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Correction of the CF defect by curcumin: hypes and disappointments.

Cystic fibrosis (CF), the most-common lethal hereditary disease in the white population, is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The mutation that is most frequently responsible for the disease, DeltaF508, causes misfolding and retention of the CFTR protein in the endoplasmic reticulum. This leads to a series of cellular dysfunctions and results in a multi-organ disease. In a recent report, Egan et al.(1) demonstrated that curcumin, a non-toxic natural product and major constituent of turmeric spice, corrected the CF defects in DeltaF508 CF mice. This paper aroused a lot of attention and hopes were raised that curcumin might produce similar effects in human, giving an efficient treatment for most CF patients. However, skepticism is growing since subsequent studies fail to reproduce these initial exciting results. Thus, although herbal medicines and dietary supplements can be desirable alternatives to classical pharmacological compounds, their efficacy needs careful evaluation both in vivo and ex vivo.

Animals↗

Inhibition of growth and survival of human head and neck squamous cell carcinoma cells by curcumin via modulation of nuclear factor-kappaB signaling.

Increased expression of proinflammatory and proangiogenic factors are associated with aggressive tumor growth and decreased survival of patients with head and neck squamous cell carcinoma (HNSCC). In as much as genes that are regulated by nuclear factor NF-kappaB suppress apoptosis, induce proliferation, and mediate inflammation, angiogenesis and tumor metastasis, agents that suppress NF-kappaB activation have potential as treatment for various cancers including HNSCC. We demonstrate that all HNSCC cell lines expressed constitutively active NF-kappaB and IkappaBalpha kinase (IKK), which is needed for NF-kappaB activation. Treatment of MDA 686LN cells with curcumin (diferuloylmethane), a pharmacologically safe chemopreventive agent, inhibited NF-kappaB activation through abrogation of IKK. As a result expression of various cell survival and cell proliferative genes including Bcl-2, cyclin D1, IL-6, COX-2 and MMP-9 was suppressed. This, in turn, inhibits proliferation of all HNSCC cell lines, arrests cell cycle in G1/S phase (MDA 686LN) and induces apoptosis as indicated by upstream and downstream caspase activation, PARP cleavage, annexin V staining in MDA 686LN cells. Suppression of NF-kappaB by cell-permeable p65-based peptide and NBD peptide also inhibited the proliferation and induced apoptosis in these cells. Our results indicate that curcumin is a potent inhibitor of cell proliferation and an inducer of apoptosis in HNSCC through suppression of IKK-mediated NF-kappaB activation and of NF-kappaB-regulated gene expression.

Animals↗

Opposing action of curcumin and green tea polyphenol in human keratinocytes.

Persistent environmental insult can convert a normal cell into a cancer cell. However, various natural chemopreventive agents called antioxidants can retard this progression. We have recently explored the effects of several chemopreventive agents, including green tea polyphenol and curcumin, on normal human keratinocyte function. Our findings suggest that a bioactive polyphenol from green tea, (-)-epigallocatechin-3-gallate (EGCG), acts to increase involucrin gene expression, suggesting that EGCG treatment enhances normal human keratinocyte differentiation. Mechanistic studies indicate that EGCG alters mitogen-activated protein kinase cascade function to activate involucrin gene transcription via a Ras, MEKK1, MEK3, ERK1/2-p38delta cascade that targets AP1 and CAATT enhancer binding protein transcription factors. These findings suggest that EGCG may inhibit disease progression by promoting keratinocyte differentiation. Parallel studies indicate that not all antioxidants produce a similar response. Curcumin, an antioxidant derived from the turmeric, antagonizes the EGCG-dependent response by interfering in this signaling pathway. These studies suggest that different antioxidant may produce antagonistic effects in tissues.

Antioxidants↗

Progressive nuclear factor-kappaB activation resistant to inhibition by contraction and curcumin in mdx mice.

