá ðçãÞ õðåñïîåéäéêïýáíéüíôïò (Ï .- 2) óôïí áããåéáêü éóôü êáé ôá êýôôáñáôïõ ìõïêáñäßïõ (Ó÷Þìá 3) 25 . Ïé ðåñéóóüôåñåò êëéíéêÝòìåëÝôåò õðïäåéêíýïõí üôé ôï NADH åßíáé êáôáëëçëüôåñïõðüóôñùìá 26,27,28,29,30 ùóôüóï õðÜñ÷ïõí ðåñéðôþóåéòüðïõ ôï NADPH õðåñéó÷ýåé 31,32 . Ç NAD(P)H ïîåéäÜóçåðÜãåôáé áðü ïñìüíåò, ìåôáâïëÝò ôùí áéìïäõíáìéêþíóõíèçêþí êáé ìåôáâïëéêÝò áëëáãÝò. Ç áããåéïôåíóßíçÉÉ 25 , ç èñïìâßíç 33 , ï áõîçôéêüò ðáñÜãïíôáò ôùíáéìïðåôáëßùí 34 (PDGF: platelet-derived growth factor),ïðáñÜãïíôáò íÝêñùóçò üãêïõ-á 35 (TNF-a: tumor necrosisfactor-a), ôï LacCer (â-D-galactosyl-(1-4)-â-D-glucosyl-(1-1’)-ceramide), ç éíôåñëåõêßíç-1 (IL-1) êáé ï åíåñãïðïéçôéêüòðáñÜãïíôáò ôùí áéìïðåôáëßùí (PAF: plateletactivatingfactor) äéåãåßñïõí ôçí êáôáëõüìåíç áðü ôïNADH Þ/êáé ôï NADPH ðáñáãùãÞ Ï .- 2. Óôá ïõäåôåñüöéëáç äñÜóç ôçò ïîåéäÜóçò ñõèìßæåôáé êáé áðü ôçí ðñùôåúíéêÞêéíÜóç C 36 (PKC) êáé óôá ßäéá êýôôáñá, ç õðåñãëõêáéìßá,ìÝóù ôçò åíåñãïðïßçóçò ôïõ ìåôáãñáöéêïýðõñçíéêïý ðáñÜãïíôá NF-êB, áõîÜíåé ôçí Ýêöñáóç ôçòõðïìïíÜäáò gp91 phox ôçò NADPH ïîåéäÜóçò.Ó÷Þìá 3: ÄïìÞ êáé äñÜóç ÍÁD(P)H ïîåéäÜóçò ôùí ïõäåôåñüöéëùí(áñéóôåñÜ) êáé ôùí ëåßùí ìõúêþí éíþí (äåîéÜ)Ó÷Þìá 2: ÏîåéäùôéêÞ öùóöïñõëßùóç5.2 Íéêïôéíáìéäï-áäåíéíïíïõêëåïôéäéêÝò(öùóöïñéêÝò) ïîåéäÜóåò (NAD(P)H ïîåéäÜóç)Ôá Ýíæõìá NAD(P)H ïîåéäÜóåò áðïôåëïýíôáé áðüõðïìïíÜäåò ðïõ åíôïðßæïíôáé ôüóï óôçí êõôôáñéêÞ ìåìâñÜíç,üóï êáé óôï êõôôáñüðëáóìá áããåéáêþí ëåéïìõïêõôôÜñùí,ïõäåôåñüöéëùí, éíïâëáóôþí, åíäïèçëéáêþíêáé ìåóáããåéáêþí êõôôÜñùí. Ç åíåñãïðïßçóç ôùí êõô-5.3 ÁöõäñïãïíÜóç ôçò îáíèßíçò (XDH)êáé ÏîåéäÜóç ôçò îáíèßíçò (XOD)Ç áöõäñïãïíÜóç ôçò îáíèßíçò (XDH) ÷ñçóéìïðïéåßôçí õðïîáíèßíç Þ ôçí îáíèßíç ùò õðüóôñùìá êáé ôï NADùò óõìðáñÜãïíôá-äÝêôç çëåêôñïíßùí ðñïò ó÷çìáôéóìüNADH êáé ïõñéêïý ïîÝïò. Óå ðáèïëïãéêÝò êáôáóôÜóåéò,üðùò óå ôåëéêÜ óôÜäéá êáñäéáêÞò áíåðÜñêåéáò 37,38 çáöõäñïãïíÜóç ôçò îáíèßíçò ìåôáôñÝðåôáé óôçí ïîåéäùìÝíçôçò ìïñöÞ (ïîåéäÜóç ôçò îáíèßíçò, XOD) ç ïðïßáäñá óôá ßäéá áêñéâþò õðïóôñþìáôá (îáíèßíç, õðïîáíèßíç)áëëÜ ÷ñçóéìïðïéåß ôï Ï 2ùò óõìðáñÜãïíôá-äåêôççëåêôñïíßùí ðñïò ó÷çìáôéóìü ïõñéêïý ïîÝïò êáé õðåñïîåéäéêïýáíéüíôïò (Ï .- 2).15

Ó÷Þìá 4. Ç ìåôáôñïðÞ ôçò áöõûäñïãïíÜóçò ôçò îáíèßíçòðñïò ïîåéäÜóç ôçò îáíèßíçò ðéèáíþò ðñáãìáôïðïéåßôáé óåóõíèÞêåò stress, äéáôáñá÷þí ôïõ åíäïêõôôáñéêïý áóâåóôßïõêáé ïîåßäùóçò èåéïëéêþí ïìÜäùí 39 . Ç ïîåéäÜóç ôçò îáíèßíçò(XOD) åßíáé ìßá óçìáíôéêÞ ðçãÞ åíåñãþí ìïñöþí ïîõãüíïõóôá ðïëõìïñöïðÞñçíá, åíäïèçëéáêÜ êáé åðéèçëéáêÜêýôôáñá êáèþò êáé óôá êýôôáñá ôïõ óõíäåôéêïý éóôïý.5.4. ÐáñáãùãÞ åëåýèåñùí ñéæþí óôçí êõôôáñéêÞìåìâñÜíç ìÝóù ôùí åíæõìáôéêþí ïäþíôïõ áñá÷éäïíéêïý ïîÝïòÇ ðáñáãùãÞ ôùí åëåõèÝñùí ñéæþí ïîõãüíïõ óôçíêõôôáñïðëáóìáôéêÞ ìåìâñÜíç åßíáé áðïôÝëåóìá ôïõ ìåôáâïëéóìïýôïõ áñá÷éäïíéêïý ïîÝïò (ÁÁ: ÁrachidonicAcid) ôçò ïîåßäùóçò ôùí ìåìâñáíéêþí ðñùôåúíþí êáé ôçòáõôïïîåßäùóçò ôùí óõíäåäåìÝíùí ìå ôç ìåìâñÜíç êõôï-÷ñùìÜôùí.Ç õðåñïîåßäùóç ôùí ìåìâñáíéêþí ëéðéäßùí -áðïôÝëåóìáôçò ïðïßáò áðïôåëåß êáé ôï áñá÷éäïíéêü ïîý - óõíôåëåßôáéåíæõìáôéêÜ áðü Ýíæõìá üðùò ïé öùóöïëéðÜóåòÁ2 (PLA2) êáé ìç åíæõìáôéêÜ áðü åíåñãÝò ìïñöÝò ïîõãüíïõ( ÏÇ . , Ï .- 2) êáé áæþôïõ (ÍÏ . ). Ç öùóöïëéðÜóç Á2åßíáé ôï êýñéï åíæõìï ãéá ôçí áðåëåõèÝñùóç áñá÷éäïíéêïýïîÝïò.Ç äñáóôéêÞ õäñïîõëéêÞ ñßæá ÏÇ . äåí áðïôåëåß ðñïúüíåíæõìáôéêÞò äñÜóçò áëëÜ ðñïêýðôåé áðü Ç 2Ï 2ðáñïõóßáìåôáëëéêþí éüíôùí êáé êõñßùò Fe 2+ êáé Cu 2+ , ìå ôçí áíôßäñáóçFenton. ÌåôÜ ôï ó÷çìáôéóìü ôçò, ç ñßæá ÏÇ . åðéäñÜóå êõôôáñéêÜ óôïé÷åßá üðùò ðïëõáêüñåóôá ëéðáñÜ ïîÝáêáé ìåìâñáíéêÜ ëéðßäéá. ÊáôÜ ôçí áíôßäñáóç ôçò ÏÇ . ìåðïëõáêüñåóôá ëéðáñÜ ïîÝá ðñïêýðôïõí áëêõëï-ñßæåò ðïõáëëçëåðéäñþíôáò ìå ìïñéáêü ïîõãüíï äßíïõí ñßæåò ROO . .Ïé ñßæåò ROO . áðïóðïýí õäñïãüíá áðü ôá ðáñáêÝéìåíáëéðáñÜ ïîÝá ðñïò ó÷çìáôéóìü ëéðéäéêþí õðåñïîåéäßùí(ROOH) íÝùí áëêõëï-ñéæþí îåêéíþíôáò Ýôóé ìéá áëõóéäùôÞáíôßäñáóç ïîåßäùóçò ôùí ëéðéäßùí.Ôï ÍÏ . ðñïêýðôåé êáôÜ ôçí åíæõìáôéêÞ ïîåßäùóç ôçòL-áñãéíßíçò ðñïò êéôñïõëßíç áðü ôéò ÍÏ óõíèåôÜóåò êáéáðïôåëåß Ýíá âáóéêü ñõèìéóôÞ áããåéáêÞò áðüêñéóçò êáéíåõñïíéêÞò äéáâßâáóçò..-Ôï õðåñïîåéäéêü áíéüí Ï 2äåí ðñïêáëåß Üìåóá ëéðéäéêÞõðåñïîåßäùóç áëëÜ áëëçëåðéäñþíôáò ìå ôï ÍÏó÷çìáôßæåé õðåñïîõíéôñþäåò áíéüí (ÏÍÏÏ - ) Ýíá éó÷õñüïîåéäùôéêü ðïõ åðÜãåé ôçí õðåñïîåßäùóç ôùí ëéðéäßùí.Ïé öùóöïëéðÜóåò Á2 (PLA2) áðïôåëïýí ìéá ìåãÜëçïéêïãÝíåéá åíæýìùí, ôá ïðïßá õäñïëýïõí ôïí åóôåñéêüäåóìü óôçí sn-2 èÝóç ôùí ãëõêåñïöùóöï-ëéðéäßùí êáéðáñÜãïõí 2-ëõóïöùóöïëéðßäéá êáé åëåýèåñá ëéðáñÜïîÝá 40 . Ç áíôßäñáóç áõôÞ ðáñïõóéÜæåé éäéáßôåñï åíäéáöÝñïíüôáí ôï åëåýèåñï ëéðáñü ïîý ðïõ áðïìáêñýíåôáéáðü ôçí sn-2 èÝóç åßíáé ôï áñá÷éäïíéêü ïîý. Ôï ðáñáãüìåíïáñá÷éäïíéêü ïîý åðáíåíóùìáôþíåôáé óôá ìåìâñáíéêÜöùóöïëéðßäéá Þ ìåôáâïëßæåôáé áðü ìßá óåéñÜ åíæýìùíðñïò ó÷çìáôéóìü ìéáò ïéêïãÝíåéáò âéïëïãéêþò åíåñãþíìåôáâïëéôþí, ôùí åéêïóáíïåéäþí. Ôñåéò óçìáíôéêÝò ïäïßìðïñïýí íá ìåôáôñÝøïõí ôï ÁÁ óå åéêïóáíïåéäÞ 41 . Óôçíðñþôç ìåôáâïëéêÞ ïäü ôï Ýíæõìï êõêëïîõãïíÜóç (COX)ðáñÜãåé èñïìâïîÜíåò, ðñïóôáãëáíäßíåò êáé ðñïóôáêõêëßíåò.Óôç äåýôåñç ïäü, ôï Ýíæõìï 5-ëéðïîõãïíÜóçðáñÜãåé ëåõêïôñéÝíéá êáé åíþóåéò õäñïîõ-åéêïóéôåôñáíïúêïýïîÝïò (ÇÅÔÅ) . Óôçí ôñßôç ïäü, ôï Ýíæõìï åðïîõãïíÜóç,ðïõ åßíáé ìÝëïò ôïõ êõôï÷ñþìáôïò P450 ðáñÜãåéåíþóåéò cis-åðüîõ-åéêïóéôåôñáíïúêïý ïîÝïò (ÅÅÔ)êáé Üëëåò åíþóåéò ÇÅÔÅ. Ïé COXs, ëéðïîõãïíÜóåò êáéåðïîõãïíÜóåò êáôáëýïõí ôçí óôåñïåéäéêÞ åéóáãùãÞ ôïõïîõãüíïõ óå äéÜöïñåò èÝóåéò óôï ÁÁ êáé êáôáíÝìïíôáéåêëåêôéêÜ óôïõò äéÜöïñïõò êõôôáñéêïýò ôýðïõò, áõîÜíïíôáòðåñáéôÝñù ôçí ðïëõðëïêüôçôá ôçò âéïëïãßáò ôùíåéêïóáíïåéäþí. Åêôüò áðü ôï áñá÷éäïíéêü ïîý âéïëïãéêþòäñáóôéêÜ ìüñéá åßíáé êáé ôá ëõóïöùóöïëéðßäéá ðïõðñïêýðôïõí áðü ôç äñÜóç ôçò PLA2 42 . ¼ôáí äå ôï ëõóïöùóöïëéðéäéêüðñïúüí ðåñéÝ÷åé ìßá êåöáëÞ ÷ïëßíçò êáéÝíáí áëêõëéêü äåóìü óôç èÝóç sn-1 áðïôåëåß ðñüäñïìïìüñéï ãéá ôïí ðáñÜãïíôá åíåñãïðïßçóçò ôùí áéìïðåôáëßùí(PAF: Platelet Activating Factor) 43 .ÊáôÜ ôï ìåôáâïëéóìü ôïõ áñá÷éäïíéêïý ïîÝïò ìÝóùôçò ïäïý ôçò êõêëïîõãïíÜóçò ðáñÜãåôáé õðåñïîåéäéêüáíéüí óôï óôÜäéï ôçò ìåôáôñïðÞò ôçò ðñïóôáãëáíäßíçòG2 óôçí ðñïóôáãëáíäßíç Ç2. Ôï áíéüí ôïõ õðåñïîåéäßïõðáñÜãåôáé åðßóçò êáé êáôÜ ôï ìåôáâïëéóìü ôïõ áñá-÷éäïíéêïý ïîÝïò óôçí ïäü ëéðïîõãïíÜóçò. Êáé óôéò äýïðåñéðôþóåéò áðáéôåßôáé ç ðáñïõóßá ôçò NADH Þ êáé ôçòNADPH ïîåéäÜ óçò .5.4.1. Ç ìåôáâïëéêÞ ïäüò ôçò êõêëïïîõãïíÜóçò (COX)Óôçí ðñþôç ïäü ìåôáâïëéóìïý ôïõ áñá÷éäïíéêïý ïîÝïò,ç êõêëïïîõãïíÜóç êáôáëýåé ôç óôáäéáêÞ ìåôáôñïðÞôïõ ÁÁ óå åíäéÜìåóç ðñïóôáãëáíäßíç G2 (PGG2) êáéH2 (PGH2) (Ó÷Þìá 5) 44 .Ó÷Þìá 5: Äéáäï÷éêÜ óôÜäéá ó÷çìáôéóìïý PGH2 áðü áñá-÷éäïíéêü ïîý16

Óôï óôÜäéï ôçò ìåôáôñïðÞò ôçò ðñïóôáãëáíäßíçò G2óôçí ðñïóôáãëáíäßíç Ç2, ðáñÜãåôáé õðåñïîåéäéêü áíéüí(Ï 2.-). Óôç óõíÝ÷åéá ç ðñïóôáãëáíäßíç Ç2 (PGH2)ìåôáâïëßæåôáé ðñïò èñïìâïîÜíç Á2(Ô×Á2), ðñïóôáêõêëßíç(PGI2) êáé Üëëåò ðñïóôáãëáíäßíåò (PGD2, PGE2,PGF2a) áðü ôá Ýíæõìá óõíèåôÜóç èñïìâïîÜíçò, óõíèåôÜóçðñïóôáêõêëßíçò êáé éóïìåñÜóç ðñïóôáãëáíäßíçòáíôßóôïé÷á 39 .-. Ïé äñáóôéêÝò ñßæåò Ï 2ðïõ ðñïêýðôïõí êáôÜôç ìåôáôñïðÞ ôçò PGG2 óå PGH2 áäñáíïðïéïýí ôá ìåôÝ-÷ïíôá óôç ìåôáâïëéêÞ ïäü ôçò êõêëïîõãïíÜóçò Ýíæõìá êáéðñïêáëïýí âëÜâåò óôá êýôôáñá (ëüãù ïîåßäùóçò ëéðéäßùíôùí êõôôáñïðëáóìáôéêþí ìåìâñáíþí). Ìå ôïí ôñüðï áõôüç ìåôáâïëéêÞ ïäüò ôçò êõêëïîõãïíÜóçò áõôïáíáóôÝëëåôáéìå óýã÷ñïíç ðáñáãùãÞ åëåõèÝñùí ñéæþí ïîõãüíïõ 45 . ÐáñÜëëçëááíáóôÝëëåôáé êáé ç ðáñáãùãÞ ôùí ðñïóôáôåõôéêþíPGE2 êáé PGI áëëÜ êáé ôçò Ô×Á2 ðïõ ðñïêáëåß áããåéïóýóðáóçêáé óõãêüëëçóç ôùí áéìïðåôáëßùí 46 .5.4.2. Ç ìåôáâïëéêÞ ïäüò ôçò ëéðïîõãïíÜóçòÇ ìåôáâïëéêÞ ïäüò ôçò 5-ëéðïîõãïíÜóçò åíåñãïðïéåßôáéóôá ëåõêïêýôôáñá óõìðåñéëáìâÜíïìÝíùí ôùí ìáóôïêõôôÜñùí,ôùí çùóéíüöéëùí, ôùí ïõäåôåñüöéëùí, ôùíâáóåüöéëùí êáé ôùí ìïíïêõôôÜñùí. Óôá êýôôáñá áõôÜ,ç 5-ëéðïîõãïíÜóç ìåôáôñÝðåé ôï áñá÷éäïíéêü ïîý óå5-õäñïûðåñïîõ-åéêïóáôåôñá-åíïéêü ïîý (5-ÇÑÅÔÅ) ôïïðïßï Ý÷åé âñá÷åßá æùÞ êáé áðïäïìåßôáé ôá÷Ýùò áðü ìéáõðåñïîåéäÜóç ðñïò 5-õäñïîõ-åéêïóáôåôñá-åíïúêï ïîý(5-ÇÅÔÅ). ÅíáëëáêôéêÜ, ìéá áöõäñïãïíÜóç ìðïñåß íáìåôáôñÝøåé ôï 5-ÇÅÔÅ óå Ýíá áóôáèÝò åðïîåßäéï, ôçíëåõêïôñéÝíç Á4 (LTA4). Áõôüò ï ìåôáâïëßôçò ìðïñåßíá õäñïëõèåß óå 5,12-äéõäñïîõ-åéêïóáôåôñåíïúêÜ ïîÝá(5,12-DiHETE) Ýíá áðü ôá ïðïßá åßíáé êáé ôï ëåõêïôñéÝíéïLTB4 Þ íá óõæåõ÷èåß åíæõìáôéêÜ ìå ôï ôñéðåðôßäéï ôçòãëïõôáèåéüíçò. ÁõôÞ ç óýæåõîç -ìÝóù ôïõ ìïñßïõ ôçò êõóôåúíçòôçò ãëïõôáèåéüíçò- ðáñÜãåé LTC4. (Ó÷Þìá 6) 47 .Ó÷Þìá 6: Ïäïß ôùí 5-,12-,15-ëéðïîõãïíáóþíÔï ëåõêïôñéÝíéï LTB4 ðïõ óõíôßèåôáé áðü êýôôáñáðïõ äéáèÝôïõí LTA4 õäñïëÜóç (ïõäåôåñüöéëá, ìïíïêýôôáñá),åßíáé éó÷õñüò ÷çìåéïôáêôéêüò ðáñÜãùí äñþíôáòóôïõò BLT1 êáé BLT2 õðïäï÷åßò ôçò êõôôáñïðëáóìáôéêÞòìåìâñÜíçò ôùí ïõäåôåñüöéëùí. Áîßæåé íá áíáöåñèåßüôé åêôüò áðü ôï ÷çìåéïôáêôéêü ôïõ ñüëï ôï ëåõêïôñéÝíéïLTB4 äéåãåßñåé ôçí åßóïäï éüíôùí Ca 2+, ôçí êéíçôïðïßçóçôïõ åíäïêõôôÜñéïõ Ca 2+ 48,49 êáé ôçí ðñüóëçøç åîïæþí (ð÷.D-ãëõêüæçò) áðü ôá ðïëõìïñöïðýñçíá. ¸ôóé ôá åíåñãïðïéçìÝíáïõäåôåñüöéëá ìåôáöÝñïõí óôïõò éóôïýò óôü÷ïõòáõîçìÝíåò ðïóüôçôåò éüíôùí Ca 2+ êáé D-ãëõêüæçò.Ôï ëåõêïôñéÝíéï LTC4 ðáñÜãåôáé óå êýôôáñá ðïõ åêöñÜæïõíôçí LTC4 óõíèåôÜóç üðùò åßíáé ôá ìáóôïêýôôáñáêáé ôá çùóéíüöéëá. Ôï LTC4 áðïôåëåß õðüóôñùìáäéáöïñåôéêþí ðñùôåáóþí, ïé ïðïßåò ðáñÜãïõí ôá âéïëïãéêÜåíåñãÜ ëåõêïôñéÝíéá LTD4 êáé LTE4. Ôá êõóôåúíéêÜëåõêïôñéÝíéá (LTC4, LTD4, LTE4) äñïõí óôïõò ìåìâñáíéêïýòõðïäï÷åßò CysLT1 êáé CysLT2 ôùí êõôôÜñùíóôü÷ùí ðñïêáëþíôáò óýóðáóç ôùí âñïã÷ïëßùí êáé ôùíáããåéáêþí ëåßùí ìõúêþí éíþí, áýîçóç ôçò ôñé÷ïåéäéêÞòäéáðåñáôüôçôáò, Ýêêñéóç âëÝííçò óôéò áåñáãùãÝò ïäïýòêáé ôï Ýíôåñï êáé ÷çìåéïôáîßá ëåõêïêõôôÜñùí.Ôá ëåõêïêýôôáñá êáé êõñßùò ôá áéìïðåôÜëéá äéáèÝôïõíåðßóçò ìéá 12-ëéðïîõãïíÜóç ç ïðïßá åíåñãïðïéåßôáéáðü áõîçôéêïýò ðáñÜãïíôåò, öëåãìïíþäåéò êõôïêßíåòêáé õðåñãëõêáéìßá 50 , êáé ìåôáôñÝðåé ôï áñá÷éäïíéêü ïîýóå 12-õäñïûðåñïîõ-åéêïóáôåôñá-åíïúêü ïîý (12-ÇPÅ-ÔÅ). ÁñêåôÜ ïîõãïíùìÝíá ðñïúüíôá áõôïý ôïõ åíæýìïõåßíáé éêáíÜ íá åíåñãïðïéÞóïõí êéíÜóåò åõáßóèçôåò óôïstress êáé ïäïýò ðïõ åíÝ÷ïíôáé ãéá ôçí áããåéáêÞ êáé íåöñéêÞíüóï, ðåñéëáìâÜíïíôáò êáé ôçí ïäü ôçò PKC, ìåáðïôÝëåóìá ôçí õðåñôñïößá ôùí ëåßùí ìõúêþí êõôôÜñùíôùí áããåßùí. Ôï 12-õäñïîõ-åéêïóáôåôñáíïúêü ïîý, (12-ÇÅÔÅ) åßíáé Ýíáò éó÷õñüò áããåéïãåíåôéêüò ðáñÜãïíôáòéêáíüò íá åíåñãïðïéåß ôïí ðõñçíéêü ðáñÜãïíôá ÍF-êÂêáé íá áõîÜíåé ôçí Ýêöñáóç ôïõ áããåéáêïý åíäïèçëéáêïýáõîçôéêïý ðáñÜãïíôá (VEGF).Ôá åíäïèçëéáêÜ êýôôáñá åêöñÜæïõí ìéá 15-ëéðïîõãïíÜóçç ïðïßá ìåôáôñÝðåé óôáäéáêÜ ôï áñá÷éäïíéêüïîý óå 15-õäñïîõåéêïóáôåôñáåíïúêï ïîý (15-ÇÅÔÅ).Óôá áèçñùìáôéêÜ áããåßá öáßíåôáé íá õðÜñ÷åé áõîçìÝíçóýíèåóç 15-ÇÅÔÅ ôï ïðïßï ìåôáôñÝðåôáé áðü åíåñãïðïéçìÝíáëåõêïêýôôáñá óå ëéðïîßíåò. Ïé êõñéüôåñåòëéðïîßíåò åßíáé ç ëéðïîßíç Á êáé ç ëéðïîßíç Â. Ç ëéðïîßíçÁ4 (LXA4), äéåãåßñåé ôçí ðáñáãùãÞ áíéüíôïò ôïõ õðåñïîåéäßïõ(O 2 .- ) áðü ôá ïõäåôåñüöéëá.5.5. Ìïíïîåßäéï ôïõ áæþôïõÇ áýîçóç ôùí åðéðÝäùí õðåñïîåéäéêïý áíéüíôïò(Ï .- 2) áðü ôçí õðåñãëõêáéìßá óçìáôïäïôåß ôçí åíåñãïðïßçóçïäþí åìðëåêüìåíùí óôçí ðáèïãÝíåóç äéáâçôéêþíåðéðëïêþí üðùò åßíáé ç åíäïèçëéáêÞ äõóëåéôïõñãßá 51,52 .Ç ðáñáãùãÞ ôïõ ìïíïîåéäßïõ ôïõ áæþôïõ (ÍÏ . ) äéáäñáìáôßæåéóçìáíôéêü ñüëï óôç ñýèìéóç ôçò åíäïèçëéáêÞòëåéôïõñãßáò, ðñïêáëþíôáò áããåéïäéáóôïëÞ, áíáóôÝëëïíôáòôçí ðñïóêüëëçóç ëåõêïêõôôÜñùí óôï åíäïèÞëéï êáéðéèáíþò åîïõäåôåñþíïíôáò ôï õðåñïîåéäéêü áíéüí 48 .Ôï ÍÏ åßíáé ðñïúüí ïîåßäùóçò ôçò L-áñãéíßíçò ðñïòL-êéôñïõëßíç. Ç áíôßäñáóç áõôÞ êáôáëýåôáé áðü ôï ÝíæõìïóõíèåôÜóç ôïõ ÍÏ . (ÍÏS) êáé áðáéôåß ôçí ðáñïõóßáNAPDH, ìïñéáêïý ïîõãüíïõ, êáëìïäïõëßíçò êáé Üëëùíóõìðáñáãüíôùí/ óõíåíæýìùí üðùò ç ôåôñáûäñïâéïðôåñßíç(BH4), ç ðñùôïðïñöõñßíç É×, ôï öëáâéíï-áäåíéíïäéíïõêëåïôßäéï(FAD) êáé ôï öëáâéíï-ìïíïíïõêëåïôßäéï(FMN). Ç óýíèåóç ÍÏ áðü L-áñãéíßíç ãßíåôáé óå äõïóôÜäéá ïîåßäùóçò. Áñ÷éêÜ ç L-áñãéíßíç ïîåéäþíåôáéðñïò Í ù -õäñïîõáñãéíßíç ðáñïõóßá ÍÁDPH êáé ôåôñáûäñïâéïðôåñßíçò(BH4). Óôç óõíÝ÷åéá ç Í ù -õäñïîõáñãé-17

