The influence of aging on biological rhythms in human- implications for the pharmacotherapy

Praca dotyczy wpływu starzenia na zmiany w rytmach okołodobowych układów hormonalnych. Do najczęstszych zmian jakie obserwujemy zaliczamy zmiany amplitudy rytmu, jego skrócenie oraz desynchronizację rytmu. Indukują one implikacje patofizjologiczne i terapeutyczne w zakresie terapii hormonalnej.This paper rewers to effects of aging on changes In hormonal circadian rhythms. To the most frequent changes related to aging belong attenuation and shortening of amplitude as well as desynchronization of rhythms. These changes may determine pathophysiological and therapeutic base for hormonal therapy

Proteomic analysis of mitochondria-enriched fraction isolated from the frontal cortex and hippocampus of apolipoprotein E knockout mice treated with alda-1, an activator of mitochondrial aldehyde dehydrogenase (ALDH2)

The role of different genotypes of apolipoprotein E (apoE) in the etiology of Alzheimer’s disease is widely recognized. It has been shown that altered functioning of apoE may promote 4-hydroxynonenal modification of mitochondrial proteins, which may result in mitochondrial dysfunction, aggravation of oxidative stress, and neurodegeneration. Mitochondrial aldehyde dehydrogenase (ALDH2) is an enzyme considered to perform protective function in mitochondria by the detoxification of the end products of lipid peroxidation, such as 4-hydroxynonenal and other reactive aldehydes. The goal of our study was to apply a differential proteomics approach in concert with molecular and morphological techniques to elucidate the changes in the frontal cortex and hippocampus of apolipoprotein E knockout (apoE−/−) mice upon treatment with Alda-1—a small molecular weight activator of ALDH2. Despite the lack of significant morphological changes in the brain of apoE−/− mice as compared to age-matched wild type animals, the proteomic and molecular approach revealed many changes in the expression of genes and proteins, indicating the impairment of energy metabolism, neuroplasticity, and neurogenesis in brains of apoE−/− mice. Importantly, prolonged treatment of apoE−/− mice with Alda-1 led to the beneficial changes in the expression of genes and proteins related to neuroplasticity and mitochondrial function. The pattern of alterations implies mitoprotective action of Alda-1, however, the accurate functional consequences of the revealed changes require further research

Mechanisms of oxidative stress in human aortic aneurysms — association with clinical risk factors for atherosclerosis and disease severity

Aortic abdominal aneurysms (AAA) are important causes of cardiovascular morbidity and mortality. Oxidative stress may link multiple mechanisms of AAA including vascular inflammation and increased metalloproteinase activity. However, the mechanisms of vascular free radical production remain unknown. Accordingly, we aimed to determine sources and molecular regulation of vascular superoxide (O2radical dot−) production in human AAA. Methods and results: AAA segments and matched non-dilated aortic samples were obtained from 40 subjects undergoing AAA repair. MDA levels (determined by HPLC/MS) were greater in plasma of AAA subjects (n = 16) than in risk factor matched controls (n = 16). Similarly, superoxide production, measured by lucigenin chemiluminescence and dihydroethidium fluorescence, was increased in aneurysmatic segments compared to non-dilated aortic specimens. NADPH oxidases and iNOS are the primary sources of O2radical dot− in AAA. Xanthine oxidase, mitochondrial oxidases and cyclooxygenase inhibition had minor or no effect. Protein kinase C inhibition had no effect on superoxide production in AAA. NADPH oxidase subunit mRNA levels for p22phox, nox2 and nox5 were significantly increased in AAAs while nox4 mRNA expression was lower. Superoxide production was higher in subjects with increased AAA repair risk Vanzetto score and was significantly associated with smoking, hypercholesterolemia and presence of CAD in AAA cohort. Basal superoxide production and NADPH oxidase activity were correlated to aneurysm size. Conclusions: Increased expression and activity of NADPH oxidases are important mechanisms underlying oxidative stress in human aortic abdominal aneurysm. Uncoupled iNOS may link oxidative stress to inflammation in AAA. Oxidative stress is related to aneurysm size and major clinical risk factors in AAA patients

Vasodilatory efficacy and impact of papaverine on endothelium in radial artery predilatation for CABG surgery : in search for optimal concentration

Abstract Objective: The aim of this study was to compare the efficacy of two different papaverine concentrations (0.5 mg/ml and 2 mg/ml) for vasospasm prevention and their impact on endothelium integrity. Methods: We have studied distal segments of radial arteries obtained by no-touch technique from coronary artery bypass graft (CABG) patients (n=10). The vasodilatory effect of papaverine (concentrations of 0.5 mg/ml and 2 mg/ml) was assessed in vitro, in isometric tension studies using ex vivo myography (organ bath technique) and arterial rings precontracted with potassium chloride (KCl) and phenylephrine. The impact of papaverine on endothelial integrity was studied by measurement of the percentage of vessel's circumference revealing CD34 endothelial marker. Results: 2 mg/ml papaverine concentration showed stronger vasodilatatory effect than 0.5 mg/ml, but it caused significantly higher endothelial damage. Response to KCl was 7.35±3.33 mN for vessels protected with papaverine 0.5 mg/ml and 2.66±1.96 mN when papaverine in concentration of 2 mg/ml was used. The histological examination revealed a significant difference in the presence of undamaged endothelium between vessels incubated in papaverine 0.5 mg/ml (72.86±9.3%) and 2 mg/ml (50.23±13.42%), P=0.002. Conclusion: Papaverine 2 mg/ml caused the higher endothelial damage. Concentration of 0.5 mg/ml caused better preservation of the endothelial lining

GTP cyclohydrolase I gene polymorphisms are associated with endothelial dysfunction and oxidative stress in patients with type 2 diabetes mellitus

