The prevalence of cardiovascular diseases has increased in the last decennia. This thesis studied the potential relationship between oxidative stress and cardiovascular diseases. The first part of... Show moreThe prevalence of cardiovascular diseases has increased in the last decennia. This thesis studied the potential relationship between oxidative stress and cardiovascular diseases. The first part of the thesis focused on anti-oxidants, which are scavengers that protect against oxidative damage. We studied the association between several lifestyle factors, diet, physical activity, sleep, alcohol intake and smoking, and antioxidant levels both in blood and urine. Subsequently, we investigated whether a higher concentration of antioxidants leads to a decrease in ischaemic stroke occurrence. Next, we aimed to study a possible cause of oxidative damage and its effect on cardiovascular disease. Mitochondrial dysfunction is one of the mechanisms that may underly this effect. Mitochondria are an important source of Reactive Oxygen Species (ROS), as an inevitable byproduct of their essential role in energy production. A disbalance in ROS production and scavenging might result in oxidative damage. Thus, we investigated the causal association between mitochondrial dysfunction and stroke using the Mendelian Randomization method. Finally, we studied how socio-demographic traits could modify the causal association between CVD risk factors and coronary artery disease. Show less
Het hoofddoel van dit proefschrift is het ontrafelen van de causale rol van oxidatieve stress, gemeten door antioxidanten spiegels in bloed en mitochondriaal DNA-kopieaantal (mtDNA-CN), bij het... Show moreHet hoofddoel van dit proefschrift is het ontrafelen van de causale rol van oxidatieve stress, gemeten door antioxidanten spiegels in bloed en mitochondriaal DNA-kopieaantal (mtDNA-CN), bij het ontstaan van chronische ziekten. In dit proefschrift is de nadruk gelegd op het onderzoek naar cardiometabole ziekten en verwante risicofactoren door het toepassen van conventionele epidemiologische technieken in combinatie met Mendeliaanse Randomisatie. De studies beschreven in dit proefschrift hebben antwoord gegeven op twee hoofdvragen na toepassing van innovatieve epidemiologische onderzoeksmethoden op populatieniveau, namelijk: 1) of mitochondriale disfunctie een causale risicofactor is in de ontwikkeling van atherosclerotische cardiovasculaire ziekten en verwante risicofactoren, en 2) of antioxidanten in de voeding klinisch relevante voordelen opleveren bij de preventie van atherosclerotische cardiovasculare ziekten. Daarnaast werpt dit proefschrift licht op de rol van ontsteking, welke een bron kan zijn van verhoogde oxidatieve stress , bij neurologische aandoeningen. Show less
During the current COVID-19 pandemic, a need for evaluation of already available drugs for treatment of the disease is crucial. Hereby, based on literature review from the current pandemic and... Show moreDuring the current COVID-19 pandemic, a need for evaluation of already available drugs for treatment of the disease is crucial. Hereby, based on literature review from the current pandemic and previous outbreaks with corona viruses we analyze the impact of the virus infection on cell stress responses and redox balance. High levels of mortality are noticed in elderly individuals infected with SARS-CoV2 and during the previous SARS-CoV1 outbreak. Elderly individuals maintain a chronic low level of inflammation which is associated with oxidative stress and inflammatory cytokine production, a condition that increases the severity of viral infections in this population. Coronavirus infections can lead to alterations of redox balance in infected cells through modulation of NAD + biosynthesis, PARP function along with altering proteasome and mitochondrial function in the cell thereby leading to enhanced cell stress responses which further exacerbate inflammation. ROS production can increase IL-6 production and lipid peroxidation resulting in cell damage. Therefore, early treatment with anti-oxidants such as NAC during COVID-19 can be a way to bypass the excessive inflammation and cell damage that lead to severe infection, thus early NAC as intervention should be evaluated in a clinical trial setting. Show less
Opioid analgesics are frequently used for pain relief. However, they may cause respiratory depression which is life-threatening. Animal studies suggest an apparent maximum in respiratory depression... Show moreOpioid analgesics are frequently used for pain relief. However, they may cause respiratory depression which is life-threatening. Animal studies suggest an apparent maximum in respiratory depression by buprenorphine regardless of drug-dose (ceiling phenomenon). In the first part of this thesis, ceiling of buprenorphine-induced respiratory depression without loss of antinociception is reported in healthy volunteers, indicating that buprenorphine may be relatively safer than other opioids which show a dose-dependent increase of respiratory depression. Furthermore, despite the high affinity of buprenorphine for µ-opioid receptors, buprenorphine-induced respiratory depression can be antagonized (reversed) by naloxone, provided high doses are given within the correct dose-window. In the second part the focus is on the mechanisms of the hypoxic and hypercapnic ventilatory responses. Previous studies showed that antioxidants are able to stimulate the carotid bodies (small organs initiating the ventilatory response to hypoxia) when their output is reduced. In humans, we observed that depression of the hypoxic response by acetazolamide is reversed by ascorbic acid and α-tocopherol. In anesthetized cats, the carbonic anhydrase inhibitor acetazolamide but not methazolamide reduced the hypoxic response indicating that this inhibiting effect on the carotid bodies is caused by an effect other than by inhibition of carbonic anhydrase. Show less