Skeletal muscle of patients with Duchenne-type muscular dystrophy and mdx mice exhibits elevated activity of the transcription factor NF-kappaB (nuclear factor-kappaB), which may play a role in muscle catabolism. We measured skeletal muscle NF-kappaB activity in mdx mice at three ages (10 days, 4 weeks, and 8 weeks) to test the hypothesis that NF-kappaB activity is elevated in an age-dependent manner in these mice. In addition, we tested the hypothesis that NF-kappaB activity could be reduced in mdx skeletal muscle by dietary supplementation with curcumin (1% w/v) or by fatiguing muscle contractions. We found that NF-kappaB activity was elevated at 4 and 8 weeks of age but not at 10 days, and was resistant to inhibition by either fatiguing contractions or dietary curcumin. We conclude that NF-kappaB activity is elevated in dystrophic skeletal muscle in an age-related manner and is resistant to inhibition by physiological and pharmacological means. These findings are consistent with a role for NF-kappaB activation in dystrophic muscle wasting but suggest that predicted interventions such as exercise or inhibitors of the early steps in the NF-kappa activation pathway may not be effective and that targeted research is needed to identify novel therapeutic strategies.

Animals↗

Enhanced apoptosis mediates inhibition of EBV-transformed lymphoblastoid cell line proliferation by curcumin.

BACKGROUND: Epstein-Barr virus (EBV)-associated B-cell lymphomas occur more frequently in immunodeficient states such as organ transplantation and HIV infection. We have previously reported that B cell immortalization with EBV was promoted by cyclosporin A (CyA) and that curcumin (Cur), a natural phenol with known antioxidant and antitumor properties, blocked EBV-induced B cell immortalization. In the following experiments we show that Cur inhibits the proliferation of EBV-transformed lymphoblastoid cell lines (LCL) via enhanced apoptosis. METHODS: LCL were generated by infecting freshly isolated human B cells with EBV (B95-8) for 12 h and coculturing with predetermined optimal concentrations of CyA (500 ng/ml) for 4 weeks. LCL were then either frozen for future use or propagated for immediate experiments. These cells were then plated in 96-well plates with 20 microM Cur or 0.1% DMSO (vehicle control). The number of immortalized colonies/well, cell count, and (3)H uptake were used as an index of immortalization. To assess apoptosis rate LCL were cultured with 0.1% DMSO or Cur (20 microM) for 0, 18, and 42 h in culture flasks and then stained with MC540 and H33342, as markers for apoptosis, and analyzed by FACS. RESULTS: A profound inhibition of proliferation was seen in the LCL with 20 microM curcumin compared to 0.1% DMSO control. The colony count reduced from 34.5 +/- 3.4 to 0/well (P = 0.005), cell number reduced from 101,250 +/- 12,093 to 3750 +/- 1500/well (P = 0.002), and (3)H uptake reduced from 40,889 +/- 3669 to 70 +/- 5.2/well (P = 0.001). The apoptosis rate of LCL in the DMSO control at 24.07 and 16.87% increased significantly with 20 microM Cur to 76.4 and 95.1% at 18 and 42 h, respectively (P = 0.02). CONCLUSION: Cur is a potent inhibitor of EBV-transformed LCL. This effect appears to be mediated through enhanced apoptosis. A further investigation of this effect may be useful in prevention and therapy of B-cell lymphoma in immunodeficient patients.

Antineoplastic Agents↗

Antioxidant properties of dehydrozingerone and curcumin in rat brain homogenates.

The present study investigates the inhibition of lipid peroxidation by dehydrozingerone and curcumin in rat brain homogenates. Both the test compounds inhibited the formation of conjugated dienes and spontaneous lipid peroxidation. These compounds also inhibited lipid peroxidation induced by ferrous ions, ferric-ascorbate and ferric-ADP-ascorbate. In all these cases, curcumin was more active than dehydrozingerone and dl-alpha-tocopherol.

Animals↗

Modulation of cyclophosphamide-induced early lung injury by curcumin, an anti-inflammatory antioxidant.