íßíç ïîåéäþíåôáé ðñïò ó÷çìáôéóìü êéôñïõëßíçò êáé ÍÏ(Ó÷Þìá 7) 53 Óå áõôü ôï óçìåßï áîßæåé íá óçìåéùèåß üôéç nNOS, áðïõóßá L-áñãéíßíçò, ìðïñåß íá óõíèÝóåé õðåñïîåéäéêüáíéüí (O 2 . ) êáé õðåñïîåßäéï ôïõ õäñïãüíïõ(Ç 2Ï 2) ìå êáôáíÜëùóç ÍÁDPH ãåãïíüò ðïõ õðïäåéêíýåéôï ñüëï ôùí öëáâéíï-óõíåíæýìùí óôç ìåôáöïñÜ çëåêôñïíßùí.Ó÷Þìá 7: ÓôÜäéá ó÷çìáôéóìïý ÍÏÕðÜñ÷ïõí 3 äéáöïñåôéêÝò éóïìïñöÝò ôçò NOS: ç åíäïèçëéáêÞóõíèåôÜóç (endothelial-eNOS), ç íåõñùíéêÞóõíèåôÜóç (neuronal-nNOS) êáé ç åðáãþãéìç óõíèåôÜóç(inducible -iNOS). Ïé eNOS êáé nNOS, âñßóêïíôáéóå ÷áìçëÜ åðßðåäá óôï êõôôáñüðëáóìá êáé åíåñãïðïéïýíôáéáðü ôï êõôôáñïðëáóìáôéêü Ca 2+ ðáñïõóßá êáëìïäïõëßíçò.Ç åßóïäïò Ca 2+ ìÝóá óå áõôÜ ôá êýôôáñá,ïäçãïýí óå Üìåóç ðáñáãùãÞ ÍO. Ç õðåñðáñáãùãÞ ôïõáíéüíôïò ôïõ õðåñïîåéäßïõ, ìåéþíåé ôçí äñáóôçñéüôçôáôçò åíäïèçëéáêÞò óõíèåôÜóçò (eNOS), áëëÜ äéá ìÝóïõôçò ðñùôåúíéêÞò êéíÜóçò C (PKC) êáé ôïõ ìåôáãñáöéêïýðõñçíéêïý ðáñÜãïíôá ÍF-êÂ, äñáóôçñéïðïéåß ôçíNAD(P)H áõîÜíïíôáò ôçí Ýêöñáóç ôïõ iNOS, ìå ôåëéêüáðïôÝëåóìá ôçí áõîçìÝíç ðáñáãùãÞ ôïõ ÍO . .ÕøçëÜ åðßðåäá ÍÏ . åõíïïýí ôï ó÷çìáôéóìü ôïõ éó÷õñïýïîåéäùôéêïý õðåñüîõíéôñþäïõò áíéüíôïò 48 (ÏÍÏÏ - ).Ôï êõôôáñïôïîéêü õðåñïîõíéôñþäåò áíéüí, ïîåéäþíåé ôéòóïõëöõäñéëéêÝò ïìÜäåò ôùí ðñùôåúíþí, óõìâÜëëïíôáòÝôóé óôçí õðåñïîåßäùóç ëéðéäßùí êáé áæùôïý÷ùí áìéíïîÝùí.Ç åðßäñáóç ôïõ õðåñïîõíéôñþäïõò áíéüíôïò óôçíôõñïóßíç åõíïåß ôçí ðáñáãùãÞ ìéáò éó÷õñüôáôçò ïîåéäùôéêÞòïõóßáò, ôçò íéôñïôõñïóßíçò ðïõ åìöáíßæåé ÜìåóáôïîéêÞ äñÜóç óôï åíäïèÞëéï ôùí áããåßùí 54 (åíäïèçëéáêÞäõóëåéôïõñãßá). ÁõîçìÝíá åðßðåäÜ íéôñïôõñïóßíçò óôïðëÜóìá äéáâçôéêþí áóèåíþí õðïäåéêíýïõí ôç óõó÷Ýôéóçôçò ïîåéäùôéêÞò áõôÞò ïõóßáò ìå ôçí ðáèïöõóéïëïãßá ôïõäéáâÞôç 55 .Ôï õðåñïîõíéôñþäåò áíéüí, åßíáé Ýíáò éó÷õñüò ðáñÜãïíôáòêáôáóôñïöÞò ôïõ DNA. Ç êáôáóôñïöÞ ôïõ DNAäéáöáßíåôáé áðü ôçí áõîçìÝíç ðáñáãùãÞ 8-õäñïîõãïõáíßíçòêáé 8-õäñïîõäåïîõãïõáíïóßíçò (äåßêôåò êáôáóôñïöÞòôïõ DNA) 56 êáé åðÜãåé ôçí åíåñãïðïßçóç ôïõ ðõñçíéêïýåíæýìïõ ðïëõ-(ADP-ñéâüæç) ðïëõìåñÜóç (PARP).Ç åíåñãïðïßçóç ôïõ ÑARP ïäçãåß óå ìåßùóç ôïõ åíäïêõôôÜñéïõNAD+ êáé ðñïÜãåé ôçí ADÑ-ñéâïæõëßùóçôïõ åíæýìïõ áöõäñïãïíÜóç ôçò 3-öùóöïñéêÞò ãëõêåñéíáëäåûäçò(GAPDH) 57 . Ç åëÜôôùóç ôïõ ÍAD+ inter Ý÷åéùò áðïôÝëåóìá ôç ìåßùóç ôïõ ñõèìïý ãëõêüëõóçò, ôçòìåôáöïñÜò çëåêôñïíßùí êáé ôïõ ó÷çìáôéóìïý ôïõ ÁÔÑ.Çãëõêåñéíáëäåûäç åßíáé áðü ôá âáóéêÜ ìåôáâïëéêÜ ðñïúüíôáôïõ êáôáññÜêôç ôçò ãëõêüëõóçò. Ç ñéâïæõëßùóç ôïõåíæýìïõ áõôïý, êáé óõíåðþò ç áíáóôïëÞ ôïõ ìåôáâïëéóìïýôïõ, Ý÷åé óáí áðïôÝëåóìá ôç óõóóþñåõóç ôùí ðñïçãïýìåíùíáðü ôç GAPDH ìåôáâïëéêþí ðñïúüíôùí ôçòãëõêüëõóçò êáé åêôñïðÞ ôïõ ìåôáâïëéóìïý áðü ôç óåéñÜôçò ãëõêüëõóçò óå Üëëåò ðáèïöõóéïëïãéêÝò ïäïýò (åîïæáìßíçò,PKC, ðïëõïëþí ).6. Åíäïãåíåßò áíôéïîåéäùôéêïß ìç÷áíéóìïßÓôï óáê÷áñþäç äéáâÞôç ôýðïõ ÉÉ åêôüò åðáãùãÞ ôïõïîåéäùôéêïý stress ðáñáôçñåßôáé óýã÷ñïíç áíåðÜñêåéáåíäïãåíþí áíôéïîåéäùôéêþí ìç÷áíéóìþí. Ôá óçìáíôéêüôåñááíôéïîåéäùôéêÜ Ýíæõìá ôïõ ïñãáíéóìïý åßíáé ç õðåñïîåéäéêÞäéóìïõôÜóç (SOD),ç êáôáëÜóç, ôá Ýíæõìá ôçòïäïý ôçò öùóöïñéêÞò ðåíôüæçò, ç áíáãùãÜóç ôçò ãëïõôáèåéüíçò(GR), ïé õðåñïîåéäÜóåò ôçò ãëïõôáèåéüíçò(GPxs), ç õðåñïîåéäÜóç êáé ç áíáãùãÜóç ôçò èåéïñåäïîßíçòêáé ï óõíÝíæõìï Q. ¢ëëåò ìç åíæõìéêÝò áíôéïîåéäùôéêÝòïõóßåò åßíáé ç ãëïõôáèåéüíç ïé èåéïáíáãùãÜóåòTRX êáé ïé ìåôáëëïèåéüíåò.ÕðåñïîåéäéêÞ äéóìïõôÜóç (SOD): ç õðåñïîåéäéêÞäéóìïõôÜóç êáôáëýåé ôç ìåôáôñïðÞ áíéüíôùí õðåñïîåéäßïõóå õðåñïîåßäéï ôïõ õäñïãüíïõ êáé åßíáé Ýíá áðü ôáðéï áðïôåëåóìáôéêÜ åíäïêõôôÜñéá åíæõìéêÜ óõóôÞìáôá.Ç äéóìïõôÜóç ôïõ õðåñïîåéäßïõ áðáíôÜ óå áñêåôÝò éóïìïñöÝò,ïé ïðïßåò äéáöÝñïõí ùò ðñïò ôç öýóç ôïõ ìåôÜëëïõôïõ åíåñãïý êÝíôñïõ, ôç óýíèåóç ôùí áìéíïîÝùí,êáèþò êáé ôïí áñéèìü ôùí õðïìïíÜäùí, ôïõò óõìðáñÜãïíôåòêáé Üëëá ÷áñáêôçñéóôéêÜ. Óôïí Üíèñùðï áðáíôïýíôñåéò ìïñöÝò SOD, ç êõôôáñïðëáóìáôéêÞ CuZn-SOD, çìéôï÷ïíäñéáêÞ MnSOD êáé ç åîùêõôôÜñéá SOD. Ç SOD-êáôáóôñÝöåé ôéò Ï 2ìå ôç äéáäï÷éêÞ ïîåßäùóç êáé ôçíáíáãùãÞ ôïõ ìåôÜëëïõ ôïõ åíåñãïý êÝíôñïõ.ÊáôáëÜóç: ç êáôáëÜóç åíôïðßæåôáé óôá õðåñïîåéóþìáôáêáé ôá ìéôï÷üíäñéá ôùí êõôôÜñùí ôçò êáñäéÜò.Äåí áíåõñßóêåôáé óôá ìéôï÷üíäñéá ôùí êõôôÜñùí Üëëùíéóôþí. Êáôáëýåé ôç ìåôáôñïðÞ ôïõ õðåñïîåéäßïõ ôïõõäñïãüíïõ óå ýäùñ êáé ïîõãüíï óå äýï óôÜäéá.¸íæõìá ôçò ïäïý ôçò öùóöïñéêÞò ðåíôüæçò: ôá ÝíæõìááõôÜ êáôáëýïõí ôéò âéï÷çìéêÝò áíôéäñÜóåéò ôçò ìåôáâïëéêÞòïäïý ôçò öùóöïñéêÞò ðåíôüæçò, ç ïðïßá áðïôåëåßôçí êýñéá åíäïêõôôÜñéá ðçãÞ NADPH.18

ÁíáãùãÜóç ôçò ãëïõôáèåéüíçò (GR): Ôüóï ç åíæõìéêÞ(äéÜ ôùí õðåñïîåéäáóþí ôçò ãëïõôáèåéüíçò) üóï êáé çìç åíæõìéêÞ áäñáíïðïßçóç ôùí åëåõèÝñùí ñéæþí áðü ôçíáíá÷èåßóá ãëïõôáèåéüíç (GSH) ïäçãåß óå ðáñáãùãÞ ïîåéäùìÝíçòãëïõôáèåéüíçò (GSSG). Ç GSSG áðïìáêñýíåôáéáðü ôï êýôôáñï, ìå áðïôÝëåóìá ìåßùóç ôçò ïëéêÞò åíäïêõôôÜñéáòãëïõôáèåéüíçò. ÐñïêåéìÝíïõ ç ãëïõôáèåéüíç íá åêðëçñþóåéôï ñüëï ôçò ùò áíôéïîåéäùôéêÞ ïõóßá, áðáéôåßôáéç äéáôÞñçóç õøçëÞò åíäïêõôôÜñéáò áíáëïãßáò áíá÷èåßóáò(GSH) ðñïò ïîåéäùìÝíç ãëïõôáèåéüíç (GSSG).Áõôü åðéôõã÷Üíåôáéìå ìéá âéï÷çìéêÞ áíôßäñáóç, ç ïðïßá åîáñôÜôáéáðüëõôá áðü ôç NADPH. H äñáóôéêüôçôá ôçò GR ìðïñåßíá áõîçèåß ìå äýï ìç÷áíéóìïýò: Áýîçóç ôùí åðéðÝäùí/äñáóôéêüôçôáò ôçò GR Þ áýîçóç ôùí åðéðÝäùí NADPH.ÕðåñïîåéäÜóåò ôçò ãëïõôáèåéüíçò (GPxs): Ïé GPxsêáôáëýïõí ôçí áíáãùãÞ ôïõ õðåñïîåéäßïõ ôïõ õäñïãüíïõÞ ôùí õäñïûðåñïîåéäßùí ôùí ëéðéäßùí, ÷ñçóéìïðïéþíôáòùò áíáãùãéêÞ ïõóßá ôç ãëïõôáèåéüíç . Áí êáé ç áíáãùãÞôïõ H 2O 2ãßíåôáé êáé áðü ôçí êáôáëÜóç, ôá ó÷åôéêÜ åðßðåäáGPxs êáé êáôáëÜóçò äéáöÝñïõí áðü éóôü óå éóôü.×áñáêôçñéóôéêÜ áíáöÝñåôáé üôé ï åãêÝöáëïò Ý÷åé ðïëý÷áìçëÜ åðßðåäá äñáóôéêüôçôáò êáôáëÜóçò êáé õøçëÜåðßðåäá äñáóôéêüôçôáò GPxs, åíþ ôï Þðáñ Ý÷åé õøçëÜåðßðåäá êáé ôùí äýï åíæýìùí.ÕðåñïîåéäÜóç êáé áíáãùãÜóç ôçò èåéïñåäïîßíçò: ç õðåñïîåéäÜóçôçò èåéïñåäïîßíçò áíÜãåé ôüóï ôï H 2O 2üóï êáéôá áëêõë-õäñïûðåñïîåßäéá óå óõíäõáóìü ìå ôçí áíáãùãÜóçôçò èåéïñåäïîßíçò, ôç èåéïñåäïîßíç êáé ôç NADPH 58,59,60 .ÓõíÝíæõìï Q: ôï CoQ áðïôåëåß ðçãÞ Ï 2 .- üôáí åßíáéìåñéêþò áíá÷èÝí, åíþ Ý÷åé áíôéïîåéäùôéêÞ äñÜóç üôáíåßíáé ðëÞñùò áíçãìÝíï.Ãëïõôáèåéüíç: ç ãëïõôáèåéüíç, Ýíá ôñéðåðôßäéï ìåáíáãùãéêÝò êáé ðõñçíüöéëåò éäéüôçôåò, áðïôåëåß ôçí êýñéááíôéïîåéäùôéêÞ èåéüëç êáé ôïí êýñéï ñõèìéóôÞ ôçò åíäïêõôôÜñéáòïîåéäïáíáãùãéêÞò ïìïéüóôáóçò 61 . ÁðáíôÜåßôå ùò áíá÷èåßóá (GSH) åßôå ùò ïîåéäùìÝíç (GSSG)ìïñöÞ êáé óõììåôÝ÷åé óôéò ïîåéäïáíáãùãéêÝò áíôéäñÜóåéòìÝóù ôçò áíáóôñÝøéìçò ïîåßäùóçò ôçò åíåñãïý èåéüëçòôçò (Ó÷Þìá 7) 62 . O ëüãïò GSH/ GSSG áðïôåëåß áîéüðéóôïìÝôñï ôïõ ïîåéäùôéêïý stress åíüò ïñãáíéóìïý 63,64 .Oé êýñéåò ðñïóôáôåõôéêÝò äñÜóåéò ôçò ãëïõôáèåéüíçòóôï ïîåéäùôéêü stress åßíáé ïé åîÞò 56 :Ó÷Þìá 8: ÄñÜóåéò ôçò ãëïõôáèåéüíçò• H ãëïõôáèåéüíç äñá ùò óõíÝíæõìï ðïëõÜñéèìùí åíæýìùíðïõ óõììåôÝ÷ïõí óôçí ðñïóôáóßá ôïõ êõôôÜñïõ,üðùò õðåñïîåéäÜóåò ãëïõôáèåéüíçò, ôñáíóöåñÜóåòãëïõôáèåéüíçò, ôñáíóöåñÜóåò èåéüëçò, áöõäñïãïíÜóçöïñìáëäåàäçò, ãëõïîáëÜóç É 65• ÓõììåôÝ÷åé óôç ìåôáöïñÜ áìéíïîÝùí ìÝóù ôçò êõôôáñïðëáóìáôéêÞòìåìâñÜíçò.• Äåóìåýåé Üìåóá ôç ñßæá õäñïîõëßïõ êáé ôï õðåñïîåéäéêüáíéüí êáé åîïõäåôåñþíåé ôï õðåñïîåßäéï ôïõ õäñïãüíïõêáé ôá õðåñïîåßäéá ôùí ëéðéäßùí ìå ôçí êáôáëõôéêÞäñÜóç ôçò õðåñïîåéäÜóçò ôçò ãëïõôáèåéüíçò.• ¸÷åé ôçí éêáíüôçôá íá åðáíáöÝñåé óôçí åíåñãü ìïñöÞôéò óçìáíôéêÝò áíôéïîåéäùôéêÝò ïõóßåò, âéôáìßíç Cêáé âéôáìßíç E, Üìåóá Þ Ýììåóá. Ç éêáíüôçôá áõôÞ ôçòãëïõôáèåéüíçò êáèïñßæåôáé áðü ôçí ïîåéäïáíáãùãéêÞêáôÜóôáóç ôïõ æåýãïõò GSH/2GSSG 66 .ÈåéïáíáãùãÜóåò TRX: Ïé èåéïáíáãùãÜóåò åßíáé ìéêñÝò,ðëåéïôñüðåò óïõëöõäñõëéêÝò ðñùôåÀíåò ìå äñáóôçñéüôçôáïîåéäïáíáãùãÜóçò. Óôïí Üíèñùðï Ý÷ïõí áíáãíùñéóôåßôñßá ãïíßäéá èåéïñåäïîßíçò (TRX1, TRX2 êáésp TRX, ç ïðïßá ðáñïõóéÜæåé õøçëÞ Ýêöñáóç óôá óðåñìáôïæùÜñéá).Ïé TRX üëùí ôùí ïñãáíéóìþí äéáèÝôïõí ÝíáåîåëéêôéêÜ óõíôçñçôéêü åíåñãü êÝíôñï, ôï ïðïßï áðïôåëåßôáéáðü ôá áìéíïîÝá Cys-Gly-Pro-Cys. Åéäéêïß ðñùôåúíïäéóïõëöéäéêïßóôü÷ïé áíáãùãÞò áðü ôçí ïìÜäá ôùí TRXåßíáé ðñùôåÀíåò üðùò ç ñéâïíïõêëåïôéäéêÞ áíáãùãÜóç,çäéóïõëöéäéêÞ éóïìåñÜóç êáé áñêåôïß ìåôáãñáöéêïß ðáñÜãïíôåò,óõìðåñéëáìâáíïìÝíùí ôùí p53, NF-ê êáé AP-1.ÅðéðëÝïí, ïé TRX áðïôåëïýí äüôåò çëåêôñïíßùí ãéá ðïëëÝòõðåñïîåéäïáíáãùãÜóåò, éäéáßôåñá óçìáíôéêÝò ãéá ôçíáíáãùãÞ ôùí õðåñïîåéäßùí. ÅðéðëÝïí, áõôÞ ç ðñùôåÀíçìðïñåß Üìåóá íá áíÜãåé ìåñéêÝò äñáóôéêÝò ñßæåò ïîõãüíïõêáèþò êáé íá áíáäéðëþóåé ïîåéäùìÝíåò ðñùôåÀíåò.Åðßóçò, åðÜãåé áõôïêñéíåßò äñÜóåéò áíÜëïãåò ìå åêåßíåòôùí áõîçôéêþí ðáñáãüíôùí êáé ôùí êõôïêéíþí.Måôáëëïèåéïíßíåò: ïé ìåôáëëïèåéïíßíåò åßíáé ìéá ïìÜäáìéêñþí ðñùôåúíþí, ðëïýóéùí óå êõóôåÀíç, ïé ïðïßåòÝ÷ïõí ôçí éäéüôçôá íá óõíäÝïõí äéáöïñåôéêÜ éüíôá ìåôÜëëùí.ÁõôÝò ïé ðñùôåÀíåò Ý÷ïõí éäéáßôåñç óçìáóßá óôçíáíôéìåôþðéóç ôçò ôïîéêüôçôáò ôùí ìåôÜëëùí, üðùò ï Cu.7. Õðåñãëõêáéìßá êáé ïäïßðïõ åíåñãïðïéïýíôáé áðü ôï stressÉn vivo ìåëÝôåò áðïêáëýðôïõí áöåíüò üôé ôï åðáãüìåíïáðü ôçí õðåñãëõêáéìßá ïîåéäùôéêü stress åõèýíåôáéãéá ôéò åðéðëïêÝò ôïõ äéáâÞôç ðñéí áõôÝò ãßíïõí êëéíéêÜåìöáíåßò êáé áöåôÝñïõ õðïäåéêíýïõí ôç óõó÷Ýôéóç ôïõïîåéäùôéêïý stress ìå ôçí ðáèïöõóéïëïãßá ôùí üøéìùíäéáâçôéêþí âëáâþí. Ôï åðáãüìåíï áðü ôçí õðåñãëõêáéìßáïîåéäùôéêü stress åíåñãïðïéåß ôéò ïäïýò ôïõ ìåôáãñáöéêïýðõñçíéêïý ðáñÜãïíôá ÍF-êÂ, ôçò p38 MAP êéíÜóçò,ôùí êéíáóþí JNK/SAPK, ôùí AGE/RAGE, ôçò ðñùôåúíéêÞòêéíÜóçò PKC, ôçò ðïëõüëçò êáé ôçò åîïæáìßíçò.7.1. Ç ïäüò ôïõ ìåôáãñáöéêïý ðõñçíéêïý ðáñÜãïíôá(NF-êB: Nuclear factor-êÂ)Ìéá áðü ôéò óçìáíôéêüôåñåò ïäïýò ðïõ åíåñãïðïéïýíôáéáðü ôç õðåñãëõêáéìßá êáé ôï ïîåéäùôéêü stress åßíáéç ïäüò ôïõ ìåôáãñáöéêïý ðõñçíéêïý ðáñÜãïíôá ê (NF-19

