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1.
Front Nutr ; 10: 1221935, 2023.
Article in English | MEDLINE | ID: mdl-37876615

ABSTRACT

Tetrahydrocurcumin (THC) has been shown to possess anti-angiogenic activities. This study aims to investigate the effects of THC on adipose angiogenesis and expression of angiogenic factors that occurs in 60% high-fat diet-induced obese mice. Male ICR mice were randomly divided into 3 groups: mice fed with a low-fat diet (LFD group); mice fed with very high fat diet (VHFD group), and mice fed with VHFD supplemented with THC (300 mg/kg/day orally) (VHFD+THC treated group) for 6 weeks. Body weight (BW), food intake, fasting blood sugar (FBS), lipid profiles and visceral fats weight (VF) were measured. The microvascular density (MVD), TNF-α, VEGF, MMP-2, and MMP-9 expressions were evaluated. The VHFD group had significantly increased total cholesterol, triglyceride, food intake, BW, VF, VF/BW ratio, adipocyte size and the number of crown-liked structures as compared to LFD group. THC supplementation markedly reduced these parameters and adipocyte hypertrophy and inflammation in white adipose tissues. MVD, TNF-α, VEGF, MMP-2, and MMP-9 were over-expressed in the VHFD group. However, THC supplementation decreased MVD and reduced expression of TNF-α, VEGF, MMP-2, and MMP-9. In conclusion, THC suppressed angiogenesis in adipose tissue by the downregulation of TNF-α, VEGF, MMP-2, and MMP-9. With its effects on lipid metabolism as well as on food consumption, THC could contribute to lower visceral fat and body weight. Overall, our study demonstrated the potential benefit of THC in mitigating obesity and associated metabolic disorders along with elucidated the suppression of adipose angiogenesis as one of its underlying mechanisms.

2.
Asian Pac J Allergy Immunol ; 36(3): 184-190, 2018 Sep.
Article in English | MEDLINE | ID: mdl-29246079

ABSTRACT

BACKGROUND: Targeting inflammatory macrophages and their products is an effective method for controlling inflammation. The pyrazole analog of curcumin (curcumin pyrazole, PYR) has been reported to possess superior anti-inflammatory activity to curcumin (CUR). However, the role of PYR anti-inflammatory activity in macrophages has not yet been elucidated. OBJECTIVE: To examine the anti-inflammatory effects of PYR and CUR in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages and determine the role of mitogen-activated protein kinases (MAPK) in their activity. METHODS: Nitrite level was investigated by the Griess assay. The expression of inducible nitric oxide (NO) synthase, cyclooxygenase-2 (COX-2), and MAPK proteins were analyzed by western blot analysis. The pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and interleukin-6 (IL-6) were measured by enzyme-linked immunosorbent assay. RESULTS: LPS-induced NO secretion in RAW 264.7 macrophages was potently inhibited by PYR (IC50 = 3.7 ± 0.16 µM), at a higher efficacy than CUR (IC50 = 11.0 ± 0.59 µM). Treatment with identical concentrations of PYR and CUR demonstrated that PYR drastically inhibited iNOS and COX-2 expression, whereas CUR only blocked COX-2. PYR reduced the LPS-induced secretion of TNF-α to a greater extent than CUR and both similarly reduced IL-1ß and IL-6 levels. Activation of c-Jun N-terminal kinase (JNK) MAPK was significantly decreased in LPS-activated RAW 264.7 macrophages upon PYR but not CUR treatment. CONCLUSION: PYR exhibited a more potent anti-inflammatory activity than CUR. This activity is partly mediated by PYR-depended inhibition of the JNK signaling pathway and underscores the utility of PYR as an anti-inflammatory agent in macrophages.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Curcumin/analogs & derivatives , Curcumin/pharmacology , MAP Kinase Signaling System/drug effects , Macrophages/drug effects , Animals , Enzyme Activation/drug effects , Inflammation/chemically induced , Inflammation/metabolism , Lipopolysaccharides/pharmacology , Macrophages/metabolism , Mice , Pyrazoles/pharmacology , RAW 264.7 Cells
3.
PLoS One ; 12(12): e0189211, 2017.
Article in English | MEDLINE | ID: mdl-29220411

