Turmeric
Selected from 1800 articles

Thangapazham RL. Sharma A. Maheshwari RK. Beneficial role of curcumin in skin diseases. [Review] [78 refs] Advances in Experimental Medicine & Biology. 595:343-57, 2007. Turmeric, derived from the plant Curcuma longa, is a gold-colored spice commonly used in the Indian subcontinent, not only for health care but also for the preservation of food and as a yellow dye for textiles. Curcumin, which gives the yellow color to turmeric, was first isolated almost two centuries ago, and its structure as diferuloylmethane was determined in 1910. Since the time of Ayurveda (1900 Bc) numerous therapeutic activities have been assigned to turmeric for a wide variety of diseases and conditions, including those of the skin, pulmonary, and gastrointestinal systems, aches, pains, wounds, sprains, and liver disorders. Extensive research within the last half century has proven that most of these activities, once associated with turmeric, are due to curcumin. Curcumin has been shown to exhibit antioxidant, anti-inflammatory, antiviral, antibacterial, antifungal, and anticancer activities and thus has a potential against various malignant diseases, diabetes, allergies, arthritis, Alzheimer's disease, and other chronic illnesses. These effects are mediated through the regulation of various transcription factors, growth factors, inflammatory cytokines, protein kinases, and other enzymes. Curcumin exhibits activities similar to recently discovered tumor necrosis factor blockers (e.g., HUMIRA, REMICADE, and ENBREL), a vascular endothelial cell growth factor blocker (e.g., AVASTIN), human epidermal growth factor receptor blockers (e.g., ERBITUX, ERLOTINIB, and GEFTINIB), and a HER2 blocker (e.g., HERCEPTIN). Considering the recent scientific bandwagon that multitargeted therapy is better than monotargeted therapy for most diseases, curcumin can be considered an ideal "Spice for Life". 

Chen J. Tang XQ. Zhi JL. Cui Y. Yu HM. Tang EH. Sun SN. Feng JQ. Chen PX. Curcumin protects PC12 cells against 1-methyl-4-phenylpyridinium ion-induced apoptosis by bcl-2-mitochondria-ROS-iNOS pathway. Apoptosis. 11(6):943-53, 2006. The aim of present study is to explore the cytoprotection of curcumin against 1-methyl-4-phenylpridinium ions (MPP(+))-induced apoptosis and the molecular mechanisms underlying in PC12 cells. Our findings indicated that MPP(+) significantly reduced the cell viability and induced apoptosis of PC12 cells. Curcumin protected PC12 cells against MPP(+)-induced cytotoxicity and apoptosis not only by inducing overexpression of Bcl-2, but also reducing the loss of mitochondrial membrane potential (MMP), an increase in intracellular reactive oxygen species (ROS) and overexpression of inducible nitric oxide synthase (iNOS). The selective iNOS inhibitor AG partly blocked MPP(+)-induced apoptosis of PC12 cells. The results of present study suggested that the cytoprotective effects of curcumin might be mediated, at least in part, by the Bcl-2-mitochondria-ROS-iNOS pathway. Because of its non-toxic property, curcumin could be further developed to treat the neurodegenerative diseases which are associated with oxidative stress, such as Parkinson's disease (PD). 

Cao J. Liu Y. Jia L. Zhou HM. Kong Y. Yang G. Jiang LP. Li QJ. Zhong LF. Curcumin induces apoptosis through mitochondrial hyperpolarization and mtDNA damage in human hepatoma G2 cells. Free Radical Biology & Medicine. 43(6):968-75, 2007. Curcumin, a major pigment of turmeric, is a natural antioxidant possessing a variety of pharmacological activities and therapeutic properties. But its mechanisms are unknown. In our previous study, we found that a 2-h exposure to curcumin induced DNA damage to both the mitochondrial DNA (mtDNA) and the nuclear DNA (nDNA) in HepG2 cells and that mtDNA damage was more extensive than nDNA damage. Therefore, experiments were initiated to evaluate the role of mtDNA damage in curcumin-induced apoptosis. The results demonstrated that HepG2 cells challenged with curcumin for 1 h showed a transient elevation of the mitochondrial membrane potential (DeltaPsim), followed by cytochrome c release into the cytosol and disruption of DeltaPsim after 6 h exposure to curcumin. Apoptosis was detected by Hoechst 33342 and annexin V/PI assay after 10 h treatment. Interestingly, the expression of Bcl-2 remained unchanged. A resistance to apoptosis for the corresponding rho0 counterparts confirmed a critical dependency for mitochondria during the induction of apoptosis in HepG2 cells mediated by curcumin. The effects of PEG-SOD in protecting against curcumin-induced cytotoxicity suggest that curcumin-induced cytotoxicity is directly dependent on superoxide anion O2- production. These data suggest that mitochondrial hyperpolarization is a prerequisite for curcumin-induced apoptosis and that mtDNA damage is the initial event triggering a chain of events leading to apoptosis in HepG2 cells. 

Pugazhenthi S. Akhov L. Selvaraj G. Wang M. Alam J. Regulation of heme oxygenase-1 expression by demethoxy curcuminoids through Nrf2 by a PI3-kinase/Akt-mediated pathway in mouse beta-cells. American Journal of Physiology - Endocrinology & Metabolism. 293(3):E645-55, 2007. Curcumin (diferuloylmethane), a component of turmeric, has been shown to have therapeutic properties. Induction of phase 2 detoxifying enzymes is a potential mechanism through which some of the actions of curcumin could proceed. Heme oxygenase-1 (HO-1), an antioxidant phase 2 enzyme, has been reported to have cytoprotective effects in pancreatic beta-cells. Curcumin on further purification yields demethoxy curcumin (DMC) and bisdemethoxy curcumin (BDMC). The objective of the present study was to determine the mechanism by which these purified curcuminoids induce HO-1 in MIN6 cells, a mouse beta-cell line. Demethoxy curcuminoids induced HO-1 promoter linked to the luciferase reporter gene more effectively than curcumin. The induction was dependent on the presence of antioxidant response element (ARE) sites containing enhancer regions (E1 and E2) in HO-1 promoter and nuclear translocation of nuclear factor-E2-related factor (Nrf2), the transcription factor that binds to ARE. Curcuminoids stimulated multiple signaling pathways that are known to induce HO-1. Inhibition of specific signaling pathways with pharmacological inhibitors and cotransfection experiments suggested the involvement of phosphotidylinositol 3-kinase and Akt. Real-time quantitative RT-PCR analysis showed significant elevation in the mRNA levels of HO-1 and two other phase 2 enzymes, the regulatory subunit of glutamyl cysteine ligase, which is needed for the synthesis of glutathione, and NAD(P)H:quinone oxidoreductase, which detoxifies quinones. DMC and BDMC induced the expression of HO-1 and translocated Nrf2 to nucleus in beta-cells of mouse islets. Our observations suggest that demethoxy curcuminoids could be used to induce a cellular defense mechanism in beta-cells under conditions of stress as seen in diabetes. 

Reinke AA. Gestwicki JE. Structure-activity relationships of amyloid beta-aggregation inhibitors based on curcumin: influence of linker length and flexibility. Chemical Biology & Drug Design. 70(3):206-15, 2007 Self-assembly of amyloid beta into fibrillar plaques is characteristic of Alzheimer's disease and oligomers of this peptide are believed to be involved in neurodegeneration. Natural organic dyes, such as congo red and curcumin, bind tightly to amyloid beta and, at higher concentrations, block its self-assembly. The ability of these molecules to prevent amyloid accumulation has generated interest in understanding which of their structural features contribute to inhibitory potency. In general, amyloid beta ligands tend to be flat, planar molecules with substituted aromatic end groups; however, a comprehensive structure-activity study has not been reported. To better understand these ligands, we surveyed the effect of three prominent features on inhibition of amyloid aggregation: the presence of two aromatic end groups, the substitution pattern of these aromatics, and the length and flexibility of the linker region. We found that modification of any one of the modules has profound effects on activity. Further, we report that the optimal length of the linker lies within a surprisingly narrow regime (6-19 A). These results offer insight into the key chemical features required for inhibiting amyloid beta aggregation. In turn, these findings help define the nature of the docking site for small molecules on the amyloid beta surface. 

