Demethoxycurcumin Research Articles

Extraction and Purification of Curcuminoids from Crude Curcumin by a Combination of Crystallization and Chromatography

In this work a method is developed for the extraction and purification of the three curcuminoids, curcumin (CUR), demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC), from commercially available crude curcumin. In a previous publication the extraction of pure curcumin by repeated crystallization has been described. The focus of this paper is on the following chromatographic treatment of the mother liquor from the crystallization to obtain pure DMC and BDMC and to increase the yield of pure CUR. In the chromatographic process, a mixture of chloroform and methanol is used as the mobile phase, and silica gel is used as the stationary phase. Each fraction isolated in the chromatographic process was characterized by high-performance liquid chromatography (HPLC) and mass spectrometry (LC-MS) techniques, and the pure CUR, DMC, and BDMC solid phases were fully characterized by powder Xray diffraction (PXRD), differential scanning calorimetry (DSC), and thermal gravimetric analysis (TGA). Stability studies we...

ABCG2 downregulation in glioma stem cells enhances the therapeutic efficacy of demethoxycurcumin.

We analyzed the role of ABCG2, a drug transporter, in determining the sensitivity of glioma stem cells (GSCs) to demethoxycurcumin (DMC). We first demonstrated that ABCG2 is more highly expressed in GSCs than primary astrocytes. Modulation of ABCG2 levels in GSCs by transfection of ABCG2 shRNA or a lentiviral vector encoding ABCG2 revealed an inverse relation between ABCG2 levels and DMC-induced GSC growth inhibition. Suppressing ABCG2 increased DMC-induced apoptosis and G0/G1 cell cycle arrest in GSCs. It also increased levels reactive oxygen species (ROS) in GSCs treated with DMC, resulting in increased cytochrome C and caspase-3 activity. When GSCs transfected with ABCG2 shRNA or overexpressing ABCG2 were xenografted and the tumor-bearing, immunodeficient mice were treated with DMC, ABCG2 expression suppressed the tumor proliferation rate (T/C %). These findings demonstrate that ABCG2 expression is critical for DMC resistance in GSCs and is a potential therapeutic target for GBM.

Neuroprotective effect of Demethoxycurcumin, a natural derivative of Curcumin on rotenone induced neurotoxicity in SH-SY 5Y Neuroblastoma cells

BackgroundMitochondrial dysfunction and oxidative stress are the main toxic events leading to dopaminergic neuronal death in Parkinson’s disease (PD) and identified as vital objective for therapeutic intercession. This study investigated the neuro-protective effects of the demethoxycurcumin (DMC), a derivative of curcumin against rotenone induced neurotoxicity.MethodsSH-SY5Y neuroblastoma cells are divided into four experimental groups: untreated cells, cells incubated with rotenone (100 nM), cells treated with DMC (50 nM) + rotenone (100 nM) and DMC alone treated. 24 h after treatment with rotenone and 28 h after treatment with DMC, cell viability was assessed using the MTT assay, and levels of ROS and MMP, plus expression of apoptotic protein were analysed.ResultsRotenone induced cell death in SH-SY5Y cells was significantly reduced by DMC pretreatment in a dose-dependent manner, indicating the potent neuroprotective effects of DMC. Rotenone treatment significantly increases the levels of ROS, loss of MMP, release of Cyt-c and expression of pro-apoptotic markers and decreases the expression of anti-apoptotic markers.ConclusionsEven though the results of the present study indicated that the DMC may serve as a potent therapeutic agent particularly for the treatment of neurodegenerative diseases like PD, further pre-clinical and clinical studies are required.

Comparison of antioxidant, anticholinesterase, and antidiabetic activities of three curcuminoids isolated from Curcuma longa L.