Cyclophosphamide causes lung injury in rats through its ability to generate free radicals with subsequent endothelial and epithelial cell damage. In order to observe the protective effects of a potent anti-inflammatory antioxidant, curcumin (diferuloyl methane) on cyclophosphamide-induced early lung injury, healthy, pathogen free male Wistar rats were exposed to 20 mg/100 g body weight of cyclophosphamide, intraperitoneally as a single injection. Prior to cyclophosphamide intoxication oral administration of curcumin was performed daily for 7 days. At various time intervals (2, 3, 5 and 7 days post insult) serum and lung samples were analyzed for angiotensin converting enzyme, lipid peroxidation, reduced glutathione and ascorbic acid. Bronchoalveolar lavage fluid was analyzed for biochemical constituents. The lavage cells were examined for lipid peroxidation and glutathione content. Excised lungs were analyzed for antioxidant enzyme levels. Biochemical analyses revealed time course increases in lavage fluid total protein, albumin, angiotensin converting enzyme (ACE), lactate dehydrogenase, N-acetyl-beta-D-glucosaminidase, alkaline phosphatase, acid phosphatase, lipid peroxide levels and decreased levels of glutathione (GSH) and ascorbic acid 2, 3, 5 and 7 days after cyclophosphamide intoxication. Increased levels of lipid peroxidation and decreased levels of glutathione and ascorbic acid were seen in serum, lung tissue and lavage cells of cyclophosphamide groups. Serum angiotensin converting enzyme activity increased which coincided with the decrease in lung tissue levels. Activities of antioxidant enzymes were reduced with time in the lungs of cyclophosphamide groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Curcumin treatment protects rat retinal neurons against excitotoxicity: effect on N-methyl-D: -aspartate-induced intracellular Ca(2+) increase.

Curcumin, an extract from the plant Curcuma longa with well-known antioxidant and anti-inflammatory activities, was tested as protective agent against excitotoxicity in rat retinal cultures. A 24 h-treatment with curcumin reduced N-methyl-D: -aspartate (NMDA)-mediated excitotoxic cell damage, estimated as decrease of cell viability and increase in apoptosis. The protection was associated with decrease of NMDA receptor-mediated Ca(2+) rise and reduction in the level of phosphorylated NR1 subunit of the NMDA receptor. These results enlighten a new pharmacological action of the plant extract, possibly mediated by a modulation of NMDA receptor activity.

Animals↗

Curcumin therapy in inflammatory bowel disease: a pilot study.

Curcumin, a natural compound used as a food additive, has been shown to have anti-inflammatory and antioxidant properties in cell culture and animal studies. A pure curcumin preparation was administered in an open label study to five patients with ulcerative proctitis and five with Crohn's disease. All proctitis patients improved, with reductions in concomitant medications in four, and four of five Crohn's disease patients had lowered CDAI scores and sedimentation rates. This encouraging pilot study suggests the need for double-blind placebo-controlled follow-up studies.

Adult↗

Effect of curcumin and eugenol on iron-induced hepatic toxicity in rats.

Male Wistar rats injected i.p. with 30 mg Fe2+/kg body weight show hepatic damage as measured by an increase in lipid peroxides which correlated with elevated serum enzymes, alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT) and lactate dehydrogenase (LDH). Oral administration of spice principles, curcumin from turmeric (30 mg/kg body weight) or eugenol from cloves (100 mg/kg body weight), for 10 days lowered the liver and serum lipid peroxide levels, serum ALAT, ASAT and LDH, enhanced by i.p. injection of iron. This study indicates that curcumin or eugenol reduces the iron-induced hepatic damage by lowering lipid peroxidation.

Alanine Transaminase↗

Reversal of aflatoxin induced liver damage by turmeric and curcumin.

The effect of certain food additives on aflatoxin production by Aspergillus parasiticus has been studied in vitro. Extracts of turmeric (Curcuma longa), garlic (Allium sativum) and asafoetida (Ferula asafoetida) inhibited the aflatoxin production considerably (more than 90%) at concentrations of 5-10 mg/ml. Similar results were also seen using butylated hydroxytoluene, butylated hydroxyanisole and ellagic acid at concentration 0.1 mM. Curcumin, the antioxidant principle from Curcuma longa did not have any effect on aflatoxin production. Turmeric and curcumin were also found to reverse the aflatoxin induced liver damage produced by feeding aflatoxin B1 (AFB1) (5 micrograms/day per 14 days) to ducklings. Fatty changes, necrosis and biliary hyperplasia produced by AFB1 were considerably reversed by these food additives.

