Als Schlüsselenzym im Renin-Angiotensin System übernimmt das Angiotensin Converting Enzyme (ACE) eine wichtige Rolle bei der Blutdruckregulierung. ACE spaltet das biologisch inaktive Angiotensin I zum vasokonstriktorisch wirksamen Angiotensin II, was zu einem Anstieg des Blutdruckes führt. Tier- und Humanstudien zeigten, dass die Aufnahme bekannter, aus dem Proteinabbau stammender ACE-Inhibitoren eine Absenkung des Blutdruckes bewirkte. In der Lebensmittelindustrie finden Hydrolysate von Milchproteinen, im speziellen von Molkenproteinen, Einsatz in hypoallergenen (HA) Säuglingsnahrungen. Obwohl das Phänomen einer ACE-Inhibierung durch HA-Nahrungen in vitro in der Literatur bereits Erwähnung fand, existieren bislang keine Angaben zu einer potentiellen Wirkung in vivo. In der vorliegenden Arbeit konnte für kommerzielle hypoallergene (HA) Säuglingsnahrung eine sehr starke ACE-Hemmung in vitro zeigen (IC50-Werte zwischen 20 und 104 mg Protein/liter), welche die für fermentierte Sauermilchprodukte dokumentierte Wirkung bei weitem überstieg.] Mittels RP-HPLC und ESI-TOF-MS konnte neben zahlreichen bekannten Peptiden mit ACE-hemmendem Effekt erstmals das aus der Primärsequenz von -Lactalbumin freigesetzte Dipeptid Ile-Trp in den HA-Nahrungen identifiziert und quantifiziert werden. Ile-Trp ist der bislang potenteste in Lebensmitteln nachgewiesene ACE-Inhibitor (IC50 = 0,7µM). HA-Nahrungen zeigten auch ex vivo im Zellsystem (HUVECs) einen stark ACE-hemmenden Effekt. Aus diesem Grunde wurde ein möglicher Einfluss der HA-Nahrungen auf den Blutdruck spontan hypertensiver Ratten untersucht. Hierfür wurden die Tiere im Rahmen einer Fütterungsstudie über 14 Wochen mit standardisiertem Futter, welchem HA-Nahrung (Gruppe 1), konventionelle Säuglingsnahrung (Gruppe 2) bzw. der bekannte ACE-Inhibitor Captopril (Gruppe 3) zugesetzt war, gefüttert. Eine vierte Gruppe mit Standardfutter diente als Kontrolle. Der Blutdruck wurde am wachen Tier nichtinvasiv mittels tail-cuff-Methode gemessen. Der systolische Blutdruck sank bei Verabreichung der HA-Nahrung nach 7 Wochen signifikant um 21 ± 8 mmHg ab im Vergleich zur Kontrollgruppe bzw. den mit konventioneller Säuglingsnahrung gefütterten Tieren. Captopril führte zur einer Blutdrucksenkung um 30 ± 7 mmHg.

Proteinhydrolysate gewinnen als Bestandteil von Lebens- und Futtermitteln zunehmend an Bedeutung. In Abhängigkeit ihrer Sequenz können darin enthaltene Peptide über Wechselwirkungen mit dem Angiotensin-Converting Enzym (ACE), welches eine Schlüsselfunktion bei der Blutdruckregulation einnimmt, physiologisch wirken und damit einen Beitrag zur Gesunderhaltung leisten oder hinsichtlich antioxidativer Eigenschaften einen positiven Effekt auf die Lagerstabilität und damit Qualität von Lebensmitteln ausüben. In der vorliegenden Arbeit wurde zunächst die ACE-inhibierende Aktivität von Pflanzenproteinen im Vergleich zum Molkenprotein hinsichtlich Struktur-Wirkbeziehungen und gegenüber den Domänen des ACEs sowie verschiedenen ACE-Spezies charakterisiert. Des Weiteren wurde eine Verkapselung von in Proteinhydrolysaten enthaltenen Dipeptiden angestrebt und der Einfluss auf deren proteolytische Stabilität untersucht. Dipeptide unterliegen während der gastrointestinalen Verdauung einem Abbau, was einen limitierenden Faktor für deren Bioaktivität darstellt. Zur Charakterisierung von Cyclodextrin-Komplexen mit aromatischen Aminosäuren sowie korrespondierenden Dipeptiden wurden UV- und fluorometrische Methoden sowie NMR-Techniken verwendet. Abschließend wurde das antioxidative Potential von Proteinhydrolysaten zunächst im Modellsystem und anschließend unter Nutzung von Lebensmittelmatrices abgeschätzt. Zusammenfassen konnte für die untersuchten Pflanzenproteinhydrolysate ein ausgesprochen gutes den potenten Milchproteinhydrolysaten vergleichbares ACE-inhibitorisches Potential als auch eine konzentrationsabhängige antioxidative Aktivität abgeleitet werden. Insbesondere Reisproteinhydrolysat erwies sich als potente Quelle physiologisch als auch antioxidativ wirksamer Peptide.