Antioxidant, anticholinesterase and antidiabetic activities of three curcuminoids isolated from the Curcuma longa were simultaneously tested and compared in this study. The highest antioxidant power was detected for curcumin with the applied methods. The drug potentials of curcuminoids for Alzheimer’s disease were controlled. Bisdemethoxycurcumin (BDMC) showed substantial inhibitory activity. The activity of demethoxycurcumin (DMC) followed BDMC, whereas curcumin showed very little acetylcholinesterase inhibition activity. Antidiabetic activity of curcuminoids was evaluated by their α-glucosidase inhibitory activities. All curcuminoids show activities with decreasing order as BDMC > curcumin > DMC. The significant activities of BDMC compared to its isomers and examination of chemical structures of isomers might be a starting point in designing new drugs for Alzheimer’s and Diabetes Mellitus.

Isolation, characterization, and quantification of curcuminoids and their comparative effects in cerebral ischemia

ABSTRACTThe study reports a rapid and short analytical technique for separation, characterization, and quantitation along with comparative pharmacological effect of curcuminoids in cerebral ischemia. Flash chromatography, using silica and diol columns along with gradient mobile phase, was utilized to separate three curcuminoids, i.e., curcumin (Cur), demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC) for the first time. The separated peaks were monitored at 200–360 nm, whereas the purity of compounds (96.2–97.6%) was determined through qualitative analysis such as infrared and 1H and 13C-nuclear magnetic resonance spectroscopy, mass spectrometry (MS), and differential scanning calorimetry. Furthermore, chitosan nanoparticles (CS-NPs) for curcuminoids were prepared and characterized through zeta sizer, zeta potential, scanning electron microscopy, and transmission electron microscopy. The developed ultra performance of liquid chromatography-electrospray ionization-quadrupole-time of flight-mass spectrometry/mass spectrometry (UPLC-ESI-Q-TOF-MS/MS) method showed simplified automation and shorter run time for Combi flash over conventional separation techniques. The CS-NPs for all the three curcuminoids and combined-curcuminoids (CCr) (combined and administered together for a synergistic effect), following intranasal administration in middle cerebral artery–occluded rats were evaluated for grip strength, locomotor activity, and histopathological examination where the anti-ischemic activity was observed, in terms of potency, for all three CS-NPs and CCr as CCr>Cur>DMC>>BDMC. Cur-CS-NPs exhibited more potency among Cur, DMC, and BDMC, whereas CCr was the more potent anti-ischemic drug compared to Cur, DMC, and BDMC. For Cur the characteristic activity is proposed because of the presence of methoxy group on the phenyl ring whereas for CCr it is synergistic effect of curcuminoids.

Effects of demethoxycurcumin on the viability and apoptosis of skin cancer cells.

The present study investigated the effects and mechanisms of demethoxycurcumin (DMC) on a human skin squamous cell carcinoma cell line, A431, and a human keratinocyte cell line, HaCaT. A431 and HaCaT cells were cultured in vitro. The effects of DMC treatment on cell viability were analyzed using the Cell Counting kit-8 (CCK-8) assay; cell cycle distribution was analyzed by flow cytometry; apoptosis was assessed by flow cytometry and Hoechst 33258 staining; and the protein expression levels of cytochrome c, B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (BAX), caspase-9 and caspase-3 were evaluated by western blotting. CCK-8 assay results demonstrated that DMC treatment significantly inhibited viability of A431 and HaCaT cells in a dose-dependent manner. Flow cytometric analysis confirmed that DMC treatment induced apoptosis in a dose-dependent manner, and significantly increased the proportion of cells in G2/M phase. Western blot analysis indicated that the protein expression levels of Bcl-2 were decreased, whereas the expression levels of BAX, caspase-9, caspase-3 and cytochrome c were increased following DMC treatment compared with in untreated cells. In conclusion, DMC treatment significantly inhibited viability of A431 and HaCaT cells, and induced cell cycle arrest in G2/M phase. The present study indicated that DMC may induce apoptosis of skin cancer cells through a caspase-dependent pathway.

Application of HPLC and response surface methodology for simultaneous determination of curcumin and desmethoxy curcumin in Curcuma syrup formulation

Liquid Chromatography and Fourier Transform Infrared Spectroscopy for quantitative analysis of individual and total curcuminoid in Curcuma longa extractRatna Wulandari, Sudjadi, Sudibyo Martono, Abdul Rohman

Demethoxycurcumin was superior to temozolomide in the inhibition of the growth of glioblastoma stem cells in vivo.