Sandur SK. Pandey MK. Sung B. Ahn KS. Murakami A. Sethi G. Limtrakul P. Badmaev V. Aggarwal BB. Curcumin, demethoxycurcumin, bisdemethoxycurcumin, tetrahydrocurcumin and turmerones differentially regulate anti-inflammatory and anti-proliferative responses through a ROS-independent mechanism. Carcinogenesis. 28(8):1765-73, 2007 Curcumin, a component of turmeric (Curcuma longa), has been shown to exhibit chemopreventive activity. Whether analogs of curcumin (Cur), such as demethoxycurcumin (DMC), bisdemethoxycurcumin (BDMC), tetrahydrocurcumin (THC) and turmerones, modulate inflammatory signaling and cell proliferation signaling to same extent as curcumin was investigated. The results indicate that the relative potency for suppression of tumor necrosis factor (TNF)-induced nuclear factor-kappaB (NF-kappaB) activation was Cur > DMC > BDMC; thus suggesting the critical role of methoxy groups on the phenyl ring. THC, which lacks the conjugated bonds in the central seven-carbon chain, was completely inactive for suppression of the transcription factor. Turmerones also failed to inhibit TNF-induced NF-kappaB activation. The suppression of NF-kappaB activity correlated with inhibition of NF-kappaB reporter activity and with down-regulation of cyclooxygenase-2, cyclin D1 and vascular endothelial growth factor, all regulated by NF-kappaB. In contrast to NF-kappaB activity, the suppression of proliferation of various tumor cell lines by Cur, DMC and BDMC was found to be comparable; indicating the methoxy groups play minimum role in the growth-modulatory effects of curcumin. THC and turmerones were also found to be active in suppression of cell growth but to a much lesser extent than curcumin, DMC and BDMC. Whether suppression of NF-kappaB or cell proliferation, no relationship of any of the curcuminoid was found with reactive oxygen species (ROS) production. Overall, our results demonstrated that different analogs of curcumin present in turmeric exhibit variable anti-inflammatory and anti-proliferative activities, which do not correlate with their ability to modulate the ROS status. 

Xu Y. Ku B. Cui L. Li X. Barish PA. Foster TC. Ogle WO. Curcumin reverses impaired hippocampal neurogenesis and increases serotonin receptor 1A mRNA and brain-derived neurotrophic factor expression in chronically stressed rats. Brain Research. 1162:9-18, 2007 Curcuma longa is a major constituent of Xiaoyao-san, the traditional Chinese medicine, which has been used to effectively manage stress and depression-related disorders in China. As the active component of curcuma longa, curcumin possesses many therapeutic properties; we have previously described its antidepressant activity in our earlier studies using the chronic unpredictable stress model of depression in rats. Recent studies show that stress-induced damage to hippocampal neurons may contribute to the phathophysiology of depression. The aim of this study was to investigate the effects of curcumin on hippocampal neurogenesis in chronically stressed rats. We used an unpredictable chronic stress paradigm (20 days) to determine whether chronic curcumin treatment with the effective doses for behavioral responses (5, 10 and 20 mg/kg, p.o.), could alleviate or reverse the effects of stress on adult hippocampal neurogenesis. Our results suggested that curcumin administration (10 and 20 mg/kg, p.o.) increased hippocampal neurogenesis in chronically stressed rats, similar to classic antidepressant imipramine treatment (10 mg/kg, i.p.). Our results further demonstrated that these new cells mature and become neurons, as determined by triple labeling for BrdU and neuronal- or glial-specific markers. In addition, curcumin significantly prevented the stress-induced decrease in 5-HT(1A) mRNA and BDNF protein levels in the hippocampal subfields, two molecules involved in hippocampal neurogenesis. These results raise the possibility that increased cell proliferation and neuronal populations may be a mechanism by which curcumin treatment overcomes the stress-induced behavioral abnormalities and hippocampal neuronal damage. Moreover, curcumin treatment, via up-regulation of 5-HT(1A) receptors and BDNF, may reverse or protect hippocampal neurons from further damage in response to chronic stress, which may underlie the therapeutic actions of curcumin. 

Park C. Moon DO. Choi IW. Choi BT. Nam TJ. Rhu CH. Kwon TK. Lee WH. Kim GY. Choi YH. Curcumin induces apoptosis and inhibits prostaglandin E(2) production in synovial fibroblasts of patients with rheumatoid arthritis. International Journal of Molecular Medicine. 20(3):365-72, 2007 Rheumatoid arthritis (RA) is a chronic inflammatory disease that is characterized by hyperplasia of the synovial fibroblasts, which is partly the result of decreased apoptosis. This study investigated the mechanisms through which curcumin, a polyphenolic compound from the rhizome of Curcuma longa, exerts its anti-proliferative action in the synovial fibroblasts obtained from patients with RA. Exposure of the synovial fibroblasts to curcumin resulted in growth inhibition and the induction of apoptosis, as measured by MTT assay, fluorescent microscopy and Annexin-V-based assay. RT-PCR and immunoblotting showed that treating the cells with curcumin resulted in the down-regulation of anti-apoptotic Bcl-2 and the X-linked inhibitor of the apoptosis protein as well as the up-regulation of pro-apoptotic Bax expression in a concentration-dependent manner. Curcumin-induced apoptosis was also associated with the proteolytic activation of caspase-3 and caspase-9, and the concomitant degradation of poly(ADP-ribose) polymerase protein. Furthermore, curcumin decreased the expression levels of the cyclooxygenase (COX)-2 mRNA and protein without causing significant changes in the COX-1 levels, which was correlated with the inhibition of prostaglandin E(2) synthesis. These results show that curcumin might help identify a new therapeutic pathway against hyperplasia of the synovial fibroblasts in RA. 

Garcia-Alloza M. Borrelli LA. Rozkalne A. Hyman BT. Bacskai BJ. Curcumin labels amyloid pathology in vivo, disrupts existing plaques, and partially restores distorted neurites in an Alzheimer mouse model. Journal of Neurochemistry. 102(4):1095-104, 2007 Alzheimer's disease (AD) is characterized by senile plaques and neurodegeneration although the neurotoxic mechanisms have not been completely elucidated. It is clear that both oxidative stress and inflammation play an important role in the illness. The compound curcumin, with a broad spectrum of anti-oxidant, anti-inflammatory, and anti-fibrilogenic activities may represent a promising approach for preventing or treating AD. Curcumin is a small fluorescent compound that binds to amyloid deposits. In the present work we used in vivo multiphoton microscopy (MPM) to demonstrate that curcumin crosses the blood-brain barrier and labels senile plaques and cerebrovascular amyloid angiopathy (CAA) in APPswe/PS1dE9 mice. Moreover, systemic treatment of mice with curcumin for 7 days clears and reduces existing plaques, as monitored with longitudinal imaging, suggesting a potent disaggregation effect. Curcumin also led to a limited, but significant reversal of structural changes in dystrophic dendrites, including abnormal curvature and dystrophy size. Together, these data suggest that curcumin reverses existing amyloid pathology and associated neurotoxicity in a mouse model of AD. This approach could lead to more effective clinical therapies for the prevention of oxidative stress, inflammation and neurotoxicity associated with AD. 

Mrudula T. Suryanarayana P. Srinivas PN. Reddy GB. Effect of curcumin on hyperglycemia-induced vascular endothelial growth factor expression in streptozotocin-induced diabetic rat retina. Biochemical & Biophysical Research Communications. 361(2):528-32, 2007 Diabetic retinopathy is one of the most devastating microvascular complications of long standing type 1 and type 2 diabetes. Neovascularization stimulated by hyperglycemia-mediated induction of vascular endothelial growth factor (VEGF) has been implicated in the pathogenesis. Various small molecules have been investigated for their ability to inhibit angiogenesis. In this study, we evaluated whether curcumin and its dietary source turmeric can inhibit VEGF expression in strepotzotocin (STZ)-induced diabetic rat retina. Diabetes was induced in 3-month-old male WNIN rats by a single intraperitoneal injection of STZ. After induction, one group of diabetic rats were fed only the AIN-93 diet and the rest of the groups were fed with AIN-93 diet containing 0.002% or 0.01% curcumin or 0.5% turmeric for a period of 8 weeks. The control rats received sham injection and fed on the AIN-93 diet. At the end of 8 weeks animals were sacrificed and retina was dissected. The VEGF expression was analyzed by both real time PCR and immunoblotting. There was an increase in VEGF expression in diabetic retina as compared to control retina at both transcript and protein level. Notably, feeding of curcumin and turmeric to diabetic rats inhibited expression of VEGF. This study highlights the importance of biologically active compounds derived from dietary agents that could be explored further for the prevention and/or treatment of diabetic retinopathy. 