Aflatoxins↗

Design, synthesis, biological evaluation and molecular docking of curcumin analogues as antioxidant, cyclooxygenase inhibitory and anti-inflammatory agents.

Curcuminoids were isolated from Curcuma longa and their pyrazole and isoxazole analogues were synthesized and evaluated for antioxidant, COX-1/COX-2 inhibitory and anti-inflammatory activities. The designed analogues significantly enhance COX-2/COX-1 selectivity and possess significant anti-inflammatory activity in carrageenan induced rat paw edema assay. Pyrazole, isoxazole analogues of curcumin (4 and 7) exhibited higher antioxidant activity than trolox. Molecular docking study revealed the binding orientations of curcumin analogues in the active sites of COX and thereby helps to design novel potent inhibitors.

Animals↗

Antioxidant and antiproliferative activity of curcumin semicarbazone.

A new semicarbazone derivative of curcumin (CRSC) was synthesized and examined for its antioxidant, antiproliferative, and antiradical activity and compared with those of curcumin (CR). The antioxidant activity was tested by their ability to inhibit radiation induced lipid peroxidation in rat liver microsomes. The antiproliferative activity was tested by studying the in vitro activity of CRSC against estrogen dependant breast cancer cell line MCF-7. Kinetics of reaction of (2,2'-diphenyl-1-picrylhydrazide) DPPH, a stable hydrogen abstracting free radical was studied to measure the antiradical activity using stopped-flow spectrophotometer. Finally one-electron oxidized radicals of CRSC were generated and characterized by pulse radiolysis. The results suggest that the probable site of attack for CRSC is both the phenolic OH and the imine carbonyl position. CRSC shows efficient antioxidant and antiproliferative activity although its antiradical activity is less than that of CR.

Animals↗

Alpha-glucosidase inhibition of natural curcuminoids and curcumin analogs.

Natural curcumin (1), demethoxycurcumin (2) and bisdemethoxycurcumin (3) isolated from Curcuma longa (turmeric), and synthetic curcumin analogs (A(1-7), B(1-7), C(1-6) and D(1-7)) were evaluated in vitro for the alpha-glucosidase inhibitory activity via UV and circular dichroism (CD) spectroscopy. The results indicated that natural curcuminoid compound 3 showed a remarkable inhibitory effect with IC(50) of 23.0 microM, and the synthetic compounds A(2), B(2), C(2) and D(2) showed potent inhibitory effects with IC(50) of 2.8, 2.6, 1.6 and 8.2 microM, respectively. Kinetic study exhibited that the mechanism of alpha-glucosidase inhibition of both 3 and C(2) was non-competitive. The structure activity relationship revealed that the ortho dihydroxyl groups could form a more tight interaction with alpha-glucosidase to exert more potential inhibitory activities.

Animals↗

Silencing of the human microsomal glucose-6-phosphate translocase induces glioma cell death: potential new anticancer target for curcumin.

G6P translocase (G6PT) is thought to play a crucial role in transducing intracellular signaling events in brain tumor-derived cancer cells. In this report, we investigated the contribution of G6PT to the control of U-87 brain tumor-derived glioma cell survival using small interfering RNA (siRNA)-mediated suppression of G6PT. Three siRNA constructs were generated and found to suppress up to 91% G6PT gene expression. Flow cytometry analysis of propidium iodide/annexin-V-stained cells indicated that silencing the G6PT gene induced necrosis and late apoptosis. The anticancer agent curcumin, also inhibited G6PT gene expression by more than 90% and triggered U-87 glioma cells death. Overexpression of recombinant G6PT rescued the cells from curcumin-induced cell death. Targeting G6PT expression may provide a new mechanistic rationale for the action of chemopreventive drugs and lead to the development of new anti-cancer strategies.

