Effects of copper on the antioxidant activity of olive polyphenols in bulk oil and oil-in-water emulsions

The antioxidant activity and interactions with copper of four olive oil phenolic compounds, namely oleuropein, hydroxytyrosol, 3,4- dihydroxyphenylethanol- elenolic acid ( 1), and 3,4- dihydroxyphenyl-ethanolelenolic acid dialdehyde ( 2), in olive oil and oil- in- water emulsions stored at 60 degrees C were studied. All four phenolic compounds significantly extended the induction time of lipid oxidation in olive oil with the order of activity being hydroxytyrosol > compound 1 > compound 2 > oleuropein > alpha- tocopherol; but in the presence of Cu( II), the stability of oil samples containing phenolic compounds decreased by at least 90%, and the antioxidant activity of hydroxytyrosol and compounds 1 and 2 became similar. In oil- in- water emulsions prepared from olive oil stripped of tocopherols, hydroxytyrosol enhanced the prooxidant effect of copper at pH 5.5 but not at pH 7.4. The stability of samples containing copper at pH 5.5 was not significantly different if oleuropein was present from that of the control. Oleuropein at pH 7.4, and compounds 1 and 2 at both pH values tested, reduced the prooxidant effect of copper. The lower stability and the higher reducing capacity of all compounds at pH 7.4 could not explain the higher stability of emulsions containing phenolic compounds at this pH value. However, mixtures containing hydroxytyrosol or oleuropein with copper showed higher 1,1-diphenyl- 2- picrylhydrazyl radical scavenging activity at pH 7.4 than at pH 5.5. Moreover, the compound 2- copper complex showed higher radical scavenging activity then the uncomplexed compound at pH 5.5. It can be concluded that the formation of a copper complex with radical scavenging activity is a key step in the antioxidant action of the olive oil phenolic compounds in an emulsion containing copper ions.

A very rare hydrogen-bridged hexanuclear CuII complex containing a triangular Cu3O core capped by an unusual triply coordinated perchlorate anion

An unusual hexanuclear Cu-II complex, [{[Cu(NHDEPO)](3)(mu(3)-O)(O3ClO)}(2)(mu-H)]center dot 7ClO(4)center dot 4H(2)O (1) was prepared starting from Cu(ClO4)(2)center dot 6H(2)O and the oxime-based Schiff base ligand NHDEPO (= 3-[3-(diethylamino)propylimino]butan-2-one oxime). Structural characterization of the complex reveals that it consists of two triangular Cu3O units, the copper ions being at the corners of an equilateral triangle, separated by an O center dot center dot center dot O distance of 2,447(5) angstrom, held together solely by a proton. In each triangle, the copper atoms are in square-pyramid environments. The equatorial plane consists of the bridging oxygen of the central OH-(O2-) group together with three atoms (N, N, O) of the Schiff base. All Unusual triply coordinated perchlorate ion (mu(3)-kappa O:kappa O':kappa O '') interacts in axial position with the three copper ions, Variable-temperature (2-300 K) magnetic susceptibility measurements show that complex 1 is antiferromagnetically Coupled (J = -148 cm(1-)). The EPR data at low temperature clearly indicates the presence of spin frustration phenomenon in the complex.

Cis–trans isomerism in diphenoxido bridged dicopper complexes: role of crystallized water to stabilize the cis isomer, variation in magnetic properties and conversion of both into a trinuclear species

The trans-[Cu2L2Cl2] (1), and cis-[Cu2L2Cl2]·H2O (2) isomers of a diphenoxido bridged Cu2O2 core have been synthesized using a tridentate reduced Schiff base ligand 2-[(2-dimethylamino-ethylamino)-methyl]-phenol. The geometry around Cu(II) is intermediate between square pyramid and trigonal bipyramid (Addison parameter, tau = 0.463) in 1 but nearly square pyramidal (tau = 0.049) in 2. The chloride ions are coordinated to Cu(II) and are trans oriented in 1 but cis oriented in 2. Both isomers have been optimized using density functional theory (DFT) calculations and it is found that the trans isomer is 7.2 kcal mol(-1) more favorable than the cis isomer. However, the hydrogen bonding interaction of crystallized water molecule with chloride ions compensates for the energy difference and stabilizes the cis isomer. Both complexes have been converted to a very rare phenoxido-azido bridged trinuclear species, [Cu3L2(mu(1,1)-N-3)(2)(H2O)(2)(ClO4)(2)] (3) which has also been characterized structurally. All the complexes are antiferromagnetically coupled but the magnitude of the coupling constants are significantly different (J = -156.60, -652.31, and -31.54 cm(-1) for 1, 2, and 3 respectively). Density functional theory (DFT) calculations have also been performed to gain further insight into the qualitative theoretical interpretation on the overall magnetic behavior of the complexes.