Sandur SK. Ichikawa H. Pandey MK. Kunnumakkara AB. Sung B. Sethi G. Aggarwal BB. Role of pro-oxidants and antioxidants in the anti-inflammatory and apoptotic effects of curcumin (diferuloylmethane). Free Radical Biology & Medicine. 43(4):568-80, 2007 Extensive research within the past half-century has indicated that curcumin (diferuloylmethane), a yellow pigment in curry powder, exhibits antioxidant, anti-inflammatory, and proapoptotic activities. We investigated whether the anti-inflammatory and proapoptotic activities assigned to curcumin are mediated through its prooxidant/antioxidant mechanism. We found that TNF-mediated NF-kappaB activation was inhibited by curcumin; and glutathione reversed the inhibition. Similarly, suppression of TNF-induced AKT activation by curcumin was also abrogated by glutathione. The reducing agent also counteracted the inhibitory effects of curcumin on TNF-induced NF-kappaB-regulated antiapoptotic (Bcl-2, Bcl-xL, IAP1), proliferative (cyclin D1), and proinflammatory (COX-2, iNOS, and MMP-9) gene products. The suppression of TNF-induced AP-1 activation by curcumin was also reversed by glutathione. Also, the direct proapoptotic effects of curcumin were inhibited by glutathione and potentiated by depletion of intracellular glutathione by buthionine sulfoximine. Moreover, curcumin induced the production of reactive oxygen species and modulated intracellular GSH levels. Quenchers of hydroxyl radicals, however, were ineffective in inhibiting curcumin-mediated NF-kappaB suppression. Further, N-acetylcysteine partially reversed the effect of curcumin. Based on these results we conclude that curcumin mediates its apoptotic and anti-inflammatory activities through modulation of the redox status of the cell. 

Kang ES. Woo IS. Kim HJ. Eun SY. Paek KS. Kim HJ. Chang KC. Lee JH. Lee HT. Kim JH. Nishinaka T. Yabe-Nishimura C. Seo HG. Up-regulation of aldose reductase expression mediated by phosphatidylinositol 3-kinase/Akt and Nrf2 is involved in the protective effect of curcumin against oxidative damage. Free Radical Biology & Medicine. 43(4):535-45, 2007 Up-regulation of aldose reductase (AR) by reactive oxygen species (ROS) and aldehyde derivatives has been observed in vascular smooth muscle cells. However, the pathophysiological consequences of the induction of AR in vascular tissues are not fully elucidated. Herein we report that an herb-derived polyphenolic compound, curcumin, elicited a dose- and time-dependent increase in AR expression. Inhibition of phosphatidylinositol 3-kinase (PI3K) and p38 mitogen-activated protein kinase (MAPK) significantly suppressed the curcumin-augmented mRNA levels and promoter activity of the AR gene. Luciferase reporter assays indicated that an osmotic response element in the promoter was essential for the responsiveness to curcumin. Curcumin accelerated the nuclear translocation of nuclear factor-erythroid 2-related factor 2 (Nrf2), and overexpression of Nrf2, but not the dominant negative Nrf2, enhanced the promoter activity of the AR gene. Cells preincubated with curcumin demonstrated resistance to ROS-induced apoptotic death. These effects were significantly attenuated in the presence of AR inhibitors or small interfering RNAs, indicating a protective role for AR against ROS-induced cell damage. Taken together, the activation of PI3K and p38 MAPK by curcumin augmented the expression of the AR gene via Nrf2, and increased AR activity may be an important cellular response against oxidative stress. 

Chainani-Wu N. Silverman S Jr. Reingold A. Bostrom A. Mc Culloch C. Lozada-Nur F. Weintraub J. A randomized, placebo-controlled, double-blind clinical trial of curcuminoids in oral lichen planus. Phytomedicine. 14(7-8):437-46, 2007 We studied the efficacy of curcuminoids in the treatment of oral lichen planus (OLP), a chronic, mucocutaneous, immunological disease. Curcuminoids are components of turmeric (Curcuma longa) that have anti-inflammatory activity. Turmeric has been used in Ayurveda (Indian traditional medicine) for centuries. A randomized, double-blind, placebo-controlled trial was conducted. In all, 100 consecutive, eligible patients with OLP presenting to the oral medicine clinic at the University of California, San Francisco, were to be selected. Two interim analyses were to be conducted during the trial. The trial was conducted between February 2003 and September 2004. The first interim analysis was conducted in October 2004 using data from the first 33 subjects. Study subjects were randomized to receive either placebo or curcuminoids at 2000 mg/day for 7 weeks. In addition, all subjects received prednisone at 60 mg/day for the first 1 week. The primary outcome was a change in symptoms from baseline. Secondary outcomes were changes in clinical signs and occurrence of side effects. The first interim analysis did not show a significant difference between the placebo and curcuminoids groups. Conditional power calculations suggested a less than 2% chance that the curcuminoids group would have a significantly better outcome as compared with the placebo group if the trial were continued to completion. Therefore, the study was ended early for futility. Reaching a conclusion regarding the efficacy of curcuminoids based on the results of this study is not possible as it was ended early for futility. Curcuminoids at this dose were well tolerated and the results suggest that for future studies a larger sample size, a higher dose and/or longer duration of curcuminoids administration should be considered; however, for the next step, an RCT of a shorter duration, using a higher dose of curcuminoids, and without an initial course of prednisone, should be considered. 

Fiala M. Liu PT. Espinosa-Jeffrey A. Rosenthal MJ. Bernard G. Ringman JM. Sayre J. Zhang L. Zaghi J. Dejbakhsh S. Chiang B. Hui J. Mahanian M. Baghaee A. Hong P. Cashman J. Innate immunity and transcription of MGAT-III and Toll-like receptors in Alzheimer's disease patients are improved by bisdemethoxycurcumin. Proceedings of the National Academy of Sciences of the United States of America. 104(31):12849-54, 2007 We have tested a hypothesis that the natural product curcuminoids, which has epidemiologic and experimental rationale for use in AD, may improve the innate immune system and increase amyloid-beta (Abeta) clearance from the brain of patients with sporadic Alzheimer's disease (AD). Macrophages of a majority of AD patients do not transport Abeta into endosomes and lysosomes, and AD monocytes do not efficiently clear Abeta from the sections of AD brain, although they phagocytize bacteria. In contrast, macrophages of normal subjects transport Abeta to endosomes and lysosomes, and monocytes of these subjects clear Abeta in AD brain sections. Upon Abeta stimulation, mononuclear cells of normal subjects up-regulate the transcription of beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase (MGAT3) (P < 0.001) and other genes, including Toll like receptors (TLRs), whereas mononuclear cells of AD patients generally down-regulate these genes. Defective phagocytosis of Abeta may be related to down-regulation of MGAT3, as suggested by inhibition of phagocytosis by using MGAT3 siRNA and correlation analysis. Transcription of TLR3, bditTLR4, TLR5, bditTLR7, TLR8, TLR9, and TLR10 upon Abeta stimulation is severely depressed in mononuclear cells of AD patients in comparison to those of control subjects. In mononuclear cells of some AD patients, the curcuminoid compound bisdemethoxycurcumin may enhance defective phagocytosis of Abeta, the transcription of MGAT3 and TLRs, and the translation of TLR2-4. Thus, bisdemethoxycurcumin may correct immune defects of AD patients and provide a previously uncharacterized approach to AD immunotherapy. 

Dhandapani KM. Mahesh VB. Brann DW. Curcumin suppresses growth and chemoresistance of human glioblastoma cells via AP-1 and NFkappaB transcription factors. Journal of Neurochemistry. 102(2):522-38, 2007 Malignant gliomas are a debilitating class of brain tumors that are resistant to radiation and chemotherapeutic drugs, contributing to the poor prognosis associated with these tumors. Over-expression of transcription factors such as NFkappaB and AP-1 contribute to the enhanced glioma survival, radioresistance, and chemoresistance. Curcumin, which may inhibit these pathways, was therefore investigated for a potential therapeutic role in glioma. The effect of curcumin on glioma survival was investigated in human (T98G, U87MG, and T67) and rat (C6) glioma cell lines. The ability of curcumin to overcome glioma cell radioresistance and chemoresistance was also explored. Curcumin reduced cell survival in a p53- and caspase-independent manner, an effect correlated with the inhibition of AP-1 and NFkappaB signaling pathways via prevention of constitutive JNK and Akt activation. Curcumin-sensitized glioma cells to several clinically utilized chemotherapeutic agents (cisplatin, etoposide, camptothecin, and doxorubicin) and radiation, effects correlated with reduced expression of bcl-2 and IAP family members as well as DNA repair enzymes (MGMT, DNA-PK, Ku70, Ku80, and ERCC-1). These findings support a role for curcumin as an adjunct to traditional chemotherapy and radiation in the treatment of brain cancer. 