ABSTRACT

The purpose of the present experiment was to investigate whether hexahydrocurcumin (HHC) attenuates brain damage and improves functional outcome via the activation of antioxidative activities, anti-inflammation, and anti-apoptosis following cerebral ischemia/reperfusion (I/R). In this study, rats with cerebral I/R injury were induced by a transient middle cerebral artery occlusion (MCAO) for 2 h, followed by reperfusion. The male Wistar rats were randomly divided into five groups, including the sham-operated, vehicle-treated, 10 mg/kg HHC-treated, 20 mg/kg HHC-treated, and 40 mg/kg HHC-treated I/R groups. The animals were immediately injected with HHC by an intraperitoneal administration at the onset of cerebral reperfusion. After 24 h of reperfusion, the rats were tested for neurological deficits, and the pathology of the brain was studied by 2,3,5-triphenyltetrazolium chloride (TTC) staining, hematoxylin and eosin (H&E) staining, and terminal deoxynucleotidyltransferase UTP nick end labeling (TUNEL) staining. In addition, the brain tissues were prepared for protein extraction for Western blot analysis, a malondialdehyde (MDA) assay, a nitric oxide (NO) assay, a superoxide dismutase (SOD) assay, a glutathione (GSH) assay, and a glutathione peroxidase (GSH-Px) assay. The data revealed that the neurological deficit scores and the infarct volume were significantly reduced in the HHC-treated rats at all doses compared to the vehicle group. Treatment with HHC significantly attenuated oxidative stress and inflammation, with a decreased level of MDA and NO and a decreased expression of NF-κB (p65) and cyclooxygenase-2 (COX-2) in the I/R rats. HHC also evidently increased Nrf2 (nucleus) protein expression, heme oxygenase-1 (HO-1) protein expression, the antioxidative enzymes, and the superoxide dismutase (SOD) activity. Moreover, the HHC treatment also significantly decreased apoptosis, with a decrease in Bax and cleaved caspase-3 and an increase in Bcl-XL, which was in accordance with a decrease in the apoptotic neuronal cells. Therefore, the HHC treatment protects the brain from cerebral I/R injury by diminishing oxidative stress, inflammation, and apoptosis. The antioxidant properties of HHC may play an important role in improving functional outcomes and may offer significant neuroprotection against I/R damage.


Subject(s)
Antioxidants/pharmacology , Curcumin/analogs & derivatives , Disease Models, Animal , Inflammation/prevention & control , Reperfusion Injury/prevention & control , Stroke/prevention & control , Animals , Curcumin/pharmacology , Rats
4.
Biomed Res Int ; 2016: 1781208, 2016.
Article in English | MEDLINE | ID: mdl-26881213

ABSTRACT

Tetrahydrocurcumin (THC) is a stable metabolite of curcumin (CUR) in physiological systems. The mechanism underlying the anticancer effect of THC is not completely understood. In the present study, we investigated the effects of THC on tumor growth and cellular signaling in cervical cancer xenografts in nude mice. Cervical cancer cells (CaSki) were subcutaneously injected in nude mice to establish tumors. One month after the injection, mice were orally administered vehicle or 100, 300, and 500 mg/kg of THC daily for 30 consecutive days. Relative tumor volume (RTV) was measured every 3-4 days. COX-2, EGFR, p-ERK1&2, p-AKT, and Ki-67 expressions were measured by immunohistochemistry whereas cell apoptosis was detected by TUNELS method. THC treatments at the doses of 100, 300, and 500 mg/kg statistically retarded the RTV by 70.40%, 76.41%, and 77.93%, respectively. The CaSki + vehicle group also showed significantly increased COX-2, EGFR, p-ERK1&2, and p-AKT; however they were attenuated by all treatments with THC. Ki-67 overexpression and a decreasing of cell apoptosis were found in CaSki + vehicle group, but these findings were reversed after the THC treatments.