A Metal-Repressed Promoter From Gram-Positive Bacillus subtilis Is Highly Active and Metal-Induced in Gram-Negative Cupriavidus metallidurans

A synthetic version of the metal-regulated gene A (mrgA) promoter from Bacillus subtilis, which in this Gram-positive bacterium is negatively regulated by manganese, iron, cobalt, or copper turned out to promote high level of basal gene expression that is further enhanced by Co(II), Cd(II), Mn(II), Zn(II), Cu(II), or Ni(II), when cloned in the Gram-negative bacterium Cupriavidus metallidurans. Promoter activity was monitored by expression of the reporter gene coding for the enhanced green fluorescent protein (EGFP), and cellular intensity fluorescence was quantified by flow cytometry. Expression levels in C. metallidurans driven by the heterologous promoter, here called pan, ranged from 20- to 53-fold the expression level driven by the Escherichia coli lac promoter (which is constitutively expressed in C. metallidurans), whether in the absence or presence of metal ions, respectively. The pan promoter did also function in E. coli in a constitutive pattern, regardless of the presence of Mn(II) or Fe(II). In conclusion, the pan promoter proved to be a powerful tool to express heterologous proteins in Gram-negative bacteria, especially in C. metallidurans grown upon high levels of toxic metals, with potential applications in bioremediation. Biotechnol. Bioeng. 2010; 107: 469-477. (C) 2010 Wiley Periodicals, Inc.

Isostructural M(RL)(2)(hfac)(2) complexes with RL=5-(4-[N-tert-butyl-N-aminoxyl]phenyl)pyrimidine

5-(4-(N-tert-Butyl-N-aminoxylphenyl)) pyrimidine (RL, 4PPN) forms crystallographically isostructural and isomorphic pseudo-octahedral M(RL)(2)(hfac)(2) complexes with M(hfac)(2), M = Zn, Cu, Ni, Co, and Mn. Multiple close contacts occur between sites of significant spin density of the organic radical units. Magnetic behavior of the Zn, Cu, Ni, Co complexes appears to involve multiple exchange pathways, with multiple close crystallographic contacts between sites that EPR (of 4PPN) indicates to have observable spin density. Powder EPR spectra at room temperature and low temperature are reported for each complex. Near room temperature, the magnetic moments of the complexes are roughly equal to those expected by a sum of non-interacting moments (two radicals plus ion). As temperature decreases, AFM exchange interactions become evident in all of the complexes. The closest fits to the magnetic data were found for a 1-D Heisenberg AFM chain model in the Zn(II) complex (J/k = (-)7 K), and for three-spin RL-M-RL exchange in the other complexes (J/k = (-)26 K, (-)3 K, (-) 6 K, for Cu(II), Ni(II), and Co(II) complexes, respectively). (C) 2008 Elsevier B.V. All rights reserved.

Potential antitumoral properties of a new copper complex with santonic acid

A new copper(II) complex of santonic acid [Cu(2)(sant)(4)(H(2)O)(2)]center dot 21/2H(2)O has been prepared and characterized by electronic, vibrational, EPR spectral studies, and stability determinations in solution. The presence of two antiferrromagnetically coupled copper centers in the solid state was detected by EPR. The dinuclear Cu(II) complex crystallizes in the tetragonal P4(3)2(1)2 space group, with a = b = 14.498(3), c = 64.07(1) angstrom. Biological studies indicate that the complex displays interesting potential antitumoral actions. (C) 2008 Elsevier Ltd. All rights reserved.