Viruset SARS-CoV-2 binder till det membranbundna enzymet angiotensinkonvertas 2 (ACE2). ACE2 är även en del av Renin-Angiotensin-Aldosteron-systemet (RAAS) och Kallikrein-Kinin-systemet (KKS). Den enzymatiska delen av ACE2 klyvs från cellmembranet vid inbindningen av viruset eller genom enzymet ADAM17 och bildar då cirkulerande ACE2 (sACE2). Syftet med den här litteraturstudien var att undersöka om sACE2 kan kopplas till allvarlighetsgraden av covid-19. Studierna visade blandade resultat. Tre artiklar visade ökande halter sACE2 vid svår covid-19. Två studier visade sjunkande halter sACE2 vid svår covid-19. Två artiklar visade ingen koppling mellan sACE2 och allvarlighetsgraden av covid-19. Då forskningsområdet omkring SARS-CoV-2 är nytt finns det stora variationer i studiernas upplägg, vilket resulterar i att resultaten är osäkra och svåra att jämföra med varandra. Eventuellt kan det finnas en koppling mellan mängden sACE2 och allvarlighetsgraden av covid-19. Mer forskning behövs för att säkerställa om sACE2 i kombination med andra tester kan användas för att upptäcka patienter i risk för allvarlig covid-19. / The virus SARS-CoV-2 binds to the enzyme Angiotensin Converting Enzyme 2 (ACE2) which causes shedding of the extracellular part of the enzyme and produces soluble ACE2 (sACE2). ACE2 is also a part of Renin-Angiotensin-Aldosterone-system (RAAS) and Kallikrein-Kinin-system (KKS). The enzyme ADAM17 also causes ACE2 to shed during inflammation. Since inflammation is an important part of the Covid-19 pathogenesis, the sACE2 levels may affect the pathogenesis of Covid-19. The purpose of this literature study was to investigate a possible connection between sACE levels and Covid-19 severity. Three articles showed high levels of sACE2 in severe Covid-19. Two articles showed low levels of sACE2 in severe Covid-19. Two articles showed no connection between severity of Covid-19 and sACE2 levels.  Due to the novelty of the research area, there are variations in the study set-up. Although inconclusive study results, sACE2 may be used as a secondary biomarker to detect indications of severe Covid-19, but more research is needed.

Magister Pharmaceuticae - MPharm / Due to the contribution of hypertension to various cardiovascular diseases, many studies are currently focused on identifying efficient bioactive compounds with antihypertensive activity and thus reducing the levels of cardiovascular disease. ACE inhibitors are an important component of the therapeutic regimen for treating hypertension, but due to the increase in the prevalence of side effects of synthetic compounds, alternative and complementary medicines which may consist of pure bioactive compound or a combination of various compounds from natural sources are gaining importance in overcoming hypertension. Hypericum perforatum has been studied for various activities including anti-bacterial, anti-depressant, anti-oxidant properties, but studies on its cardiovascular effects specifically ACE inhibitory activity have not yet been explored. In this study, ACEI assay-guided fractionation of the ethanol extract of Hypericum perforatum was carried out other to isolate a compound with ACE inhibition. A compound – (3-hydroxy 4, 4 dimethyl-4-butyrolactone) was isolated from an active fraction of the plant extract and was tested for ACE inhibition and its chemical structure elucidated using 1HNMR and C13NMR spectrometry and further characterized using mass spectrometry and FTIR.