Subject(s)
Curcumin/analogs & derivatives , Uterine Cervical Neoplasms/drug therapy , Uterine Cervical Neoplasms/genetics , Animals , Apoptosis/drug effects , Cell Line, Tumor , Curcumin/administration & dosage , Cyclooxygenase 2/biosynthesis , ErbB Receptors/biosynthesis , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Ki-67 Antigen/biosynthesis , MAP Kinase Signaling System/drug effects , Mice , Proto-Oncogene Proteins c-akt/biosynthesis , Uterine Cervical Neoplasms/pathology , Xenograft Model Antitumor Assays
5.
Neurotox Res ; 29(1): 80-91, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26358194

ABSTRACT

Amyloid-ß peptides (Aß), a major component of senile plaques, play an important role in the development and progression of Alzheimer's disease. Several lines of evidence have demonstrated that Aß-induced neuronal death is mediated by oxidative stress. The present study aimed to evaluate the potential involvement of di-O-demethylcurcumin, an analog of curcuminoid, on Aß-induced neurotoxicity in culture neuroblastoma cells (SK-N-SH cells) through the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway and the suppression of nuclear factor-κB (NF-κB) signaling pathway and their downstream targets. The results showed that pretreatment with di-O-demethylcurcumin elevated cell viability and decreased the level of reactive oxygen species. Moreover, treatment with di-O-demethylcurcumin promoted the translocation of Nrf2 protein from the cytoplasm to the nucleus, increased the expression of Nrf2-ARE pathway-related downstream proteins including heme oxygenase (HO-1), NAD(P)H:quinone oxidoreductase 1 and glutamate-cysteine ligase catalytic subunit, and increased the activity of superoxide dismutase enzymes. On the other hand, di-O-demethylcurcumin suppressed the degradation of IκBα, translocation of the p65 subunit of NF-κB from cytoplasm to nucleus and thereby, attenuated the expression of inducible nitric oxide synthase protein and nitric oxide production. Taken together, these results suggest that neuroinflammatory effect of di-O-demethylcurcumin might potentially be due to inhibit NF-κB and activate Nrf2 signaling pathways induced by Aß25-35.


Subject(s)
Amyloid beta-Peptides/toxicity , Curcumin/pharmacology , NF-E2-Related Factor 2/metabolism , NF-kappa B/metabolism , Neuroprotective Agents/pharmacology , Peptide Fragments/toxicity , Analysis of Variance , Cell Line, Tumor , Cell Survival/drug effects , Humans , Neuroblastoma/pathology , Nitrites/metabolism , Reactive Oxygen Species/metabolism
6.
J Med Assoc Thai ; 99 Suppl 4: S23-31, 2016 Jul.
Article in English | MEDLINE | ID: mdl-29916670

ABSTRACT

Background: Tetrahydrocurcumin (THC) demonstrated an anti-cancer and anti-angiogenic effects in cervical cancer. Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, have also shown anticancer effect. However, the combinational treatment effect of THC and celecoxib on tumor growth and tumor angiogenesis, especially, using cervical cancer (CaSki)-implanted nude mice has yet not been reported. Objective: To evaluate the combinational treatment effect of THC and celecoxib on tumor progression and tumor angiogenesis in cervical cancer (CaSki)-implanted nude mice. Material and Method: CaSki cells were inoculated in mice to establish subcutaneous tumors. One month after inoculation, vehicle, THC100 mg/kg, Celecoxib100 mg/kg, or THC50 + Celecoxib50 mg/kg was orally administered every day for 28 consecutive days. The tumor volume was measured every 3-4 days. The microvascular density (MVD) was evaluated using the CD31 expression. VEGF, COX-2, and EGFR expression were also detected by immunohistochemistry. Results: THC, celecoxib, and the combination treatments statistically retarded the tumor volume by 70.40, 65.11 and 77.04%, respectively. The MVD was significantly increased in CaSki + vehicle group, but THC, celecoxib, and the combination treatments markedly attenuated the MVD. VEGF, COX-2, and EGFR were up-regulated in CaSki + vehicle group; however, they were attenuated by THC, celecoxib, and the combination treatments. Conclusion: The combinational treatment effect of THC and celecoxib causing inhibition of tumor growth and tumor angiogenesis via down-regulation of VEGF, COX-2 and EGFR expression. However, this combined treatment did not show the synergistic effect on inhibiting the tumor growth and tumor angiogenesis in cervical cancer (CaSki)-implanted nude mice model.