Antineoplastic Agents↗

Chemopreventive effects of embelin and curcumin against N-nitrosodiethylamine/phenobarbital-induced hepatocarcinogenesis in Wistar rats.

The effects of embelin (50 mg/kg/day), a benzoquinone derivative of Embelia ribes, and the effects of curcumin (100 mg/kg/day), the active principle of Curcuma longa, against N-nitrosodiethylamine (DENA)-initiated and phenobarbital (PB)-promoted hepatocarcinogenesis were studied in Wistar rats. They were able to prevent the induction of hepatic hyper plastic nodules, body weight loss, increase in the levels of hepatic diagnostic markers, and hypoproteinemia induced by DENA/PB treatment. Hence, results of our study suggest the possible chemopreventive effects of embelin (EMB) and curcumin (CUR) against DENA/PB-induced hepatocarcinogenesis in Wistar rats.

Animals↗

Zedoariae rhizoma and curcumin inhibits platelet-derived growth factor-induced proliferation of human hepatic myofibroblasts.

During the course of liver fibrogenesis, hepatic myofibroblast cells (hMF), mostly derived from hepatic stellate cells (HSC), proliferate and synthesize excessive amounts of extracellular matrix (ECM) components. To evaluate the antiproliferative effect of a traditional herbal medicine, Zedoariae rhizoma water extracts (ZR) was examined on the growth inhibition of human hMF since proliferation of hMF is known to be central for the development of fibrosis during liver injury, and factors that may limit their growth are potential antifibrotic agents. The aim of this study was to test the effects of ZR on the proliferation and to clarify the molecular mechanisms of ZR inhibition of HSC proliferation in cultured human hMF. The cells were stimulated by platelet-derived growth factor (PDGF)-BB in the presence or absence of ZR. Proliferation was determined by bromodeoxy-uridine (BrdU) incorporation. The mRNA expressions of collagen alpha1(I) and (IV) were evaluated by a quantitative reverse transcription-polymerase chain reaction (RT-PCR). PDGF-receptor tyrosine phosphorylation was detected using anti-phosphotyrosine antibody. PDGF-receptor radioligand binding assay was performed by [125I]PDGF-BB. ZR inhibited the PDGF-BB-induced cell-proliferation and collagen alpha1(I) and (IV) mRNA expressions. ZR reduced the autophosphorylation of the PDGF-receptor. ZR blocked PDGF-BB binding to its receptor in a non-competitive manner. Furthermore, the 80% aqueous acetone extract of ZR was also found to show a decreasing effect against the proportion of S phase cells after PDGF stimulation. To clarify the active compounds, the principal constituents of seven sesquiterpenes (curdione, dehydrocurdione, germacrone, curcumenol, isocurcumenol, zedoarondiol and curcumenone) and a diarylheptanoid (curcumin) were examined. Among them, curcumin was found to decrease the proportion of S phase cells after PDGF stimulation at a dose of 30-50 microM. Potent antiproliferative and antifibrogenic effects of ZR toward hMF indicated that ZR might have therapeutic implications in chronic liver disease, indicating a novel role for ZR as a growth inhibitory mediator and pointing out its potential involvement in the negative regulation of liver fibrogenesis. In conclusion, ZR has an inhibitory effect on PDGF-induced proliferation of hMF and the blocking of PDGF-BB binding to its receptor may be the mechanism behind this effect.

Actins↗

Effect of curcumin on the expression of LDL receptor in mouse macrophages.

To investigate the molecular mechanisms of lipid-lowering drug, Rhizoma Curcumae Longae, we treated the mouse macrophages with curcumin, which was purified from the ethanol extraction of Rhizoma Curcumae Longae. The LDL receptors expressed in the macrophages were determined by ELISA, FLISA and assay of LDL uptake. Here for the first time, we found that curcumin obviously up-regulated the expression of LDL receptor in mouse macrophages, and the dose-effect relationship was demonstrated.

Animals↗