êB) 67,68 . Ï NF-êB åíåñãïðïéåßôáé áðü Ýíá ìåãÜëï åýñïòåíäïêõôôÜñéùí êáé åîùêõôôÜñéùí åðáãùãÝùí üðùò çõðåñãëõêáéìßá, ôá õøçëÜ åðßðåäá åëåýèåñùí ëéðáñþíïîÝùí, ïé åíåñãÝò ìïñöÝò ïîõãüíïõ, ï ðáñÜãïíôáò íÝêñùóçòüãêïõ-á (TNF-á), ç éíôåñëåõêßíç 1â (IL-1â),Üëëåò ðñïöëåãìïíþäåéò êõôïêßíåò, ôá óõíäåäåìÝíá óôïíõðïäï÷Ýá ôïõò (RAGE) ðñïúüíôá ôåëéêÞò ãëõêïæõëßùóçò(ÁGE), ç p38 ÌÁÑ êéíÜóç, ç êáôáóôñïöÞ ôïõ DNA, çðñïóâïëÞ áðü éü êáé ç õðåñéþäçò áêôéíïâïëßá UV 69 . ÏðáñÜãïíôáò NF-êB äéáäñáìáôßæåé óçìáíôéêü ñüëï óôçñýèìéóç ôçò áðüðôùóçò, ôùí áíïóïëïãéêþí êáé öëåãìïíïäþíáðïêñßóåùí . Ç áíþìáëç ñýèìéóç ôïõ NF-êB ó÷åôßæåôáéìå Ýíá ìåãÜëï áñéèìü ÷ñüíéùí íïóçìÜôùí üðùò ïäéáâÞôçò êáé ç áèçñùìÜôùóç.Áðïõóßá åñåèéóìÜôùí, ï NF-êB ðáñáìÝíåé óôï êõôôáñüðëáóìáùò áíåíåñãü åôåñïäéìåñÝò áðïôåëïýìåíïáðü ôéò õðïìïíÜäåò p50 êáé p65 óõìðëåãìÝíåò ìå ôçíáíáóôáëôéêÞ ðñùôåÀíç ÉêÂ. Ç Éê ðñùôåÀíç ðáñåìðïäßæåéìéá NLS ðåñéï÷Þ ðÜíù óôïí NF-êB (NuclearLocalization Sequense, áëëçëïõ÷ßá åíôïðéóìïý óôïíðõñÞíá) ðïõ ñõèìßæåé ôç ìåôÜâáóÞ ôïõ NF-êB óôïíðõñÞíá 70 . Ðáñïõóßá åñåèéóìÜôùí, åíåñãïðïéåßôáé ÝíáòêáôáññÜêôçò êéíÜóçò óåñßíçò ðïõ ïäçãåß óå öùóöïñõëßùóçôçò IêB ðñùôåÀíçò 71 . Áõôü Ý÷åé ùò áðïôÝëåóìá ôçíáðåëåõèÝñùóç ôïõ NF-êB åôåñïäéìåñïýò êáé ôç ìåôÜâáóÞôïõ óôïí ðõñÞíá (Ó÷Þìá 9) 72 . Ï NF-êB ñõèìßæåé ôçíÝêöñáóç ðëçèþñáò ãïíéäßùí óõìðåñéëáìâáíïìÝíùíãïíéäßùí áõîçôéêþí ðáñáãüíôùí ( áããåéáêüò åíäïèçëéáêüòáõîçôéêüò ðáñÜãïíôáò, VEGF), ðñïöëåãìïíùäþíêõôïêéíþí (TNF-á,IL-1â), RAGE (õðïäï÷Ýùí ðñïúüíôùíôåëéêÞò ãëõêïæõëßùóçò), ìïñßùí ðñïóêüëëçóçò(áããåéáêü ìüñéï ðñïóêüëëçóçò-1, VCAM-1) êáé Üëëá.Ðñïúüíôá ãïíéäßùí ðïõ åðÜãïíôáé áðü ôïí NF-êB üðùòôá VEGF, TNF-á, IL-1â êáé RAGE ìðïñïýí íá åíåñãïðïéÞóïõíåê íÝïõ ôïí NF-êB.Ôï ðñùôáñ÷éêü óôÜäéï åíåñãïðïßçóçò ôïõ NF-êÂåßíáé ç öùóöïñõëßùóç ôçò Iê ðñùôåúíçò. Ôï Ýíæõìïðïõ åßíáé õðåýèõíï ãéá ôç öùóöïñõëßùóç áõôÞ åßíáé çÉêÂ-ÊéíÜóç (ÉÊÊ) 64,65 , Ýíá åôåñïôñéìåñÝò óýìðëïêï áðïôåëïýìåíïáðü äõï êáôáëõôéêÝò õðïìïíÜäåò ÉÊÊá (ÞÉÊÊ1) êáé ÉÊÊâ (Þ ÉÊÊ2) êáé ìßá ñõèìéóôéêÞ õðïìïíÜäáôçí ÉÊÊã 73,74 . Ç ÉÊÊ åíåñãïðïéåßôáé ìåôÜ áðü öùóöïñõëßùóçåðáãþìåíç áðü ôéò êéíÜóåò óåñßíçò ÍÉÊ 75 (NF-êBinducingkinase) êáé ÍÁÊ 76 (NF-êB-activating kinase).7.2. Ç ïäüò ôùí Jun áìéíïôåëéêþí/åðáãüìåíùí áðü ôïïîåéäùôéêü stress êéíáóþí (JNK/SAPK: c-Jun N-terminal kinase /stress-activated protein kinase)Ïé JNK (Þ áëëéþò SAPK) êáé ïé p38 ÌÁPÊs êéíÜóåòåßíáé ìÝëç ôçò ïéêïãÝíåéáò ôùí MAP ðñùôåúíéêþí êéíáóþíóåñßíçò/ èñåïíßíçò. Óôçí ßäéá ïéêïãÝíåéá áíÞêïõíêáé ïé ÅRKs êéíÜóåò 77 . Óå áíôßèåóç ìå ôéò ERKs,ïé ïðïßåòåíåñãïðïéïýíôáé áðü ìéôïãüíá, ïé JNK/SAPK êáép38MAPK åíåñãïðïéïýíôáé áðü åíäïãåíåßò êáé åîùãåíåßòóôñåóïãüíïõò ðáñÜãïíôåò üðùò ç õðåñãëõêáéìßá ïéåíåñãÝò ìïñöÝò ïîõãüíïõ, ôï ïîåéäùôéêü stress, ôï ùóìùôéêüstress, ïé ðñïöëåãìïíþäåéò êõôïêßíåò, ôï èåñìéêüóïê êáé ç õðåñéþäçò áêôéíïâïëßá UV 78 (ãéá ôï ëüãï áõôü÷áñáêôçñßæïíôáé ùò êéíÜóåò ðïõ åíåñãïðïéïýíôáé áðü ôïstress : stress-activated kinases Þ stress-kinases).Ó÷Þìá 9: Ìç÷áíéóìüò åíåñãïðïßçóçò ÍF-êBÏé åíåñãïðïéçìÝíåò êéíÜóåò JNK/SAPKs ðñïóäÝíïíôáéêáé öùóöïñõëéþíïõí ôïí ðáñÜãïíôá cJun (Ó÷Þìá10) 79 , ðïõ åßíáé ôìÞìá ôïõ ìåôáãñáöéêïý ðáñÜãïíôá ÁÑ-1 (Ï ìåôáãñáöéêüò ðáñÜãïíôáò ÁÑ-1,activator protein-1,åßíáé Ýíá åôåñïäéìåñÝò Þ ïìïäéìåñÝò óýìðëïêï áðïôåëïýìåíïáðü ìÝëç ôùí Jun,Fos êáé ATF, DNA-ðñïóäåíüìåíùíðñùôåúíþí). Ç åðßäñáóç ôùí JNK/SAPKs óôïícJun áõîÜíåé ôçí Ýêöñáóç ãïíéäßùí ìå ðåñéï÷Ýò áíáãíùñßóéìåòáðü ôï ìåôáãñáöéêü ðáñÜãïíôá ÁÑ-1 . ÅðåéäÞ ôïãïíßäéï ôïõ cJun öÝñåé êáé áõôü ðåñéï÷Ýò ðïõ áíáãíùñßæïíôáéáðü ôçí ÁÑ-1 äçìéïõñãåßôáé Ýíáò âñüã÷ïò èåôéêÞòáíáôñïöïäüôçóçò 80 . Ç ïîåéäïáíáãùãéêÞ ñýèìéóç (redoxregulation) ôïõ ÁÑ-1 ìåëåôÜôáé åíôáôéêÜ êáèþò áðïôåëåßðñüôõðï ïîåéäïáíáãùãéêÞò ñýèìéóçò êáé Üëëùíìåôáãñáöéêþí ðáñáãüíôùí üðùò ï NF-ê êáé ï ÁTF-2(activating transcription factor-2). Óôçí ßäéá ïéêïãÝíåéáìåôáãñáöéêþí ðáñáãüíôùí áíÞêåé êáé ï ìåôáãñáöéêüòðáñÜãïíôáò AP-2 (activator protein -2). Ï ÁÑ-2 åíåñãïðïéåßôáéáðü öëåãìïíþäåéò êõôïêßíåò êáé ðñïóôáãëáíäßíåòóå êáëëéÝñãåéåò ìåóáããåéáêþí êõôôÜñùí 81 êáé çéêáíüôçôá ðñüóäåóçò óôï DNA ñõèìßæåôáé åðßóçò áðüïîåéäùôéêÝò äéáäéêáóßåò 82 . Ç åíåñãïðïßçóç ôïõ ÁÑ-2ó÷åôßæåôáé ìå åëáôôùìÝíç Ýêöñáóç ôïõ áíôéïîåéäùôéêïýåíæýìïõ õðåñïîåéäéêÞ äéóìïõôÜóç 2 (SOD2) 83 .H óçìáíôéêüôåñç ëåéôïõñãßá ðïõ áðïäßäåôáé óôçí ïäüôùí JNK/SAPK êéíáóþí åßíáé ç åðáãùãÞ ôçò áðüðôùóçò 84 .Ç áíáóôïëÞ ôçò ïäïý ôùí JNK/SAPK åõíïåß ôçí åðéâßù-20

Ó÷Þìá 10: Ç ïäüò ôùí JNK/SAPK êéíáóþíóç ôùí êõôôÜñùí. Ç ïäüò ôùí JNK/SAPK êéíáóþí åíåñãïðïéåßôáéáðü ôï (åðáãüìåíï áðü ôç õðåñãëõêáéìßá)ïîåéäùôéêü stress êáé åìðëÝêåôáé (óôçí åðáãüìåíç áðüôçí õðåñãëõêáéìßá) áðüðôùóç ôùí åíäïèçëéáêþí êõôôÜñùí. Áîßæåé íá óçìåéùèåß üôé ç ðáñáãùãÞ Ç 2Ï 2, ç äñÜóçôùí JNK/SAPK êéíáóþí êáé ç åðáêüëïõèç áðüðôùóçðïõ åðÜãåôáé áðü ôçí õðåñãëõêáéìßá, êáôáóôÝëëåôáé áðüôçí áíôéïîåéäùôéêÞ âéôáìßíç C 85 . Åðéðñüóèåôá, ç áããåéïôåíóßíçÉÉ 86 êáé ôá ðñïúüíôá ôçò ïäïý ôçò ëéðïîõãïíÜóçòóôá êýôôáñá ñRIN m5F áíáóôÝëëïõí ôçí åíåñãïðïßçóçôùí JNK/SAPK êéíáóþí áðü ôçí õðåñãëõêáéìßá 87 .7.3. Ç ïäüò ôçò ìéôïãüíïõ ðñùôåúíéêÞò êéíÜóçò(p38 MAPÊ)Ç åíåñãïðïßçóç ôçò p38 ÌÁÑ êéíÜóçò åðçñåÜæåé ìßáðëçèþñá êõôôáñéêþí äéáäéêáóéþí üðùò ç öëåãìïíÞ êáéç áíïóßá, ç êõôôáñéêÞ áíÜðôõîç êáé áðüðôùóç, ïé áðïêñßóåéòôùí äéáöüñùí éóôþí óôï stress ìÝóù ñýèìéóçò ôçòãïíéäéáêÞò Ýêöñáóçò, ç åíåñãïðïßçóç óçìáôïäïôéêþíïäþí (NF-êÂ, áñá÷éäïíéêü ïîý, êõôôáñïêßíåò ê.Ü.) êáé çáíáäéïñãÜíùóç ôïõ êõôôáñïóêåëåôïý (Ó÷Þìá 11) 88 . Åðéðñüóèåôá,ç p38 ÌÁÑ êéíÜóç ñõèìßæåé ôç äñÜóç Üëëùíêéíáóþí óåñßíçò 70 . ×ñüíéá åíåñãïðïßçóç ôçò ïäïý ôçòp38 ÌÁÑÊ ó÷åôßæåôáé ìå ôç öõóéïëïãßá ðáèïëïãéêþí êáôáóôÜóåùíüðùò ç öëåãìïíÞ, ïé íåõñïëïãéêÝò áóèÝíåéåò,ïé ìïëýíóåéò êáé ïé âëÜâåò éó÷áéìßáò-åðáíáéìÜôùóçò 89 .Ãéá ôï ëüãï áõôü ç ÷ñÞóç åêëåêôéêþí áíáóôïëÝùí ôçòp38 ÌÁÑÊ ùò áíôéöëåãìïíùäþí ðáñáãüíôùí áðïôåëåßáíôéêåßìåíï êëéíéêþí åñåõíþí 90,91,92 .Ó÷Þìá 11: Ç ïäüò ôçò p38 MAP êéíÜóçòÇ p38 ÌÁÑÊ åíåñãïðïéåßôáé ùò áðüêñéóç óôçíõðåñãëõêáéìßá êáé ôï äéáâÞôç. Óå áïñôéêÜ ëåßá ìõúêÜêýôôáñá åðéìýùí ç áãùãÞ ìå ãëõêüæç ôåôñáðëáóßáóå ôáåðßðåäá ôçò p38 ÌÁÑ êéíÜóçò 93 . Óå óðåéñÜìáôá åðéìýùíðïõ êáôáóôÞèçêáí äéáâçôéêïß ìå óôñåðôïæïôïêßíç, áõîÞèçêåôüóï ç äñáóôçñéüôçôá ôçò p38 ÌÁÑÊ üóï êáé çöùóöïñõëßùóç ôçò ðñùôåúíçò èåñìéêïý óïê 24 (Hsp-25)ç ïðïßá áðïôåëåß õðüóôñùìá ãéá ôçí p38 MAPK 94 . Ôáãåãïíüôá áõôÜ öáßíåôáé íá åßíáé áðïôÝëåóìá ôçò áõîçìÝíçòðáñáãùãÞò åíåñãþí ìïñöþí ïîõãüíïõ. Åðéðñüóèåôá,óôï íåõñéêü éóôü áóèåíþí ìå óáê÷áñþäç äéáâÞôçÝ÷ïõí åíôïðéóôåß áõîçìÝíá åðßðåäá JNÊ/SAPK êáé p38ÌÁÑÊ êéíáóþí.ÓõìðåñáóìáôéêÜ, öáßíåôáé ðùò ïé ïäïß ôïõ ìåôáãñáöéêïýðáñÜãïíôá ÍF-ê êáé ôùí êéíáóþí JNÊ/SAPKêáé p38 ÌÁÑ åßíáé åõáßóèçôá-óôï-stress óçìáôïäïôéêÜóõóôÞìáôá êáé ç ÷ñüíéá åíåñãïðïßçóÞ ôïõò ìðïñåß íáïäçãÞóåé óôéò üøéìåò åðéðëïêÝò ôïõ äéáâÞôç.7.4. H ïäüò ôùí ðñïúüíôùí ôåëéêÞò ãëõêïæõëßùóçò(AGEs: Advanced Glycation End product)Ç ãëõêüæç êáé ïñéóìÝíá ðáñÜãùãá ôçò áíôéäñïýíìå ðñùôåÀíåò, ðõñçíéêÜ ïîÝá êáé ëéðßäéá ðñïêáëþíôáòôç ãëõêïæõëßùóÞ ôïõò. Ïé áñ÷éêÝò áíôéäñÜóåéò ôçòãëõêïæõëßùóçò åßíáé áíôéóôñåðôÝò, ôá ôåëéêÜ ðñïúüíôáüìùò Ý÷ïõí óôáèåñÞ äïìÞ êáé äåí äéáóðþíôáé åýêïëá.Ïé ôåëéêÝò áíôéäñÜóåéò ãëõêïæõëßùóçò åßíáé åðïìÝíùò ìçáíôéóôñåðôÝò.Ðñïúüíôá ðñï÷ùñçìÝíçò ãëõêïæõëßùóçò âñßóêïíôáé21