Subject(s)
Celecoxib/administration & dosage , Curcumin/analogs & derivatives , Cyclooxygenase 2 Inhibitors/administration & dosage , Neovascularization, Pathologic/drug therapy , Uterine Cervical Neoplasms/drug therapy , Angiogenesis Inhibitors/administration & dosage , Animals , Apoptosis/drug effects , Celecoxib/pharmacology , Combined Modality Therapy , Curcumin/administration & dosage , Curcumin/pharmacology , Cyclooxygenase 2 Inhibitors/pharmacology , Dose-Response Relationship, Drug , Female , Mice , Mice, Nude , Neovascularization, Pathologic/pathology , Sulfonamides/administration & dosage , Uterine Cervical Neoplasms/pathology
7.
Phytother Res ; 29(11): 1806-13, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26360646

ABSTRACT

This study was designed to examine the vasorelaxant effects of hexahydrocurcumin (HHC), one of the major natural metabolites of curcumin from Curcuma longa, on rat isolated aortic rings, and the underlying mechanisms. Isometric tension of the aortic rings was recorded using organ bath system. HHC (1 nM to 1 mM) relaxed the endothelium-intact aortic rings pre-contracted with PE and KCl in a concentration-dependent manner. Removal of the endothelium did not alter the effect of HHC-induced relaxation. In Ca(2+)-free Krebs solution, HHC significantly inhibited the CaCl2-induced contraction in high K(+) depolarized rings and suppressed the transient contraction induced by PE and caffeine in a concentration-dependent manner. HHC was also observed to relax phobal-12-myristate-13-acetate (PMA), an activator of protein kinase C (PKC), precontracted aortic rings in a concentration-dependent manner with EC50 values equivalent to 93.36 ± 1.03 µM. In addition, pre-incubation with propranolol (a ß-adrenergic receptor blocker) significantly attenuated the HHC-induced vasorelaxation. These results suggest that the vasorelaxant effect of HHC is mediated by the endothelium-independent pathway, probably because of the inhibition of extracellular Ca(2+) influx through voltage-operated Ca(2+) channels and receptor-operated Ca(2+) channels, the inhibition of Ca(2+) mobilization from intracellular stores, as well as inhibition of PKC-mediated Ca(2+)-independent contraction. Moreover, HHC produces vasorelaxant effects probably by stimulating the ß-adrenergic receptor.


Subject(s)
Curcuma , Vasodilation/drug effects , Vasodilator Agents/pharmacology , Animals , Aorta, Thoracic/drug effects , Endothelium, Vascular/drug effects , Male , Rats
8.
Neurotoxicology ; 50: 92-100, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26264395

ABSTRACT

Endoplasmic reticulum (ER) stress is involved in neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Therefore, interventions that attenuate ER stress may contribute to induction in apoptotic cell death. This study aimed to evaluate the potential involvement of O-demethyldemethoxycurcumin, an analog of curcuminoids, on thapsigargin-induced apoptosis in cultured neuroblastoma (SK-N-SH) cells through the ER stress signaling pathway. The results showed that O-demethyldemethoxycurcumin reduced thapsigargin induced cell death in SK-N-SH cells and the release of lactate dehydrogenase (LDH) by decreasing the apoptotic cell death induced by thapsigargin. Consistent with these findings, O-demethyldemethoxycurcumin inhibited the thapsigargin-induced activation of cleavagecaspase-12. Moreover, O-demethyldemethoxycurcumin attenuated the intracellular Ca(2+) level and the expression of the calpain protein. O-demethyldemethoxycurcumin also downregulated the expression of ER stress signaling proteins, including the phosphorylation of PKR-like endoplasmic reticulum kinase (p-PERK), the phosphorylation of inositol-requiring enzyme 1 (p-IRE1), activating transcription factor 6 (ATF6), binding immunoglobulin protein (BiP) and C/EBP homologous protein (CHOP). Our findings suggest that O-demethyldemethoxycurcumin could protect against thapsigargin-induced ER stress in SK-N-SH cells.