Temozolomide (TMZ) is widely used in the treatment of glioblastoma multiforme (GBM) as it can effectively inhibit the growth of GBM for some months; however, this cancer type is still incurable. The existence of glioma stem cells (GSCs) is thought to be responsible for the invariable recurrence of GBM after treatment, but GSCs are insensitive to TMZ. Our recent research showed that demethoxycurcumin (DMC), a component of curcumin, was superior to TMZ in its ability to inhibit proliferation and induce apoptosis of GSCs in vitro. In addition, the combined treatment of TMZ + DMC induced more obvious anti-GSC effects. However, in this study, no obvious synergistic anti-GSC effects of TMZ + DMC were found in vivo, while DMC was still superior to TMZ with respect to growth inhibition of GSCs in vivo. Furthermore, immunohistochemistry for proliferating cell nuclear antigen (PCNA) showed that such inhibitory effects were mainly related to the inhibition of cell proliferation rather than to apoptosis. However, a high concentration of DMC (50mg/kg) alone or combined with TMZ could also induce approximately 10% of the cells to undergo apoptosis according to a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Finally, an investigation of the underlying mechanism revealed that the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) 3 signaling pathway played an important role in the anti-GSC effects. When the JAK inhibitor AG490 was applied, the anti-GSC effects of DMC were enhanced. Taken together, the present work reveals that DMC is superior to TMZ with respect to its anti-GSC effects in vivo, which are mediated through the inhibition of the activation of the JAK/STAT3 pathway; however, DMC demonstrated no synergistic effects with TMZ.

The Effectiveness of Natural Diarylheptanoids against Trypanosoma cruzi: Cytotoxicity, Ultrastructural Alterations and Molecular Modeling Studies.

Curcumin (CUR) is the major constituent of the rhizomes of Curcuma longa and has been widely investigated for its chemotherapeutic properties. The well-known activity of CUR against Leishmania sp., Trypanosoma brucei and Plasmodium falciparum led us to investigate its activity against Trypanosoma cruzi. In this work, we tested the cytotoxic effects of CUR and other natural curcuminoids on different forms of T. cruzi, as well as the ultrastructural changes induced in epimastigote form of the parasite. CUR was verified as the curcuminoid with more significant trypanocidal properties (IC50 10.13 μM on epimastigotes). Demethoxycurcumin (DMC) was equipotent to CUR (IC50 11.07 μM), but bisdemethoxycurcumin (BDMC) was less active (IC50 45.33 μM) and cyclocurcumin (CC) was inactive. In the experiment with infected murine peritoneal macrophages all diarylheptanoids were more active than the control in the inhibition of the trypomastigotes release. The electron microscopy images showed ultrastructural changes associated with the cytoskeleton of the parasite, indicating tubulin as possible target of CUR in T. cruzi. The results obtained by flow cytometry analysis of DNA content of the parasites treated with natural curcuminoids suggested a mechanism of action on microtubules related to the paclitaxel`s mode of action. To better understand the mechanism of action highlighted by electron microscopy and flow cytometry experiments we performed the molecular docking of natural curcuminoids on tubulin of T. cruzi in a homology model and the results obtained showed that the observed interactions are in accordance with the IC50 values found, since there CUR and DMC perform similar interactions at the binding site on tubulin while BDMC do not realize a hydrogen bond with Lys163 residue due to the absence of methoxyl groups. These results indicate that trypanocidal properties of CUR may be related to the cytoskeletal alterations.

