Antioxidants in cardiovascular therapy : panacea or false hope?

Date of Acceptance:10/06/2015 Acknowledgments KG’s Ph.D. was funded by the EU North Sea Region Programme (www.ClimaFruit.com), a European Regional Development Fund initiative.Peer reviewedPublisher PD

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

Bencyclane - a new aspect of the mechanism of action in patients with peripheral arterial occlusive disease. Open-label, prospective, randomized trial

Wstęp. Bencyklan wywiera korzystny efekt terapeutyczny u pacjentów ze schorzeniami naczyń obwodowych, jednak mechanizmu jego działania całkowicie nie wyjaśniono. Podjęto próbę wyjaśnienia mechanizmu działania bencyklanu na podstawie wybranych parametrów badań klinicznych i laboratoryjnych u chorych na miażdżycę tętnic kończyn dolnych (PAOD), ze szczególnym uwzględnieniem jego działania przeciwpłytkowego i fibrynolitycznego. Materiał i metody. Grupę porównawczą stanowili pacjenci otrzymujący pentoksyfilinę. Badaniem objęto grupę 36 chorych na PAOD w II stadium według klasyfikacji Fontaine’a w wieku 43-69 lat (śr. 56 lat). Pacjentów podzielono losowo na 2 grupy 18-osobowe, uwzględniając datę urodzenia. W grupie stosującej bencyklan chorzy otrzymywali w godzinach porannych 200 mg preparatu w 250 ml 0,9-procentowego NaCl w kroplowej infuzji dożylnej oraz 200 mg doustnie w godzinach wieczornych przez 14 dni. W grupie stosującej pentoksyfilinę pacjenci otrzymywali 300 mg pentoksyfiliny w 250 ml 0,9-procentowego NaCl w kroplowej infuzji dożylnej w godzinach porannych oraz 400 mg pentoksyfiliny w godzinach wieczornych przez 14 dni. Badania kliniczne wykonywano przed rozpoczęciem leczenia oraz po jego zakończeniu. Badania laboratoryjne przeprowadzano przed rozpoczęciem terapii i po zakończonej 2-godzinnej dożylnej infuzji leków w pierwszym i ostatnim dniu leczenia. Wyniki. Bencyklan w porównaniu z pentoksyfiliną wykazywał silniejsze działanie przeciwpłytkowe hamujące agregację krwinek czerwonych i fibrynolityczne przy podobnym działaniu naczyniorozszerzającym, natomiast w mniejszym stopniu wpływał na odkształcalność krwinek czerwonych. Wniosek. Działania przeciwpłytkowe i fibrynolityczne, obniżenie stężenia PAI-1 oraz wzrost stężeń t-PA i 6-keto PGF1α a mogą sugerować śródbłonkowopochodny mechanizm działania bencyklanu.Background. Bencyclane provides a favourable therapeutic effect in patients with peripheral vascular disease; however, its mechanism of action has not been completely explained. We have attempted to clarify bencyclane’s mechanism of action in patients with peripheral arterial occlusive disease (PAOD), taking into particular consideration antiplatelet and fibrinolytic activity of the drug, on the basis of particular clinical and laboratory parameters. Materials and methods. The study was performed on 36 patients with PAOD according to Fontaine stage II, aged 43-69 years (mean 56 years). We used patients receiving pentoxifylline as a control group. Patients were randomised into two groups of 18 subjects each, based on date of birth. All patients in group A (bencyclane) received 200 mg of bencyclane in 250 ml of normal saline as an i.v. infusion in the morning and 200 mg of the drug orally in the evening for 14 days. In a control group B (pentoxifylline) patients were given 300 mg of pentoxifylline in 250 ml of normal saline as an i.v. infusion in the morning and 400 mg of pentoxifylline orally in the evening for 14 days. Clinical examinations were performed before the start and at the end of the therapy and laboratory estimations were made before the start of the therapy and after finishing a 2-hour drug infusion on the first and last days of treatment. Results. In comparison with pentoxifylline, bencyclane is characterized by stronger antiplatelet, fibrinolytic and antiaggregatory activity, with comparable vasodilating effects and to a lesser extent it influences erythrocyte deformability. Conclusion. Antiplatelet and fibrinolytic activity, as well as lowering the PAI-1 level and rising concentrations of t-PA and 6-keto PGF1α, may suggest that bencyclane’s mechanism of action is endothelial-derived

Co-ingestion of Antioxidant Drinks With an Unhealthy Challenge Meal Fails to Prevent Post-prandial Endothelial Dysfunction: An Open-Label, Crossover Study in Older Overweight Volunteers

