interleukin-8 and fisetin

A growing body of evidence indicates that inflammation is associated with tumorigenesis, metastasis and chemotherapeutic resistance in patients with colorectal cancer (CRC). Natural flavonoids are promising agents for inflammation-related tumor progression in patients with CRC. This study aimed to assess the efficacy of flavonoid fisetin supplementation on the inflammatory status and matrix metalloproteinase (MMP) levels in these patients. In this double-blind, randomized placebo-controlled clinical trial, 37 CRC patients undergoing chemotherapy were assigned to receive either 100 mg fisetin (n = 18) or placebo (n = 19) for seven consecutive weeks. The supplementation began one week before chemotherapy and continued until the end of the second chemotherapy cycle. Levels of interleukin (IL)-8, IL-10, high-sensitivity C-reactive protein (hs-CRP), MMP-7, and MMP-9 were measured in plasma using ELISA, before and after the intervention. The trial was registered at http://www.irct.ir (code: IRCT2015110511288N9). The participants were 55.59 ± 15.46 years old with 62.16% being male. After the intervention, the plasma levels of IL-8 and hs-CRP reduced significantly in the fisetin group (p < 0.04 and p < 0.01, respectively). Additionally, fisetin supplementation suppressed the values of MMP-7 levels (p < 0.02). However, significant changes were observed only in IL-8 concentrations in the fisetin group when compared with the placebo group (p < 0.03). The changes in the levels of other metabolic factors were not statistically significant. According to the results, fisetin could improve the inflammatory status in CRC patients, suggesting it as a novel complementary antitumor agent for these patients and warranting further studies.

Topics: Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; C-Reactive Protein; Chemotherapy, Adjuvant; Colorectal Neoplasms; Dietary Supplements; Double-Blind Method; Down-Regulation; Female; Flavonoids; Flavonols; Humans; Interleukin-10; Interleukin-8; Iran; Male; Matrix Metalloproteinase 7; Matrix Metalloproteinase 9; Middle Aged; Neoplasm Staging

Fisetin (3,7,3',4'-tetrahydroxyflavone), a natural flavonoid, is a therapeutic agent for respiratory inflammatory diseases such as chronic obstructive pulmonary disease (COPD). However, detailed molecular mechanisms regarding the target protein of fisetin remain unknown. Fisetin significantly reduces tumour necrosis factor alpha (TNF-α)-induced interleukin (IL)-8 levels by inhibiting both nuclear factor kappa B (NF-κB) transcriptional activity and the phosphorylation of its upstream effectors. We show that fisetin prevents interactions between protein kinase C (PKC)δ and TNF receptor-associated factor 2 (TRAF2), thereby inhibiting the inhibitor of kappa B kinase (IKK)/NF-κB downstream signalling cascade. Furthermore, we found that fisetin directly binds to PKCδ in vitro. Our findings provide evidence that fisetin inhibits the TNF-α-activated IKK/NF-κB cascade by targeting PKCδ, thereby mediating inflammatory diseases such as COPD. These data suggest that fisetin is a good therapeutic drug for the treatment of inflammatory lung diseases, such as COPD, by inhibiting the TNF-α/NF-κB signalling pathway.

Topics: Epithelial Cells; Flavonoids; Flavonols; HEK293 Cells; Humans; Interleukin-8; Molecular Docking Simulation; NF-kappa B; Phosphorylation; Protein Binding; Protein Kinase C-delta; Signal Transduction; TNF Receptor-Associated Factor 2; Tumor Necrosis Factor-alpha

Fisetin, an active compound isolated from flowering plants in the family Fabaceae, was reported to have antiviral, neuroprotective, and anti-inflammatory effects. Vascular inflammatory processes have been suggested to play key roles in the initiation and progression of atherosclerosis, a major complication of diabetes mellitus. Thus, we determined the ability of fisetin to suppress vascular inflammatory processes induced by high glucose (HG) in primary human umbilical vein endothelial cells (HUVECs) and mice.. The effects of fisetin on HG-induced vascular inflammation were determined by measuring vascular permeability, leukocyte adhesion and migration, cell adhesion molecule (CAM) expression levels, reactive oxygen species (ROS) formation, and nuclear factor (NF)-κB activation.. HG markedly increased vascular permeability, monocyte adhesion, expressions of CAMs, formation of ROS, and activation of NF-κB. Remarkably, all of the observed vascular inflammatory effects induced by HG were inhibited by pretreatment with fisetin.. Vascular inflammatory responses induced by HG are critical events underlying the development of diabetic complications; therefore, our results suggest that fisetin possesses significant therapeutic effects against diabetic complications and atherosclerosis.