Enhanced Cognitive Effects of Demethoxycurcumin, a Natural Derivative of Curcumin on Scopolamine-Induced Memory Impairment in Mice

In the present study, we examined the ameliorating effects of demethoxycurcumin (DMC) on memory impairment induced by scopolamine using passive avoidance and Morris water maze tests in mice. Moreover, to determine the neurobiological effects underlying the ameliorating effects of the DMC, choline acetyltransferase (ChAT) immunoreactivity was evaluated in mice exposed to scopolamine. Our results demonstrated that chronic oral administration (28 days) of DMC (10 mg/kg) improved scopolamine-induced learning impairment in the passive avoidance task and memory impairment in the Morris water maze. Moreover, Choline acetyltransferase (ChAT) activity in the DMC-treated group was significantly increased to 33.03% compared with the control group. Our present finding suggests that DMC ameliorates memory impairments induced by scopolamine treatment through reversing the reduction of hippocampal ChAT expression in mice.

Amyloid binding properties of curcumin analogues in Alzheimer’s disease postmortem brain tissue

The presence of β-amyloid (Aβ) containing plaques in the brain is a hallmark of Alzheimer’s disease (AD) and serves as a biomarker for confirmation of diagnosis postmortem. Early diagnosis is of great importance for optimal treatment and for monitoring disease progression in the brain. Highly specific and sensitive biomarkers are thus greatly needed to assess therapeutic efficacy, not only clinically, but also in terms of clearance of histopathological lesions and decelerated neurodegeneration. The objective of the present study was to give more insight into the binding of curcumin analogues, curcuminoids, to Aβ containing plaques in postmortem tissue from AD patients. In vitro autoradiography was utilized to explore affinity and displacement of the curcuminoids; curcumin, demethoxycurcumin (DMC), bisdemethoxycurcumin (BDMC) and dimethoxycurcumin (DIMC). We found that BDMC had the highest affinity for Aβ containing plaques in cortical AD brain tissue in comparison to other curcuminoids. Subsequently, [3H]BDMC showed significantly higher specific binding in cortical AD brain tissue compared to control subjects. These findings suggest that curcumin analogues, especially BDMC, may serve as a potential radioligands for Aβ plaque neuroimaging.

Intratumoral Concentrations and Effects of Orally Administered Micellar Curcuminoids in Glioblastoma Patients

ABSTRACTBackground: The oral bioavailability of curcuminoids is low, but can be enhanced by incorporation into micelles. The major curcuminoid curcumin has antitumor effects on glioblastoma cells in vitro and in vivo. We therefore aimed to determine intratumoral concentrations and the clinical tolerance of highly bioavailable micellar curcuminoids in glioblastoma patients. Methods: Thirteen glioblastoma patients ingested 70 mg micellar curcuminoids [57.4 mg curcumin, 11.2 mg demethoxycurcumin (DMC), and 1.4 mg bis-demethoxycurcumin (BDMC)] three times per day for 4 days (total amount of 689 mg curcumin, 134 mg DMC, and 17 mg BDMC) prior to planned resection of their respective brain tumors. Tumor and blood samples were taken during the surgery and analyzed for total curcuminoid concentrations. 31P magnetic resonance spectroscopic imaging was performed before and after curcuminoid consumption. Results: Ten patients completed the study. The mean intratumoral concentration of curcumin was 56 pg/mg of tissue (range 9–151), and the mean serum concentration was 253 ng/ml (range 129–364). Inorganic phosphate was significantly increased within the tumor (P = 0.034). The mean ratio of phosphocreatine to inorganic phosphate decreased, and the mean intratumoral pH increased (P = 0.08) after curcuminoid intervention. Conclusion: Oral treatment with micellar curcuminoids led to quantifiable concentrations of total curcuminoids in glioblastomas and may alter intratumoral energy metabolism.

Protective Effects of Minor Components of Curcuminoids on Hydrogen Peroxide-Treated Human HaCaT Keratinocytes.