Xu PH. Long Y. Dai F. Liu ZL. The relaxant effect of curcumin on porcine coronary arterial ring segments. Vascular Pharmacology. 47(1):25-30, 2007 Curcumin is a naturally occurring phenolic compound isolated as a yellow pigment from turmeric (curcuma longa). This compound has received much attention due to its diversity of biological and pharmacological activities. The purpose of this study was to assess the effect of curcumin on porcine coronary arteries and to investigate the mechanism of its action, if any. The isometric tension of coronary arterial rings taken from porcine hearts was measured and its response to curcumin (10(-11)-10(-5) mol/l) was studied. It was found that curcumin significantly reduced the isomeric tension of both quiescent and prostaglandin F2alpha (PGF2alpha) precontracted porcine coronary arterial rings. The relaxing effect of curcumin on coronary arteries was significantly reduced by removal of endothelium, and by the addition of N-nitro-L-arginine (L-NNA), methylene blue or propranolol, but not by indomethacin. These results suggest that curcumin-induced relaxation of isolated porcine coronary arteries might involve the action of nitric oxide (NO), cyclic guanosine monophosphate (cGMP) and adrenergic beta-receptor, but not involve the synthesis of prostaglandin. 

Nonn L. Duong D. Peehl DM. Chemopreventive anti-inflammatory activities of curcumin and other phytochemicals mediated by MAP kinase phosphatase-5 in prostate cells. Carcinogenesis. 28(6):1188-96, 2007 As inflammation emerges as a risk factor for prostate cancer (PCa), there is potential for chemoprevention by anti-inflammatory agents. Dietary phytochemicals have been shown to have chemopreventive properties which may include anti-inflammatory activities. In this study, we demonstrate a role for mitogen-activated protein kinase phosphatase-5 (MKP5) in mediating anti-inflammatory activities of the phytochemicals curcumin, resveratrol and [6]-gingerol. We utilized the cytokines tumor necrosis factor-alpha (TNFalpha) and interleukin (IL)-1beta to increase p38-dependent nuclear factor kappa-B (NFkappaB) activation and expression of pro-inflammatory genes cyclooxygenase-2 (COX-2), IL-6 and IL-8 in normal prostatic epithelial cells. MKP5 over-expression decreased cytokine-induced NFkappaB activation, COX-2, IL-6 and IL-8 in normal prostatic epithelial cells, suggesting potent anti-inflammatory activity of MKP5. Pretreatment of cells with a p38 inhibitor mimicked the results observed with MKP5 over-expression, further implicating p38 inhibition as the main activity of MKP5. Curcumin, the phytochemical found in turmeric, up-regulated MKP5, subsequently decreasing cytokine-induced p38-dependent pro-inflammatory changes in normal prostatic epithelial cells. Resveratrol and [6]-gingerol, phytochemicals present in red wine and ginger, respectively, also up-regulated MKP5 in normal prostate epithelial cells. Moreover, we found that PCa cell lines DU 145, PC-3, LNCaP and LAPC-4 retained the ability to up-regulate MKP5 following curcumin, resveratrol and [6]-gingerol exposure, suggesting utility of these phytochemicals in PCa treatment. In summary, our findings show direct anti-inflammatory activity of MKP5 in prostate cells and suggest that up-regulation of MKP5 by phytochemicals may contribute to their chemopreventive actions by decreasing prostatic inflammation. 

Xu M. Deng B. Chow YL. Zhao ZZ. Hu B. Effects of curcumin in treatment of experimental pulmonary fibrosis: a comparison with hydrocortisone. Journal of Ethnopharmacology. 112(2):292-9, 2007 To compare curcumin with hydrocortisone for treating bleomycin-induced pulmonary fibrosis (BLMPF), four groups of rats were injected with 1.5 mg/kg bleomycin intratracheally. Then the Group HC rats were treated with three injections of 2mg/kg hydrocortisone i.p.; Group CH and CL rats, respectively, were orally given 500 or 250 mg/kg curcumin daily; and Group PC rats were given deionized water alone. After 28 days of treatment, lung samples were examined by H-E staining, Masson's staining and immunohistochemical analyses and pulmonary type I collagen (Col-I), inducible nitric oxide synthetase (iNOS) and transforming growth factor-beta1 (TGF-beta1) were determined by Western blotting and real-time RT PCR analyses. The results showed that (1) Group PC rats had histopathological characteristics of BLMPF with significant increase in their protein/mRNA expressions of Col-I (+114%/+173%), iNOS (+146%/+523%) and TGF-beta1 (+476%/+527%) (P<0.01); (2) in Group HC, CH and CL rats, protein/mRNA expressions of Col-I (-39%/-52%, -31%/-57%, -33%/-58%), iNOS (-31%/-51%, -31%/-79%, -31%/-47%) and TGF-beta1 (-64%/-78%, -75%/-74%, -81%/-79%) were significantly lower than Group PC (P<0.05); (3) except for levels of TGF-beta1 protein, there was no significant difference among Group CH, CL and HC rats (P>0.05). It suggests that curcumin may play a similar role as hydrocortisone in preventing BLMPF. 

Bright JJ. Curcumin and autoimmune disease. [Review] [166 refs] Advances in Experimental Medicine & Biology. 595:425-51, 2007. The immune system has evolved to protect the host from microbial infection; nevertheless, a breakdown in the immune system often results in infection, cancer, and autoimmune diseases. Multiple sclerosis, rheumatoid arthritis, type 1 diabetes, inflammatory bowel disease, myocarditis, thyroiditis, uveitis, systemic lupus erythromatosis, and myasthenia gravis are organ-specific autoimmune diseases that afflict more than 5% of the population worldwide. Although the etiology is not known and a cure is still wanting, the use of herbal and dietary supplements is on the rise in patients with autoimmune diseases, mainly because they are effective, inexpensive, and relatively safe. Curcumin is a polyphenolic compound isolated from the rhizome of the plant Curcuma longa that has traditionally been used for pain and wound-healing. Recent studies have shown that curcumin ameliorates multiple sclerosis, rheumatoid arthritis, psoriasis, and inflammatory bowel disease in human or animal models. Curcumin inhibits these autoimmune diseases by regulating inflammatory cytokines such as IL-1beta, IL-6, IL-12, TNF-alpha and IFN-gamma and associated JAK-STAT, AP-1, and NF-kappaB signaling pathways in immune cells. Although the beneficial effects of nutraceuticals are traditionally achieved through dietary consumption at low levels for long periods of time, the use of purified active compounds such as curcumin at higher doses for therapeutic purposes needs extreme caution. A precise understanding of effective dose, safe regiment, and mechanism of action is required for the use of curcumin in the treatment of human autoimmune diseases. 

Osawa T. Nephroprotective and hepatoprotective effects of curcuminoids. [Review] [58 refs] Advances in Experimental Medicine & Biology. 595:407-23, 2007. Curcumin (U1) has a wide spectrum of therapeutic effects such as antitumor and anti-inflammatory effects, including antibacterial, antiviral, antifungal, and antispasmodic activities. By comparison of the structure-activity relationship, tetrahydrocurcumin (THU1), one of the major metabolites, showed the highest antioxidative activity in both in vitro and in vivo systems. U1 has been reported to have the nephroprotective effect to improve creatinine and urea clearance and also protected the chronic renal allograft nephropathy. These beneficial effects have been explained by the protection of oxidative stress and the induction of antioxidative enzymes. The protective effect of THU1 against ferric nitrilotriacetate (Fe-NTA)-induced oxidative renal damage using male ddY mice was greater than that of U1, by monitoring not only radical scavenging activity measured by ESR, and TBARS, 4-HNE-modified protein and 8-OHdG formation but also induction of anioxidative enzymes and detoxification enzymes. THU1 was also expected to improve redox regulation through glutathione and suppress the oxidative stress in diabetic nephropathy and neuropathy. Earlier studies reported that U1 reduced the iron-induced hepatic damage, aflatoxin- and benzo[a]pyrene- induced mutagenicity and hepatocarcinogenecity and also the formation of the DNA adduct by inhibiting cytochrome P450 in the liver. The hepatoprotective role of U1 has been examined using carbone terachloride-induced liver damage in rats and alcoholic liver disease model rats, but not examined using THU1. Our recent data suggests that THU1 is a more promising hepatprotective agent because of its strong induction activity of antioxidant and phase 2-metabolizing enzymes in liver compared to kidney, although more detaied examinations are required. 

Venkatesan N. Punithavathi D. Babu M. Protection from acute and chronic lung diseases by curcumin. [Review] [71 refs] Advances in Experimental Medicine & Biology. 595:379-405, 2007. The aim of this review has been to describe the current state of the therapeutic potential of curcumin in acute and chronic lung injuries. Occupational and environmental exposures to mineral dusts, airborne pollutants, cigarette smoke, chemotherapy, and radiotherapy injure the lungs, resulting in acute and chronic inflammatory lung diseases. Despite major advances in treating lung diseases, until now disease-modifying efficacy has not been demonstrated for any of the existing drugs. Current medical therapy offers only marginal benefit; therefore, there is an essential need to develop new drugs that might be of effective benefit in clinical settings. Over the years, there has been increasing evidence that curcumin, a phytochemical present in turmeric (Curcuma longa), has a wide spectrum of therapeutic properties and a remarkable range of protective effects in various diseases. Several experimental animal models have tested curcumin on lung fibrosis and these studies demonstrate that curcumin attenuates lung injury and fibrosis caused by radiation, chemotherapeutic drugs, and toxicants. The growing amount of data from pharmacological and animal studies also supports the notion that curcumin plays a protective role in chronic obstructive pulmonary disease, acute lung injury, acute respiratory distress syndrome, and allergic asthma, its therapeutic action being on the prevention or modulation of inflammation and oxidative stress. These findings give substance to the possibility of testing curcumin in patients with lung diseases.  