Topics: Animals; Anti-Inflammatory Agents; Capillary Permeability; Cell Adhesion; Cell Line; Cells, Cultured; Chemokine CCL2; E-Selectin; Flavonoids; Flavonols; Glucose; Human Umbilical Vein Endothelial Cells; Humans; Hydrogen Peroxide; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-8; Male; Mice, Inbred C57BL; NF-kappa B; RNA, Messenger; Vascular Cell Adhesion Molecule-1

There is growing evidence that amorphous silica nanoparticles (SiO₂-NP) can cause an inflammatory response in the lung. We studied in vitro the effects of exposing human lung submucosal cells to SiO₂-NP of various sizes (10, 150, and 500 nm) for 2-24 h. Cell survival, reactive oxygen species (ROS), malondialdehyde (MDA) levels, cytokine production, inflammatory gene expression, and genotoxicity were measured after exposure of Calu-3 cells to 10SiO₂-NP in the presence or absence of the flavanoid fisetin and an antioxidant enzyme catalase. The exposure of Calu-3 cells to 10SiO₂-NP resulted in (1) increased cytotoxicity and cell death in a time- and concentration-dependent manner, with a lethal concentration (LC₅₀) of 9.7 μg/mL after 24 h; (2) enhanced gene expression of interleukin (IL)-6, IL-8, and matrix metalloproteinase-9; (3) a significant correlation between increases in MDA and cytotoxicity at 18 h; (4) ROS production; (5) IL-6 and IL-8 release; and (6) up-regulation of the pro-apoptotic genes, p53 and caspase-3. Cell death and inflammatory reactions were attenuated by fisetin and catalase. We observed that 150- and 500SiO₂-NP exerted no toxic effects on Calu-3 cells. In conclusion, the nanotoxicity of amorphous 10SiO₂-NP on submucosal cells is associated with inflammation, the release of ROS leading to apoptosis, and decreased cell survival. The nanotoxic effects of 10SiO₂-NP can be decreased by fisetin and catalase treatment, implicating oxidative stress in this injury.

Topics: Caspase 3; Cell Death; Cell Line; Cytotoxins; Flavonoids; Flavonols; Humans; Inflammation; Interleukin-6; Interleukin-8; Lung; Malondialdehyde; Matrix Metalloproteinase 9; Nanoparticles; Particle Size; Reactive Oxygen Species; Silicon Dioxide; Up-Regulation

Thermal burn injury induces inflammatory cell infiltrates in the dermis and thickening of the epidermis. Following a burn injury, various mediators, including reactive oxygen species (ROS), are produced in macrophages and neutrophils, exposing all tissues to oxidative injury. The anti-oxidant activities of flavonoids have been widely exploited to scavenge ROS. In this study, we observed that several flavonoids-kaempferol, quercetin, fisetin, and chrysin-inhibit LPS-induced IL-8 promoter activation in RAW 264.7 cells. In contrast with quercetin and fisetin, pretreatment of kaempferol and chrysin did not decrease cell viability. Inflammatory cell infiltrates in the dermis and thickening of the epidermis induced by burn injuries in mice was relieved by kaempferol treatment. However, the injury was worsened by fisetin, quercetin, and chrysin. Expression of TNF-a induced by burn injuries was decreased by kaempferol. These findings suggest the potential use of kaempferol as a therapeutic in thermal burn-induced skin injuries. [BMB reports 2010; 43(1): 46-51].

Topics: Animals; Burns; Cell Differentiation; Cell Line, Tumor; Flavonoids; Flavonols; Interleukin-8; Kaempferols; Lipopolysaccharides; Mice; Quercetin; Reactive Oxygen Species; Skin; Tumor Necrosis Factor-alpha

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.

Topics: Aged; Chromones; Cytokines; Diabetes Mellitus, Type 2; Enzyme Inhibitors; Flavonoids; Flavonols; Humans; Interleukin-1; Interleukin-10; Interleukin-8; Lipopolysaccharides; Male; Middle Aged; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Pulmonary Disease, Chronic Obstructive; Tumor Necrosis Factor-alpha