Hydrogen peroxide, one of the reactive oxygen species (ROS), can cause intracellular oxidative stress associated with skin aging and/or photoaging. Curcumin, a polyphenol in turmeric, has been reported to exhibit biological activity. In this study, five naturally occurring curcuminoids [curcumin, demethoxycurcumin (DMC), bisdemethoxycurcumin (BDMC), monohydroxy-DMC, and monohydroxy-BDMC] were used to investigate their protective roles against hydrogen peroxide-induced oxidative stress in the immortalized human keratinocyte cell lines (HaCaT cells). These five curcuminoids at 10 μM, but not at 5 μM, were shown to exhibit cytotoxicities toward HaCaT keratinocytes. Therefore, a 5 μM concentration of the five curcuminoids was selected for further investigations. Cells were pretreated with or without curcuminoids for 2.5 h before 24-h hydrogen peroxide (150 μM) treatments. Pretreatments with the minor components monohydroxy-DMC or monohydroxy-BDMC, but not curcumin, DMC, and BDMC, showed protective activity, elevating cell viability compared to cells with direct hydrogen peroxide treatments. Pretreatments with monohydroxy-DMC and monohydroxy-BDMC showed the best protective effects, reducing apoptotic cell populations and intracellular ROS, as demonstrated by flow cytometry, as well as reducing the changes of the mitochondrial membrane potential compared to cells with direct hydrogen peroxide treatments. The pretreatments with monohydroxy-DMC and monohydroxy-BDMC reduced c-jun and c-fos mRNA expression and p53 tumor suppressor protein expression and increased HO-1 protein expression and glutathione peroxidase (GPx) activity, respectively, compared to cells with direct hydrogen peroxide treatments. The five curcuminoids exhibited similar hydrogen peroxide-scavenging activity in vitro. It was proposed that monohydroxy-DMC and monohydroxy-BDMC could induce antioxidant defense systems better than curcumin, DMC, or BDMC could against hydrogen peroxide-induced oxidative stress and apoptosis of HaCaT keratinocytes and that they may have potential as ingredients in antiaging cosmetics for skin care.

Determination of Curcuminoids and Their Degradation Products in Turmeric (Curcuma longa) Rhizome Herbal Products by Non-aqueous Capillary Electrophoresis with Photodiode Array Detection

Non-aqueous capillary electrophoresis (NACE) method was optimised for simultaneous determination of major bioactive curcuminoids (CCD) viz., curcumin (CC), desmethoxycurcumin (DC) and bisdesmethoxycurcumin (BC), and some of the degradation products viz., vanillin (VN), vanillic acid (VA), ferulic acid (FA) and 4-hydroxybenzaldehyde (HB) in turmeric milk and herbal products. Separation was achieved using non-aqueous background electrolyte (NA-BGE), consisting of a mixture of sodium tetraborate, sodium hydroxide, methanol and 1-propanol in a single run by capillary electrophoresis (CE). In the present study, a novel ultrasonication-assisted phase separation method (US-PS) was used for extracting the analytes in turmeric milk and the extract was directly injected into the capillary without any pretreatment. High-performance thin layer chromatographic (HPTLC) method for the separation of the analytes was also evaluated on pre-coated silica gel plate. Two different high-performance liquid chromatographic (HPLC) conditions were reported in the literature for the separation of above-mentioned target compounds. The proposed method NACE is simple, fast, convenient and economical.

Levels of curcuminoid and essential oil compositions in turmerics (Curcuma longa L.) grown in Korea

Levels of curcuminoids and essential oil compositions from eighteen turmerics (Curcuma longa L.) grown in Jeju were analyzed. 0.5 g of turmeric samples was extracted with 20 mL of methanol for 7 h by shaking and was ultra-sonicated for 30 min. The extracts were analyzed by high-pressure liquid chromatography-diode array detector using Brownlee SPP C18 column (4.6 × 100 mm, 2.7 µm) after filtration. Curcumin (CUR), demethoxycurcumin (DEM), and bisdemethoxycurcumin (BIS) were monitored at the wavelength of 420 nm. Total curcuminoids in turmerics ranged from 53.9 ± 1.0 to 5396.0 ± 101.8 µg/g dry turmeric weight. In decreasing order, curcuminoids found were CUR (4669.7 µg/g) > DEM (565.3 µg/g) > BIS (160.9 µg/g). K145023 variety contains the highest amount of curcuminoids and variety number 10 contains the least amount. Essential oils were extracted with steam distillation method and analyzed with GC–MS. The major components of turmeric oil were α-zingiberene (27.70–36.75 %), aromatic-turmerone (19.54–32.24 %), β-sesquiphellandrene (13.14–18.23 %), α-turmerone (3.72–6.50 %), β-turmerone (2.86–5.60 %), and β-bisabolene (2.50–3.46 %).