Subject(s)
Curcumin/analogs & derivatives , Endoplasmic Reticulum Stress/drug effects , Enzyme Inhibitors/pharmacology , Thapsigargin/pharmacology , Activating Transcription Factor 6/metabolism , Annexin A5/metabolism , Apoptosis/drug effects , Calcium/metabolism , Calpain/metabolism , Cell Line, Tumor , Cell Survival/drug effects , Curcumin/chemistry , Curcumin/pharmacology , Diarylheptanoids , Dose-Response Relationship, Drug , Endoplasmic Reticulum Chaperone BiP , Extracellular Fluid/drug effects , Extracellular Fluid/metabolism , Gene Expression Regulation, Neoplastic/drug effects , Heat-Shock Proteins/metabolism , Humans , L-Lactate Dehydrogenase/metabolism , Neuroblastoma/pathology , Time Factors , Transcription Factor CHOP/metabolism , eIF-2 Kinase/metabolism
9.
Biomed Res Int ; 2015: 391748, 2015.
Article in English | MEDLINE | ID: mdl-25789317

ABSTRACT

Tetrahydrocurcumin (THC), one of the important in vivo metabolites of curcumin, inhibits tumor angiogenesis. Its effects on angiogenesis in cervical cancer- (CaSki-) implanted nude mice and its mechanisms on hypoxia-inducible factor-1α and vascular endothelial growth factor expression were investigated. Female BALB/c nude mice were divided into control (CON) and CaSki-implanted groups (CaSki group). One month after the injection with cervical cancer cells, mice were orally administered vehicle or 100, 300, and 500 mg/kg of THC daily for 30 consecutive days. The microvascular density (MVD) was evaluated using the CD31 expression. VEGF, VEGFR-2, and HIF-1α expression were also detected by immunohistochemistry. The MVD in CaSki + vehicle group was significantly increased compared to the CON + vehicle group. Interestingly, when treated with THC at all doses, the CaSki group showed a significant smaller number of the MVD. The CaSki + vehicle group also showed significantly increased VEGF, VEGFR-2, and HIF-1α expressions, but they were downregulated when mice were treated with THC at all doses. THC demonstrated an inhibitory effect against tumor angiogenesis in CaSki-implanted nude mice model. This effect is likely to be mediated by the downregulation of HIF-1-α, VEGF expression, and its receptor. THC could be developed into a promising agent for cancer therapy in the future.


Subject(s)
Angiogenesis Inhibitors/pharmacology , Curcumin/analogs & derivatives , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Neovascularization, Pathologic/drug therapy , Uterine Cervical Neoplasms/pathology , Vascular Endothelial Growth Factor A/genetics , Animals , Cell Line, Tumor , Curcumin/pharmacology , Down-Regulation/drug effects , Down-Regulation/genetics , Female , Mice , Mice, Inbred BALB C , Mice, Nude , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/pathology , Platelet Endothelial Cell Adhesion Molecule-1/genetics , Uterine Cervical Neoplasms/genetics , Vascular Endothelial Growth Factor Receptor-2/genetics
10.
Neurochem Int ; 80: 110-9, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25451798