1,4-Diamino-2-butanone, a wide-spectrum microbicide, yields reactive species by metal-catalyzed oxidation

The alpha-aminoketone 1,4-diamino-2-butanone (DAB), a putrescine analogue, is highly toxic to various microorganisms, including Trypanosoma cruzi. However, little is known about the molecular mechanisms underlying DAB`s cytotoxic properties. We report here that DAB (pK(a) 7.5 and 9.5) undergoes aerobic oxidation in phosphate buffer, pH 7.4, at 37 degrees C, catalyzed by Fe(II) and Cu(II) ions yielding NH(4)(+) ion, H(2)O(2), and 4-amino-2-oxobutanal (oxoDAB). OxoDAB, like methylglyoxal and other alpha-oxoaldehydes, is expected to cause protein aggregation and nucleobase lesions. Propagation of DAB oxidation by superoxide radical was confirmed by the inhibitory effect of added SOD (50 U ml(-1)) and stimulatory effect of xanthine/xanthine oxidase, a source of superoxide radical. EPR spin trapping studies with 5,5-dimethyl-1-pyrroline-1-oxide (DMPO) revealed an adduct attributable to DMPO-HO(center dot), and those with alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone or 3,5-dibromo-4-nitrosobenzenesulfonic acid, a six-line adduct assignable to a DAB(center dot) resonant enoyl radical adduct. Added horse spleen ferritin (HoSF) and bovine apo-transferrin underwent oxidative changes in tryptophan residues in the presence of 1.0-10 mM DAB. Iron release from HoSF was observed as well. Assays performed with fluorescein-encapsulated liposomes of cardiolipin and phosphatidylcholine (20:80) incubated with DAB resulted in extensive lipid peroxidation and consequent vesicle permeabilization. DAB (0-10 mM) administration to cultured LLC-MK2 epithelial cells caused a decline in cell viability, which was inhibited by preaddition of either catalase (4.5 mu M) or aminoguanidine (25 mM). Our findings support the hypothesis that DAB toxicity to several pathogenic microorganisms previously described may involve not only reported inhibition of polyamine metabolism but also DAB pro-oxidant activity. (C) 2011 Elsevier Inc. All rights reserved.

The use of a gold disc microelectrode for the determination of copper in human sweat

A novel approach of using a gold disc microelectrode to analyze sweat samples for copper ions by anodic square wave stripping voltammetry (SW stripping voltammetry) is described Sweat was collected from the lower back of four subjects after physical exercise and the sample volume required for the determinations was 100 mu L. Under the optimized conditions the calibration plot was linear over the range 1-100 mu mol L(-1) Cu(II) with a limit of detection of 0 25 mu mol L(-1) The precision was evaluated by carrying out five replicate measurements in a 1 mu mol L(-1) Cu(II) solution and the standard deviation was found to be 1 5% Measurements were performed by inserting the microelectrode into sweat drops and Cu(II) concentrations in the analyzed samples ranged from 09 to 28 mu mol L(-1) Values obtained by the proposed voltammetric method agreed well with those found using graphite furnace atomic absorption spectroscopy (GFAAS) (C) 2010 Elsevier B V All rights reserved

Supramolecular assemblies of a new class of nonplanar cationic metalloporphyrins and anionic metallophthalocyanines

The heteroaggregation behavior between a new class of nonplanar cationic beta-octabrominated meso-alkylpyridinium zinc(II)-porphyrins (beta-Br(8)(ZnP)) and anionic tetrasulfonated metallophthalocyanines (MTSPc, M = Ni(II) and Cu(II)) has been studied by UV-Vis electronic spectroscopy, in dimethylsulfoxide (DMSO) solution. The heteroaggregate stoichiometry and the association constants were determined by means of Job plots. Dimers and unexpected trimers, taking into account the existence of axially coordinated DMSO molecules to the central metal in both beta-Br(8)(ZnP) and MTSPc complexes, are formed in solution. The spectroscopic properties of the heteroaggregates are markedly different from those observed in the correspondent planar cationic derivatives, the heteroaggregates showing major changes predominantly in the beta-Br(8)(ZnP) Soret band region and minor effects in the MTSPc Q bands. The observed changes in the Soret band region (red/blue shifts, decrease in the absorption intensities) depend on the nature of the alkyl substituent attached to the meso-pyridinium group. The greater versatility of the nonplanar porphyrins accommodating the meso-substituents in out-of-plane and in-plane conformations is proposed to explain the observed stoichiometries and the differences on the heteroaggregates spectroscopic properties for each beta-Br(8)(ZnP) compound. The likely conformations assumed by the meso-substituents in these beta-Br(8)(ZnP) compounds and its spectroscopic characteristics are in accordance with the participation of the substituents as the main factor on the extent of the observed red-shifted spectra in nonplanar porphyrins. The obtained association constants (K(IP)) for the dimers and trimers are lower than those previously found for the similar planar cationic porphyrin systems, due to the lack of extensive pi-pi interactions and to the less effective approximation between the ionic groups, resulting in loosened heteroaggregates, particularly for the trimeric systems. Furthermore, the experimental results suggest that the NiTSPc is more distorted in DMSO solution than the CuTSPc derivative, favoring the interaction with the nonplanar beta-Br(8)(ZnP) compounds. (C) 2007 Elsevier B.V. All rights reserved.