óå áõîçìÝíï ðïóïóôü óå åîùêõôôÜñéåò äïìÝò ôùí áããåßùíôïõ áìöéâëçóôñïåéäïýò 95 êáé ôïõ óðåéñÜìáôïò 96 äéáâçôéêþíáôüìùí. Áñ÷éêÜ, äéáôõðþèçêå ç Üðïøç üôé ôá ðñïúüíôááõôÜ ðñïÝñ÷ïíôáé áðü ôç ìç åíæõìéêÞ ãëõêïæõëßùóçåîùêõôôÜñéùí ðñùôåúíþí. ÔåëéêÜ, Ý÷åé äéáðéóôùèåß üôéôá åíäïêõôôáñßùò ðáñáãüìåíá ðñïúüíôá áõôïïîåßäùóçòôçò ãëõêüæçò Ý÷ïõí ôçí éêáíüôçôá íá ãëõêïæõëéþíïõíðñùôåÀíåò ìå ôá÷ýôçôá ðïëý ìåãáëýôåñç óå ó÷Ýóç ìå ôçãëõêüæç 87 . ÓÞìåñá, êõñéáñ÷åß ç Üðïøç üôé ç áýîçóç ôçòóõãêÝíôñùóçò ôçò ãëõêüæçò ìÝóá óôá êýôôáñá åõèýíåôáéãéá ôçí ðáñáãùãÞ ôùí AGEs ôüóï åíäïêõôôáñßùò üóïêáé Ýîù áðü ôá êýôôáñá 97 .Ç áýîçóç ôïõ ó÷çìáôéóìïý ôùí AGEs ìðïñåß íáðñïîåíÞóåé âëÜâåò óôá êýôôáñá ìå ôñåéò êõñßùò ìç÷áíéóìïýò.- Ïé åíäïêõôôÜñéåò ðñùôåÀíåò, üôáí ãëõêïæõëéþíïíôáé,äõóëåéôïõñãïýí- Ïé áëëçëåðéäñÜóåéò ôùí ãëõêïæõëéùìÝíùí óõóôáôéêþíìå ôá ëïéðÜ óõóôáôéêÜ ôçò äéÜìåóçò åîùêõôôÜñéáò ïõóßáòáëëÜ êáé ìå õðïäï÷åßò óôçí åðéöÜíåéá ôùí êõôôÜñùí(éíôåãêñßíåò) äéáôáñÜóóïíôáé- Ïé ãëõêïæõëéùìÝíåò ðñùôåÀíåò ôïõ ðëÜóìáôïò óõíäÝïíôáéìå AGE-õðïäï÷åßò, ðïõ âñßóêïíôáé óôçí åðéöÜíåéáïñéóìÝíùí êõôôÜñùí, üðùò åßíáé ôá ìáêñïöÜãá,ôá åíäïèçëéáêÜ êýôôáñá êáé ôá ìåóáããåéáêÜ êýôôáñá,ìå áðïôÝëåóìá íá ðõñïäïôïýíôáé äéÜöïñïé âëáðôéêïßìç÷áíéóìïß, ðïõ ìå ôç óåéñÜ ôïõò Ý÷ïõí ùò áðïôÝëåóìáôçí ìéôï÷ïíäñéáêÞ ðáñáãùãÞ Ç 2Ï 2êáé ôçí ðáèïëïãéêÞÝêöñáóç ðïëëþí ãïíéäßùí 98 (Ó÷Þìá 12) 99 .ÌÝóá óôá åíäïèçëéáêÜ êýôôáñá, ï ó÷çìáôéóìüò ôùíAGEs ãßíåôáé ôá÷ýôáôá. 15 ¸íáò áðü ôïõò êýñéïõò óôü-÷ïõò ôçò ãëõêïæõëßùóçò åßíáé ï âáóéêüò áõîçôéêüò ðáñÜãïíôáòôùí éíïâëáóôþí (b-FGF:basic fibroblast growthfactor) 100 . Ç ãëõêïæõëßùóç ôïõ b-FGF áíáóôÝëëåé ôéò ìéôùôéêÝòäéáéñÝóåéò ôùí åíäïèçëéáêþí êõôôÜñùí.Ìéá áðü ôéò ðñùôåÀíåò ôçò åîùêõôôÜñéáò ïõóßáò ðïõãëõêïæõëéþíïíôáé åßíáé ôï êïëëáãüíï, êõñßùò ïé ôýðïé Éêáé IV, ìå óõíÝðåéá ôçí áëëïßùóç ôùí ëåéôïõñãéêþí ôïõéäéïôÞôùí 101 . Óå ðåéñáìáôüæùá, ç ãëõêïæõëßùóç ôïõ êïëëáãüíïõôïõ ôïé÷þìáôïò ôùí ìåãÜëùí áããåßùí êáèéóôÜôá áããåßá áõôÜ áíåëáóôéêÜ 102 .Ó÷Þìá 12: Ðéèáíüò ìç÷áíéóìüò äñÜóçò ÁGEs óôá ìåóáããåéáêÜêýôôáñá ôïõ óðåéñÜìáôïòÏé ãëõêïæõëéùìÝíåò ðñùôåÀíåò ôïõ ðëÜóìáôïòóõíäÝïíôáé ìå AGE-õðïäï÷åßò ðïõ âñßóêïíôáé óôçíåðéöÜíåéá ïñéóìÝíùí êõôôÜñùí 103 . Óå êõôôáñïêáëëé-Ýñãåéåò, ôá ìáêñïöÜãá êáé ôá êýôôáñá ôïõ ìåóáããåßïõôïõ óðåéñÜìáôïò, üôáí ïñéóìÝíïé õðïäï÷åßò óôçíåðéöÜíåéá ôïõò óõíäåèïýí ìå AGEs, ðáñÜãïõí êõôôáñïêßíåòêáé áõîçôéêïýò ðáñÜãïíôåò (IL-1:éíôåñëåõêßíç1, IGF-I: insulin-like growth factor-I, TNFa :tumor necrosis factor-á, TGFb: transforming growthfactor-b, MCSF : macrophage colony stimulating factor,MGCSF :macrophage granulocyte colony stimulatingfactor êáé PDGF: platelet derived growth factor ) 104,105,106 ,åíþ ôá åíäïèçëéáêÜ êýôôáñá åêöñÜæïõí ìüñéá ðïõ áõîÜíïõíôçí ðñïóêüëëçóç ôùí áéìïðåôáëßùí óôçí åðéöÜíåéáôïõ áããåßïõ êáé åðÜãïõí ôç öëåãìïíÞ [VCAM-1:vascular cell adhesion molecule-1,thrombomodulin, éóôéêüòðáñÜãïíôáò) 107 .¸íáò åéäéêüò ôýðïò õðïäï÷Ýá ãéá ôá AGEs, ïRAGE 108 (receptor for AGEs), ôïõ ïðïßïõ ç äïìÞ ìïéÜæåéìå åêåßíç ôùí áíïóïóöáéñéíþí, üôáí óõíäåèåß ìå AGEsðñïêáëåß ôçí áðåëåõèÝñùóç åëåõèÝñùí ñéæþí ïîõãüíïõêáé åíåñãïðïéåß ôï ìåôáãñáöéêü ðõñçíéêü ðáñÜãïíôáNF-êB, ðïõ ìå ôç óåéñÜ ôïõ ðñïêáëåß ôçí ðáèïëïãéêÞ Ýêöñáóçðïëëþí ãïíéäßùí.7.5. Ç ïäüò ôçò ðñùôåúíéêÞò êéíÜóçò C (PKC)Ç ðñùôåúíéêÞ êéíÜóç C (PKC) áðïôåëåß ìéá ïìÜäáåíæýìùí (õðÜñ÷ïõí éóüìïñöåò áðü á Ýùò å) ðïõ ðáñåìâáßíïõíóôç ìåôáöïñÜ ìéáò öùóöïñéêÞò ïìÜäáò áðüôï ÁÔÑ óå åéäéêÞ èÝóç óå ìéá ðñùôåÀíç-óôü÷ï. Äñïõí,äçëáäÞ, öùóöïñõëéþíïíôáò ôï õðüóôñùìá ôçò. Ãéá ôçíåíåñãïðïßçóç ôçò êéíÜóçò áðáéôåßôáé öùóöáôéäõëéêÞ óåñßíç,éüíôá Ca ++ êáé äéáêõëïãëõêåñüëç (DAG).Ç õðåñâïëéêÞ êáé óõíå÷Þò åíåñãïðïßçóç ôçò PKC åßíáéÝíáò áðü ôïõò ìç÷áíéóìïýò ìå ôïõò ïðïßïõò ç õðåñãëõêáéìßáðñïêáëåß âëÜâåò óôïõò éóôïýò. Ç õðåñãëõêáéìßáðñïêáëåß de novo óýíèåóç DAG ìÝóù ôùí öùóöïñéêþíôñéïæþí, ïé óõãêåíôñþóåéò ôùí ïðïßùí áõîÜíïõíëüãù ôçò áõîçìÝíçò ãëõêüëõóçò 109 . ÅðéðëÝïí, ç áýîçóçôïõ ëüãïõ NADH/NAD+, ðïõ ïöåßëåôáé óôç ìåôáôñïðÞôçò óïñâéôüëçò óå öñïõêôüæç, êáé ç áíáóôïëÞ ôïõ åíæýìïõGADPH (áöõäñïãïíÜóç ôçò 3-öùóöï-ñéêÞò ãëõêåñáëäåàäçò)áðü ôéò åëåýèåñåò ñßæåò ïîõãüíïõ, ðïõ ðáñÜãïíôáéóôá ìéôï÷üíäñéá, åêôñÝðïõí ôçí 3-öùóöïñéêÞãëõêåñáëäåàäç áðü ôçí ïäü ôçò ãëõêüëõóçò ðñïò ôçíðáñáãùãÞ öùóöïñéêÞò äéõäñïîõ-áêåôüíçò êáé DAG.Åíåñãïðïßçóç ôçò PKC åðßóçò ðñïêáëåßôáé áðü ôç óýíäåóçôùí AGEs ìå ôïõò õðïäï÷åßò ôïõò óôçí åðéöÜíåéáôùí êõôôÜñùí 110 . Ç õðåñãëõêáéìßá åíåñãïðïéåß êõñßùòôéò â êáé ä éóüìïñöåò ôçò PKC, óôá åíäïèçëéáêÜ êýôôáñá,óôïí áìöéâëçóôñïåéäÞ êáé óôï óðåßñáìá. ÅðéðëÝïí,åíåñãïðïßçóç êáé ôùí Üëëùí éóüìïñöùí ôçò PKC Ý÷åéäéáðéóôùèåß óå äéáâçôéêïýò åðßìõåò, üðùò ôçò PKC-áêáé ôçò PKC-å óôïí áìöéâëçóôñïåéäÞ êáé ôçò PKC-á êáéPKC-ä óôï óðåßñáìá 111,112 .Ç åíåñãïðïßçóç ôçò PKC-â ìåéþíåé ôç ñïÞ áßìáôïòóôïí áìöéâëçóôñïåéäÞ êáé ôï íåöñü 113 , ðéèáíüí ìÝóùìåéùìÝíçò ðáñáãùãÞò ìïíïîåéäßïõ ôïõ áæþôïõ (NO), ôïïðïßï, ùò ãíùóôü, åßíáé áããåéïäéáóôáëôéêüò ðáñÜãïíôáò,Þ êáé áýîçóçò ôçò áðåëåõèÝñùóçò ôçò åíäïèçëßíçò-122

(ÅÔ-1), ïõóßáò ìå áããåéïóõóðáóôéêÞ äñÜóç. Óå ðåéñáìáôüæùá,Ý÷åé âñåèåß üôé ç åíåñãïðïßçóç ôçò PKC ìåéþíåéôçí ðáñáãùãÞ NO óôï óðåßñáìá 114 êáé ôá ëåßá ìõúêÜêýôôáñá 115 , åíþ óå êáëëéÝñãåéåò åíäïèçëéáêþí êõôôÜñùíåìðïäßæåé ôçí åîáñôþìåíç áðü ôçí éíóïõëßíç åíåñãïðïßçóçôçò åíäïèçëéáêÞò óõíèåôÜóçò ôïõ NO (endothelialnitric oxide synthase, e-NOS) 116 . Ç õðåñãëõêáéìßá áõîÜíåéôçí éêáíüôçôá ôçò ÅÔ-1 íá äéåãåßñåé ôç MAPK (mitogenactivated protein kinase) óôá êýôôáñá ôïõ ìåóáããåßïõ,ìÝóù åíåñãïðïßçóçò éóüìïñöùí ôçò PKC 117 . Ç åíåñãïðïßçóçôçò PKC áðü ôçí õðåñãëõêáéìßá áõîÜíåé åðßóçòôç äéáðåñáôüôçôá ôïõ åíäïèçëßïõ 118 . Ç PKC áõîÜíåéôçí Ýêëõóç ôïõ ðáñÜãïíôá VEGF (vascular endothelialgrowth factor) áðü ôá ëåßá ìõúêÜ êýôôáñá 119 . Ï VEGFåßíáé ðáñÜãïíôáò ðïõ áõîÜíåé ôç äéáðåñáôüôçôá ôùí áããåßùí.Ç PKC ðéèáíüí åõèýíåôáé, ôïõëÜ÷éóôïí åí ìÝñåé,ãéá ôçí áýîçóç ôçò åíáðüèåóçò ôçò éíùäïíåêôßíçò êáé ôïõêïëëáãüíïõ ôýðïõ IV óôçí åîùêõôôÜñéá ïõóßá ôïõ ìåóáããåßïõ÷þñïõ ôïõ óðåéñÜìáôïò 120,121 Ç õðåñãëõêáéìßá,ìÝóù åíåñãïðïßçóçò ôçò ðñùôåúíéêÞò êéíÜóçò, Ý÷åé åíï-÷ïðïéçèåß ãéá ôçí áýîçóç ôçò äñáóôéêüôçôáò ôïõ áíáóôïëÝáôçò éíùäüëõóçò êáé ôïõ PAI-1 (plasminogen activatorinhibitor-1) 122 ,êáèþò êáé ãéá ôçí åíåñãïðïßçóç ôïõ ìåôáãñáöéêïýðáñÜãïíôá NF-êB 123 Ç åíåñãïðïßçóç, åðïìÝíùò,ôçò ðñùôåúíéêÞò êéíÜóçò áðü ôçí õðåñãëõêáéìßáðñïêáëåß äéáôáñá÷Ýò ôçò ñïÞò êáé ôçò ðçêôéêüôçôáò ôïõáßìáôïò, áýîçóç ôïõ ðÜ÷ïõò ôçò âáóéêÞò ìåìâñÜíçò ôïõåíäïèçëßïõ êáé ôçò äéáðåñáôüôçôáò ôùí áããåßùí êáé ôçíðáèïëïãéêÞ Ýêöñáóç ðïëëþí ãïíéäßùí (Ó÷Þìá 13) 124 .7.6. Ç ïäüò ôùí ðïëõïëþíÔï êõñéüôåñï Ýíæõìï ôçò ïäïý ôùí ðïëõïëþí åßíáé çáíáãùãÜóç ôçò áëäüæçò. Óôçí ïäü áõôÞ ÷ñçóéìïðïéåßôáéùò óõíÝíæõìï NADPH (áíá÷èÝí öùóöïñéêü íéêïôé-íáìé-Ó÷Þìá 13: Ðéèáíïß ìç÷áíéóìïß äçìéïõñãßáò ìéêñï-áããåéáêþíåðéðëïêþí áðü ôçí åíåñãïðïßçóç ôçò PKCäï-áäåíéíï-äéíïõêëåïôßäéï) êáé ùò õðüóôñùìá ãëõêüæç.Ùò õðüóôñùìá ÷ñçóéìïðïéïýíôáé åðßóçò äéÜöïñá óÜê-÷áñá êáé ðáñÜãùãá ôïõò, ðïõ ìåôáôñÝðïíôáé óôéò áíôßóôïé÷åòáëêïüëåò (ðïëõüëåò). Ç ãëõêüæç ìåôáôñÝðåôáéóå óïñâéôüëç êáé ç ãáëáêôüæç óå ãáëáêôéôüëç.Ç óïñâéôüëç ïîåéäþíåôáé, óôç óõíÝ÷åéá, óå öñïõêôüæçáðü ôï Ýíæõìï áöõäñïãïíÜóç ôçò óïñâéôüëçò. Óôçäåýôåñç áõôÞ áíôßäñáóç ÷ñçóéìïðïéåßôáé NAD + (ïîåéäùèÝííéêïôéíáìéäï-áäåíéíï-äéíïõêëåïôßäéï), ôï ïðïßïáíÜãåôáé óå NADH (áíá÷èÝí íéêïôéíáìéäï-áäåíéíï-äéíïõêëåïôßäéï).Ôï ñõèìéóôéêü Ýíæõìï ôçò ïäïý ôùí ðïëõïëþí åßíáé çáíáãùãÜóç ôçò áëäüæçò. Ôï Ýíæõìï áõôü âñßóêåôáé óôáíåýñá, óôïí áìöéâëçóôñïåéäÞ, óôïõò öáêïýò ôïõ ïöèáëìïý,óôï óðåßñáìá êáé óôï ôïß÷ùìá ôùí áããåßùí. Óôïõòéóôïýò áõôïýò, ç ðñüóëçøç ãëõêüæçò ãßíåôáé ìå ìåôáöïñåßòãëõêüæçò Üëëïõò ðëçí ôïõ GLUT 4 êáé ãéá ôçí åßóïäïôçò ãëõêüæçò óôá êýôôáñá áõôþí ôùí éóôþí äåí åßíáéáðáñáßôçôç ç ðáñïõóßá éíóïõëßíçò. Ç óõãêÝíôñùóç ôçòãëõêüæçò ìÝóá óôá óõãêåêñéìÝíá êýôôáñá âáßíåé ðáñÜëëçëáìå ôç óõãêÝíôñùóç ôçò óôï áßìá. Ç ÷çìéêÞ óõããÝíåéáôçò áíáãùãÜóçò ôçò áëäüæçò ãéá ôç ãëõêüæç åßíáéìéêñÞ (õøçëÞ K m) êáé, åðïìÝíùò, ç ïäüò ôùí ðïëõïëþíåßíáé öõóéïëïãéêÜ áíåíåñãÞò. ¼ôáí üìùò, ëüãù õðåñãëõêáéìßáò,ç óõãêÝíôñùóç ôçò ãëõêüæçò ìÝóá óôá êýôôáñááõôÜ áõîçèåß, áõîÜíåé êáé ï ìåôáâïëéóìüò ìÝóù ôçò ïäïýôùí ðïëõïëþí. Ìéá áðü ôéò öõóéïëïãéêÝò ëåéôïõñãßåò ôçòáíáãùãÜóçò ôçò áëäüæçò åßíáé ç áäñáíïðïßçóç ôùí ãëõêïôïîéíþí,üðùò ð.÷. ôçò ìåèõëïãëõïîÜëçò, ïõóéþí ðïõÝ÷ïõí ôç äõíáôüôçôá íá ãëõêïæõëéþíïõí ðñùôåÀíåò êáéÜëëá ìüñéá ìå ôá÷ýôçôá ðïëý ìåãáëýôåñç óå ó÷Ýóç ìå ôçãëõêüæç 125 . ÐñÜãìáôé, ç ìåèõëïãëõïîÜëç áðïôåëåß ôï êáôáëëçëüôåñïõðüóôñùìá ãéá ôçí áíáãùãÜóç ôçò áëäüæçò(Ý÷åé ôç ÷áìçëüôåñç K m).ÄéÜöïñïé ìç÷áíéóìïß Ý÷ïõí ðñïôáèåß ãéá íá åîçãÞóïõíôç óçìáóßá ôçò åíåñãïðïßçóçò ôçò ïäïý ôùí ðïëõïëþíêáé ôçò ðñüêëçóçò, ôåëéêÜ, âëáâþí óôá êýôôáñá.Ïé êõñéüôåñïé áðü áõôïýò åßíáé:• Ç ðñïêáëïýìåíç áðü ôç óïñâéôüëç ïóìùôéêÞ ëýóç ôùíêõôôÜñùí• Ç áäñáíïðïßçóç ôùí äéáýëùí Na + -K + ðïõ åîáñôþíôáéáðü ôï ÁÔÑ• Ç áýîçóç ôïõ ëüãïõ NADH/NAD + óôï êõôôáñüðëáóìá• Ç ìåßùóç ôçò óõãêÝíôñùóçò ôïõ NADPH óôï êõôôáñüðëáóìá.Ç óïñâéôüëç äåí äéá÷Ýåôáé åëåýèåñá ìÝóù ôçò êõôôáñéêÞòìåìâñÜíçò. ¼ôáí ç ïäüò ôçò ðïëõüëçò åíåñãïðïéåßôáé,ç åíäïêõôôÜñéá óõãêÝíôñùóç óïñâéôüëçòáõîÜíåé. Áñ÷éêÜ, åß÷å õðïôåèåß üôé ç áýîçóç ôçò óõãêÝíôñùóçòôçò óïñâéôüëçò óôá åíäïèçëéáêÜ êáé ôá íåõñéêÜêýôôáñá ðñïêáëåß ôçí åßóïäï ýäáôïò êáé ôçí ïóìùôéêÞëýóç ôùí êõôôÜñùí. Ïé óõãêåíôñþóåéò üìùò ôçò óïñâéôüëçòóôá áããåßá êáé ôá íåýñá ôùí äéáâçôéêþí áóèåíþíÝ÷ïõí ìåôñçèåß êáé âñÝèçêáí íá åßíáé ÷áìçëÝò.Óýìöùíá ìå ôç äåýôåñç õðüèåóç, ç åíåñãïðïßçóç ôçòïäïý ôùí ðïëõïëþí ðñïêáëåß ìåßùóç ôçò äñáóôéêüôçôáòôïõ åíæýìïõ Na + - Ê + -ÁÔÑÜóç, áäñáíïðïßçóç äçëáäÞôùí åîáñôþìåíùí áðü ôï ÁÔÑ äéáýëùí Na + -K + , ëüãù ìåéùìÝíçòóýíèåóçò ôçò öùóöáôéäõëï-éíïóéôüëçò. Ç áäñá-23