Reyes-Gordillo K. Segovia J. Shibayama M. Vergara P. Moreno MG. Muriel P. Curcumin protects against acute liver damage in the rat by inhibiting NF-kappaB, proinflammatory cytokines production and oxidative stress. Biochimica et Biophysica Acta. 1770(6):989-96, 2007. Curcumin, an anti-inflammatory and antioxidant compound, was evaluated for its ability to suppress acute carbon tetrachloride-induced liver damage. Acute hepatotoxicity was induced by oral administration of CCl4 (4 g/kg, p.o.). Curcumin treatment (200 mg/kg, p.o.) was given before and 2 h after CCl4 administration. Indicators of necrosis (alanine aminotransferase) and cholestasis (gamma-glutamyl transpeptidase and bilirubins) resulted in significant increases after CCl4 intoxication, but these effects were prevented by curcumin treatment. As an indicator of oxidative stress, GSH was oxidized and the GSH/GSSG ratio decreased significantly by CCl4, but was preserved within normal values by curcumin. In addition to its antioxidants properties, curcumin is capable of preventing NF-kappaB activation and therefore to prevent the secretion of proinflammatory cytokines. Therefore, in this study we determined the concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6) mRNA, and NF-kappaB activation. CCl4-administered rats depicted significant increases in TNF-alpha, IL-1beta, and IL-6 production, while curcumin remarkably suppressed these mediators of inflammation in liver damage. These results were confirmed by measuring TNF-alpha, and IL-1beta protein production using Western Blot analysis. Accordingly, these proteins were increased by CCl4 and this effect was abolished by curcumin. Administration of CCl4 induced the translocation of NF-kappaB to the nucleus; CCl4 induced NF-kappaB DNA binding activity was blocked by curcumin treatment. These findings suggest that curcumin prevents acute liver damage by at least two mechanisms: acting as an antioxidant and by inhibiting NF-kappaB activation and thus production of proinflammatory cytokines. 

Bruck R. Ashkenazi M. Weiss S. Goldiner I. Shapiro H. Aeed H. Genina O. Helpern Z. Pines M. Prevention of liver cirrhosis in rats by curcumin. Liver International. 27(3):373-83, 2007. BACKGROUND AND AIM: Curcumin, the major polyphenolic compound in turmeric, has been shown to attenuate hepatic damage in several animal models of liver injury. The aim of the present study was to examine the efficacy of curcumin in preventing thioacetamide-induced cirrhosis and to unravel the mechanism of curcumin's effect on hepatic fibrosis in rats. METHODS: Liver cirrhosis was induced by thioacetamide (TAA; 200 mg/kg, i.p.) twice weekly for 12 weeks. One group of rats concomitantly received curcumin (300 mg/kg/day, by gavage for 12 weeks); the control group received the solvent at identical amounts and duration. RESULTS: TAA administration induced liver cirrhosis, which was inhibited by curcumin. Liver histopathology, hydroxyproline levels and spleen weights were significantly lower in the rats treated with TAA+curcumin compared with TAA only (P<0.001). Immunohistochemical studies and in situ hybridization demonstrated inhibition of hepatic stellate cell (alpha smooth muscle actin-positive) activation and collagen alpha1 (I) gene expression in the livers of the TAA+curcumin-treated rats. Curcumin reduced oxidative stress as shown by the decreased hepatic nitrotyrosine staining in the curcumin+TAA-treated rats. Curcumin treatment had no effect on pre existing liver cirrhosis. As determined by in vitro studies using the rat HSC-T6 cell line, curcumin had no direct inhibitory effect on collagen alpha1 (I) messenger RNA expression. Further studies in these cells using reverse transcriptase-polymerase chain reaction demonstrated that curcumin had no effect on the expression of PDGF-induced TIMP-1 and TIMP-2, TGFbeta1, TGFbeta2 and MCP-1 but significantly inhibited tumor necrosis factor alpha expression. Curcumin had no effect on hepatic stellate cells proliferation. Zymography showed that curcumin had no effect on matrix metalloproteinase-2 activity. CONCLUSIONS: Curcumin inhibited the development of TAA-induced liver cirrhosis mainly due to its anti-inflammatory activities and not by a direct anti-fibrotic effect. As curcumin ingestion is safe in humans, it may be reasonable to assess in clinical studies the beneficial effect of curcumin in slowing the development of liver cirrhosis. 

Zhou Y. Zheng S. Lin J. Zhang QJ. Chen A. The interruption of the PDGF and EGF signaling pathways by curcumin stimulates gene expression of PPARgamma in rat activated hepatic stellate cell in vitro. Laboratory Investigation. 87(5):488-98, 2007. Activation of hepatic stellate cells (HSC), the major effector in hepatic fibrogenesis, is coupled with sequential alterations in expression of genes, including the upregulation of platelet-derived growth factor-beta receptor (PDGF-betaR) and epidermal growth factor receptor (EGFR), as well as the down-regulation of the peroxisome proliferator-activated receptor-gamma (PPARgamma). However, the relationship among the alterations in expression of the genes and the activation of their signaling in activated HSC remains obscure. We recently showed that curcumin, the yellow pigment in curry, inhibited cell growth and induced gene expression of endogenous PPARgamma in activated HSC in vitro. The present study is to elucidate the underlying mechanisms, focusing on the impacts of PDGF and EGF signaling. It is hypothesized that the interruption of the PDGF and EGF signaling pathways by curcumin might stimulate gene expression of PPARgamma in activated HSC. Our results in this report indicate that the activation of PDGF or EGF signaling by exogenous PDGF or EGF inhibits PPARgamma gene expression in passaged HSC. Curcumin interrupts PDGF and EGF signaling demonstrated by inhibiting tyrosine phosphorylation of PDGF-betaR and EGFR and by reducing the levels of phosphorylated phosphatidylinositol-3 kinase (PI-3K/AKT), extracellular signal-regulated kinase (ERK) and the Jun N-terminal kinase (JNK). The blockade of PI-3K/AKT, ERK or JNK signaling negatively regulates PPARgamma gene expression in activated HSC, leading to the reduction in cell growth, including inducing cell arrest and apoptosis. Our results collectively demonstrate that the interruption of the PDGF and EGF signaling pathways by curcumin stimulates gene expression of PPARgamma in activated HSC. These results provide novel insights into the mechanisms of curcumin in the induction of PPARgamma gene expression in activated HSC. 

Jiang J. Wang W. Sun YJ. Hu M. Li F. Zhu DY. Neuroprotective effect of curcumin on focal cerebral ischemic rats by preventing blood-brain barrier damage. European Journal of Pharmacology. 561(1-3):54-62, 2007. Curcumin, a member of the curcuminoid family of compounds, is a yellow colored phenolic pigment obtained from powdered rhizome of C. longa Linn. Recent studies have demonstrated that curcumin has protective effects against cerebral ischemia/reperfusion injury. However, little is known about its mechanism. Disruption of the blood-brain barrier occurs after stroke. Protection of the blood-brain barrier has become an important target of stroke interventions in experimental therapeutic. The objective of the present study was to determine whether curcumin prevents cerebral ischemia/reperfusion injury by protecting blood-brain barrier integrity. We report that a single injection of curcumin (1 and 2 mg/kg, i.v.) 30 min after focal cerebral ischemia/reperfusion in rats significantly diminished infarct volume, improved neurological deficit, decreased mortality, reduced the water content of the brain and the extravasation of Evans blue dye in ipsilateral hemisphere in a dose-dependent manner. In cultured astrocytes, curcumin significantly inhibited inducible nitric oxide synthase (iNOS) expression and NO(x) (Nitrites/nitrates contents) production induced by lipopolysaccharide (LPS)/tumor necrosis factor alpha (TNF(alpha)). Furthermore, curcumin prevented ONOO(-) donor SIN-1-induced cerebral capillaries endothelial cells damage. We concluded that curcumin ameliorates cerebral ischemia/reperfusion injury by preventing ONOO(-) mediated blood-brain barrier damage. 