Raman, IR, UV-vis and EPR characterization of two copper dioxolene complexes derived from L-dopa and dopamine

The anionic complexes [Cu(L(1-))(3)](1-), L(-) = dopasemiquinone or L-dopasemiqui none, were prepared and characterized. The complexes are stable in aqueous solution showing intense absorption bands at ca. 605 nm for Cu(II)-L-dopasemiquinone and at ca. 595 nm for Cu(II)-dopasemiquinone in the UV-vis spectra, that can be assigned to intraligand transitions. Noradrenaline and adrenaline, under the same reaction conditions, did not yield Cu-complexes, despite the bands in the UV region showing that noradrenaline and adrenaline were oxidized during the process. The complexes display a resonance Raman effect, and the most enhanced bands involve ring modes and particularly the vCC + vCO stretching mode at ca. 1384 cm(-1). The free radical nature of the ligands and the oxidation state of the Cu(II) were confirmed by the EPR spectra that display absorptions assigned to organic radicals with g= 2.0005 and g = 2.0923, and for Cu(II) with g = 2.008 and g = 2.0897 for L-dopasemiquinone and dopasemiquinone, respectively. The possibility that dopamine and L-dopa can form stable and aqueous-soluble copper complexes at neutral pH, whereas noradrenaline and adrenaline cannot, may be important in understanding how Cu(II)-dopamine crosses the cellular membrane as proposed in the literature to explain the role of copper in Wilson disease. (c) 2008 Elsevier B.V. All rights reserved.

Evaluation of a carbon paste electrode modified with organofunctionalised SBA-15 nanostructured silica in the simultaneous determination of divalent lead, copper and mercury ions

The performance of a carbon paste electrode (CPE) modified with SBA-15 nanostructured silica organofunctionalised with 2-benzothiazolethiol in the simultaneous determination of Pb(II), Cu(II) and Hg(II) ions in natural water and sugar cane spirit (cachaca) is described. Pb(II), Cu(II) and Hg(II) were pre-concentrated on the surface of the modified electrode by complexing with 2-benzothiazolethiol and reduced at a negative potential (-0.80 V). Then the reduced products were oxidised by DPASV procedure. The fact that three stripping peaks appeared on the voltammograms at the potentials of -0.48 V (Pb2+), -0.03 V (Cu2+) and +0.36 V (Hg2+) in relation to the SCE, demonstrates the possibility of simultaneous determination of Pb2+, Cu2+ and Hg2+. The best results were obtained under the following optimised conditions: 100 mV pulse amplitude, 3 min accumulation time, 25 mV s(-1) scan rate in phosphate solution pH 3.0. Using such parameters, calibration graphs were linear in the concentration ranges of 3.00-70.0 x 10(-7) mol L-1 (Pb2+), 8.00-100.0 X 10(-7) mol L-1 (Cu2+) and 2.00-10.0 x 10(-6) mol L-1 (Hg2+). Detection limits of 4.0 x 10(-8) mol L-1 (Pb2+), 2.0 x 10(-7) mol L-1 (Cu2+) and 4.0 x 10(-7) mol L-1 (Hg2+) were obtained at the signal noise ratio (SNR) of 3. The results indicate that this electrode is sensitive and effective for simultaneous determination of Pb2+, Cu2+ and Hg2+ in the analysed samples. (C) 2008 Published by Elsevier B.V.