This thesis deals with electronic signature in the area of accounting. It includes characteristic of electronic signature, certification authority and time stamp. This thesis explains these fundamental concepts related to the electronic signature and also shows some practical application of it -- such as electronic invoicing, archiving, and communication with state-administration through data boxes or through electronic registries. In this thesis there is also detaily described and depicted the procedure of making electronic invoices and authentication of the certificate of the electronic signature.

Oxidative stress is associated with development and progression of cardiovascular disease. Angiotensin II produces oxidative stress and endothelial dysfunction, and its actions may be attenuated by the activity of angiotensin converting enzyme type 2 (ACE2) which converts angiotensin II to the vasoprotective peptide angiotensin (1-7). Similarly, increased oxidative stress is associated with aortic valve stenosis in humans and mice. In my thesis studies, I explore mechanisms of modulation and generation of oxidative stress in cerebral arteries and heart valves. First, I tested the hypothesis that ACE2 deficiency increases oxidative stress and vasomotor dysfunction in cerebral arteries, and examined the role of ACE2 in vascular aging. Vasomotor function was assessed in the basilar artery ex vivo of adult and old ACE2 deficient (ACE2-/y) and wild type (WT or ACE2+/y) mice. ACE2 was present, but at relatively low levels in cerebral arteries. Systolic blood pressure was similar in adult and old ACE2-/y and ACE2+/y mice. Maximal dilatation to acetylcholine was impaired in the basilar artery from adult ACE2-/y mice compared to adult ACE2+/y. In old mice, maximal vasodilatation to acetylcholine was impaired in ACE2+/y mice and severely impaired in ACE2-/y mice. The antioxidant tempol improved responses to acetylcholine in adult and old ACE2-/y and ACE2+/y mice. Nitrotyrosine staining in the basilar artery was increased in adult ACE2-/y mice and in old ACE2-/y and ACE2+/y mice relative to adult ACE2+/y, which indicates that oxidative stress was higher in cerebral arteries from ACE2 deficient mice and old mice. Expression of NADPH oxidase subunits Nox2 and p47phox, and of pro-inflammatory molecules Rcan1 and TNF alpha; was increased in cerebral arteries from old ACE2-/y and ACE2+/y mice. Additionally, I tested the hypothesis that serotonin induces oxidative stress in human heart valves, and examined mechanisms by which serotonin may increase reactive oxygen species (ROS). Superoxide (O2.-) was measured in heart valves from explanted human hearts that were not used for transplantation. Superoxide levels (lucigenin-enhanced chemiluminescence) were increased in homogenates of cardiac valves and pulmonary artery after incubation with serotonin. A non-specific inhibitor of flavin-oxidases (DPI), or inhibitors of monoamine oxidase-MAO (tranylcypromine and clorgyline), prevented serotonin-induced increase in O2.-. Dopamine, another MAO substrate which is increased in patients with carcinoid syndrome, also increased superoxide levels in heart valves, and this effect was attenuated by clorgyline. Apocynin did not prevent increases in O2.- during serotonin treatment. Addition of serotonin to recombinant human MAO-A generated superoxide, and this effect was prevented by an MAO inhibitor. In conclusion, I have demonstrated that ACE2 deficiency impairs vasomotor function in cerebral arteries from adult mice and augments endothelial dysfunction during aging. Oxidative stress plays a critical role in cerebrovascular dysfunction induced by ACE2 deficiency and aging. I have also identified a novel mechanism whereby MAO-A can contribute to increased oxidative stress in human heart valves and pulmonary artery exposed to serotonin and dopamine.