Shakibaei M. John T. Schulze-Tanzil G. Lehmann I. Mobasheri A. Suppression of NF-kappaB activation by curcumin leads to inhibition of expression of cyclo-oxygenase-2 and matrix metalloproteinase-9 in human articular chondrocytes: Implications for the treatment of osteoarthritis. Biochemical Pharmacology. 73(9):1434-45, 2007. Pro-inflammatory cytokines such as interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) play a key role in the pathogenesis of osteoarthritis (OA). Anti-inflammatory agents capable of suppressing the production and catabolic actions of these cytokines may have therapeutic potential in the treatment of OA and a range of other osteoarticular disorders. The purpose of this study was to examine the effects of curcumin (diferuloylmethane), a pharmacologically safe phytochemical agent with potent anti-inflammatory properties on IL-1beta and TNF-alpha signalling pathways in human articular chondrocytes maintained in vitro. The effects of curcumin were studied in cultures of human articular chondrocytes treated with IL-1beta and TNF-alpha for up to 72h. Expression of collagen type II, integrin beta1, cyclo-oxygenase-2 (COX-2) and matrix metalloproteinase-9 (MMP-9) was monitored by western blotting. The effects of curcumin on the expression, phosphorylation and nuclear translocation of protein components of the NF-kappaB system were studied by western blotting and immunofluorescence, respectively. Treatment of chondrocytes with curcumin suppressed IL-1beta-induced NF-kappaB activation via inhibition of IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 phosphorylation and p65 nuclear translocation. Curcumin inhibited the IL-1beta-induced stimulation of up-stream protein kinase B Akt. These events correlated with down-regulation of NF-kappaB targets including COX-2 and MMP-9. Similar results were obtained in chondrocytes stimulated with TNF-alpha. Curcumin also reversed the IL-1beta-induced down-regulation of collagen type II and beta1-integrin receptor expression. These results indicate that curcumin has nutritional potential as a naturally occurring anti-inflammatory agent for treating OA through suppression of NF-kappaB mediated IL-1beta/TNF-alpha catabolic signalling pathways in chondrocytes. 

Kumar P. Padi SS. Naidu PS. Kumar A. Possible neuroprotective mechanisms of curcumin in attenuating 3-nitropropionic acid-induced neurotoxicity. Methods & Findings in Experimental & Clinical Pharmacology. 29(1):19-25, 2007. 3-Nitropropionic acid (3-NP) is a well known fungic toxin causing neurotoxicity. Systemic administration of 3-NP causes motor and cognitive deficits that are associated with excessive free radical generation. Recently, curcumin has been implicated as a neuroprotectant in the treatment of various neurological disorders. The present study was designed to investigate the effects of curcumin in 3-NP-induced cognitive impairment and oxidative stress in rats. Curcumin, a potent antioxidant of dietary polyphenol, containing a standardized extract of Curcuma longa root (Zingiberaceae), has been reported to possess free radical scavenging, iron chelating and antiinflammatory activities. Intraperitoneal administration of 3-NP (20 mg/kg for 4 days) showed loss in body weight, declined motor function, poor retention of memory and changes in oxidative stress (lipid peroxidation, reduced glutathione and nitrite level) parameters in brain. Chronic treatment with curcumin (10, 20 and 50 mg/kg, p.o.) once daily for a period of 8 days beginning 4 days prior to 3-NP administration dose-dependently improved the 3-NP-induced motor and cognitive impairment. Biochemical analysis revealed that curcumin administration significantly attenuated 3-NP-induced oxidative stress (lipid peroxidation estimation, reduced glutathione and nitrite activity) in the brains of rats. It also significantly restored the decreased succinate dehydrogenase activity. The results of the present study clearly indicate that curcumin by its antioxidant activity showed neuroprotection against 3-NP-induced behavioral and biochemical alteration. 

Alaikov T. Konstantinov SM. Tzanova T. Dinev K. Topashka-Ancheva M. Berger MR. Antineoplastic and anticlastogenic properties of curcumin. Annals of the New York Academy of Sciences. 1095:355-70, 2007 Curcumin is the pigment of turmeric and has been reported as a signal transduction modulator and inhibitor of transcription factors, for example, NF-kappaB. In our article we found a concentration-dependent cytotoxic activity of curcumin in a panel of eight leukemic cell lines (SKW-3, CEM, U-937, HL-60, HL-60/Dox, K-562, LAMA-84, and AR-230). Additive to synergistic interactions was recorded for combinations with bendamustine and idarubicine in SKW-3 and LAMA-84 cells. Noteworthy, in multiple myeloma cells (RPMI-8226 and U-266) a potentiation of the efficacy of bendamustine by curcumin application was found. Moreover, curcumin increased the bendamustine cytotoxicity in cultures of cells isolated from the bone marrow of a patient with non-Hodgkin's lymphoma (NHL). The increased bendamustine efficacy could be explained by NF-kappaB inhibition, because this factor is activated in many cancers, especially leukemia and multiple myeloma. Curcumin is characterized by low toxicity and was described to have a chemoprotective activity. Therefore, the level of reduced glutathione (GSH) was measured and a concentration-dependent increase of GSH levels was recorded in AR-230 and SKW-3 cells (concentration range 5-25 muM). Experiments with mice showed significant protection against cisplatin-induced chromosomal aberrations (clastogenic effect) and inhibition of mitoses in bone marrow cells. Curcumin alone caused reduction of the mitotic index. In combination with cisplatin, however, this parameter was increased when compared to cisplatin alone. Our data indicate that curcumin has pleiotropic effects on signal transduction by inhibiting transcription thus exerting antitumor activity. In addition, curcumin has protective and anticlastogenic activity by enhancing the scavenging of free radicals. 

Sharma S. Chopra K. Kulkarni SK. Effect of insulin and its combination with resveratrol or curcumin in attenuation of diabetic neuropathic pain: participation of nitric oxide and TNF-alpha. Phytotherapy Research. 21(3):278-83, 2007 Diabetic neuropathic pain, an important microvascular complication in diabetes mellitus, is recognized as one of the most difficult types of pain to treat. The underlying mechanisms of painful symptoms may be closely associated with hyperglycaemia but a lack of the understanding of its proper aetiology, inadequate relief, development of tolerance and potential toxicity of classical antinociceptives warrant the investigation of newer agents to relieve this pain. The aim of the present study was to explore the antinociceptive effect of insulin and its combinations with resveratrol and curcumin in attenuating diabetic neuropathic pain. The study also aimed to examine the effect of these combinations on tumour necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) levels in streptozotocin (STZ) induced diabetic mice. Four weeks after a single intraperitoneal injection of streptozotocin (200 mg/kg), mice were tested in the tail immersion and hot-plate assays. Diabetic mice exhibited significant hyperalgesia along with increased plasma glucose and decreased body weights compared with control mice. Chronic treatment with insulin (10 IU/kg/day, s.c.) and its combinations with antioxidants (resveratrol 20 mg/kg or curcumin 60 mg/kg, p.o.) for 4 weeks starting from the 4th week of STZ injection significantly attenuated thermal hyperalgesia and the hot-plate latencies. There was a significant inhibition of TNF-alpha and NO levels when these drugs were given in combination compared with their effects per se. These results indicate an antinociceptive activity of resveratrol and curcumin and point towards the beneficial effect of these combinations with insulin in attenuating diabetic neuropathic pain, possibly through the participation of NO and TNF-alpha. 

Cho JW. Lee KS. Kim CW. Curcumin attenuates the expression of IL-1beta, IL-6, and TNF-alpha as well as cyclin E in TNF-alpha-treated HaCaT cells; NF-kappaB and MAPKs as potential upstream targets. International Journal of Molecular Medicine. 19(3):469-74, 2007 TNF-alpha induces some proinflammatory cytokines including IL-1beta, IL-6, IL-8, and itself by activation of NF-kappaB or MAPKs (p38, JNK, ERK). These cytokines play important roles in various inflammatory skin diseases, such as psoriasis. Recently it was also reported that expression of cyclin E is up-regulated by ERK pathway after TNF-alpha treatment. However, it was unknown whether curcumin, showing inhibitory effects on NF-kappaB and MAPKs, attenuates the expression of TNF-alpha-induced IL-1beta, IL-6, IL-8, and TNF-alpha as well as cyclin E expression in HaCaT cells. In this study, we investigated the inhibitory effect of curcumin on expression of proinflammatory cytokines and cyclin E in TNF-alpha-treated HaCaT cells. We found that curcumin inhibited the expression of TNF-alpha-induced IL-1beta, IL-6, and TNF-alpha, but not IL-8, in TNF-alpha-treated HaCaT cells as well as the TNF-alpha-induced cyclin E expression. In addition, curcumin inhibited the activation of MAPKs (JNK, p38 MAPK, and ERK) and NF-kappaB in TNF-alpha-treated HaCaT cells. Taken together, curcumin exerts anti-inflammatory and growth inhibitory effects in TNF-alpha-treated HaCaT cells through inhibition of NF-kappaB and MAPK pathways. 