íïðïßçóç ôùí åîáñôþìåíùí áðü ôï ÁÔÑ äéáýëùí Na + -K +ðáñáôçñåßôáé ðñÜãìáôé óôï äéáâÞôç, öáßíåôáé üìùò üôéïöåßëåôáé óôçí åíåñãïðïßçóç ôçò ðñùôåúíéêÞò êéíÜóçò C(PKC), ðïõ, ìå ôç óåéñÜ ôçò, áõîÜíåé ôçí ðáñáãùãÞ äýïáíáóôïëÝùí ôçò Na + -K + -ÁÔÑÜóçò, ôïõ áñá÷éäïíéêïýïîÝïò êáé ôçò ðñïóôáãëáíäßíçò E 2(PGE 2) 126 .Óýìöùíá ìå ìéá ðéï ðñüóöáôç õðüèåóç, ç ïîåßäùóçôçò óïñâéôüëçò áðü ôï NAD + áõîÜíåé ôï ëüãï ôïõ NADH/NAD + óôï êõôôáñüðëáóìá, ìå óõíÝðåéá ôçí áäñáíïðïßçóçôïõ åíæýìïõ áöõäñïãïíÜóç ôçò 3-öùóöïñéêÞò ãëõêåñáëäåàäçò(Glyceraldehydes-3-phosphate dehydrogenase,GADPH). Ç áäñáíïðïßçóç áõôïý ôïõ åíæýìïõ Ý÷åé ùòáðïôÝëåóìá ôçí áýîçóç ôùí óõãêåíôñþóåùí ôùí öùóöïñéêþíôñéïæþí, ðïõ ìå ôç óåéñÜ ôïõò, áõîÜíïõí ôï ó÷çìáôéóìüìåèõëïãëõïîÜëçò êáé äéáêõëïãëõêåñüëçò (DAG).Ç ìåèõëïãëõïîÜëç ãëõêïæõëéþíåé ôá÷Ýùò ðñùôåÀíåò êáéïäçãåß óôï ó÷çìáôéóìü ðñïúüíôùí ðñï÷ùñçìÝíçò ãëõêïæõëßùóçò(AGEs), åíþ ç DAG åíåñãïðïéåß ôçí PKC.Óýìöùíá ìå ôçí ôÝôáñôç õðüèåóç, ç áíáãùãÞ ôçò ãëõêüæçòóå óïñâéôüëç ðñïêáëåß êáôáíÜëùóç ôïõ NADPH.To NADPH åßíáé áðáñáßôçôï ãéá ôçí áíáãÝííçóç ôçòáíá÷èåßóáò ãëïõôáèåéüíçò, ç ïðïßá åßíáé óçìáíôéêüòáäñáíïðïéçôÞò ôùí åëåõèÝñùí ñéæþí ïîõãüíïõ, êáé ç Ýëëåéøçôçò ïðïßáò ðñïêáëåß ïîåéäùôéêÞ êáôáðüíçóç ôùíêõôôÜñùí 127 . ÅðéðëÝïí, ç õðåñãëõêáéìßá áäñáíïðïéåßôçí áöõäñïãïíÜóç ôçò 6-öùóöïñéêÞò ãëõêüæçò, ðïõ áðïôåëåßôç óçìáíôéêüôåñç ðçãÞ ôïõ NADPH, ìåéþíïíôáòðåñáéôÝñù ôéò óõãêåíôñþóåéò ôïõ NADPH óå ïñéóìÝíááããåéáêÜ êáé íåõñéêÜ êýôôáñá 128 .7.7. Ç ïäüò ôçò åîïæáìßíçòÐñüóöáôá, ðáñïõóéÜóôçêå ç õðüèåóç üôé ç õðåñãëõêáéìßáðñïêáëåß âëÜâåò ìÝóù åêôñïðÞò ôïõ ìåôáâïëéóìïýôçò ãëõêüæçò äéÜ ôçò ïäïý ôçò åîïæáìßíçò 129,130,131 .(Ó÷Þìá 14) 132 . Ç ãëõêüæç ìåôáôñÝðåôáé óå 6-öùóöïñéêÞöñïõêôüæç, ç ïðïßá áêïëïýèùò áíôéäñÜ ìå ãëïõôáìßíç. Çáíôßäñáóç êáôáëýåôáé áðü ôï Ýíæõìï áìéäïôñáíóöåñÜóçôçò ãëïõôáìßíçò-6-öùóöïñéêÞò öñïõêôüæçò (glutaminefructose-6-phosphateamidotransferase, GFAD), ðïõáðïôåëåß ôï ñõèìéóôéêü Ýíæõìï ôçò ïäïý ôçò åîïæáìßíçò.Ôï Ýíæõìï áõôü áíáóôÝëëåôáé áðü ôçí áæáóåñßíç.Tá ðñïúüíôá ôçò áíôßäñáóçò åßíáé ãëïõôáìéêü ïîý êáé6-öùóöïñéêÞ ãëõêïæáìßíç, ç ïðïßá ìåôáôñÝðåôáé óôç óõíÝ÷åéáóå ïõñéäõë-äéöùóöïñéêÞ-Í-áêåôõëï-ãëõêïæáìßíç(UDP-GluNac). Ç åíåñãïðïßçóç ôçò ïäïý ôçò åîïæáìßíçòáõîÜíåé ôç ìåôáãñáöÞ ïñéóìÝíùí ãïíéäßùí, üðùò ôïõTGFa,ôïõ TGFb êáé ôïõ ÑÁÉ-1 118,119,133 ìå ôñüðï ðïõ äåíåßíáé áðüëõôá ãíùóôüò.Óýìöùíá ìå ôá ìÝ÷ñé ôþñá äåäïìÝíá, ç åíåñãïðïßçóçôùí ãïíéäßùí áõôþí ïöåßëåôáé óôç ãëõêïæõëßùóç ôïõìåôáãñáöéêïý ðáñÜãïíôá Spl (ï Spl ìåôáôñÝðåôáé óå Spl-O-GlcNAc êáé áõôÞ ç ìåôáôñïðÞ ôïí åíåñãïðïéåß) 134 . Åíäå÷ïìÝíùò,ìå ôçí åíåñãïðïßçóç ôçò ïäïý ôçò åîïæáìßíçòãëõêïæõëéþíïíôáé êáé Üëëïé ìåôáãñáöéêïß ðáñÜãïíôåòðïõ äåí Ý÷ïõí åíôïðéóôåß ìÝ÷ñé óÞìåñá.ÓõíïëéêÜ, ç åíåñãïðïßçóç ôçò ïäïý ôçò åîïæáìßíçòáðü ôçí õðåñãëõêáéìßá öáßíåôáé íá ðñïêáëåß ôçíðáèïëïãéêÞ Ýêöñáóç ïñéóìÝíùí ãïíéäßùí êáé ôç äõóëåéôïõñãßáïñéóìÝíùí ðñùôåúíþí êáé íá óõììåôÝ÷åé óôçíðáèïãÝíåéá ôùí åðéðëïêþí ôïõ äéáâÞôç.Ó÷Þìá 14: Ïäüò ôçò åîïæáìßíçò8. Ïîåéäùôéêü stress êáé áíôßóôáóç óôç äñÜóçôçò éíóïõëßíçòÔï ïîåéäùôéêü stress äåí åìðëÝêåôáé ìüíï óôçí ðáèïöõóéïëïãßáôùí äéáâçôéêþí åðéðëïêþí áëëÜ ó÷åôßæåôáéêáé ìå ôçí áíôï÷Þ óôç äñÜóç ôçò éíóïõëßíçò 135,136,137,138 (ôïöáéíüìåíï áõôü êáëåßôáé éíóïõëéíïáíôï÷Þ Þ éíóïõëéíïáíôßóôáóç).In vivo äïêéìÝò óå äéáâçôéêÜ ðåéñáìáôüæùáõðïäåéêíýïõí üôé ôá áíôéïîåéäùôéêÜ åíéó÷ýïõí ôçí åõáéóèçóßáóôçí éíóïõëßíç. ÐåñáéôÝñù êëéíéêÝò ìåëÝôåò óåäéáâçôéêïýò áóèåíåßò ìå áíôï÷Þ óôçí éíóïõëßíç áðÝäåéîáíüôé ç èåñáðåßá ìå áíôéïîåéäùôéêÜ üðùò ïé âéôáìßíåò C êáéE, ôï ëéíïëåúêü ïîý (LA) êáé ç ãëïõôáèåéüíç âåëôßùóáíôçí áíôáðüêñéóç ôùí êõôôÜñùí óôçí éíóïõëßíç 139,140,141,142 .8.1.Åíåñãïðïßçóç åõáßóèçôùí óôï stress êéíáóþí, öùóöïñõëßùóçIRS êáé áíôï÷Þ óôçí éíóïõëßíçÔï ïîåéäùôéêü stress åíåñãïðïéåß ìßá ðëçèþñá êéíáóþíóåñßíçò 143,144,145 . Óôü÷ïé ôùí êéíáóþí åßíáé ï õðïäï-÷Ýáò éíóïõëßíçò (ÉR) êáé ïé ðñùôåÀíåò ôïõ õðïóôñþìáôïòôïõ éíóïõëéíéêïý õðïäï÷Ýá (IRS: Insuline ReseptorSubstrate). Ç áõîçìÝíç öùóöïñõëßùóç êáôáëïßðùí óåñßíçòêáé èñåïíßíçò óôá IRS êáé IR ðåñéïñßæåé ôç öùóöïñõëßùóçôùí õðïëåéììÜôùí ôõñïóßíçò ôïõò êáé óõíåðþòôç äñÜóç ôçò éíóïõëßíçò 146,147,148,149,150,151 . Ôá ìüñéá ôùíIRS ðïõ äéáèÝôïõí öùóöïñõëéùìÝíá êáôÜëïéðá óåñßíçòêáé èñåïíßíçò ðáñïõóéÜæïõí ìéêñüôåñç óõããÝíåéá ìå ôïíéíóïõëéíéêü õðïäï÷Ýá êáé ôçí 3-ÊéíÜóç öùóöáôéäõëïúíïóéôüëç 134,152 (PI3K) . Ôï ãåãïíüò áõôü ðåñéïñßæåé ôç äñÜóçôçò éíóïõëßíçò,ôçí åíåñãïðïßçóç ôçò ðñùôåúíéêÞ êéíÜóçòêáé ôç ìåôáöïñÜ ôçò ãëõêüæçò óôá êýôôáñá 153,154,155 .Óôá 3T3-L1 ëéðïêýôôáñá ç åðáãùãÞ ôïõ ïîåé-24

äùôéêïý stress ìå Ç 2O 2ðáñåìðïäßæåé ôçí ìåôáöïñÜãëõêüæçò 156,157,158 . ¼ðùò óôá ëéðïêýôôáñá Ýôóé êáé óôáL6ìõúêÜ êýôôáñá ç åíåñãïðïßçóç ôùí p38 MAP êéíáóþíáðü ôï ïîåéäùôéêü stress (Ç 2O 2) áíáóôÝëëåé ôç ìåôáöïñÜãëõêüæçò 159 . Åðéðñüóèåôá, ï ðáñÜãïíôáò íÝêñùóçòüãêïõ-á (TNF-á) äéåãåßñåé ôéò JNK/SAPK êéíÜóåò áõîÜíïíôáòÝôóé ôç öùóöïñõëßùóç êáôáëïßðùí óåñßíçò ôïõõðïóôñþìáôïò ôïõ éíóïõëéíéêïý õðïäï÷Ýá IRS-1 139,160 .¸ôóé, ç (åðáãüìåíç áðü ôçí éíóïõëßíç) öùóöïñõëßùóçõðïëåéììÜôùí ôõñïóßíçò ôïõ IRS-1 åëáôôþíåôáé êáé çäñÜóç ôçò éíóïõëßíçò ðåñéïñßæåôáé óçìáíôéêÜ.8.2. ÉÊÊâ õðïìïíÜäá, IRS ðñùôåÀíåò(ðñùôåÀíåò õðïóôñþìáôïò éíóïõëéíéêïý õðïäï÷Ýá)êáé áíôï÷Þ óôçí éíóïõëßíçÓå ìõúêÜ êýôôáñá ìå áíôï÷Þ óôçí éíóïõëßíç, Ý÷ïõíðáñáôçñçèåß õøçëÜ åðßðåäá ÉÊÊâ õðïìïíÜäáò ôïõ ÉÊÊóõìðëÝãìáôïò ôï ïðïßï åíåñãïðïéåß ôï ìåôáãñáöéêü ðõñçíéêüðáñÜãïíôá NF-êB 161 . Ç åíåñãïðïßçóç ôçò ÉÊÊâõðïìïíÜäáò ðáñåìðïäßæåé ôç äñÜóç ôçò éíóïõëßíçò .Áíôßóôñïöá, ç áíáóôïëÞ ôçò ÉÊÊâ áðü óáëéêõëéêÜ êáéPPARã áãùíéóôÝò 162,163 áðïêáèéóôÜ ôçí áíôáðüêñéóçóôçí éíóïõëßíç ôüóï in vitro üóï êáé in vivo 164,165 .Ç èåñáðåßáìå áóðéñßíç êáé óáëéêõëéêÜ åëáôôþíåé ôç öùóöïñõëßùóçôùí ìïñßùí óåñßíçò êáé áõîÜíåé ôç öùóöïñõëßùóçôçò ôõñïóßíçò óôéò ðñùôåÀíåò ôïõ IRS 152,153 . Íåüôåñá äåäïìÝíáäåß÷íïõí üôé ç åõáéóèçôïðïßçóç óôçí éíóïõëßíçðïõ ðñïêáëåß ç áäéðïíåêôßíç, ïöåßëåôáé óå áíáóôïëÞ ôçòåíåñãïðïßçóçò ôïõ NF-ê 166,167,168 .ÐåñáéôÝñù ìåëÝôåò óå êõôôáñïêáëëéÝñãåéåò,ãåíåôéêÜôñïðïðïéçìÝíá ðåéñáìáôüæùá êáé áíèñþðïõò, áðïäåéêíýïõíôç óðïõäáéüôçôá IRS-ðñùôåúíþí óôç ñýèìéóçôçò ëåéôïõñãßáò ôùí â-êõôôÜñùí ôïõ ðáãêñÝáôïò 169,170,171 .Ç öùóöïñõëßùóç êáôáëïßðùí óåñßíçò/èñåïíßíçò ôïõéíóïõëéíéêïý õðïäï÷Ýá (IR) êáé ôïõ õðïóôñþìáôüòôïõ (IRS) áðü êéíÜóåò åõáßóèçôåò óôï stress (ÍÁÊ,p38MAPK, JNK/SAPK êáé Üëëåò êéíÜóåò óåñßíçò/èñåïíßíçò)áðïôåëåß Ýíá ìç÷áíéóìü ðïõ åðéôñÝðåé ôç óõó÷Ýôéóçôùí ïäþí ðïõ åíåñãïðïéïýíôáé áðü ôï stress ìå ðïéêßëåòðáèïëïãéêÝò êáôáóôÜóåéò ôùí êõôôÜñùí.8.3.Ïîåéäùôéêü stress,ôõñïóéíéêÞ öùóöáôÜóçêáé áíôï÷Þ óôçí éíóïõëßíçÇ äéáôáñá÷Þ ôçò ïîåéäïáíáãùãéêÞò ïìïéüóôáóçòìðïñåß íá ïäçãÞóåé óå ïîåßäùóç êáé áðåíåñãïðïßçóç ôçòôõñïóéíéêÞò öùóöáôÜóçò (PTP) 172,173,174 . Åßíáé ãíùóôü üôéç öùóöïñõëßùóç ôçò ôõñïóßíçò åßíáé áðáñáßôçôç ãéá ôçí(éíóïõëéíï-åðáãüìåíç) ìåôáöïñÜ ãëõêüæçò óôá ìõúêÜêýôôáñá êáé ôá ëéðïêýôôáñá 175,176 . Ðáñüëï ðïõ ç åêëåêôéêÞêáé áíôéóôñåðôÞ áíáóôïëÞ óõãêåêñéìÝíùí PTPáóþíüðùò ôçò ÑÔÑ-1 áõîÜíåé ôç äñÜóç ôçò éíóïõëßíçò 177,178 ,ç ïîåßäùóç êõóôåúíéêþí êáôáëïßðùí óôá åíåñãÜ êÝíôñáôùí ÑÔÑáóùí, ôéò áðåíåñãïðïéåß êáé ïäçãåß óå éíóïõëéíïáíôï÷Þin vitro 163,164 .Ôï ïîåéäùôéêü stress åíåñãïðïéåß ôéò ïäïýò ôïõ NFêB,ôùí p38 MAP êáé JNK/SAPK êéíáóþí. Ç äå åíåñãïðïßçóçáõôþí ôùí ïäþí åëáôôþíåé ôçí åõáéóèçóßá óôçäñÜóç ôçò éíóïõëßíçò. Åêôüò áðü ôçí éíóïõëéíïáíôßóôáóç,ôï åðáãüìåíï áðü ôçí õðåñãëõêáéìßá ïîåéäùôéêü stressåõèýíåôáé êáé ãéá ôéò üøéìåò äéáâçôéêÝò åðéðëïêÝò.9. Ïîåéäùôéêü stress êáé äõóëåéôïõñãßá â-êõôôÜñùíôïõ ðáãêñÝáôïòÇ éíóïõëßíç ðáñÜãåôáé áðïêëåéóôéêÜ áðü ôá â-êýôôáñáôùí íçóßäùí ôïõ Langerhans ôïõ ðáãêñÝáôïò. Ôáâ-êýôôáñá ôïõ ðáãêñÝáôïò åßíáé åðéññåðÞ óôéò âëÜâåòðïõ ðñïêáëïýíôáé áðü ôï ïîåéäùôéêü stress. Ïé GLUT-2ìåôáöïñåßò ãëõêüæçò 179,180 , ç ãëõêïêéíÜóç 181,182,183 êáé êõñßùòï ìåôáâïëéóìüò ôçò ãëõêüæçò áðü ôá ìéôï÷üíäñéá ôùíâ-êõôôÜñùí, åõíïïýí ôçí Ýêêñéóç éíóïõëßíçò óå ðïóüôçôááíÜëïãç ôïõ åñåèßóìáôïò. Ðáñüëï ðïõ ïé áêñéâåßòìïñéáêïß ìç÷áíéóìïß ìå ôïõò ïðïßïõò ïé ìåôáâïëßôåò ôçòãëõêüæçò ñõèìßæïõí ôç óýíèåóç éíóïõëßíçò äåí åßíáé ãíùóôïß,åßíáé âÝâáéï üôé ï ìåôáâïëéóìüò ôïõò óôï åðßðåäïôùí ìéôï÷ïíäñßùí êáßñéáò óçìáóßáò 184,185 . Ôá ìéôï÷üíäñéááðïôåëïýí ôüðï ðáñáãùãÞò áëëÜ êáé óôü÷ï åëåõèÝñùíñéæþí. ¸ôóé ç êáôáóôñïöÞ ôùí ìéôï÷ïíäñßùí áðü äñáóôéêÝòìïñöÝò ïîõãüíïõ êáé áæþôïõ åßíáé áíáìåíüìåíï íáðåñéïñßæåé ôçí Ýêêñéóç éíóïõëßíçò.Ç åðáãüìåíç áðü ôç ÷ñüíéá õðåñãëõêáéìßá åîÜíôëçóçôùí â-êõôôÜñùí ìåëåôÞèçêå in vivo óå ãåíåôéêÜ ðñïäéáôåèåéìÝíáäéáâçôéêÜ ðåéñáìáôüæùá 186 êáé óå öõóéïëïãéêÜ ðåéñáìáôüæùáðïõ Ý÷ïõí õðïóôåß ìåñéêÞ ðáãêñåáôåêôïìÞ 174Þ ðïõ Ý÷ïõí ëÜâåé áãùãÞ ìå streptozotocin 174 (ïõóßá ôïîéêÞãéá ôá â-êýôôáñá). Óôéò in vivo áõôÝò ìåëÝôåò ï äéá÷ùñéóìüòôïí åðéðôþóåùí ðïõ ðñïêëÞèçêáí ëüãù õðåñãëõêáéìßáòáðü áõôÝò ðïõ ðñïêëÞèçêáí ëüãù Üëëùí íåõñïëïãéêþí,åíäïêñéíéêþí êáé äéáôñïöéêþí ðáñáãüíôùí Þôáí éäéáßôåñáðïëýðëïêïò. ÅðéðëÝïí ç õðåñãëõêáéìßá åëáôôþíåé ôçíçðáôéêÞ êÜèáñóç ôçò éíóïõëßíçò in vivo, ìå áðïôÝëåóìá ôáåðßðåäá ôçò éíóïõëßíçò óôç ãåíéêÞ êõêëïöïñßá íá ðáñáìÝíïõíáìåôÜâëçôá áêüìá êáé üôáí ìåéþíåôáé ç ÝêêñéóÞ ôçòáðü ôá â-êýôôáñá 187 .Én vitro, ç áíß÷íåõóç ôùí åðéðëïêþí ðïõ ðñïêáëïýíôáéáðü ÷ñüíéá Ýêèåóç óå ãëõêüæç, åßíáé éäéáßôåñá äýóêïëçóå êýôôáñá ðåéñáìáôüæùùí ÷ùñßò ãåíåôéêÞ ðñïäéÜèåóçóôï äéáâÞôç. ÅîÜìçíç åðþáóç (óå õøçëÜ åðßðåäá ãëõêüæçò)êõôôáñïêáëëéåñãåéþí áðü â-êýôôáñá ôñùêôéêþí,åëÜôôùóå ôçí Ýêêñéóç éíóïõëßíçò, ôï mRNA ôçò éíóïõëßíçòêáé ôçí ðñüóäåóç ôùí ìåôáãñáöéêþí ðáñáãüíôùí ôïõmRNA ôçò éíóïõëßíçò 188,189 . Ùóôüóï, ðáñüìïéåò ìåëÝôåòäå äéáðßóôùóáí ìåßùóç óôçí Ýêêñéóç éíóïõëßíçò êáôÜ ôçíÝêèåóç óå ãëõêüæç. Áõôü åíäå÷ïìÝíùò íá ïöåßëåôáé óôçíÝêêñéóç ôùí åíäïêõôôÜñéùí áðïèåìÜôùí éíóïõëßíçò áðüôá â-êýôôáñá. Áîßæåé íá áíáöåñèåß üôé ç ôá áðïèÝìáôáéíóïõëßíçò ðïéêßëïõí óôá äéÜöïñá ôìÞìáôá ôùí â-êõôôÜñùí.Ôáðáñáêåßìåíá óôçí êõôôáñïðëáóìáôéêÞ ìåìâñÜíçêõóôßäéá ðáñïõóéÜæïõí ìåãÜëç äéáèåóéìüôçôá éíóïõëßíçòðïõ ìðïñåß íá åêêñéèåß. ÁíôéèÝôùò,ôüóï éíóïõëßíçðïõ ðñïïñßæåôáé ãéá áðïóýíèåóç üóï êáé ç éíóïõëßíçêáé ðñïúíóïõëßíç ôïõ åíäïðëáóìáôéêïý äéêôýïõ êáé ôïõóõìðëÝãìáôïò Golgi äåí äéáôßèåíôáé ãéá Ýêêñéóç. Åðéðñüóèåôá,ôõ÷üí ìåßùóç ôïõ mRNA ôçò éíóïõëßíçò äåíåßíáé ãíùóôü áí èá åëáôôþóåé áðáñáßôçôá êáé ôç óýíèåóçéíóïõëßíçò ëüãù åìðëïêÞò ìç÷áíéóìþí ôçò ìåôÜöñáóçò.9.1. Ï ñüëïò ôùí åëåýèåñùí ëéðáñþí ïîÝùí óôçí éíóïõëéíïáíôï÷Þêáé ôç äõóëåéôïõñãßá ôùí â-êõôôÜñùíôïõ ðáãêñÝáôïò¸÷ïõí äéáôõðùèåß ðïëëÝò èåùñßåò ó÷åôéêÜ ìå ôçí åðßäñáóçôùí åëåýèåñùí ëéðáñþí ïîÝùí (FFA: Free Fatty25