Bisdemethoxycurcumin Inhibits Adipogenesis in 3T3-L1 Preadipocytes and Suppresses Obesity in High-Fat Diet-Fed C57BL/6 Mice.

Obesity is caused by excessive accumulation of body fat and is closely related to complex metabolic diseases. Adipogenesis is a key process that is required in adipocyte hypertrophy in the development of obesity. Curcumin (Cur) has been reported to inhibit adipocyte differentiation, but the inhibitory effects of other curcuminoids present in turmeric, such as demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC), on adipogenesis have not been investigated. Here, we investigated the effects of curcuminoids on adipogenesis and the molecular mechanisms of adipocyte differentiation. Among three curcuminoids, BDMC was the most effective suppressor of lipid accumulation in adipocytes. BDMC suppressed adipogenesis in the early stage primarily through attenuation of mitotic clonal expansion (MCE). In BDMC-treated preadipocytes, cell cycle arrest at the G0/G1 phase was found after initiation of adipogenesis and was accompanied by downregulation of cyclin A, cyclin B, p21, and mitogen-activated protein kinase (MAPK) signaling. The protein levels of the adipogenic transcription factors peroxisome proliferator-activated receptor (PPAR)γ and CCAAT/enhancer-binding proteins (C/EBP)α were also reduced by BDMC treatment. Furthermore, 0.5% dietary BDMC (w/w) significantly lowered body weight gain and adipose tissue mass in high-fat diet (HFD)-fed mice. The results of H&E staining showed that dietary BDMC reduced hypertrophy in adipocytes. These results demonstrate for the first time that BDMC suppressed adipogenesis in 3T3-L1 adipocytes and prevented HFD-induced obesity. Our results suggest that BDMC has the potential to prevent obesity.

Demethoxycurcumin Preserves Renovascular Function by Downregulating COX-2 Expression in Hypertension.

Hypertension-associated endothelial dysfunction is largely due to the exaggerated vasoconstrictor generation by cyclooxygenase-2 (COX-2). COX-2 is induced under inflammatory condition. Demethoxycurcumin (DMC) is a major component of Curcuma longa L, which possesses anti-inflammatory action. This study aimed to examine whether DMC protects endothelial function in hypertension by modulating COX-2. Changes in isometric tension showed that in vivo and ex vivo treatment with DMC rescued the attenuated endothelium-dependent relaxations (EDRs) and elevated endothelium-dependent contractions (EDCs) in the renal arteries of SHR, which were also corrected by acute usage of the COX-2 inhibitor celecoxib. The restoration of renovascular activity by DMC was accompanied by the normalization of COX-2 expression. The enhanced COX-2 expression observed in the renal arteries of hypertensive patients was suppressed by incubation of excised arteries with DMC for 12 hrs. In the renal arteries of Wistar-Kyoto rats (WKY), DMC prevented the endothelial dysfunction caused by angiotensin II. The reduction in the generation of nitric oxide (NO) and expression of eNOS phosphorylation (Ser1177) in human umbilical vein endothelial cells caused by angiotensin II (Ang II) were restored by DMC or celecoxib. Our findings suggest that DMC may decrease COX-2 expression and improve endothelial function in hypertension.

