curcumin and phorbolol-myristate-acetate

Inflammation‑associated damage may occur in any tissue following infection, exposure to toxins, following ischemia, and in allergic and auto‑immune reactions. Inflammation may also result from mast cell degranulation induced by the intracellular calcium concentration. The inflammatory process may be inhibited by compounds that affect mast cells. Bisdemethoxycurcumin [1,7‑bis(4‑hydroxyphenyl) hepta‑1,6‑diene‑3,5‑dione, BDCM] is the active component of turmeric. It has anticancer, antioxidant and antibacterial properties. To investigate the molecular mechanism associated with the anti‑inflammatory activity of BDCM, human mast cell line 1 (HMC‑1) cells were treated with phorbol‑12‑myristate‑13‑acetate (PMA) and calcium ionophore A23187 (A23187) to induce the inflammatory process. Various HMC‑1 cells were pretreated with BDCM prior to stimulation of inflammation. BDCM inhibited the inflammation‑triggered production of cytokines including interleukin (IL)‑6, IL‑8, and tumor necrosis factor (TNF)‑α. BDCM inhibition extended to the gene level. In activated HMC‑1 cells, phosphorylation levels of extracellular signal‑regulated kinase, c‑jun N‑terminal kinase and p38 mitogen‑activated protein kinase were decreased by treatment with BDCM. BDCM also inhibited nuclear factor‑(NF)‑κB activation and IκB degradation. In conclusion, BDCM suppresses the expression of TNF‑α, IL‑8, and IL‑6 by inhibiting the NF‑κB and mitogen activated protein kinase signaling pathways.

Topics: Calcimycin; Cell Line; Curcumin; Diarylheptanoids; Gene Expression Regulation; Humans; Inflammation; Mast Cells; Mitogen-Activated Protein Kinase Kinases; NF-kappa B; Signal Transduction; Tetradecanoylphorbol Acetate; Transcription Factor RelA

We have previously shown that curcumin (CUR) may increase lipid accumulation in cultured human acute monocytic leukaemia cell line THP-1 monocytes/macrophages, but that tetrahydrocurcumin (THC), an in vivo metabolite of CUR, has no such effect. In the present study, we hypothesised that the different cellular uptake and/or metabolism of CUR and THC might be a possible explanation for the previously observed differences in their effects on lipid accumulation in THP-1 monocytes/macrophages. Chromatography with tandem MS revealed that CUR was readily taken up by THP-1 monocytes/macrophages and slowly metabolised to hexahydrocurcumin sulphate. By contrast, the uptake of THC was low. In parallel with CUR uptake, increased lipid uptake was observed in THP-1 macrophages but not with the uptake of THC or another CUR metabolite and structurally related compounds. From these results, it is possible to deduce that CUR and THC are taken up and metabolised differently in THP-1 cells, which determine their biological activity. The remarkable differential cellular uptake of CUR, relative to THC and other similar molecules, may imply that the CUR uptake into cells may occur via a transporter.

Topics: Biological Transport; Carcinogens; Cell Differentiation; Cell Line; Chromatography, High Pressure Liquid; Curcumin; Diarylheptanoids; Glucuronides; Humans; Kinetics; Lipid Metabolism; Macrophages; Monocytes; Sulfates; Tandem Mass Spectrometry; Tetradecanoylphorbol Acetate