Kvinnors upplevelser av fosterrörelser i slutet av graviditeten

Bakgrund: Det finns begränsad kunskap om hur kvinnor upplever fosterrörelser i slutet av graviditeten. Ökad kunskap om fosterrörelser kan bidra till bättre möjligheter att identifiera foster som riskerar att dö intrauterint. Syfte: Att utforska hur gravida kvinnor upplever fosterrörelser i slutet av en okomplicerad graviditet samt hur mammor som mist ett barn i livmodern upplevt kontakten med barnet tiden före beskedet att barnet hade dött. Metod: Delstudie I, djupintervjuer med 26 mammor vars barn dött före födelsen, efter 28 fullgångna graviditetsveckor. Delstudie II, frågeformulär till 393 kvinnor med okomplicerad graviditet som besvarades i graviditetsvecka 37 till 42. Svaren analyserades i båda studierna med kvalitativ innehållsanalys. Resultat: 22 mammor i delstudie I beskrev att de hade haft en föraning om att något kunde ha hänt deras barn innan de fick besked att barnet dött intrauterint. Föraningen grundades på att mammorna hade upplevt minskade eller uteblivna fosterrörelser. Det är något som inte stämmer; formulerades som ett sammanfattande tema på mammornas föraning. Processen mot insikten om att deras barn dött beskrivs i olika steg; Inte känna kontakt med barnet; Känna oro; Känna att något är fel; Inte begripa det ofattbara; Vilja få besked; Vara säker på att barnet har dött. I delstudie II beskrev 383 (96 %) kvinnor i fullgången okomplicerad graviditet olika rörelser som klassificerades som kraftfulla rörelser. De flesta kvinnorna beskrev flera typer av rörelser, tio (4 %) kvinnor beskrev fosterrörelser som inte inkluderade någon rörelse i kategorin kraftfulla rörelser. Konklusion: Mammor som mist sitt barn före födelsen hade känt en föraning om att deras väntade barn kunde må dåligt, de hade upplevt att de tappat kontakten med barnet innan de fick besked att barnet hade dött i livmodern men normaliserade känslan. De flesta kvinnor med okomplicerad, fullgången graviditet, beskriver att barnet rör sig med kraft och tryck, få kvinnor beskriver rörelser som inte kan kategoriseras som kraftfulla. Implikationer: Blivande mammor bör uppmanas att lita på sin upplevelse av att det är något som inte stämmer och kontakta sjukvården direkt om de är bekymrade över sitt ofödda barns rörelser. Bedömning av fosterrörelser i fullgången graviditet kan inkludera: förekomst, frekvens och intensitet. Nyckelord: Innehållsanalys, fosterdöd, fosterrörelser, fullgången graviditet, upplevelser

Att minska risken för våld och att främja återhämtning i den rättspsykiatriska vården : Patienters och personalens erfarenheter av vägen mot återhämtning