Zhang L. Fiala M. Cashman J. Sayre J. Espinosa A. Mahanian M. Zaghi J. Badmaev V. Graves MC. Bernard G. Rosenthal M. Curcuminoids enhance amyloid-beta uptake by macrophages of Alzheimer's disease patients. Journal of Alzheimer's Disease. 10(1):1-7, 2006 Treatment of Alzheimer's disease (AD) is difficult due to ignorance of its pathogenesis. AD patients have defects in phagocytosis of amyloid-beta (1-42) (Abeta) in vitro by the innate immune cells, monocyte/macrophages and in clearance of Abeta plaques [5]. The natural product curcuminoids enhanced brain clearance of Abeta in animal models. We, therefore, treated macrophages of six AD patients and 3 controls by curcuminoids in vitro and measured Abeta uptake using fluorescence and confocal microscopy. At baseline, the intensity of Abeta uptake by AD macrophages was significantly lower in comparison to control macrophages and involved surface binding but no intracellular uptake. After treatment of macrophages with curcuminoids, Abeta uptake by macrophages of three of the six AD patients was significantly (P<0.001 to 0.081) increased. Confocal microscopy of AD macrophages responsive to curcuminoids showed surface binding in untreated macrophages but co-localization with phalloidin in an intracellular compartment after treatment. Immunomodulation of the innate immune system by curcuminoids might be a safe approach to immune clearance of amyloidosis in AD brain. 

Amoli MM. Mousavizadeh R. Sorouri R. Rahmani M. Larijani B. Curcumin inhibits in vitro MCP-1 release from mouse pancreatic islets. Transplantation Proceedings. 38(9):3035-8, 2006 OBJECTIVES: Monocyte chemoattractant proteins (MCP-1) belongs to the CC family of chemokines secreted from islets of the pancreas, producing recruitment of inflammatory cells leading to an acute immune response with graft rejection in clinical transplantation. Expression and release of many inflammatory cytokines and chemokines, including MCP-1 is regulated by the nuclear factor (NF)-kappaB pathway. Curcumin is an NF-kappaB inhibitor with a variety of biological activities anti-inflammatory, antitumor, antioxidant, and antichemotactic effects. The aim of this study was to examine the effect of curcumin on in vitro MCP-1 release from pancreatic islets. METHODS: Mouse pancreatic islets in 18-hour cultures were treated with 0 or 10 or 20 micromol/L curcumin and with LPS for an additional 24 hours. MCP-1 levels in culture supernates of islets with versus without curcumin treatment were measured by an ELISA assay. RESULTS: We observed that curcumin at the concentration of 20 micromol/L significantly decreased MCP-1 release from mouse islets compared to the control group (P = .005). In addition at both of 10 micromol/L and 20 micromol/L curcumin concentrations there was a decreased level of MCP-1 released from LPS-treated versus control islets (P = .01). 

Gupta KK. Bharne SS. Rathinasamy K. Naik NR. Panda D. Dietary antioxidant curcumin inhibits microtubule assembly through tubulin binding. FEBS Journal. 273(23):5320-32, 2006 Curcumin, a component of turmeric, has potent antitumor activity against several tumor types. However, its molecular target and mechanism of antiproliferative activity are not clear. Here, we identified curcumin as a novel antimicrotubule agent. We have examined the effects of curcumin on cellular microtubules and on reconstituted microtubules in vitro. Curcumin inhibited HeLa and MCF-7 cell proliferation in a concentration-dependent manner with IC(50) of 13.8 +/- 0.7 microm and 12 +/- 0.6 microm, respectively. At higher inhibitory concentrations (> 10 microm), curcumin induced significant depolymerization of interphase microtubules and mitotic spindle microtubules of HeLa and MCF-7 cells. However, at low inhibitory concentrations there were minimal effects on cellular microtubules. It disrupted microtubule assembly in vitro, reduced GTPase activity, and induced tubulin aggregation. Curcumin bound to tubulin at a single site with a dissociation constant of 2.4 +/- 0.4 microm and the binding of curcumin to tubulin induced conformational changes in tubulin. Colchicine and podophyllotoxin partly inhibited the binding of curcumin to tubulin, while vinblastine had no effect on the curcumin-tubulin interactions. The data together suggested that curcumin may inhibit cancer cells proliferation by perturbing microtubule assembly dynamics and may be used to develop efficacious curcumin analogues for cancer chemotherapy. 

Panchatcharam M. Miriyala S. Gayathri VS. Suguna L. Curcumin improves wound healing by modulating collagen and decreasing reactive oxygen species. Molecular & Cellular Biochemistry. 290(1-2):87-96, 2006 Wound healing consists of an orderly progression of events that re-establish the integrity of the damaged tissue. Several natural products have been shown to accelerate the healing process. The present investigation was undertaken to determine the role of curcumin on changes in collagen characteristics and antioxidant property during cutaneous wound healing in rats. Full-thickness excision wounds were made on the back of rat and curcumin was administered topically. The wound tissues removed on 4th, 8th and 12th day (post-wound) were used to analyse biochemical and pathological changes. Curcumin increased cellular proliferation and collagen synthesis at the wound site, as evidenced by increase in DNA, total protein and type III collagen content of wound tissues. Curcumin treated wounds were found to heal much faster as indicated by improved rates of epithelialisation, wound contraction and increased tensile strength which were also confirmed by histopathological examinations. Curcumin treatment was shown to decrease the levels of lipid peroxides (LPs), while the levels of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), activities were significantly increased exhibiting the antioxidant properties of curcumin in accelerating wound healing. Better maturation and cross linking of collagen were observed in the curcumin treated rats, by increased stability of acid-soluble collagen, aldehyde content, shrinkage temperature and tensile strength. The results clearly substantiate the beneficial effects of the topical application of curcumin in the acceleration of wound healing and its antioxidant effect. 

Funk JL. Frye JB. Oyarzo JN. Kuscuoglu N. Wilson J. McCaffrey G. Stafford G. Chen G. Lantz RC. Jolad SD. Solyom AM. Kiela PR. Timmermann BN. Efficacy and mechanism of action of turmeric supplements in the treatment of experimental arthritis. Arthritis & Rheumatism. 54(11):3452-64, 2006 OBJECTIVE: Scientific evidence is lacking for the antiarthritic efficacy of turmeric dietary supplements that are being promoted for arthritis treatment. Therefore, we undertook studies to determine the antiarthritic efficacy and mechanism of action of a well-characterized turmeric extract using an animal model of rheumatoid arthritis (RA). METHODS: The composition of commercial turmeric dietary supplements was determined by high-performance liquid chromatography. A curcuminoid-containing turmeric extract similar in composition to these supplements was isolated and administered intraperitoneally to female Lewis rats prior to or after the onset of streptococcal cell wall-induced arthritis. Efficacy in preventing joint swelling and destruction was determined clinically, histologically, and by measurement of bone mineral density. Mechanism of action was elucidated by analysis of turmeric's effect on articular transcription factor activation, microarray analysis of articular gene expression, and verification of the physiologic effects of alterations in gene expression. RESULTS: A turmeric fraction depleted of essential oils profoundly inhibited joint inflammation and periarticular joint destruction in a dose-dependent manner. In vivo treatment prevented local activation of NF-kappaB and the subsequent expression of NF-kappaB-regulated genes mediating joint inflammation and destruction, including chemokines, cyclooxygenase 2, and RANKL. Consistent with these findings, inflammatory cell influx, joint levels of prostaglandin E(2), and periarticular osteoclast formation were inhibited by turmeric extract treatment. CONCLUSION: These translational studies demonstrate in vivo efficacy and identify a mechanism of action for a well-characterized turmeric extract that supports further clinical evaluation of turmeric dietary supplements in the treatment of RA. 

Bala K. Tripathy BC. Sharma D. Neuroprotective and anti-ageing effects of curcumin in aged rat brain regions. Biogerontology. 7(2):81-9, 2006 This study investigated the influence of chronically administered curcumin on normal ageing-related parameters: lipid peroxidation, lipofuscin concentration and intraneuronal lipofuscin accumulation, activities of the enzymes superoxide dismutase (SOD), glutathione peroxidase (GPx), and Na(+), K(+), -adenosine triphosphatase (Na(+), K(+), -ATPase) in different brain regions (cerebral cortex, hippocampus, cerebellum and medulla) of 6- and 24-month-old rats. In normal ageing, lipid peroxidation and lipofuscin concentration were found to increase with ageing, the activities of SOD, GPx and Na(+), K(+), -ATPase, however, decreased with ageing. Chronic curcumin treatment of both 6 and 24 months old rats resulted in significant decreases in lipid peroxide and the lipofuscin contents in brain regions, the activities of SOD, GPx and Na(+), K(+), -ATPase however, showed significant increase in various brain regions. The present study, thus, demonstrated the antioxidative, antilipofusinogenesic and anti-ageing effects of curcumin in the brain. 