Curcumin (CUR), demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC) have been demonstrated as having antioxidant, anticarcinogenic, and hypocholesterolemic activities. We report the diverse antiatherogenic effects and mechanisms of curcuminoids.. We found that CUR was the most potent antioxidant against copper-mediated LDL oxidation as measured by thiobarbituric acid-reactive substances assay, oxidized LDL (oxLDL) ELISA, and electrophoretic mobility. CUR upregulated heme oxygenase-1, modifier subunit of glutamate-cysteine ligase (GCLM), and CD36 expression in undifferentiated THP-1 cells, supporting the possible involvement of Nrf2 pathway in CD36 expression. Monocyte-to-macrophage differentiation plays a vital role in early atherogenesis. BDMC reduced oxLDL uptake most effectively, while CUR was the best inhibitor for CD36, scavenger receptor A, and lectin-like oxidized LDL receptor-1 expression during phorbol 12-myristate 13-acetate (PMA)-induced THP-1 differentiation. In PMA-differentiated THP-1 macrophages, CUR and DMC effectively induced heme oxygenase-1 expression, but attenuated oxLDL-induced CD36 expression, leading to decreased oxLDL uptake.. This result indicates curcuminoids, despite structural similarities, exert different atheroprotective effects. Curcuminoids, especially CUR and DMC, are hormetic compounds, which induce Phase II enzyme expression and confer resistance to PMA- and oxLDL-induced scavenger receptor expression and activity.

Topics: Antioxidants; Biomarkers; CD36 Antigens; Cell Differentiation; Cell Line, Tumor; Copper; Curcumin; Diarylheptanoids; Foam Cells; Gene Expression Regulation; Glutamate-Cysteine Ligase; Heme Oxygenase-1; Humans; Lipid Peroxidation; Lipoproteins, LDL; Monocytes; Scavenger Receptors, Class A; Scavenger Receptors, Class E; Tetradecanoylphorbol Acetate; Thiobarbituric Acid Reactive Substances; Up-Regulation

The effect of YS 51, a synthetic 1-(beta-naphtylmethyl)6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline alkaloid, on the expression of manganese-superoxide dismutase (Mn-SOD), an antioxidant enzyme, was examined in sheep pulmonary artery endothelial cells (SPAEC) and a human cervical carcinoma cell line (Hela). YS 51 alone or in combination with cytokines enhanced the expression of Mn-SOD mRNA in SPAEC and Hela cells. YS 51 also showed synergistic effects on the induction of Mn-SOD mRNA with phorbol-12-myristate-13-acetate (TPA) and/or tumor necrosis factor-alpha (TNF-alpha). In Hela cells, the induction of Mn-SOD mRNA by YS 51 was in a time- and dose-dependent manner and the expression of Mn-SOD mRNA was increased to a maximum of 4-fold in 9 h. Enhancement of Mn-SOD mRNA by YS 51 was completely abolished by actinomycin D but not cycloheximide, suggesting that the induction of Mn-SOD mRNA byYS 51 is independent of new protein synthesis. Pretreatment of curcumin, an inhibitor of c-jun N-terminal kinase (JNK), dose-dependently suppressed the induction of Mn-SOD mRNA by YS 51, but not by 2'-amino-3'-methoxyflavone (PD98059) and 4-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)-5-(4-pyridyl)imidazol (SB203580), inhibitors of mitogen-activated protein kinase. Also, YS 51 induced the phosphorylation activity of JNK in a time-dependent manner without affecting the phosphorylation activity of the extracellular signal-regulated kinase 1 (ERK1) and p38 MAP kinase. These results implicated that the JNK pathway appears to play a crucial role in mediating the YS 51-induced Mn-SOD gene expression, and that up-regulation of Mn-SOD would contribute to the anti-inflammatory actions mediated by YS 51.

Topics: Animals; Blotting, Northern; Curcumin; Cycloheximide; Dactinomycin; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Endothelial Cells; Endothelium, Vascular; Enzyme Induction; Flavonoids; Gene Expression Regulation, Enzymologic; HeLa Cells; Humans; Imidazoles; Indoles; JNK Mitogen-Activated Protein Kinases; Maleimides; Mitogen-Activated Protein Kinase 3; p38 Mitogen-Activated Protein Kinases; Phorbol Esters; Phosphorylation; Pulmonary Artery; Pyridines; RNA, Messenger; Sheep; Superoxide Dismutase; Tetradecanoylphorbol Acetate; Tetrahydroisoquinolines; Tumor Necrosis Factor-alpha