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

Ethical, legal and social aspects of human cerebral organoids and their governance in Germany, the United Kingdom and the United States

Human cerebral organoids (HCOs) are model systems that enable researchers to investigate the human brain in ways that had previously been impossible. The emergence of HCOs was accompanied by both expert and layperson discussions concerning the possibility of these novel entities developing sentience or consciousness. Such concerns are reflected in deliberations about how to handle and regulate their use. This perspective article resulted from an international and interdisciplinary research retreat “Ethical, Legal and Social Aspects of Human Cerebral Organoids and their Governance in Germany, the United Kingdom and the United States”, which took place in Tübingen, Germany, in August 2022. The retreat focused on whether HCO research requires new ethical and regulatory approaches. It addressed epistemic issues around the detection and theorisation of consciousness, ethical concerns around moral status and research conduct, difficulties for legislation and guidelines managing these entities, and public engagement

MYC is a major determinant of mitotic cell fate

Taxol and other antimitotic agents are frontline chemotherapy agents but the mechanisms responsible for patient benefit remain unclear. Following a genome-wide siRNA screen, we identified the oncogenic transcription factor Myc as a taxol sensitizer. Using time-lapse imaging to correlate mitotic behavior with cell fate, we show that Myc sensitizes cells to mitotic blockers and agents that accelerate mitotic progression. Myc achieves this by upregulating a cluster of redundant pro-apoptotic BH3-only proteins and suppressing pro-survival Bcl-xL. Gene expression analysis of breast cancers indicates that taxane responses correlate positively with Myc and negatively with Bcl-xL. Accordingly, pharmacological inhibition of Bcl-xL restores apoptosis in Myc-deficient cells. These results open up opportunities for biomarkers and combination therapies that could enhance traditional and second-generation antimitotic agents

Auf dem Nikolaus-Schlitten in die Verfassungswidrigkeit?

Ein neueres Urteil des Bundessozialgerichts wirkt auf den ersten Blick vergleichsweise unscheinbar, wirft bei näherem Hinsehen aber ein Schlaglicht auf die Defizite der "Nikolaus-Rechtsprechung" des Bundesverfassungsgerichts und des § 2 Abs. 1a SGB V als der sie kodifizierenden Leistungsnorm. Die besondere Sachverhaltskonstellation hat zu der paradoxen Situation geführt, dass gerade die strikte Anwendung höchstrichterlich – und insbesondere auch verfassungsgerichtlich – ausgeformter Grundsätze und Kriterien nicht mit dem Grundgesetz in Einklang zu bringen ist, und zeigt paradigmatisch auf, was passiert, wenn vermeintlichen Prinzipien gegenüber sachgerechten Ergebnissen der Vorzug gewährt wird

Finding glory in interception

"Disease Interception" bedeutet, Krankheiten abzufangen, bevor sie ausgebrochen sind. Das Konzept klingt hoffnungsvoll, geht aber mit diversen Herausforderungen und Veränderungen einher: Betroffen sind das Recht der gesetzlichen Krankenversicherung, in dem möglicherweise die passenden Anspruchsnormen fehlen, Forschende, die auf Gesundheitsdaten und Künstliche Intelligenz zurückgreifen (möchten), Krankenhäuser, die sich zunehmend digitalisieren oder gar in "Smart Hospitals" transformieren, Ärzte, die sich mit neuen Aufgaben konfrontiert sehen und die Gesellschaft insgesamt, die einen Umgang mit den neuen Möglichkeiten zur Prädiktion, Frühdiagnostik und (vorbeugenden) Intervention finden muss