Chen C. Johnston TD. Wu G. Ranjan D. Curcumin has potent liver preservation properties in an isolated perfusion model. Transplantation. 82(7):931-7, 2006. BACKGROUND: Curcumin has profound antioxidant and anti-inflammatory properties. This research assessed the effect of curcumin on liver preservation. METHODS: Sprague-Dawley rat livers were flushed with different preservation solutions [Euro-Collins solution (EC), phosphate buffer saline (PBS), University of Wisconsin solution (UW)] with or without curcumin (25-200 microM) and stored at 4 degrees C for 24-48 hours. Livers were then perfused for 120 minutes via the portal vein with oxygenated Krebs-Henseleit bicarbonate buffer solution at a pressure of 18 cm H2O in a perfusion apparatus. The livers in the normal (NL) group were flushed with EC, PBS, or UW, then immediately perfused (zero preservation time). RESULTS: We found that curcumin at 100 microM concentration had the optimal preservation characteristics. Portal flow rates and bile production were significantly higher and liver enzymes (alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase) were significantly lower in the EC+C livers and PBS+C livers than in the EC or PBS with optimum concentration of 100 microM of curcumin. Comparing UW+C vs. UW livers, at 24 hours there was no difference in these parameters; however, at 36 hours and 48 hours, portal flow rates and bile production were significantly higher in UW+C livers. CONCLUSIONS: We found that curcumin has inherent organ preservation quality as it enhanced liver preservation in PBS. In addition, curcumin enhanced the preservation quality of EC and UW solutions, thereby extending the preservation time while maintaining the organ quality. 

Sharma S. Kulkarni SK. Chopra K. Curcumin, the active principle of turmeric (Curcuma longa), ameliorates diabetic nephropathy in rats. Clinical & Experimental Pharmacology & Physiology. 33(10):940-5, 2006 Chronic hyperglycaemia in diabetes leads to the overproduction of free radicals and evidence is increasing that these contribute to the development of diabetic nephropathy. Among the spices, turmeric (Curcuma longa) is used as a flavouring and colouring agent in the indian diet every day and is known to possess anti-oxidant properties. The present study was designed to examine the effect of curcumin, a yellow pigment of turmeric, on renal function and oxidative stress in streptozotocin (STZ)-induced diabetic rats. Diabetes was induced by a single intraperitoneal injection of STZ (65 mg/kg) in rats. Four weeks after STZ injection, rats were divided into four groups, namely control rats, diabetic rats and diabetic rats treated with curcumin (15 and 30 mg/kg, p.o.) for 2 weeks. Renal function was assessed by creatinine, blood urea nitrogen, creatinine and urea clearance and urine albumin excretion. Oxidative stress was measured by renal malonaldehyde, reduced glutathione and the anti-oxidant enzymes superoxide dismutase and catalase. Streptozotocin-injected rats showed significant increases in blood glucose, polyuria and a decrease in bodyweight compared with age-matched control rats. After 6 weeks, diabetic rats also exhibited renal dysfunction, as evidenced by reduced creatinine and urea clearance and proteinuria, along with a marked increase in oxidative stress, as determined by lipid peroxidation and activities of key anti-oxidant enzymes. Chronic treatment with curcumin significantly attenuated both renal dysfunction and oxidative stress in diabetic rats. These results provide confirmatory evidence of oxidative stress in diabetic nephropathy and point towards the possible anti-oxidative mechanism being responsible for the nephroprotective action of curcumin. 

Olszanecki R. Jawie J. Gajda M. Mateuszuk L. Gebska A. Korabiowska M. Chlopicki S. Korbut R. Effect of curcumin on atherosclerosis in apoE/LDLR-double knockout mice. Journal of Physiology & Pharmacology. 56(4):627-35, 2005. It is widely appreciated that inflammation and oxidant stress contribute to atherogenesis. Curcumin, a polyphenolic natural compound has been reported to possess anti-inflammatory and anti-oxidant actions. We hypothesized that curcumin could inhibit the development of atherosclerosis in the apoE/LDLR-double knockout mice fed with Western diet (21% fat, 0.15% cholesterol w/w, without cholic acid). Curcumin (purity>or=98%), premixed with diet, was given for 4 months at a dose of 0.3 mg/ per day/ per mouse. In this model curcumin inhibited atherogenesis, measured both by "en face" method (25,15+/-2,9% vs. 19,2+/-0,6%, p<0,05) and "cross-section" method (565867+/-39764 microm2 vs. 299201+/-20373 microm2, p<0,05). Importantly, curcumin influenced neither the concentrations of cholesterol and triglycerides in blood nor animal body weight. To our knowledge, this is the first report that shows the anti-atherogenic effect of low dose of curcumin in fine model of atherosclerosis: gene-targeted apoE/LDLR-double knockout mice. 

Siddiqui AM. Cui X. Wu R. Dong W. Zhou M. Hu M. Simms HH. Wang P. The anti-inflammatory effect of curcumin in an experimental model of sepsis is mediated by up-regulation of peroxisome proliferator-activated receptor-gamma.[see comment]. Critical Care Medicine. 34(7):1874-82, 2006. OBJECTIVE: Although phytochemical curcumin has been shown to possess anti-inflammatory properties, it remains unknown whether this agent has any beneficial effects in sepsis. The purpose of this study was to demonstrate whether curcumin protects septic animals and, if so, whether activation of peroxisome proliferator-activated receptor (PPAR)-gamma, an anti-inflammatory nuclear receptor, plays any role. DESIGN: Prospective, controlled, and randomized animal study. SETTING: A research institute laboratory. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: A bolus injection of 0.2 micromol of curcumin was given intravenously to male adult rats, followed by continuous infusion of curcumin (0.24 micromol/day) for 3 days via a primed 2-mL mini-pump. The rats were then subjected to sepsis by cecal ligation and puncture (CLP). MEASUREMENTS AND MAIN RESULTS: Serum levels of liver enzymes (alanine aminotransferase and aspartate aminotransferase), lactate, albumin, and tumor necrosis factor (TNF)-alpha were measured at 20 hrs after CLP (i.e., late stage of sepsis). In addition, a 10-day survival curve was conducted following CLP and cecal excision with or without curcumin treatment. Furthermore, macrophages cell line RAW 264.7 cells were treated with curcumin followed by stimulation with endotoxin. TNF-alpha and PPAR-gamma expression were then measured. The results indicate that intravenous administration of curcumin before the onset of sepsis attenuated tissue injury, reduced mortality, and decreased the expression of TNF-alpha in septic animals. Similar results were also found when curcumin was administered after the onset of sepsis. Moreover, the down-regulated PPAR-gamma in the liver at 20 hrs after CLP was significantly improved by curcumin treatment. Concurrent administration of curcumin and GW9662, a specific PPAR-gamma antagonist, completely abolished the beneficial effects of curcumin under such conditions. In cultured RAW 264.7 cells, curcumin inhibited endotoxin-induced increases in TNF-alpha expression and markedly up-regulated PPAR-gamma expression without affecting cell viability. Curcumin also prevented morphologic alterations in macrophages induced by endotoxin. CONCLUSIONS: The protective effect of curcumin makes it or its analogues strong candidates as a novel therapy for sepsis. The beneficial effect of curcumin appears to be mediated by up-regulation of nuclear receptor PPAR-gamma. 

Singh S. Khar A. Biological effects of curcumin and its role in cancer chemoprevention and therapy. [Review] [135 refs] Current Medicinal Chemistry - Anti-Cancer Agents. 6(3):259-70, 2006 Curcumin, a natural component of the rhizome of curcuma longa has emerged as one of the most powerful chemopreventive and anticancer agents. Its biological effects range from antioxidant, anti-inflammatory to inhibition of angiogenesis and is also shown to possess specific antitumoral activity. The molecular mechanism of its varied cellular effects has been studied in some details and it has been shown to have multiple targets and interacting macromolecules within the cell. Curcumin has been shown to possess anti-angiogenic properties and the angioinhibitory effects of curcumin manifest due to down regulation of proangiogenic genes such as VEGF and angiopoitin and a decrease in migration and invasion of endothelial cells. One of the important factors implicated in chemoresistance and induced chemosensitivity is NFkB and curcumin has been shown to down regulate NFkB and inhibit IKB kinase thereby suppressing proliferation and inducing apoptosis. Cell lines that are resistant to certain apoptotic inducers and radiation become susceptible to apoptosis when treated in conjunction with curcumin. Besides this it can also act as a chemopreventive agent in cancers of colon, stomach and skin by suppressing colonic aberrant crypt foci formation and DNA adduct formation. This review focuses on the various aspects of curcumin as a potential drug for cancer treatment and its implications in a variety of biological and cellular processes vis-a-vis its mechanism of action.