The potential of flaxseed (Linum usitatissimum L.) protein to release bioactive peptides upon enzymatic hydrolysis was evaluated. Flaxseed protein released angiotensin I-converting enzyme inhibitory (ACEI) peptides during in vitro simulated gastrointestinal (GI) digestion in a static (no removal of digested products) and a dynamic model (removal of <1 kDa molecules in the intestinal phase). The ACEI activity of the gastric plus intestinal digest (absorbed fraction-IC50: 0.04 mg N/mL; retained fraction-IC50: 0.05 mg N/mL; degree of hydrolysis, DH: 46.78 %) of the dynamic model was significantly higher (P<0.05) than that of the static model (IC50: 0.39 mg N/mL; DH: 43.95 %). Polypeptides of 48, 41, 29 and 20 kDa could be releasing these ACEI peptides. Six peptides in the highest ACEI fraction (0.5-1 kDa) of the absorbable gastric plus intestinal digest were identified via de novo sequencing. Only digests of the static model exhibited hydroxyl radical (OH) scavenging activity (IC50: 0.40 mg N/mL), suggesting the inappropriateness of such models in this type of research. Presence of mucilage and oil interfered with the in vitro digestibility of flaxseed protein, which could limit the release of ACEI peptides during GI digestion. The protein digestibility of milled whole flaxseed (12.61 %) was significantly improved (P<0.05) with the removal of mucilage (51.00 %) and oil together with mucilage (66.79 %). The digestibility of isolated flaxseed protein was 68.00 %.<p> Flaxseed protein, hydrolyzed (DH: 11.94-70.62 %) with Flavourzyme® in a central composite rotatable design, possessed bioactivities with identified optimum enzyme/substrate and time of hydrolysis combinations, including ACEI activity (71.59-88.29 %, 83.7 LAPU/g protein, 19.9 h), scavenging of OH (12.48-22.08 %, 30.2 LAPU/ g protein, 1.5 h) and superoxide radical (O2-) (26.33-39.41 %, 4.9 LAPU/ g protein, 16.3 h) and inhibiting linoleic acid oxidation (0.71-94.33 %, 1.6 LAPU/ g protein, 12.6 h). The degradation pattern of polypeptides during enzymatic hydrolysis indicated that 48 and 13 kDa molecules could be releasing these bioactive peptides. De novo sequencing identified two ACEI and five OH scavenging peptides in the hydrolysate fractions (0.5-1.05 kDa) with the highest bioactivities. The findings suggest the importance of flaxseed protein as a source of cardioprotective bioactive peptides.

Vi står inför en förändring, att minska vårt beroende av fossil energi till förmån för en ökad användning av förnybar energi. Incitament i form av ökade punktskatter på fossilt bränsle påskyndar omställningen för företag till förnybar energi och- eller energieffektivisering av sin produktion. Konsekvensen blir en successivt fördyrad kostnad för produktion av fjärrvärme med eldningsolja till tillverkningsindustrin. Punktskatt på eldningsolja stiger med 41 procent, från 2010 till 2015 för företagen. Att konvertera befintliga oljepannor med träpulverbrännare är en lösning för att hålla produktionskostnaden nere och behålla sin konkurrenskraft. I detta examensarbete utreds möjligheten att konvertera oljepannor i storleksklassen 5-10 MW. Studien tar ett helhetsgrepp om RMT´s fjärrvärmeproduktion för att söka svaret på, om det är möjligt att göra en konvertering ur ett tekniskt, hållbarhets och ekonomiskt perspektiv. Det kända behovet av spetslast från oljepannorna vid -3°C visade sig inte stämma utan brytpunkten hamnade vid -6°C. Resultatet pekar på att en 10 MW oljepanna kan konverteras till 5 MW träpulver men ändå behålla sin ursprungliga effekt genom en kombibrännare. Tidigare problem som fanns med träpulveranläggningar är åtgärdade och referensanläggningar i den aktuella storleksklassen finns i drift. Ett förfrågningsunderlag skickades ut för att få in budgetpris på konvertering av 5 och 10 MW oljepannor för utvärdering. Trots att alla leverantörer gavs samma förutsättningar så varierade budgetpriserna väldigt mycket. En stor överraskning var den korta payoff tid på konverteringar med liten värmeeffekt. Att en konvertering av en 10 MW OP har en återbetalningstid på 20 månader var rätt osannolikt innan studien utfördes. Denna studie kan även ses som en inspirationskälla till andra företag som har mindre spetslastpannor och vill fasa ut sitt fossila beroende med förnybar energi, samtidigt behålla sin konkurrenskraft. I fjärrvärmebranschen är dessa 5 och 10 MW oljepannor vanliga som spetslastpannor. Det finns ca 1000 oljepannor i storleken 5-10 MW i Sverige så det bör finnas en stor potential i att konvertera oljepannor till träpulver. / We are facing a change, to reduce our dependency on fossil fuels in favor of increased use of renewable energy. Incentives in the form of increased excise taxes on fossil fuels for companies accelerate the conversion to renewable energy or energy efficiency of its production. The consequence is a progressively more expensive cost for district heating with fuel oil to manufacturing industry. Excise tax on fuel oil rises by 41 percent, from 2010 to 2015 for those companies. To convert existing oil boilers with woodpowderburner is a solution to keep production costs down and remain competitive. In this thesis studied the possibility of converting oil boilers in the size range of 5 to 10 MW. The study takes a holistic approach to RMT's district heating to search the answer, if it is possible to do a conversion from a technical, sustainability and economic perspective. The felt need for peak load from oil boilers at -3° C appeared not to sue; it ended up at -6° C. The results indicate that a 10 MW oil boiler can be converted to 5 MW wood powder and while retaining its original power through a combination burner. Previously problems with woodpowderplant are taken care of and reference facilities in the current magnitude are in operation. An inquiry was sent out to get budget prices at a conversion of 5 and 10 MW oil boilers for evaluation. Even though all the suppliers was given the same opportunities so varied budget prices very much. A big surprise was the short payoff time on conversions of small oil boilers. The conversion of a 10 MW OP has a payback period of 20 months and that was rather unlikely before the study was performed. This study can also be seen as a source of inspiration to other companies that have small peak load boilers and want to phase out their fossil fuel dependence with renewable energy, and retain their competitiveness. In the district heating sector, these 5 and 10 MW oil boilers are ordinary peak load boilers. There are about 1000 oil boilers in the size from 5 to 10 MW in Sweden so it should be a large potential in converting oil boilers to wood powder