Background: The genetic background of atherosclerosis in type 2 diabetes mellitus (T2DM) is complex and poorly understood. Studying genetic components of intermediate phenotypes, such as endothelial dysfunction and oxidative stress, may aid in identifying novel genetic components for atherosclerosis in diabetic patients.<p></p> Methods: Five polymorphisms forming two haplotype blocks within the GTP cyclohydrolase 1 gene, encoding a rate limiting enzyme in tetrahydrobiopterin synthesis, were studied in the context of flow and nitroglycerin mediated dilation (FMD and NMD), intima-media thickness (IMT), and plasma concentrations of von Willebrand factor (vWF) and malondialdehyde (MDA).<p></p> Results: Rs841 was associated with FMD (p = 0.01), while polymorphisms Rs10483639, Rs841, Rs3783641 (which form a single haplotype) were associated with both MDA (p = 0.012, p = 0.0015 and p = 0.003, respectively) and vWF concentrations (p = 0.016, p = 0.03 and p = 0.045, respectively). In addition, polymorphism Rs8007267 was also associated with MDA (p = 0.006). Haplotype analysis confirmed the association of both haplotypes with studied variables.<p></p> Conclusions: Genetic variation of the GCH1 gene is associated with endothelial dysfunction and oxidative stress in T2DM patients

Pleiotropic effects of simvastatin in patients with peripheral arterial occlusive disease

Wstęp. Simwastatyna ma ugruntowaną pozycję w pierwotnej i wtórnej prewencji zaburzeń sercowo-naczyniowych u pacjentów z grupy wysokiego ryzyka. Oprócz działania hipolipemizującego może ona zmieniać funkcję śródbłonka, stabilizować blaszki miażdżycowe, działać przeciwzakrzepowo i przeciwzapalnie.Celem pracy było sprawdzenie działania plejotropowego simwastatyny u pacjentów z miażdżycą naczyń obwodowych (PAOD) oraz współistniejącą normo- i hipercholersterolemią. Materiał i metody. Badaniem objęto 20 mężczyzn z PAOD: 10 z normocholesterolemią (NCH) i 10 z hipercholesterolemią (HCH) w wieku 41-75 lat (średnia 58 ± 9,4 roku). Pacjenci otrzymywali doustnie raz dziennie 40 mg simwastatyny (Zocor) przez 3 miesiące. Przed rozpoczęciem terapii, po miesiącu i 3 miesiącach leczenia oznaczano stężenie lipidów oraz przeprowadzano badania kliniczne oceniające skuteczność terapii. Badania laboratoryjne przeprowadzono przed rozpoczęciem terapii i po 3 godzinach od przyjęcia simwastatyny. Te same oznaczenia wykonywano po miesiącu i 3 miesiącach leczenia, zwykle 12 godzin po przyjęciu wieczornej dawki i po 3 godzinach od przyjęcia simwastatyny. Wyniki. Simwastatyna powodowała redukcję stężeń całkowitego cholesterolu (TC), lipoprotein o małej gęstości (LDL), triglicerydów (TG) w obu badanych grupach. Nie stwierdzono znamiennych różnic w stężeniu cholesterolu frakcji HDL. W grupie osób z NCH nastąpił wzrost wartości wskaźnika kostkowo-ramieniowego (ABI) i rozszerzalności tętnicy ramieniowej (FMD). Natomiast w grupie badanych z HCH stwierdzono znamienne wydłużenie obu dystansów i wzrost FMD przy braku zmian w ABI. W obu badanych grupach wykazano statystycznie znamienne działanie fibrynolityczne i przeciwpłytkowe silniej wyrażone w grupie HCH, natomiast nie stwierdzono zmian w stężeniu antygenu tkankowego aktywatora plazminogenu (t-PA), odkształcalności i agregacji krwinek czerwonych. Wnioski. Simwastatyna powodowała kliniczną poprawę u pacjentów z PAOD, niezależnie od jej działania hipolipemizującego. Te korzystne efekty mogą być wynikiem działania plejotropowego, poprawy funkcji śródbłonka naczyniowego i stabilizacji blaszek miażdżycowych.Background. Simvastatin has a consolidated position in the primary and secondary prevention of cardiovascular disease in high risk patients. Simvastatin, independently of its hypolipaemic action, changes endothelial function, stabilises atheromatous plaques and exerts antithrombotic and anti-inflammatory action. The purpose of this paper was to verify the pleiotropic action of simvastatin in PAOD patients with normo- and hypercholesterolaemia. Material and methods. Twenty patients with peripheral aterial occlusive disease (PAOD): 10 normocholesterolaemic (NCH) and 10 hypercholesterolaemic (HCH), 41-75 years, old were included in the study. The patients were treated with 40 mg of simvastatin daily for 3 months. At the beginning of the therapy, after one month and three months of treatment lipid levels and clinical investigations were performed. Laboratory estimations were determined before starting therapy and 3 hours after ingestion of simvastatin tablets. The same procedure was repeated after one month and three months of therapy, always 12 hours after the last dose and 3 hours after intake of the tablet. Results. Simvastatin caused significant reduction of TC, LDL and TG levels in both study groups. No changes in HDL levels were observed. An increase of ABI and FMD in the NCH group were observed. A significant increase of FMD, of pain-free and total walking distances were seen In HCH patients; no changes in ABI were observed. In both study groups significant fibrinolytic and antiplatelet action were observed, more distinct in the HCH group. No changes in the levels of t-PA antigen, RBC deformability and aggregability were seen in both study groups. Conclusions. Simvastatin therapy caused clinical improvement in PAOD patients independently of its lipid lowering properties. These beneficial simvastatin effects may be related to the pleiotropic action and restoration of endothelial function