title: Poly (ADP-ribose) polymerase-1-inhibiting flavonoids attenuate cytokine release in blood from male patients with chronic obstructive pulmonary disease or type 2 diabetes.
abstract: Recently, we identified several flavonoids as inhibitors of the nuclear enzyme poly(ADP-ribose) polymerase (PARP)-1 in vitro and in vivo. PARP-1 is recognized as coactivator of nuclear factor-kappaB and plays a role in the pathophysiology of diseases with low-grade systemic inflammation, such as chronic obstructive pulmonary disease (COPD) and type 2 diabetes (T2D). In this study, we assessed the antiinflammatory effects of flavonoids with varying PARP-1-inhibiting effects in whole blood from male patients with COPD or T2D and healthy men. A total of 10 COPD, 10 T2D patients, and 10 healthy volunteers matched for age and BMI were recruited. Blood from each participant was exposed to 1 microg/L lipopolysaccharide (LPS) over 16 h with or without preincubation with 10 micromol/L of flavone, fisetin, morin, or tricetin. Concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, -8, and -10 were measured in the supernatant. Preincubation with fisetin and tricetin strongly attenuated LPS-induced increases in concentrations of TNFalpha in blood from COPD patients [mean (+/- SEM): -41 +/- 4% (fisetin) and -31 +/- 4% (tricetin); P < 0.001] and IL-6 in blood from T2D patients [-31 +/- 5% (fisetin) and -29 +/- 6% (tricetin); P < or = 0.001]. Moreover, LPS-induced changes in TNFalpha and IL-6 concentrations were positively correlated with the extent of reduction by fisetin and tricetin. The PARP-1-inhibiting flavonoids fisetin and tricetin were able to attenuate LPS-induced cytokine release from leukocytes of patients with chronic systemic inflammation, indicating a potential application as nutraceutical agents for these patient groups.
authors.affiliation: Department of Health Risk Analysis and Toxicology, Maastricht University Medical Centre+, Maastricht 6200 MD, The Netherlands. a.weseler@farmaco.unimaas.nl
authors.forename: Antje R
authors.initials: AR
authors.lastname: Weseler
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Geraets
authors.forename: Harald J J
authors.initials: HJ
authors.lastname: Moonen
authors.forename: Ralph J F
authors.initials: RJ
authors.lastname: Manders
authors.forename: Luc J C
authors.initials: LJ
authors.lastname: van Loon
authors.forename: Herman-Jan
authors.initials: HJ
authors.lastname: Pennings
authors.forename: Emiel F M
authors.initials: EF
authors.lastname: Wouters
authors.forename: Aalt
authors.initials: A
authors.lastname: Bast
authors.forename: Geja J
authors.initials: GJ
authors.lastname: Hageman