The potential of flaxseed (Linum usitatissimum L.) protein to release bioactive peptides upon enzymatic hydrolysis was evaluated. Flaxseed protein released angiotensin I-converting enzyme inhibitory (ACEI) peptides during in vitro simulated gastrointestinal (GI) digestion in a static (no removal of digested products) and a dynamic model (removal of <1 kDa molecules in the intestinal phase). The ACEI activity of the gastric plus intestinal digest (absorbed fraction-IC50: 0.04 mg N/mL; retained fraction-IC50: 0.05 mg N/mL; degree of hydrolysis, DH: 46.78 %) of the dynamic model was significantly higher (P<0.05) than that of the static model (IC50: 0.39 mg N/mL; DH: 43.95 %). Polypeptides of 48, 41, 29 and 20 kDa could be releasing these ACEI peptides. Six peptides in the highest ACEI fraction (0.5-1 kDa) of the absorbable gastric plus intestinal digest were identified via de novo sequencing. Only digests of the static model exhibited hydroxyl radical (OH) scavenging activity (IC50: 0.40 mg N/mL), suggesting the inappropriateness of such models in this type of research. Presence of mucilage and oil interfered with the in vitro digestibility of flaxseed protein, which could limit the release of ACEI peptides during GI digestion. The protein digestibility of milled whole flaxseed (12.61 %) was significantly improved (P<0.05) with the removal of mucilage (51.00 %) and oil together with mucilage (66.79 %). The digestibility of isolated flaxseed protein was 68.00 %.<p> Flaxseed protein, hydrolyzed (DH: 11.94-70.62 %) with Flavourzyme® in a central composite rotatable design, possessed bioactivities with identified optimum enzyme/substrate and time of hydrolysis combinations, including ACEI activity (71.59-88.29 %, 83.7 LAPU/g protein, 19.9 h), scavenging of OH (12.48-22.08 %, 30.2 LAPU/ g protein, 1.5 h) and superoxide radical (O2-) (26.33-39.41 %, 4.9 LAPU/ g protein, 16.3 h) and inhibiting linoleic acid oxidation (0.71-94.33 %, 1.6 LAPU/ g protein, 12.6 h). The degradation pattern of polypeptides during enzymatic hydrolysis indicated that 48 and 13 kDa molecules could be releasing these bioactive peptides. De novo sequencing identified two ACEI and five OH scavenging peptides in the hydrolysate fractions (0.5-1.05 kDa) with the highest bioactivities. The findings suggest the importance of flaxseed protein as a source of cardioprotective bioactive peptides.

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