Detta avhandlingsarbete är utfört inom en rättspsykiatrisk vårdkontext och återspeglar patienters[1] och personals[2] erfarenheter och upplevelser av vändpunkter i samband med minskad risk för våld och återhämtning. Med utgångspunkt från ett holistiskt och salutogent hälsovetenskapligt perspektiv har avhandlingen ett tvärvetenskapligt förhållningssätt.   Teoretiska ämnesdiscipliner såsom psykiatrisk omvårdnad, kriminologi och sociologi har influerat arbetet. Avhandlingens övergripande syfte var att utifrån de salutogena aspekterna i det rättspsykiatriska omvårdnadsarbetet undersöka vad som är relaterat till vändpunkter i samband med minskad risk för våld och vad som bidrar till återhämtning. Avhandlingen baseras på fyra olika studier. Syftet med den inledande kvantitativa delstudien (I) var att identifiera och jämföra rättspsykiatriska patienter som sänkt sin bedömda risk för våld med 30 % eller mer enligt riskbedömningsinstrument HCR-20. Resultatet visade att den bedömda risken för våld minskade över tid. En demografisk analys genomfördes för att studera skillnader mellan de patienter som sänkt sin bedömda risk för våld och de som inte sänkt sin risk. Det framgick att rättspsykiatriska patienter som bedömts med hjälp av riskbedömningsinstrumentet HCR-20, minskade den bedömda risken för våld, både på kort och på lång sikt. Den rättspsykiatriska vården fungerade bäst när det gällde att förbättra de kliniska riskfaktorerna (C-skalan). Riskhanteringen (R-skalan) gällande eventuell utskrivning och framtida friförmåner visade inte samma goda progress. Demografiska karaktäristika såsom ålder, alkohol och drogmissbruk och psykiatriska diagnoser var inte relaterade till minskad risk för våld, dock var kvinnliga patienter och patienter utan psykopatidiagnos mer benägna att sänka sin risk för våld. Ett urval av de patienter som minskade sin risk för våld med 30 % eller mer utgjorde basen för delstudie II och III. I delstudie II intervjuades tretton rättspsykiatriska patienter om upplevelser och erfarenheter kring vad som bidrar till minskad respektive ökad risk för våld inne på en rättspsykiatrisk avdelning. Data analyserades med hjälp av en tolkande beskrivning (Interpretive Description). Studien visade att orsakerna till ökad respektive minskad risk för våld var processrelaterad, där interaktioner mellan personal och patienter bidrog till en utveckling som antingen präglades av välbefinnande eller disharmoni. Delstudie II utgjorde en viktig kunskapskälla som präglade ansatsen i delstudie III och IV. Detta med hänvisning till att flertalet patienter i delstudie II lämnade intressanta beskrivningar av vändpunkter i samband med minskad risk för våld och återhämtning. Sålunda intervjuades i delstudie III, tio rättspsykiatriska patienter om deras upplevelser av förändringsprocesser i samband med vändpunkter och återhämtning. Dataanalysen skedde med hjälp av en kvalitativ innehållsanalys. Processen beskrevs utifrån tre faser där man i högriskfasen upplevde kaotiska och överväldigande känslor. Vändpunkten upplevdes som ett känsligt skede som präglades av att tvingas hitta en ny, konstruktiv väg i livet. Återhämtningsfasen präglades av ett accepterande och en mognad. Stöd och erkännande från omgivningen ansåg främja dessa processer. Delstudie IV bestod av intervjuer med tretton personal. Syftet var att belysa upplevelser och erfarenheter kring rättspsykiatriska patienters vändpunkter och återhämtning. Kvalitativ innehållsanalys användes för att analysera data. Beskrivningar kring hur en vändpunkt kunde bevaras och främjas baserades på vikten av att vara uppmärksam, lyhörd och att inte skynda på processen. En vändpunkt upplevdes genom att patienten uppvisade synbara positiva förändringar. Sammansättningen på personalen och patienterna ansågs påverka atmosfären på avdelningen, och bidrog till huruvida processen mot vändpunkter och återhämtning underlättades eller försvårades. Avhandlingen visar hur ett ständigt växelspel mellan patienter och mellan personal bidrog till huruvida vårdatmosfären upplevdes såsom hälsofrämjande eller ej. Vidare framgår att processer kring vändpunkter i samband med minskad risk för våld och återhämtning präglades av känslor av sårbarhet och utsatthet. Processen beskrevs som ett känsligt förlopp som behövde understödjas av förtroendefulla relationer med andra, samt möjligheter att få vistas i en trygg miljö. [1] Den vetenskapliga litteraturen använder sig av begrepp såsom client, consumer, service user eller forensic patient för att beteckna människor som är inskrivna inom den rättspsykiatriska vården. Inom det psykiatriska svenska fältet kan begreppen brukare, vårdtagare eller patient förekomma. I denna avhandling kommer begreppet patient och vårdtagare omväxlande att användas för att beteckna de människor som är föremål för den rättspsykiatriska vården. De patienter som deltagit i avhandlingens två delstudier kommer omväxlande att benämnas såsom deltagare eller patienter, för att åstadkomma en varierande och läsvänlig text. [2] I denna avhandling anser begreppet personal den personalkategori som arbetar med omvårdnad inom en rättspsykiatrisk kontext. Det är främst sjuksköterskor och skötare som inkluderas i begreppet omvårdnadspersonal inom den vetenskapliga litteraturen. Sjuksköterskor benämns såsom registered mental health nurses eller registered nurses. Övrig omvårdnadspersonal tituleras till exempel som nurse manager eller assistant nurses. När begreppen personal, vårdare eller omvårdnadspersonal används i denna avhandling avses då den personalkategori som arbetar närmast patienten med omvårdnad och ingen åtskillnad kommer att göras mellan de båda yrkesgrupperna. Personalen som deltar i delstudie IV har omväxlande kallats för personal eller vårdare.