Purity Determination of Three Curcuminoids Found in Ten Commercially Available Turmeric Dietary Supplements Using a Reverse Phase HPLC Method

The main active component present in turmeric is curcumin and is subsequently responsible for some of its therapeuticeffects. Turmeric, however, contains two other active molecules, namely demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC). Collectively, these three molecules are known as curcuminoids. Commercially available dietary supplements vary in these components. In this study the curcuminoids were analyzed using a reverse phase ion-pairing HPLC method. UV detection was used to detect the three curcuminoids at a single wavelength of 430 nm. The validation of the method was carried to ICH guidelines. Good repeatability of the method was achieved at concentrations of curcumin, DMC and BDMC equivalent to 136, 148 and 162 μM, respectively, with R.S.D. values of 2.25, 1.93 and 1.64%, respectively. Similarly, good reproducibility and linearity of the method was obtained for curcumin, DMC and BDMC. On completion of the validation, 10 commercially available turmeric dietary supplements were analyzed for their curcuminoid content. Results showed two of the turmeric dietary supplements to contain near pure curcumin. The other supplements tested contained significant amounts of DMC and BDMC. Similarly, there was a significant increase in curcuminoid content between supplements that contained turmeric extract and those that contained raw turmeric. Interestingly, supplements containing turmeric extract contained a significantly higher proportion of curcumin compared to DMC and BDMC, reflected in the ratio of curcumin: DMC: BDMC.

Low-Dose DMC Significantly Enhances the Effect of TMZ on Glioma Cells by Targeting Multiple Signaling Pathways Both In Vivo and In Vitro.

Temozolomide (TMZ) is widely used for treating glioblastoma (GBM), which can effectively inhibit the GBM growth for some months; however, it still cannot prevent the invariable recurrence of GBM. Improving the chemotherapeutic sensitization becomes an urgent agenda. In this study, we found low-dose demethoxycurcumin (DMC) could enhance the sensitivity of TMZ on glioma cells, and high-dose DMC has more significant effects on GBM cells compared with TMZ treatment alone both in vitro and in vivo. And co-administration of DMC and TMZ resulted in a significant increase in GBM apoptosis and a marked inhibition of cell growth pathogenesis of GBM. Mechanistically, DMC and TMZ synergistically increase intracellular level of reactive oxygen species (ROS) production, activate caspase-3-dependent apoptotic pathway, and inactivate of JAK/STAT3 signaling pathway in GBMs, which account for the cell apoptosis and proliferation inhibition. Together, these data implicate that low-dose DMC combined with TMZ represents an effective therapy regimen against GBMs by targeting multiple signaling pathways.

Curcuminoids Modulate the PKCδ/NADPH Oxidase/Reactive Oxygen Species Signaling Pathway and Suppress Matrix Invasion during Monocyte-Macrophage Differentiation.

Monocyte recruitment and invasion play critical roles in the initiation and progression of atherosclerosis. The reduction in monocyte adhesion and infiltration is thought to exert antiatherosclerotic effects. Curcumin, demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC) are the major active components of curcuminoids and exhibit several biological activities, including anti-inflammatory, anticarcinogenic, and hypocholesterolemic activities. The aim of this study was to investigate the antiatherogenic effects and mechanisms of curcuminoids during monocyte to macrophage differentiation. The results showed that curcumin, DMC, and BDMC (20 μM) suppressed matrix invasion from 100.0 ± 5.0% to 24.8 ± 1.4%, 26.6 ± 2.9%, and 33.7 ± 1.7%, respectively, during PMA-induced THP-1 differentiation. We found that curcuminoids significantly reduced PMA-induced CD11b and MMP-9 expression by THP-1 cells. Production of reactive oxygen species (ROS) induced by PMA (126.7 ± 2.1%) was markedly attenuated by curcumin, DMC, and BDMC to 99.5 ± 7.8%, 87.8 ± 8.2%, and 89.8 ± 7.6%, respectively, resulting in the down-regulation of CD11b and MMP-9 expression. We demonstrated that curcuminoids inhibited NADPH oxidase through the down-regulation of NOX2 expression and the reduction of p47phox membrane translocation. Moreover, we found involvement of PKCδ in the PMA-induced NOX2, CD11b, and MMP-9 mRNA expression. Curcumin, DMC, and BDMC decreased the active form of PKCδ protein stimulated by PMA in THP-1 cells. Overall, our results reveal that curcuminoids suppress matrix invasion through the inhibition of the PKCδ/NADPH oxidase/ROS signaling pathway during monocyte-macrophage differentiation.