Acids) óôçí áíÜðôõîç áíôï÷Þò óôçí éíóïõëßíç. Óýìöùíáìå ôç èåùñßá ôïõ P.J. Randle 190,191 õøçëÞ äéáèåóéìüôçôáFFA áõîÜíåé ôïõò ëüãïõò acetyl-CoA/CoA êáé NADH/NAD + ìå áðïôÝëåóìá:(á) ôçí áðåíåñãïðïßçóç ôïõ óõìðëüêïõ ðõñïóôáöõëéêÞòáöõäñïãïíÜóçò(â) ôçí åëÜôôùóç ïîåßäùóçò ôçò ãëõêüæçò êáé ôçí áýîçóçôïõ åíäïêõôôÜñéïõ êéôñéêïý ïîÝïò(ã) ôçí áíáóôïëÞ ôçò öùóöïöñïõêôïêéíÜóçò(ä) ôç óõóóþñåõóç ôçò öùóöáôÜóçò ôçò 6-öùóöï-ãëõêüæçòêáé(å) ôçí áíáóôïëÞ ôçò äñÜóçò ôçò åîïêéíÜóçò ÉÉ. ÊáôÜ ôïíRandle, ôá ãåãïíüôá áõôÜ ïäçãïýí óå åíäïêõôôÜñéáóõóóþñåõóç ãëõêüæçò êáé åëáôôùìÝíç ìåôáöïñÜ ãëõêüæçòóôá ìõúêÜ êýôôáñá.Óå áíôßèåóç ìå ôç èåùñßá ôïõ P.J. Randle, íåþôåñåòÝñåõíåò Ýäåéîáí üôé ç åëÜôôùóç óýíèåóçò ìõúêïý ãëõêïãüíïõìåôÜ áðü åðþáóç ìå åëåýèåñá ëéðáñÜ ïîÝá ÝãéíåìÝóù ìåßùóçò -êáé ü÷é áýîçóçò- ôùí åðéðÝäùí ôçò öùóöáôÜóçòôçò 6-öùóöï-ãëõêüæçò 192 . ÄçëáäÞ, ôá íåþôåñáäåäïìÝíá õðïóôçñßæïõí üôé ôá åëåýèåñá ëéðáñÜ ïîÝáåëáôôþíïõí ôçí åíäïêõôôÜñéá óõãêÝíôñùóç ãëõêüæçò.Óå êÜèå ðåñßðôùóç, ôï óýóôçìá ìåôáöïñÜò ôçò ãëõêüæçòóôá êýôôáñá åßíáé ôï ñõèìéóôéêü óôÜäéï ãéá ôçí åðáãüìåíçáðü ôá FFA éíóïõëéíïáíôï÷Þ 193 .Óå ìïñéáêü åðßðåäï, ðáñáôçñÞèçêå üôé ôá õøçëÜåðßðåäá åëåýèåñùí ëéðáñþí ïîÝùí ðáñåìðïäßæïõí ôçí(åðáãüìåíç áðü ôçí éíóïõëßíç) öùóöïñõëßùóç ôùí êáôáëïßðùíôõñïóßíçò óôï IRS-1 êáé áíáóôÝëëïõí ôç äñÜóçôçò PI3K (3-ÊéíÜóç öùóöáôéäõëïúíïóéôüëç) 180 .Ç üðùò óõìâáßíåé ìå ôçí õðåñãëõêáéìßá, ç åðßäñáóçôùí åëåýèåñùí ëéðáñþí ïîÝùí óôç ëåéôïõñãßá ôùíâ-êõôôÜñùí ôïõ ðáãêñÝáôïò åßíáé éäéáßôåñá ðïëýðëïêç.ÁõîçìÝíá åðßðåäá FFA ðáñåìðïäßæïõí ôçí Ýêêñéóç éíóïõëßíçòôüóï in vivo üóï êáé in vitro 194 ãåãïíüò ðïõ áðïäßäåôáéóôç óõóóþñåõóç åóôÝñùí áêåôõëï-óõíåíæýìïõ Áóôï êõôôáñüðëáóìá 182,195 . 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When compensatoryresponse from the endogenous antioxidant networkis absent or deficient, imbalance between ROSsynthesis and damage leads to the activation of stresssensitiveintracellular signaling pathways. Activationof signaling pathways is connected with insulinresistance, impaired insulin secretion (through â-celldysfunction) and diabetic complications. The presentreview attempts to present the biochemical pathwaysby which hyperglycemia- and FFA-induced oxidativestress causes insulin resistance, â-cell dysfunction andcomplications of diabetes.The ability of antioxidants to protect against invitro, along with the clinical benefits often reportedfollowing Clinical trials antioxidant therapy, supportsthe causative role of oxidative stress in mediating and/or worsening these abnormalities. 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ÁÑÈÑÏ ÅÐÉÓÊÏÐÇÓÇÓÐåñßëçøçÓýíôïìç Áíáóêüðçóç ôïõ Âéïëïãéêïý Ñüëïõêáé ôùí Öáñìáêåõôéêþí ÉäéïôÞôùí ôçò Ôáõñßíçò.×ñÞóåéò, åöáñìïãÝò êáé ðñïïðôéêÝò.Ó. ÊÝëëá 1 , Ð. ÐëáãåñÜò 2 , Á. ÐáðáúùÜííïõ 2 , É. Áíáóôáóïðïýëïõ 1 , È. Èåïöáíßäçò 11. Åèíéêü Ìåôóüâéï Ðïëõôå÷íåßï, Ó÷ïëÞ ×çìéêþí Ìç÷áíéêþí, Áêôéíï÷çìåßá & Âéïöáóìáôïóêïðßá,Ðïëõôå÷íåéïýðïëç ÆùãñÜöïõ, 15780 ÆùãñÜöïõ, ÁèÞíá2. Ôå÷íïëïãéêü Åêðáéäåõôéêü ºäñõìá ËÜñéóáò, ÔìÞìá Éáôñéêþí åñãáóôçñßùí,ÔïìÝáò Âéï÷çìåßáò-ÊëéíéêÞò ×çìåßáòÅéóáãùãÞÇ ôáõñßíç (2-áìéíï-áéèáíï-óïõëöïíéêü ïîý) åßíáéÝíá “êáôÜ óõíèÞêç áðáñáßôçôï” áìéíïîý ìå ðïëõÜñéèìåòöáñìáêåõôéêÝò ôçò éäéüôçôåò. Áðïôåëåß ôï “óïõëöïíéêü”áíÜëïãï ôçò â-áëáíßíçò, åöüóïí óôçí èÝóç ôçò êáñâïîõëéêÞòïìÜäáò ðåñéÝ÷åé óïõëöïíéêÞ ïìÜäá êáé åðïìÝíùòìðïñåß íá áðïêáëåßôáé óïõëöïíéêü áìéíïîý.Ç ôáõñßíç áíáêáëýöèçêå óôçí ÷ïëÞ ôáýñïõ ôï 1827êáé ìüëéò ôï 1975 Üñ÷éóå íá ãßíåôáé áíôéëçðôÞ ç óðïõäáéüôçôÜôçò óôç äéáôñïöÞ.×áñáêôçñéóôéêÝò öáñìáêåõôéêÝò äñÜóåéò ôçò ôáõñßíçòåßíáé ç áíôéïîåéäùôéêÞ, êáñäéáããåéáêÞ, ìåôáâïëéêÞ,êáé áðïôïîéíùôéêÞ ôçò äñÜóç. Ç ôáõñßíç åðéðëÝïí ÷ñçóéìåýåéãéá ôçí ðÝøç ôùí ëéðþí, ôçí áðïññüöçóç ôùí ëéðïäéáëõôþíâéôáìéíþí êáé ãéá ôïí Ýëåã÷ï ôùí åðéðÝäùí÷ïëçóôåñüëçò óôï áßìá. ÓõììåôÝ÷åé óôçí äéáôÞñçóç ôçòáêåñáéüôçôáò ôçò êõôôáñéêÞò ìåìâñÜíçò, óôçí ðñïöýëáîçôùí óðåñìáôïæùáñßùí êáé óôçí ñýèìéóç ôçò ïóìùôéêÞòðßåóçò. Ðáßæåé åðßóçò ïõóéþäç ñüëï óôçí ëåéôïõñãßáôùí íåõñþíùí, óôçí áíáðáñáãùãÞ ôùí êõôôÜñùí êáéóôçí ðñïþèçóç ôçò ãëõêüëõóçò.Ç ôáõñßíç äñá óå ðÜñá ðïëëÜ âéïëïãéêÜ óõóôÞìáôá,üðùò óôï êáñäéáããåéáêü óýóôçìá, óôï Þðáñ, óôá ìÜôéá,óôï êåíôñéêü íåõñéêü óýóôçìá, óôï áíáðáñáãùãéêü óýóôçìá,óôïõò ìýåò. ÅðéðëÝïí ï ñüëïò ôçò ôáõñßíçò óôçíáíÜðôõîç êáé ôçí åðéâßùóç ôùí êõôôÜñùí åßíáé õøßóôçòóçìáóßáò. Ç ðáñïõóßá ôçò öáßíåôáé íá åßíáé êáèïñéóôéêÞóôçí áíáðáñáãùãÞ êáé ôçí âéùóéìüôçôá ôùí êõôôÜñùí.Ç ÷ñÞóç ôçò ôáõñßíçò ãéá èåñáðåõôéêïýò óêïðïýò ÷ñÞæåéðåñáéôÝñù äéåñåýíçóçò, ðñéí ãßíåé îåêÜèáñïò ï ñüëïòôçò óå êÜðïéåò ðáèÞóåéò, éäéáßôåñá óôçí åðéëçøßá êáé ôïíáëêïïëéóìü. Åðßóçò ðñÝðåé íá ìåëåôçèåß ðåñéóóüôåñï çáëëçëåðßäñáóÞ ôçò ìå Üëëá äéáôñïöéêÜ óôïé÷åßá, üðùò ïéâéôáìßíåò êáé ôá ìÝôáëëá êáé íá äïèåß éäéáßôåñç ðñïóï÷Þóôç óçìáóßá ðïõ ìðïñåß íá Ý÷åé ç ÷áìçëÞ óõãêÝíôñùóÞôçò óôï áßìá áóèåíþí ìå êáñêßíï. Ç ÷ñçóéìüôçôÜ ôçò óôçíäéáôñïöÞ êáé óôçí ðñïëçðôéêÞ éáôñéêÞ åßíáé óáöþò êáôáäåäåéãìÝíçêáé äéêáßùò ÷áñáêôçñßóôçêå ùò “êáôÜ óõíèÞêç”áðáñáßôçôï áìéíïîý.Ç ôáõñßíç, åêôüò ôùí èåñáðåõôéêþí ôçò äñÜóåùíêáé éäéïôÞôùí, åßíáé êáé Ýíáò äõíçôéêüò õðïêáôáóôÜôçò(ligand) óå åíþóåéò óõíáñìïãÞò ìå ìåôáëëéêÜ éüíôá, ëüãùôçò äïìÞò ôçò. Ç óïõëöïíéêÞ ïìÜäá êáé ç áìéíïìÜäá ðïõäéáèÝôåé ôï ìüñéï åßíáé äõíáôüí íá óõíäåèïýí ìå ìåôáëëéêÜéüíôá, ìÝóù ôùí áôüìùí Ï êáé Í áíôßóôïé÷á.34REVIEW ARTICLEÖÁÑÌÁÊÅÕÔÉÊÇ 24, I-II, 34-39, 2012 PHARMAKEFTIKI 24, I-II, 34-39, 2012Ç ôáõñßíç (2-áìéíï-áéèáíï-óïõëöïíéêü ïîý) Ý÷åéáðáó÷ïëÞóåé ôéò ôåëåõôáßåò äåêáåôßåò ôï åðéóôçìïíéêüåíäéáöÝñïí þóôå íá êáèïñéóôåß ï âéïëïãéêüò ñüëïò ôçòêáé ïé ðïëõÜñéèìåò öáñìáêåõôéêÝò ôçò éäéüôçôåò, åöüóïíï ìç÷áíéóìüò äñÜóçò ôçò äåí Ý÷åé áðïëýôùò äéåõêñéíéóèåß,üðùò öáßíåôáé áðü ôçí ÄéåèíÞ Âéâëéïãñáößá. Çôáõñßíç Ýãéíå ãíùóôÞ óôï åõñý êïéíü êáé óáí óõóôáôéêüôùí áíáøõêôéêþí åíÝñãåéáò, üðùò åßíáé ôï Red Bull.Ç ôáõñßíç åßíáé Ýíá êáôÜ óõíèÞêç áðáñáßôçôï áìéíïîý,ôï ïðïßï äåí ëáìâÜíåé ìÝñïò óôçí ðñùôåúíéêÞ óýíèåóç,áëëÜ óõíáíôÜôáé åëåýèåñï Þ óå áðëÜ ðåðôßäéá 1 . Çôáõñßíç ìðïñåß íá èåùñçèåß ôï “óïõëöïíéêü” áíÜëïãïôçò â-áëáíßíçò, ãéáôß óôçí èÝóç ôçò êáñâïîõëéêÞò ïìÜäáòðåñéÝ÷åé óïõëöïíéêÞ ïìÜäá êáé åðïìÝíùò ìðïñåß íááðïêáëåßôáé óïõëöïíéêü áìéíïîý. Óôï Ó÷Þìá 1a öáßíåôáéï ÷çìéêüò ôýðïò ôçò ôáõñßíçò, åíþ óôï Ó÷Þìá 1b äßíåôáéç äééïíôéêÞ (switterionic) ìïñöÞ ôçò, ç ïðïßá áðïêôÜôáéáìÝóùò ìå ôçí äéÜëõóç óôï íåñü, áêüìá êáé óå öõóéïëïãéêüpH. Ôï Ó÷Þìá 2 åßíáé ç ôñéóäéÜóôáôç áðåéêüíéóç ôïõìïñßïõ ôçò ôáõñßíçò.Ó÷Þìá 1. a ×çìéêüò ôýðïò ôçò ôáõñßíçòb Äééüí (switterion) ôáõñßíçòÓ÷Þìá 2. ÌïñéáêÞ áðåéêüíéóç ôçò ôáõñßíçò

×çìéêÞ ÄïìÞ-ÐñïÝëåõóçÇ ôáõñßíç áíáêáëýöèçêå óôçí ÷ïëÞ ôáýñïõ ôï 1827,áðü ôïí áõóôñéáêü åðéóôÞìïíá Friedrich Tiedemann êáéôïí Ãåñìáíü Leopold Gmellin 2 . Ãéá ìåãÜëï äéÜóôçìáåèåùñåßôï ùò ôåëéêü ðñïúüí ôïõ ìåôáâïëéóìïý ôùí èåéïý÷ùíáìéíïîÝùí êáé ìüëéò ôï 1975 Üñ÷éóå íá ãßíåôáéáíôéëçðôÞ ç óðïõäáéüôçôÜ ôçò óôç äéáôñïöÞ 3,4 . ÓÞìåñáÝ÷åé ðëÝïí áðïäåé÷ôåß üôé ç ôáõñßíç åßíáé áðáñáßôçôç ãéáôçí áíÜðôõîç ôùí èçëáóôéêþí 5 êáé Ýñåõíåò Ý÷ïõí äåßîåéüôé ÷áìçëÜ åðßðåäá ôáõñßíçò óôïí ïñãáíéóìü óõíäÝïíôáéìå ðïéêßëåò ðáèïëïãéêÝò êáôáóôÜóåéò, üðùò êáñäéïìõïðÜèåéá,åêöõëéóìü ôïõ áìöéâëçóôñïåéäÞ ÷éôþíá ôïõìáôéïý 6 , êáèõóôÝñçóç ôçò áíÜðôõîçò 7 , áäõíáìßá ôùí êõôôÜñùííá åðéâéþóïõí, ìåéùìÝíç åãêåöáëéêÞ ëåéôïõñãßá,óáê÷áñþäç äéáâÞôç, áêüìá êáé åðéëçøßá.Óôéò ðïëõÜñéèìåò âéïëïãéêÝò êáé öáñìáêåõôéêÝòäñÜóåéò ôçò ôáõñßíçò óõãêáôáëÝãïíôáé ç áíôéïîåéäùôéêÞ,êáñäéáããåéáêÞ, ìåôáâïëéêÞ, êáé áðïôïîéíùôéêÞ ôçòäñÜóç 8 . Ç ôáõñßíç ÷ñçóéìåýåé ãéá ôçí ðÝøç ôùí ëéðþí,ôçí áðïññüöçóç ôùí ëéðïäéáëõôþí âéôáìéíþí êáé ãéá ôïíÝëåã÷ï ôùí åðéðÝäùí ÷ïëçóôåñüëçò óôï áßìá. ÓõììåôÝ÷åéóôçí äéáôÞñçóç ôçò áêåñáéüôçôáò ôçò êõôôáñéêÞò ìåìâñÜíçò,óôçí ðñïöýëáîç ôùí óðåñìáôïæùáñßùí êáé óôçíñýèìéóç ôçò ïóìùôéêÞò ðßåóçò 9 . Ðáßæåé åðßóçò ïõóéþäçñüëï óôçí ëåéôïõñãßá ôùí íåõñþíùí, óôçí áíáðáñáãùãÞôùí êõôôÜñùí êáé óôçí ðñïþèçóç ôçò ãëõêüëõóçò 10 .Ç ôáõñßíç âñßóêåôáé óå áöèïíßá óôï æùéêü âáóßëåéï 10 ,åíþ áðïõóéÜæåé ðëÞñùò áðü ôï öõôéêü âáóßëåéï. Âñßóêåôáéóå õøçëÝò óõãêåíôñþóåéò óôïõò óêåëåôéêïýò ìõò,óôçí êáñäéÜ, óôïõò íåõñþíåò, óôá öáãïêýôôáñá, óôïíåãêÝöáëï, óôï åíôåñéêü óýóôçìá êáé óå ðïëëïýò Üëëïõòéóôïýò. Ïé åíÞëéêåò, áëëÜ ü÷é ôá ðáéäéÜ, Ý÷ïõí ôçí éêáíüôçôáíá óõíèÝôïõí ôáõñßíç óå ìéêñÝò ðïóüôçôåò, ãé áõôüèåùñåßôáé üôé ç ôáõñßíç ðñÝðåé íá ëáìâÜíåôáé ìÝóù ôçòäéáôñïöÞò.ÂéïëïãéêÞ ÄñÜóçÇ ôáõñßíç äñá óå ðÜñá ðïëëÜ âéïëïãéêÜ óõóôÞìáôá 11 .• Êáñäéáããåéáêü óýóôçìáÓôçí êáñäéÜ áðáíôÜôáé ðåñéóóüôåñï áðü ôï ìéóüôïõ óõíïëéêïý áðïèÝìáôïò ôáõñßíçò óôïí ïñãáíéóìü. Çôáõñßíç åðçñåÜæåé èåôéêÜ ôçí éêáíüôçôá óýóðáóçò ôïõêáñäéáêïý ìõüò (éíïôñïðéêÞ äñÜóç) 13,14 êáé ìåéþíåé ôçíðßåóç ôïõ áßìáôïò 15,16 . Ç ðñïóôáóßá ðïõ ðáñÝ÷åé óôïíêáñäéáêü éóôü, ðïëý ðéèáíüí íá ïöåßëåôáé óôçí éêáíüôçôÜôçò íá ñõèìßæåé ôá åíäïêõôôáñéêÜ åðßðåäá ôùí éüíôùíCa 2+ , ìåôáâÜëëïíôáò ôçí éïíôéêÞ åíåñãüôçôá ôùíêáíáëéþí ìåôáêßíçóÞò ôïõò äéáìÝóïõ ôçò êõôôáñéêÞòìåìâñÜíçò 17,18 . Ç åíäïêõôôÜñéá óõóóþñåõóç ìåãÜëçò ðïóüôçôáòéüíôùí áóâåóôßïõ ïäçãåß óå êõôôáñéêü èÜíáôï.Ç ðáñïõóßá ôçò ôáõñßíçò áðïôñÝðåé ôï öáéíüìåíï áõôüêáé êáôÜ óõíÝðåéá ôçí ìõïêáñäéáêÞ âëÜâç 19 . Ç ôáõñßíç,ëüãù ôïõ åõêßíçôïõ õäñïãüíïõ ðïõ ðåñéÝ÷åé ðáñåìâáßíåéðñïóôáôåõôéêÜ óôïí êáñäéáêü éóôü êáé ìÝóù ôùí áíôéïîåéäùôéêþíôçò éäéïôÞôùí 20 . Äåóìåýåé ôéò åëåýèåñåò ñßæåòðïõ ðáñÜãïíôáé áðü ôçí áíáðíåõóôéêÞ äñáóôçñéüôçôáôùí ïõäåôåñüöéëùí, êáôÜ ôçí öëåãìïíþäç áíôßäñáóçóôçí áðïêáôÜóôáóç ôçò áéìÜôùóçò ôïõ éóôïý, ìåôÜ áðüéó÷áéìéêü åðåéóüäéï, ðñïëáìâÜíïíôáò ìå ôçí äñÜóç ôçòáõôÞ, ôçí ðñüêëçóç âëÜâçò.• ¹ðáñÔï Þðáñ áðïôåëåß äåîáìåíÞ ÷ïëéêþí ïîÝùí, ôá ïðïßáÝ÷ïõí áðïññõðáíôéêÞ äñÜóç óôçí ãáëáêôùìáôïðïßçóçêáé áðïññüöçóç ôùí ëéðéäßùí êáé ôùí ëéðïäéáëõôþí âéôáìéíþí.Ôçí äñÜóç áõôÞ ôçí áóêïýí ìÝóù ôùí ÷ïëéêþíáëÜôùí, ôá ïðïßá åîáéôßáò ôùí ëéðüöéëùí êáé õäñüöéëùíôìçìÜôùí ôïõ ìïñßïõ ôïõò, åëáôôþíïõí ôçí åðéöáíåéáêÞôÜóç, ó÷çìáôßæïíôáò ìéêêýëéá. Áðü ôïí çðáôéêü ìåôáâïëéóìüôçò ÷ïëçóôåñüëçò ðáñÜãïíôáé ÷ïëéêÜ ïîÝá 2 . Ç äé-Üëõóç ôùí ïîÝùí áõôþí, ãßíåôáé ìå ôçí óõíáñìïãÞ ôïõòìå ôçí ãëõêßíç êáé ôçí ôáõñßíç, ìÝóù ðåðôéäéêïý äåóìïý,ïðüôå ðñïêýðôïõí ÷ïëéêÜ Üëáôá, ðïõ åßíáé ðëÞñùò éïíéóìÝíáóå öõóéïëïãéêü pH êáé åðïìÝíùò ðëÞñùò äéáëõôÜ,óå áíôßèåóç ìå ôá áíôßóôïé÷á åëåýèåñá ÷ïëéêÜ ïîÝá. Ôá÷ïëéêÜ Üëáôá ôçò ôáõñßíçò åßíáé ðéï õäáôïäéáëõôÜ áð’áõôÜ ôçò ãëõêßíçò êáé ðáñáìÝíïõí éïíéóìÝíá áêüìá êáéóå ðéï üîéíåò óõíèÞêåò 21 . Ï éïíéóìüò åßíáé áðáñáßôçôïòãéáôß åìðïäßæåé ôçí êáôáâýèéóç ôùí ÷ïëéêþí ïîÝùí. Ç óõíáñìïãÞôçò ôáõñßíçò óôá ÷ïëéêÜ Üëáôá Ý÷åé óçìáíôéêÞåðßäñáóç óôçí äéáëõôüôçôá ôçò ÷ïëçóôåñüëçò, áõîÜíïíôáòôçí áðïâïëÞ ôçò áðü ôïí ïñãáíéóìü êáé ìåéþíïíôáòôá åðßðåäÜ ôçò óôïí ïñü ôïõ áßìáôïò 22 .• ÏöèáëìïßÏ áìöéâëçóôñïåéäÞò ÷éôþíáò åßíáé ï éóôüò ìå ôçíõøçëüôåñç óõãêÝíôñùóç ôáõñßíçò. ¸ñåõíåò (óå ãÜôåò)Ýäåéîáí üôé ç Ýëëåéøç ôáõñßíçò åðéöÝñåé áëëáãÝòóôïõò öùôïäÝêôåò Ýùò êáé ìüíéìï åêöõëéóìü ôïõáìöéâëçóôñïåéäïýò 23 . Ðéóôåýåôáé üôé ç ôáõñßíç ðñïóôáôåýåéêáé äéáôçñåß ôçí äïìÞ êáé ôçí ëåéôïõñãßá ôùí êõôôÜñùíáõôþí, ñõèìßæïíôáò ôçí ïóìùôéêÞ ðßåóç, ðáñåìðïäßæïíôáòôçí öùóöïñõëßùóç ôùí ìåìâñáíéêþí ðñùôåúíþíêáé áðïôñÝðïíôáò ïîåéäùôéêÝò äñÜóåéò 24 .• Êåíôñéêü íåõñéêü óýóôçìáÇ ôáõñßíç åßíáé ôï ìïíáäéêü áìéíïîý ôïõ åãêåöÜëïõ,ôïõ ïðïßïõ ç óõãêÝíôñùóç ìåéþíåôáé êáôÜ ôçí áíÜðôõîç,ãåãïíüò ðïõ õðïäçëþíåé üôé ç ôáõñßíç ðéèáíüí íá óõíäÝåôáéìå ôçí áíÜðôõîç ôïõ åãêåöÜëïõ. ×áñáêôçñéóôéêüåðßóçò åßíáé ôï üôé óå áíôßèåóç ìå ôçí ðïóüôçôá ôáõñßíçòôùí Üëëùí ïñãÜíùí, ôá åðßðåäá ôçò óôïí åãêÝöáëï äéáôçñïýíôáéóå ðåñéðôþóåéò áíåðÜñêåéáò 25 . ÐéèáíÝò äñÜóåéòôçò ôáõñßíçò óôïí åãêÝöáëï åßíáé ç ñýèìéóç ôçò äéåãåñôéêüôçôáòôùí íåõñþíùí, ç äéáôÞñçóç ôçò ëåéôïõñãßáò ôçòðáñåãêåöáëßäáò êáé ç ñýèìéóç ôçò Ýêêñéóçò ïñìïíþí.Äñá åðßóçò óáí áíáóôáëôéêüò íåõñïäéáâéâáóôÞò êáé óáíáíôéóõóôáëôéêü ìÝóï 26 . Ç ôáõñßíç ìåéþíåé ôçí äéÝãåñóçôùí íåõñþíùí, ðïëþíïíôáò ôéò ìåìâñÜíåò, ïðüôå áõîÜíïõíôçí äéáðåñáôüôçôá ôùí éüíôùí ÷ëùñßïõ. Ôçí äñÜóçáõôÞ, íá óôáèåñïðïéåß ôéò ìåìâñÜíåò êáôÜ ôçí äéÝãåñóç,ç ôáõñßíç ôçí áóêåß óå üëïõò ôïõò éóôïýò ðïõ äÝ÷ïíôáéåñåèßóìáôá 27 .35