Copper in disorders with neurological symptoms: Alzheimer`s, Menkes, and Wilson Diseases

Copper is an essential element for the activity of a number of physiologically important enzymes. Enzyme-related malfunctions may contribute to severe neurological symptoms and neurological diseases: copper is a component of cytochrome c oxidase, which catalyzes the reduction of oxygen to water, the essential step in cellular respiration. Copper is a cofactor of Cu/Zn-superoxide-dismutase which plays a key role in the cellular response to oxidative stress by scavenging reactive oxygen species. Furthermore, copper is a constituent of dopamine-β-hydroxylase, a critical enzyme in the catecholamine biosynthetic pathway. A detailed exploration of the biological importance and functional properties of proteins associated with neurological symptoms will have an important impact on understanding disease mechanisms and may accelerate development and testing of new therapeutic approaches. Copper binding proteins play important roles in the establishment and maintenance of metal-ion homeostasis, in deficiency disorders with neurological symptoms (Menkes disease, Wilson disease) and in neurodegenerative diseases (Alzheimer’s disease). The Menkes and Wilson proteins have been characterized as copper transporters and the amyloid precursor protein (APP) of Alzheimer’s disease has been proposed to work as a Cu(II) and/or Zn(II) transporter. Experimental, clinical and epidemiological observations in neurodegenerative disorders like Alzheimer’s disease and in the genetically inherited copper-dependent disorders Menkes and Wilson disease are summarized. This could provide a rationale for a link between severely dysregulated metal-ion homeostasis and the selective neuronal pathology.

PET imaging of tumours with a 64Cu labeled macrobicyclic cage amine ligand tethered to Tyr3-octreotate

The use of copper radioisotopes in cancer diagnosis and radionuclide therapy is possible using chelators that are capable of binding Cu(II) with sufficient stability in vivo to provide high tumour-to-background contrast. Here we report the design and synthesis of a new bifunctional chelator, 5-(8-methyl-3,6,10,13,16,19-hexaaza-bicyclo[6.6.6]icosan-1-ylamino)-5-oxopentanoic acid (MeCOSar), that forms copper complexes of exceptional stability by virtue of a cage amine (sarcophagine) ligand and a new conjugate referred to as SarTATE, obtained by the conjugation of MeCOSar to the tumour-targeting peptide Tyr(3)-octreotate. Radiolabeling of SarTATE with (64)Cu(II), a radioisotope suitable for positron emission tomography (PET), was fast (~20 min), easily performed at room temperature and consistently resulted in high radiochemical purity (>99%). In vitro and in vivo evaluation of (64)CuSarTATE demonstrated its high selectivity for tumour cells expressing somatostatin receptor 2 (sstr2). Biodistribution and PET imaging comparisons were made between (64)CuSarTATE and (64)Cu-labeled DOTA-Tyr(3)-octreotate ((64)CuDOTATATE). Both radiopharmaceuticals showed excellent uptake in sstr2-positive tumours at 2 h post-injection. While tumour uptake of (64)CuDOTATATE decreased significantly at 24 h, (64)CuSarTATE activity was retained, improving contrast at later time points. (64)CuSarTATE accumulated less than (64)CuDOTATATE in the non-target organs, liver and lungs. The uptake of (64)CuSarTATE in the kidneys was high at 2 h but showed significant clearance by 24 h. The new chemistry and pre-clinical evaluation presented here demonstrates that MeCOSar is a promising bifunctional chelator for Tyr(3)-octreotate that could be applied to a combined imaging and therapeutic regimen using a combination of (64)Cu- and (67)CuSarTATE complexes, owing to improved tumour-to-non-target organ ratios compared to (64)CuDOTATATE at longer time points.