Eating a high calorie meal is known to induce endothelial dysfunction and it is reported that consuming drinks rich in antioxidants may be protective against this. In this study we assessed the effects of three antioxidant drinks with considerable disparity in their antioxidant content on endothelial function. Seven apparently healthy overweight and older adults (BMI 25–35; mean age 57 ± 3 years; one male, six females) completed four trials in a randomized counterbalanced design. Water (control), orange juice, green tea, or red wine were consumed with a high calorie meal (> 900 kcal). Endothelial function was measured by flow-mediated dilatation immediately before (fasted, baseline) and 2 h after the meal. Blood samples were also obtained for lipid and glucose analysis, plasma nitrite (NO−2) and oxidized low-density lipoprotein (ox-LDL). Participants returned after a minimum 3 days washout to complete the remaining arms of the study. The results found that the high calorie meal induced a substantial increase in triglycerides, but not cholesterol or glucose, at 2 h after meal ingestion. FMD was significantly reduced by ∼35% at this timepoint, but the effect was not attenuated by co-ingestion of any of the antioxidant drinks. Reduced FMD was mirrored by a reduction in NO−2, but ox-LDL was not increased at 2 h after the meal. None of the undertaken measures were influenced by the antioxidant drinks. We conclude that co-ingestion of none of our test antioxidant drinks protected against the substantial post-prandial endothelial dysfunction induced by an unhealthy meal challenge in our sample population at a 2 h timepoint

Natural Biflavonoids Modulate Macrophage-Oxidized LDL Interaction In Vitro and Promote Atheroprotection In Vivo

ABSTARCT: The accumulation of oxidized ApoB-100-containing lipoproteins in the vascular intima and its subsequent recognition by macrophages results in foam cell formation and inflammation, key events during atherosclerosis development. Agents targeting this process are considered potentially atheroprotective. Since natural biflavonoids exert antioxidant and anti-inflammatory effects, we evaluated the atheroprotective effect of biflavonoids obtained from the tropical fruit tree Garcinia madruno. To this end, the pure biflavonoid aglycones morelloflavone (Mo) and volkensiflavone (Vo), as well as the morelloflavone's glycoside fukugiside (Fu) were tested in vitro in primary macrophages, whereas a biflavonoid fraction with defined composition (85% Mo, 10% Vo, and 5% Amentoflavone) was tested in vitro and in vivo. All biflavonoid preparations were potent reactive oxygen species (ROS) scavengers in the oxygen radical absorbance capacity assay, and most importantly, protected low-density lipoprotein particle from both lipid and protein oxidation. In biflavonoid-treated macrophages, the surface expression of the oxidized LDL (oxLDL) receptor CD36 was significantly lower than in vehicle-treated macrophages. Uptake of fluorescently labeled oxLDL and cholesterol accumulation were also attenuated in biflavonoid-treated macrophages and followed a pattern that paralleled that of CD36 surface expression. Fu and Vo inhibited oxLDL-induced ROS production and interleukin (IL)-6 secretion, respectively, whereas all aglycones, but not the glucoside Fu, inhibited the secretion of one or more of the cytokines IL-1β, IL-12p70, and monocyte chemotactic protein-1 (MCP-1) in lipopolysaccharide (LPS)-stimulated macrophages. Interestingly, in macrophages primed with low-dose LPS and stimulated with cholesterol crystals, IL-1β secretion was significantly and comparably inhibited by all biflavonoid preparations. Intraperitoneal administration of the defined biflavonoid fraction into ApoE-/- mice was atheroprotective, as evidenced by the reduction of the atheromatous lesion size and the density of T cells and macrophages infiltrating the aortic root; moreover, this treatment also lowered the circulating levels of cholesterol and the lipid peroxidation product malondialdehyde. These results reveal the potent atheroprotective effects exerted by biflavonoids on key events of the oxLDL-macrophage interphase: (i) atheroligand formation, (ii) atheroreceptor expression, (iii) foam cell transformation, and (iv) prooxidant/proinflammatory macrophage response. Furthermore, our results also evidence the antioxidant, anti-inflammatory, hypolipemiant, and atheroprotective effects of Garcinia madruno's biflavonoids in vivo

BacHBerry: BACterial Hosts for production of Bioactive phenolics from bERRY fruits

BACterial Hosts for production of Bioactive phenolics from bERRY fruits (BacHBerry) was a 3-year project funded by the Seventh Framework Programme (FP7) of the European Union that ran between November 2013 and October 2016. The overall aim of the project was to establish a sustainable and economically-feasible strategy for the production of novel high-value phenolic compounds isolated from berry fruits using bacterial platforms. The project aimed at covering all stages of the discovery and pre-commercialization process, including berry collection, screening and characterization of their bioactive components, identification and functional characterization of the corresponding biosynthetic pathways, and construction of Gram-positive bacterial cell factories producing phenolic compounds. Further activities included optimization of polyphenol extraction methods from bacterial cultures, scale-up of production by fermentation up to pilot scale, as well as societal and economic analyses of the processes. This review article summarizes some of the key findings obtained throughout the duration of the project