• Áíáðáñáãùãéêü óýóôçìáÇ ôáõñßíç äéáôçñåß ôçí êéíçôéêüôçôá ôùí óðåñìáôïæùáñßùíêáé åíéó÷ýåé ôçí éêáíüôçôÜ ôïõò ãéá ãïíéìïðïßçóç,âåëôéþíïíôáò Ýôóé ôçí ãïíéìüôçôá 9 .• Ìõéêü óýóôçìáÇ ôáõñßíç ðáßæåé óôáèåñïðïéçôéêü ñüëï ãéá ôéò ìåìâñÜíåòôùí ìõþí. ÁõîÜíåé êáé áíáðáñÜãåé ôçí ôïíéêüôçôáôùí ìõþí. ÊáôÜ ôçí äéÜñêåéá ìõúêÞò ðñïóðÜèåéáò,ìðïñåß íá ðáñáôçñçèåß ÝëëåéøÞ ôçò, ãé áõôü ç ôáõñßíçìðïñåß íá ÷áñáêôçñéóôåß ùò ïõóßá ôçò äýíáìçò• ÕðïãëõêáéìéêÞ äñÜóçÓçìáíôéêÞ åßíáé ç äñÜóç ôçò ôáõñßíçò ùò õðïãëõêáéìéêüòðáñÜãïíôáò. Åðéôõã÷Üíåé ìåßùóç ôùí åðéðÝäùíãëõêüæçò óôï áßìá, éó÷õñïðïéþíôáò ôçí äñÜóç ôçò éíóïõëßíçòìåéþíïíôáò ôçí ÝêêñéóÞ ôçò êáé êáô’ åðÝêôáóç ôçíóõãêÝíôñùóÞ ôçò óôï áßìá. Áõôü ðéèáíüí íá ïöåßëåôáéóôçí áëëçëåðßäñáóç ôçò ôáõñßíçò ìå ôïõò õðïäï÷åßò ôçòéíóïõëßíçò 28 . Ìéá Üëëç åðßóçò ðïëý óçìáíôéêÞ äñÜóç,åßíáé ç áðïôïîéíùôéêÞ ôçò äñÜóç, ðïõ ðçãÜæåé áðü ôçíéêáíüôçôÜ ôçò íá åîïõäåôåñþíåé ôïîéêÝò êáé ìåôáëëáîéïãüíåòïõóßåò, ðïõ ðáñÜãïíôáé óôï áíèñþðéíï óþìáÞ ðïõ åéóÝñ÷ïíôáé óôïí ïñãáíéóìü áðü ôï åîùôåñéêüðåñéâÜëëïí 24 . Äåí åßíáé ôõ÷áßï ôï ãåãïíüò üôé ç óõãêÝíôñùóÞôçò åßíáé ìåãÜëç óôïõò éóôïýò, óôïõò ïðïßïõò ðáñÜãïíôáéõøçëÜ åðßðåäá ïîåéäùôéêþí ïõóéþí. Ôï õðï-÷ëùñéêü ïîý (HClO), ðïõ ðñïÝñ÷åôáé áðü ôçí äñÜóç ôùíïõäåôåñüöéëùí, åßíáé Ýíá ðïëý éó÷õñü ïîåéäùôéêü, ôïïðïßï áíôéäñÜ ìå ìéá óåéñÜ âéï÷çìéêþí åíþóåùí, óõìðåñéëáìâáíïìÝíùíôùí áìéíïîÝùí, ó÷çìáôßæïíôáò åîáéñåôéêÜôïîéêÝò áëäåàäåò, ðïõ ðñïîåíïýí âëÜâç óôï DNA.Ç ìïíáäéêÞ äïìÞ ôçò ôáõñßíçò, ìå ôçí óïõëöïíéêÞ ïìÜäáóôç èÝóç ôçò êáñâïîõëéêÞò, ôçò åðéôñÝðåé, áíôéäñþíôáòìå ôï õðï÷ëùñéêü ïîý, íá ó÷çìáôßæåé áíôß ôçò ôïîéêÞò áëäåàäçòìéá ó÷åôéêÜ óôáèåñÞ ÷ëùñáìßíç 29 , ëåéôïõñãþíôáòêõôôáñïðñïóôáôåõôéêÜ. ÕðÜñ÷ïõí áíáöïñÝò êáé ãéá ôçíðñïóôáôåõôéêÞ äñÜóç ôçò ôáõñßíçò êáôÜ ôçò ôïîéêüôçôáòôïõ ôåôñá÷ëùñÜíèñáêá (CCl 4) ðïõ åíÝ÷åé êéíäýíïõò ãéáôá çðáôïêýôôáñá 30 , üðùò åðßóçò õðÜñ÷ïõí áíáöïñÝòãéá ôçí ðñïóôáóßá ðïõ ðáñÝ÷åé áðü âëÜâåò, ðïõ ìðïñåßíá ðñïêëçèïýí áðü âáêôçñéáêÝò åíäïôïîßíåò åíôåñéêÞòðñïÝëåõóçò 31 . Ç ÷ïñÞãçóÞ ôçò ãéá áðïôïîéíùôéêïýò óêïðïýòðñïÝñ÷åôáé áðü ôçí éêáíüôçôÜ ôçò íá âéïìåôáôñÝðåéêáé íá åîïõäåôåñþíåé ôïîéêÝò êáé åðéâëáâåßò ïõóßåò.• Ôáõñßíç óôï êõôôáñéêü åðßðåäïÏ ñüëïò ôçò ôáõñßíçò óôçí áíÜðôõîç êáé ôçí åðéâßùóçôùí êõôôÜñùí åßíáé õøßóôçò óçìáóßáò. Ç ðáñïõóßá ôçòöáßíåôáé íá åßíáé êáèïñéóôéêÞ óôçí áíáðáñáãùãÞ êáé ôçíâéùóéìüôçôá ôùí êõôôÜñùí. Óýìöùíá ìå ìéá õðüèåóç 12 ,äýï åßíáé ôá ðåäßá äñÜóçò ôçò. Ôï ðñþôï åßíáé ç êõôôáñéêÞìåìâñÜíç. Ç ïìïéüôçôá ôçò äé-éïíéêÞò (switterionic) äïìÞòôçò ìå ôçí äïìÞ ôùí ïõäÝôåñùí öùóöïëéðéäßùí ôçò êõôôáñéêÞòìåìâñÜíçò, öùóöáôéäõëï÷ïëßíçò êáé öùóöáôéäõëïáéèáíïëáìßíçò,åðéöÝñåé áëëáãÞ óå êÜðïéåò ìåìâñáíéêÝòëåéôïõñãßåò, åéäéêÜ ó’ áõôÝò óôéò ïðïßåò åìðëÝêåôáé ôïáóâÝóôéï. Ïé êýñéåò èÝóåéò óýíäåóçò ôùí êáôéüíôùí áóâåóôßïõ(Ca 2+ ) óôéò êõôôáñéêÝò ìåìâñÜíåò, åßíáé ïé üîéíåòïìÜäåò ôùí öùóöïëéðéäßùí, ìå ôéò ïðïßåò ç ôáõñßíç ìðïñåßíá áëëçëåðéäñÜ, ó÷çìáôßæïíôáò æåýãç éüíôùí, ìå óõíÝðåéáôçí ìåôáâïëÞ ôçò äéáìüñöùóçò ôùí ìåìâñáíþí, áëëÜ êáéôçò ÷çìéêÞò óõããÝíåéáò êáé ôïõ áñéèìïý ôùí èÝóåùí óõíáñìïãÞòôùí êáôéüíôùí 32 . Ç åðßäñáóç ôçò ôáõñßíçò óôéòêõôôáñéêÝò ìåìâñÜíåò åðçñåÜæåé êáé Üëëá ëéðéäï-åîáñôþìåíáöáéíüìåíá, üðùò åßíáé ç ëåéôïõñãßá ôùí êáíáëéþíìåôáöïñÜò éüíôùí, ç óýíäåóç äéáöüñùí åíæýìùí óôéò ìåìâñÜíåòêáé ç öùóöïñõëßùóç ôùí ðñùôåúíþí.Åðßóçò, ç áëëçëåðßäñáóç ôçò ôáõñßíçò ìå ôçí ìåìâñÜíçôïõ êõôôÜñïõ åíäå÷ïìÝíùò íá ïöåßëåôáé êáé óôçíäõíáôüôçôÜ ôçò íá ó÷çìáôßæåé äåóìïýò õäñïãüíïõ. ¼ðùòöáßíåôáé óôï Ó÷Þìá 3Á ïé äåóìïß õäñïãüíïõ ó÷çìáôßæïíôáéìåôáîý åíüò áôüìïõ õäñïãüíïõ ôçò áìéíïìÜäáò êáéåíüò áôüìïõ ïîõãüíïõ ôçò óïõëöïíéêÞò ïìÜäáò åíüò ìïñßïõôáõñßíçò êáé ôùí áôüìùí ïîõãüíïõ êáé õäñïãüíïõôùí áíôßóôïé÷ùí ïìÜäùí åíüò Üëëïõ ìïñßïõ ôáõñßíçò. Çóýíäåóç áõôÞ ó÷çìáôßæåé äáêôýëéï. Åßíáé üìùò äõíáôüííá áíáðôõ÷èïýí äåóìïß õäñïãüíïõ áíÜìåóá óå äõï ãåéôïíéêÜìüñéá ôáõñßíçò óå ãñáììéêÞ äéÜôáîç, üðùò öáßíåôáéóôï Ó÷Þìá 3Â.Ó÷Þìá 3. Ó÷çìáôéêÞ ðáñÜóôáóç ôùí äåóìþí õäñïãüíïõìåôáîý ôùí ìïñßùí ôçò ôáõñßíçò. Á: êõêëéêÞ äéÜôáîç,Â: åõèýãñáììç äéÜôáîçÔï äåýôåñï ðåäßï äñÜóçò ôçò ôáõñßíçò åßíáé ôï êõôôáñüðëáóìá.Ç ôáõñßíç èåùñåßôáé Ýíáò ðïëý êáëüò ñõèìéóôÞòôçò ïóìùôéêÞò ðßåóçò ôïõ êõôôÜñïõ. Ðñïóáñìüæåôáéðïëý ãñÞãïñá óôéò ïóìùôéêÝò ìåôáâïëÝò åðéôñÝðïíôáò ôçíåðéâßùóç ôïõ êõôôÜñïõ óå ïðïéïäÞðïôå åîùêõôôáñéêü ðåñéâÜëëïí.Ç éêáíüôçôÜ ôçò áõôÞ ðñïÝñ÷åôáé áðü ôçí ÷çìéêÞêáé ìåôáâïëéêÞ ôçò áäñÜíåéá, áëëÜ êáé áðü ôçí ìéêñÞëéðïäéáëõôüôçôÜ ôçò, ðïõ äåí ôçò åðéôñÝðåé íá âãáßíåé Ýîùáðü ôï êýôôáñï, Ýôóé þóôå íá äéáôçñåßôáé ï êõôôáñéêüòüãêïò êáé ôá õøçëÜ åíäïêõôôÜñéá åðßðåäÜ ôçò 2,32 .36

ÖáñìáêåõôéêÝò åöáñìïãÝòÇ ôáõñßíç âñßóêåé ðïëõÜñéèìåò öáñìáêåõôéêÝò åöáñìïãÝò,ëüãù ôùí åõåñãåôéêþí ôçò áðïôåëåóìÜôùí óå ðïëëÜóõóôÞìáôá ôïõ ïñãáíéóìïý. Ìðïñåß íá ÷ñçóéìïðïéçèåßãéá ôçí áíáêïýöéóç ôùí óõìðôùìÜôùí ôïõ åìöñÜãìáôïòôïõ ìõïêáñäßïõ, ÷ùñßò ðáñåíÝñãåéåò 33 êáé ùò ìÝóï êáôÜôùí áññõèìéþí. ¸ñåõíåò Ýäåéîáí üôé óôçí õðåñ÷ïëçóôåñéíáéìßáç ôáõñßíç áõîÜíåé ôçí äéáëõôüôçôá ôçò ÷ïëçóôåñüëçòêáé åðïìÝíùò ôçí áðÝêêñéóÞ ôçò áðü ôïí ïñãáíéóìü,ìåéþíïíôáò ôá åðßðåäÜ ôçò óôïí ïñü ôïõ áßìáôïò 22 .Ìðïñåß íá ÷ïñçãçèåß ôáõñßíç óôçí êõóôéêÞ ßíùóç, óôçíïðïßá ïé áóèåíåßò õðïöÝñïõí áðü êáêÞ áðïññüöçóç ôùíôñïöþí, åðåéäÞ áðïäåß÷ôçêå üôé ðåñéïñßæåé ôá óõìðôþìáôáôçò íüóïõ áõôÞò 34 . Ç èåôéêÞ ôçò åðßäñáóç Ý÷åé áðïäåé÷ôåßêáé ãéá ôçí ïîåßá çðáôßôéäá 35 êáé ôïí óáê÷áñþäçäéáâÞôç. Ç ôáõñßíç äåí ÷ñçóéìïðïéåßôáé óôçí êëéíéêÞðñÜîç ãéá ôçí íüóï Alzheimer, ðáñÜ ôï ãåãïíüò üôé ôáåðßðåäÜ ôçò âñÝèçêáí ÷áìçëÜ óôï åãêåöáëïíùôéáßï õãñüáóèåíþí óå ðñï÷ùñçìÝíá óôÜäéá ôçò íüóïõ êáé ðáñüôéôá ðïëý ÷áìçëÜ åðßðåäá ôïõ íåõñïäéáâéâáóôÞ áêåôõëï-÷ïëßíç, ðïõ åßíáé ôï ÷áñáêôçñéóôéêü ôçò íüóïõ, áõîÞèçêáíìåôÜ áðü ÷ïñÞãçóç ôáõñßíçò óå ðåéñáìáôüæùá 36 . Ç÷ñÞóç ôçò óå ïöèáëìïëïãéêÝò ðáèÞóåéò åíéó÷ýåôáé áðüôï ãåãïíüò üôé ç ôáõñßíç åßíáé ôñïöéêüò ðáñÜãïíôáò ôïõáìöéâëçóôñïåéäÞ 37 êáé ôïí ðñïóôáôåýåé áðü åêöõëéóìü.Ôá ïöÝëç áðü ôçí ÷ñÞóç ôçò óå ìõúêÝò ðáèÞóåéò (ìõïôïíéêÞäõóôñïößá) Ý÷ïõí áðïäåé÷ôåß óå ìåëÝôåò 38 . Áðïôåëåßôñïöéêü ðáñÜãïíôá óôçí áíÜðôõîç ôïõ êåíôñéêïý íåõñéêïýóõóôÞìáôïò, áëëÜ êáé óôïõò åíÞëéêåò åßíáé ãíùóôÞ ç÷ñÞóç ôçò óáí áíôéóõóôáëôéêü êáé óôáèåñïðïéçôéêü ìÝóïêáôÜ ôçí äéÝãåñóç ôùí êõôôÜñùí êáé ôç íåõñïäéáâßâáóçôùí åñåèéóìÜôùí 39 . Ç ÷ñÞóç ôçò óáí áíôéåðéëçðôéêü äåíåßíáé åðéâåâáéùìÝíç ãéá ôçí áðïôåëåóìáôéêüôçôÜ ôçò. ÇáíôéåðéëçðôéêÞ ôçò äñÜóç öÜíçêå óå êÜðïéá ðåéñáìáôéêÜìïíôÝëá, áëëÜ ï ñüëïò ôçò óôçí óõíáðôéêÞ äéáâßâáóç ðáñáìÝíåéáâÝâáéïò. Ðñïöáíþò ï ëéðüöïâïò ÷áñáêôÞñáòôçò êáé ç ìéêñïý âáèìïý äéåßóäõóç ìÝóù ôïõ áéìáôïåãêåöáëéêïýöñáãìïý (blood-brain barrier), áðïôåëïýí ðåñéïñéóôéêïýòðáñÜãïíôåò ãéá ôçí áíôéåðéëçðôéêÞ äñÜóç ôçòôáõñßíçò. ×ñçóéìïðïéåßôáé åðßóçò êáé ãéá ôçí áíôéìåôþðéóçôïõ áëêïïëéóìïý. Ç ÷ïñÞãçóÞ ôçò óå áóèåíåßò ðïõõðïâÜëëïíôáé óå èåñáðåßá áðåîÜñôçóçò áðü ôï áëêïüë,öÜíçêå íá Ý÷åé ðëåïíåêôÞìáôá ó÷åôéêÜ ìå ôïí âáèìü êáéôçí äéÜñêåéá áðï÷Þò áðü ôï áëêïüë. Ï ìç÷áíéóìüò äñÜóçòôçò äåí Ý÷åé áðïóáöçíéóôåß åíôåëþò, ðéóôåýåôáé üìùòüôé åðçñåÜæåé ôá íåõñïäéáâéâáóôéêÜ óõóôÞìáôá êáé ôçíñïÞ ôùí éüíôùí áóâåóôßïõ, ìå ôñüðï äéáöïñåôéêü áð’ áõôüíôçò áéèáíüëçò, ç ïðïßá ìåéþíåé ôçí éïíéêÞ ìåôáöïñÜìÝóù ôùí ìåìâñáíþí 40 .Ïé áíåðéèýìçôåò åíÝñãåéåò áðü ôçí ÷ñÞóç ôçò ôáõñßíçòÞ áðü õðåñäïóïëïãßá äåí åßíáé óõíÞèåéò, üìùò äåí åêëåßðïõíåíôåëþò 2 . ¸÷ïõí áíáöåñèåß áíåðéèýìçôåò åíÝñãåéåòêáôÜ ôçí áíôéìåôþðéóç äåñìáôïëïãéêþí ðáèÞóåùí(øùñßáóç), åðéëçðôéêÝò êáôáóôÜóåéò êáé åíäïêñéíéêÝòäéáôáñá÷Ýò (åðéíåöñéäéêÞ áíåðÜñêåéá), üðïõ ìðïñåß íáðáñáôçñçèåß õðïèåñìßá êáé êáñäéáêÞ áññõèìßá. Ìðïñåßáêüìá íá ðñïêáëÝóåé áðþëåéá ìíÞìçò êáé êáôáóôïëÞ ôïõêåíôñéêïý íåõñéêïý óõóôÞìáôïò. Åßíáé åðßóçò äõíáôüí íáåðçñåÜóåé ôçí ëåéôïõñãßá ôùí íåöñþí êáé ôïõ Þðáôïò.Ç ÷ñÞóç ôçò ôáõñßíçò ãéá èåñáðåõôéêïýò óêïðïýò÷ñÞæåé ðåñáéôÝñù äéåñåýíçóçò 2 , ðñéí ãßíåé îåêÜèáñïòï ñüëïò ôçò óå êÜðïéåò ðáèÞóåéò, éäéáßôåñá óôçí åðéëçøßáêáé ôïí áëêïïëéóìü. Åðßóçò ðñÝðåé íá ìåëåôçèåßðåñéóóüôåñï ç áëëçëåðßäñáóÞ ôçò ìå Üëëá äéáôñïöéêÜóôïé÷åßá, üðùò ïé âéôáìßíåò êáé ôá ìÝôáëëá êáé íá äïèåßéäéáßôåñç ðñïóï÷Þ óôç óçìáóßá ðïõ ìðïñåß íá Ý÷åé ç÷áìçëÞ óõãêÝíôñùóÞ ôçò óôï áßìá áóèåíþí ìå êáñêßíï.ÐáñÜ ôá åñùôçìáôéêÜ ðïõ ðñÝðåé íá áêüìá íá áðáíôçèïýí,ç ÷ñçóéìüôçôÜ ôçò óôçí äéáôñïöÞ êáé óôçí ðñïëçðôéêÞéáôñéêÞ åßíáé óáöþò êáôáäåäåéãìÝíç êáé äéêáßùò÷áñáêôçñßóôçêå ùò “êáôÜ óõíèÞêç” áðáñáßôçôï áìéíïîý(“conventional” essential amino acid)Ç ôáõñßíç, åêôüò ôùí èåñáðåõôéêþí ôçò äñÜóåùíêáé éäéïôÞôùí, åßíáé êáé Ýíáò äõíçôéêüò õðïêáôáóôÜôçò(ligand) óå åíþóåéò óõíáñìïãÞò ìå ìåôáëëéêÜ éüíôá, ëüãùôçò äïìÞò ôçò. Ç óïõëöïíéêÞ ïìÜäá êáé ç áìéíïìÜäá ðïõäéáèÝôåé ôï ìüñéï åßíáé äõíáôüí íá óõíäåèïýí ìå ìåôáëëéêÜéüíôá, ìÝóù ôùí áôüìùí Ï êáé Í áíôßóôïé÷á. ÐïëëïßåñåõíçôÝò èÝëçóáí íá åêìåôáëëåõôïýí ôçí óõíáñìïóôéêÞéêáíüôçôá ôçò ôáõñßíçò ìå ìÝôáëëá, åîáéôßáò ôùí ðïëýóçìáíôéêþí öõóéïëïãéêþí ëåéôïõñãéþí êáé âéïëïãéêþíñüëùí ðïõ åðéôåëåß. Óôï ðëáßóéï ôïõ ïëïÝíá áõîáíüìåíïõåíäéáöÝñïíôïò ãéá ôçí ôáõñßíç, Üñ÷éóáí íá ãßíïíôáéðñïóðÜèåéåò ãéá ôçí óýíèåóç óõìðëüêùí ìå ìÝôáëëá, ìåóôü÷ï, ôïõëÜ÷éóôïí ôá ôåëåõôáßá ÷ñüíéá, íá åíéó÷õèïýíïé éäéüôçôÝò ôçò, óõíäõáæüìåíåò ì’ áõôÝò ôùí ìåôÜëëùí,þóôå íá áðïôåëåß Ýíá éó÷õñüôåñï äéáôñïöéêü êáé öáñìáêåõôéêüìÝóï ãéá ôá âéïëïãéêÜ óõóôÞìáôá.Âéâëéïãñáößá1. Birdsall T.C. Therapeutic Applications of Taurine.Alternative Medicine Review, 3, 128-136, 1998.2. Kendler B.S. Taurine: An Overview of its role inPreventive Medicine. Preventive Medicine, 18, 79-100,1989.3. Raiha N., Rassin D., Heinonen K., Gaull G.E. Milkprotein quality and quantity: Biochemical and growtheffects in low birth weight infants. Pediatr. Res., 9, 370,1975.4. Geggel H.S., Ament M.E., Heckenlively J.R., etal. Nutritional requirement for taurine in patientsreceiving long-term parenteral nutrition. N. Engl. J.Med., 312, 142-146,1985.5. Sturman J.A. Taurine in development. Physiol. Rev.,73, 119-147, 1993.6. Hayes K.C., Carey R.E., Schmidt S.Y. Science, 188,949-991, 1975.7. Sheik K., Toskes P., Dawson W. Taurine deficiency andretinal defects associated with small intestinal bacterialovergrowth. Gastroenterology, 80, 1363, 1981.37

Brief overview of the biological role andpharmaceutical properties of taurine.Uses, applications and perspectives.S. Kella 1 , P. Plageras 2 , A. Papaioannou 2 ,I. Anastassopoulou 1 , Th.Theofanidis 11. Section of Materials Science and Engineering,School of Chemical Engineering, National and TechnicalUniversity of Athens, Zografou Camppus, 9 IroonPolytechniou str., Athens, Greece2. Clinical Chemistry–Biochemistry Section, Departmentof Medical Laboratories,Education & Technological Institute of Larissa,41110, Larissa, GreeceSummaryTaurine (2-amino-ethan-sulfonic acid) is a “conventional”essential amino acid with numerous medicinalproperties. It is a substance similar to beta-alanine, withthe difference that it contains a sulfonate group in theposition of the carboxyl group and may therefore becalled sulfonic amino acid.Taurine was found in the bile of the bull in 1827 andits importance in nutrition began to be appreciated onlyin 1975. It became widely known as an ingredient of energydrinks such as Red Bull.This paper presents a short overview of the pharmacologicalproperties of taurine, its biological role aswell as its uses and perspectives existing in the field ofits coordination with metal ions in order to extend itsuse as therapeutic agent.At present it has been proven that taurine is essentialfor the development of mammals and that low taurinelevels in the body are associated with various pathologicalconditions such as cardiomyopathy, degeneration ofthe retina, growth retardation, failure of cells to survive,decreased brain function, diabetes and even epilepsy.Typical pharmaceutical actions of taurine are theantioxidant, cardiovascular, metabolic and detoxifyingaction. Taurine also serves the digestion of fats, theabsorption of fat-soluble vitamins and the control ofblood cholesterol levels. It participates in maintainingthe integrity of the cell membrane, in the preventionof spermatoblasts and in the regulation of the osmoticpressure. It plays an essential role in the neuronal function,the reproduction of cells and the promotion ofglycolysis.Taurine acts in many biological systems such asthe cardiovascular system, liver, eyes, central nervoussystem, reproductive system and the muscular system.Moreover, the role of taurine on growth and survival ofcells is of paramount importance. Its presence seems tobe crucial to the reproduction and the viability of cells.The use of taurine for therapeutic reasons requiresfurther investigation to clarify its role in some diseases,especially in epilepsy and alcoholism. Also, its interactionwith other nutrients such as vitamins and mineralshas to be studied further. Special attention has to begiven to the importance that low concentrations of taurinein the blood of patients with cancer may have. Itsusefulness in nutrition and preventive medicine is howeverclearly demonstrated and thus taurine is rightlycharacterized as “conventional” essential amino acid.Because of its structure, taurine is a potential ligandin coordination compounds with metal ions, in additionto its therapeutic actions and properties. The sulphonategroup and the aminogroup in the molecule maybe coordinated with metal ions through the O and Natoms, respectively. In this scope, many attempts havebeen made to bind taurine with metal ions in order tocreate more effective drugs combining properties ofboth taurine and metal ions.8. Mozaffari M.S., Tan B.H., Lucia M.A., Schaffer S.W.Biochem. Pharmacol., 35, 985-990, 1986.9. Birdi M., Choay P. Taurine: a particular aminoacidwith multiple functions. Ann. Pharm. Fr., 61, 385-391,2003.10. Huxtable R.J. Physiological actions of taurine. Physiol.Rev., 72, 101-163, 1992.11. Huxtable R.J., Sebring L.A. Viewpoint Towards aunifying theory for the actions of taurine, Elsevier SciencePublishers, Amsterdam, 1986.12. Jacobsen J.G., Smith L.H. Biochemistry and physiologyof taurine and taurine derivatives. Physiol. Rev., 48,424-511, 1968.13. Huxtable R.J., Sebring L.A. Cardiovascular actionsof taurine. In: Sulfur Amino Acids: Biochemical andClinical Aspects, eds. Kuriyama K., Huxtable R., IwataH., Alan R., Liss, New York, pp. 5-37, 1983.14. Nara Y., Yamori Y., Lovenberg W. Effects of dietarytaurine on blood pressure in spontaneously hypertensiverats. Biochem. Pharmacol., 27, 2689-2692, 1978.15. Bousquet P., Feldman J., Bloch R., Schwartz J. Centralcardiovascular effects of taurine: comparison withhomotaurine and muscimol. J. Pharmacol. Exp. Ther.,219, 213-218, 1981.16. Satoh H. Cardioprotective actions of taurine againstintracellular and extracellular Ca 2+ -induced effects.Adv. Exp. Med. Biol., 359, 181-196, 1994.17. Satoh H., Sperelakis N. Review of some actions oftaurine on ion channels of cardiac muscle cells andothers. Gen. Pharmac., 30, 451-463, 1998.18. Kramer J.H., Chovan J.P., Schaffer S.W. Effect oftaurine in calcium paradox and ischemic heart failure.Am. J. Physiol., 240, H238-H246, 1981.19. Raschke P., Massoudy P., Becker B.F. Taurine protects38

the heart from neutrophil-induced reperfusion injury.Free Radic. Biol. Med., 19, 461-471, 1995.20. Hofmann A.F., Small D.M. Detergent properties ofbile salts: Correlation with physiological function.Annu. Rev. Med., 18, 333-376, 1967.21. Mizushima S., Nara Y., Sawamura M., Yamori Y.Effects of oral taurine supplementation on lipids andsympathetic nerve tone. Adv. Exp. Med. Biol., 403, 615-622, 1996.22. Sturman J.A. Nutritional taurine and central nervoussystem development. Ann. NY Acad. Sci., 477, 196-213,1986.23. Wright C.E., Tallan H.H., Lin Y.Y. Taurine : Biologicalupdate. Annu. Rev. Biochem., 55, 427-453, 1985.24. Sturman J.A., Gaull G.E. Taurine in the brain and liverof the developing human and monkey. J. Neurochem.,25, 813-835, 1975.25. Oja S.S., Kontro P. In: Handbook of Neurochemistry,2nd edition, ed. Lajtha A., Plenum, New York, vol. 3,p. 501, 1983.26. Van Gelder N.M., Barbeau A. In: Taurine: Biologicalactions and Clinical Perspectives, eds. Oja S.S., AhteeL., Kontro P., Paasonen M.K., A.R. Liss, New York, ,p. 149, 1985.27. Kulakowski E.C., Maturo J. Hypoglycemic propertiesof taurine not mediated by enhanced insulin release.Biochem. Pharmacol., 33, 2835-2838, 1984.28. Kozumbo W.J., Agarwal S., Koren H.S. Breakage andbinding of DNA by reaction products of hypochlorousacid with aniline, l-naphthylamine or l-naphthol.Toxicol. Appl. Pharmacol., 115, 107-115, 1992.29. Nakashima T., Taniko T., Kuriyama K. Therapeuticeffects of taurine administration on carbontetrachloride-induced hepatic injury. Jpn. J. Pharmacol.,32, 583-589, 1982.30. Roth R.A., Harkema J.R., Pestka J.P., Ganey P.E.Is exposure to bacterial endotoxin a determinant ofsusceptibility to intoxication from xenobiotic agents?Toxicol. Appl. Pharmacol., 147, 300-311, 1997.31. Thurston J.H., Hauhart H.E., Dirgo J.A. Life Sci., 26,1961-1968, 1980.32. Azuma J., Takihara K., Awata N., et al. Taurine andfailing heart: experimental and clinical aspects. Prog.Clin. Biol. Res., 179, 195-213, 1985.33. Carrasco S., Codoceo R., Prieto E., et al. Effect of taurinesupplements on growth, fat absorption and bile acid oncystic fibrosis. Acta Univ. Carol., 36, 152-156, 1990.34. Matsuyama Y., Morita T., Higuchi M., Tsujii T. Theeffect of taurine administration on patients with acutehepatitis. Prog. Clin. Biol. Res., 125, 461-468, 1983.35. Csernansky J.G., Bardgett M.E., Sheline Y.I., et al.CSF excitatory amino acids and severity of illness inAlzheimer’s disease. Neurology, 46, 1715-1720, 1996.36. Lima L., Cubillos S. Taurine might be acting as a trophicfactor in the retina by modulating phosphoryliation ofcellular proteins. J. Neurosci. Res., 53, 377-384, 1998.37. Durelli L., Mutani R., Fassio F. The treatment ofmyotonia: Evaluation of chronic oral taurine therapy.Neurology, 33, 599-603, 1983.38. Wu H., Jin Y., Wei J., et al. Mode of action of taurineas a neuroprotector. Brain Research, 1038, 123-131,2005.39. Wilde M.I., Wagstaff A.J., Acamprosate. A Review of itspharmacology and clinical potential in the managementof alcohol dependence after detoxification. Drugs, 53,1038-1053, 1997.39

ÅÑÅÕÍÇÔÉÊÇ ÅÑÃÁÓÉÁÐåñßëçøçÇ åðïõëùôéêÞ äñÜóç ôïõ õðåñéêïý ôïõ äéÜôñçôïõ(H.p) óôçí åðïýëùóç ôñáýìáôïò Þôáí Þäç ãíùóôÞ áðüôçí åðï÷Þ ôïõ ÉððïêñÜôç.Óêïðüò ôçò åñãáóßáò åßíáé äéåñåýíçóç ôçò ðïéüôçôáòåðïýëùóçò ôÝìíïíôïò ôñáýìáôïò ìÞêïõò 3 cm óôç ñÜ÷çåðéìýùí Wistar (250 ±15 g) ìåôÜ áðü ôïðéêÞ ÷ïñÞãçóçåðß ðåíèÞìåñïí åëáéþäïõò åê÷õëßóìáôïò õðåñéêïý(Rotoel ® {Jukunda}ìå10% Hypericum herba). ×ñçóéìïðïéÞèçêáíäýï ïìÜäåò ðåéñáìáôïæþùí (n=10 åêÜóôç, ÁìÜñôõñåò,  ðåéñáìáôéêÞ). Ôñåéò ôïìÝò (5ì) äåéãìÜôùíäÝñìáôïò åêôéìÞèçêáí ìå öùôïìéêñïóêüðéï (x20 óå ÷ñþóçáéìáôïîõëßíçò- çùóßíçò).Ôá ðåéñáìáôüæùá õðü áãùãÞ ìå H.p. åß÷áí ôá÷ýôåñïó÷çìáôéóìü êïêêéùìáôþäïõò éóôïý óå ó÷Ýóç ìå ôïõò ìÜñôõñåò.Ôá åñãáóôçñéáêÜ åõñÞìáôá õðïäåéêíýïõí áýîçóçôùí ðáñáìÝôñùí öëåãìïíÞò (CRP, ïëéêÝò ðñùôåÀíåò, áëâïõìßíç)óôïõò ìÜñôõñåò óå ó÷Ýóç ìå ôçí ðåéñáìáôéêÞ ïìÜäá.Åíäå÷üìåíá ôá åõñÞìáôá áõôÜ áðïäßäïíôáé óôá öëáâïíïåéäÞêáé ôéò öëáâüíåò ðïõ ðåñéÝ÷ïíôáé óôï õðåñéêü.ÅéóáãùãÞÇ èåñáðåõôéêÞ áíôéìåôþðéóç ôùí ôñáõìÜôùí, Þôáí ôïðñþôï ìÝëçìá üëùí ëáþí . ¹äç áðü ôçí åðï÷Þ ôïõ ÏìÞñïõï Üíèñùðïò ðñïóðÜèçóå íá áíáêïõöéóôåß áðü ôïíðüíï êáé íá åðéôá÷ýíåé ôçí åðïýëùóç ôùí ôñáõìÜôùí ôïõ, ìå öõôéêÜ ìÝóá.Ìå ôçí åîÝëéîç ôïõ ðïëéôéóìïý, ôï ôñáýìá Ý÷åé ðÜøåé ,ôïõëÜ÷éóôïí óôéò âéïìç÷áíïðïéçìÝíåò êïéíùíßåò, íá áðïôåëåßóõíÝðåéåò ðïëåìéêþí óõãêñïýóåùí áðü ðõñïâüëáüðëá, åêñÞîåéò êëð.Ùóôüóï, ç ëýóç ôçò óõíå÷åßáò ôïõ äÝñìáôïò áðüåãêáýìáôá Þ èëáóôéêÜ ôñáýìáôá äéáöüñïõ óïâáñüôçôáòêáé Ýêôáóçò, áíÜëïãá ìå ôéò óõíèÞêåò ðñüêëçóçò, õðüêåéôáéóå äéÜöïñá óôÜäéá åðïýëùóçò.ÐëÞèïò ìåëåôþí Ý÷ïõí áöéåñùèåß óôçí åðïýëùóç –åðáíüñèùóç (remodeling) üóïí áöïñÜ ôçí ðïéüôçôá ôïõêïêêéþäïõò óõíäåôéêïý éóôïý êáé ôçí ôá÷ýôçôá ôçò åðïõëùôéêÞòäéåñãáóßáò. Åêôüò ôùí óõíèåôéêþí ðñïúüíôùí,ðëçèþñá öõôéêþí ðáñáóêåõáóìÜôùí Ý÷åé ðñïôáèåß ãéáôçí êáëýôåñç ðáñÝìâáóç óôçí åðïõëùôéêÞ äéåñãáóßá.¹äç ï ÉððïêñÜôçò óôï «ðåñß ãõíáéêåßùí» ÷ñçóéìïðïéïýóåðáñáóêåõÜóìáôá áðü õðåñéêü ôçò ïéêïãåíåßáòÕðåñéêïåéäþí ãéá ôçí åðïýëùóç ôñáõìÜôùí, ôçí åðéëü-÷åéá áðïêáôÜóôáóç ôùí ãåííçôéêþí ïñãÜíùí êëð. (1)Ï óêïðüò ôçò åñãáóßáò Þôáí íá ìåëåôçèåß ç ðïéüôçôáôçò åðïõëùôéêÞò äéåñãáóßáò óå ôïìÞ äÝñìáôïò 3cmìÞêïõò êáé 0,5 cm âÜèïõò óôç ñÜ÷ç åðéìýùí ôïõ ãÝíïõòWistar õðü ôçí åðßäñáóç åëáéþäïõò åê÷õëßóìáôïò õðåñéêïýôïõ äéÜôñçôïõ (Hypericum perforatum L) ðåñéåêôéêüôçôáò10% (Hypericum herba).40RESEARCH ARTICLEÖÁÑÌÁÊÅÕÔÉÊÇ 24, I-II, 40-41, 2012 PHARMAKEFTIKI 24, I-II, 40-41, 2012Åðßäñáóç ôïõ Yðåñéêïý ôïõ ÄéÜôñçôïõ (Hypericum perforatum L)óôçí Eðïýëùóç Tñáýìáôïò ÄÝñìáôïò Åðéìýùí.ÓáðïõíÜêçò Êùíóôáíôßíïò, ×áôæçãéÜííç Åììõ, Êþôóéïõ Aíôùíßá, ÔåóóåñïììÜôç ×ñéóôßíá.ÅñãáóôÞñéï Öáñìáêïëïãßáò ÉáôñéêÞ Ó÷ïëÞ ÅÊÐÁÕëéêü -ÌÝèïäïò×ñçóéìïðïéÞèçêáí 2 ïìÜäåò áñóåíéêþí ëåõêþí åðéìýùíáðü 10 æþá åêÜóôç (150g ±10) çëéêßáò 5 – 6 åâäïìÜäùí,ïìÜò Á ìÜñôõñåò ïìÜò  ðåéñáìáôéêÞ.Ôá æþá êáé ôùí 2 ïìÜäùí, õðÝóôçóáí áðïøßëùóç ôùíôñé÷þí ôçò ñÜ÷çò êáé óôç óõíÝ÷åéá äéåíåñãÞèç ðåéñáìáôéêüôñáýìá ôïõ äÝñìáôïò. Ôá æþá ôçò ïìÜäáò  åðáëåßöïíôáéåðß ðåíèÞìåñï ìå ôï åëáéþäåò åê÷ýëéóìá ôïõ õðåñéêïýôïõ äéÜôñçôïõ (Rotoel ® Jukunda), åíþ ôá æþá ôçòïìÜäáò Á åðáëåßöïíôáé ìå åëáéüëáäï.Ôçí 5ç çìÝñá ôá æþá èáíáôþèçêáí ìå áðïêåöáëéóìüêáé åëÞöèç áßìá ãéá âéï÷çìéêü Ýëåã÷ï. ÐáñÜëëçëá, áðïìïíþèçêåôï ôìÞìá ôïõ äÝñìáôïò ðïõ åß÷å õðïóôåß ôïìÞ ôüóïóôïõò ìÜñôõñåò üóï êáé óôçí ðåéñáìáôéêÞ ïìÜäá, ôïðïèåôÞèçêåóå äéÜëõìá öïñìáëäåàäçò 10% ãéá ðåñáéôÝñù ìéêñïéóôïëïãéêÞÝñåõíá. ÅëÞöèçóáí 3 äåßãìáôá ôïìþí áðü êÜèåðáñáóêåýáóìá (20ì ðÜ÷ïõò). ×ñçóéìïðïéÞèçêå ÷ñþóç áéìáôïîõëßíçòçùóßíçò (ÇÅ). Ç áîéïëüãçóç ôùí ðáñáóêåõáóìÜôùíÝãéíå ìå ôç âïÞèåéá öùôïìéêñïóêïðßïõ (x20).ÁðïôåëÝóìáôá-ÓõæÞôçóçÔá âéï÷çìéêÜ åõñÞìáôá Ýäåéîáí ðáñïõóßá öëåãìïíÞòêáé êáôáâïëéêÞò äéåñãáóßáò ìå áýîçóç ôçò CRP, åëÜôôùóçôçò áëâïõìßíçò, óôáôéóôéêÜ óçìáíôéêÜ (p

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19th EuroQSARKnowledge Enabled Ligand DesignVienna, AustriaAugust 26-30, 2012The EuroQSAR Symposia have been taking place since1973 and constitute major scientific events in the fieldof computational drug design, with further applicationsin agricultural and environmental sciences. The 2012symposium will not only follow the tradition of previousevents in presenting latest trends in QSAR and molecularmodeling, it will also explore new grounds, such asintegrated approaches and open innovation strategies indrug discovery.The 19th EuroQSAR 2012 symposium, entitled“Knowledge Enabled Ligand Design” will focus on:• Integrative Approaches - Predicting in vivo Data• Open Source, Open Access, Open Data• Proteins - Structure, Function, Modulation, Interaction• In silico Profiling - PhysChem Meets Biology• Translational Informatics• Probing Biological SystemsAustria’s capital Vienna lies on the shore of the DanubeRiver in a valley protected by the foothills of the Alps.Few cities in the world glide so easily between the presentand the past like Vienna. Its splendid historical face iswell recognized: grand imperial palaces and bombasticbaroque interiors, museums flanking magnificent squaresand, above all, the Hofburg – where the Habsburg dynastyreigned for several centuries over most of Europe.The conference will take place right in the center ofVienna in the main building of the University of Vienna.Founded in 1365 by Duke Herzog Rudolf IV, theUniversity of Vienna is the oldest in the Germanspeakingpart of Europe and one of the biggest Universities inCentral Europe.We are looking forward to your active participation !ONLINE REGISTRATION IS NOW OPENEFMC-ISMC 201222nd International Symposiumon Medicinal ChemistryBerlin, GermanySeptember 2 - 6, 2012EFMC-ISMC 2012 is jointly organised by the GermanChemical Society (GDCh) Division of MedicinalChemistry and the German Pharmaceutical Society(DPhG) Section of Pharmaceutical/Medicinal Chemistry,on behalf of the European Federation for MedicinalChemistry (EFMC).This symposium is recognized worldwide as one ofthe leading Medicinal Chemistry meetings, as provenby its large international attendance, which variesbetween 1200 and 1500 participants from all over theworld. It traditionally attracts experts in drug discoveryand development, in particular medicinal and syntheticchemists, together with scientists active in the fieldsof computer assisted drug design, biology, DMPK,pharmacology, early toxicology, as well as chemical andpharmaceutical development.The EFMC-ISMC 2012 will continue its traditionand will cover drug discovery advances in all majortherapeutic areas as well as the most recent advancesin lead identification and optimization strategies, drugdesign and profiling technologies. Particular emphasiswill be put on first time disclosures. ISMC 2012 will alsoillustrate the impact of the -omics and biomarker areason the interfaces between chemistry, informatics, biologyand experimental medicine.42