ABSTRACT

Alzheimer's disease (AD) is a neurodegenerative and progressive disorder. The hallmark of pathological AD is amyloid plaque which is the accumulation of amyloid ß (Aß) in extracellular neuronal cells and neurofibrillary tangles (NFT) in neuronal cells, which lead to neurotoxicity via reactive oxygen species (ROS) generation related apoptosis. Loss of synapses and synaptic damage are the best correlates of cognitive decline in AD. Neuronal cell death is the main cause of brain dysfunction and cognitive impairment. Aß activates neuronal death via endoplasmic reticulum (ER) stress and mitochondria apoptosis pathway. This study investigated the underlying mechanisms and effects of di-O-demethylcurcumin in preventing Aß-induced apoptosis. Pretreatment with di-O-demethylcurcumin for 2 h, which was followed by Aß25-35 (10 µM) in human neuroblastoma SK-N-SH cells improved cell viability by using MTS assay and decreased neuronal cell apoptosis. Pretreatment with di-O-demethylcurcumin attenuated the number of nuclear condensations and number of apoptotic cells in Aß25-35-induced group in a concentration-dependent manner by using transmission electron microscope (TEM) and flow cytometry, respectively. Di-O-demethylcurcumin also increased the ratio of Bcl-XL/Bax protein, and reduced intracellular ROS level, cytochrome c protein expression, cleaved caspase-9 protein expression, and cleaved caspase-3 protein expression. Additionally, di-O-demethylcurcumin treatment also reduced the expression of ER stress protein markers, including protein kinase RNA like endoplasmic reticulum kinase (PERK) phosphorylation, eukaryotic translation initiation factor 2 alpha (eIF2α) phosphorylation, inositol-requiring enzyme 1 (IRE1) phosphorylation, X-box-binding protein-1 (XBP-1), activating transcription factor (ATF6), C/EBP homologous protein (CHOP), and cleaved caspase-12 protein. CHOP and cleaved caspase-12 protein are the key mediators of apoptosis. Our data suggest that di-O-demethylcurcumin is a candidate protectant against neuronal death through its suppression of the apoptosis mediated by mitochondrial death and ER stress pathway.


Subject(s)
Amyloid beta-Peptides/toxicity , Apoptosis/drug effects , Curcumin/analogs & derivatives , Curcumin/pharmacology , Endoplasmic Reticulum/drug effects , Mitochondria/drug effects , Peptide Fragments/toxicity , Apoptosis/physiology , Cell Line, Tumor , Cell Survival/drug effects , Cell Survival/physiology , Cytoprotection/drug effects , Cytoprotection/physiology , Dose-Response Relationship, Drug , Endoplasmic Reticulum/metabolism , Humans , Mitochondria/metabolism
11.
J Pharm Pharmacol ; 67(1): 87-95, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25176340

ABSTRACT

OBJECTIVES: Phosphodiesterase (PDE)-5 inhibitors are useful as vasodilators for the treatment of pulmonary arterial hypertension. We aimed to study curcumin analogues for PDE5 inhibitory activity and vasorelaxation of rat pulmonary arteries. METHODS: Three natural curcuminoids (1-3) and six synthetic analogues (4-9) were tested for PDE5 and PDE6 inhibitory activities using enzymatic radioassay. Their vasorelaxation was measured using freshly isolated segments of rat pulmonary artery and aorta. KEY FINDINGS: Curcuminoids (1-3) mildly inhibited PDE5 (half maximal inhibitory concentration (IC50 ) = 18 µm): the metamethoxyl of curcumin was important for PDE5 inhibition. But hydroxyl rearrangements, removing both methoxyls and one ketomethylene, yielded the potent 7 and 9 (IC50 = 4 µm) (compared with sildenafil, IC50 = 0.03 µm). Only 1, 3 and 4 were PDE5 selective over PDE6. Triazole-carboxylic addition provided water-solubility while preserving potency. All analogues possessed concentration-dependent vasorelaxant activity on pulmonary arteries (40% of maximal effective concentration (EC40 ) = 29-90 µm, maximum response = 60-90% at 300 µm), while compounds (1-8) were weakly acting in aorta (maximum response <40%). Only demethoxycurcumin (2) and analogues 5, 8, 9 had endothelium-dependent actions. Sildenafil was highly potent (EC40 = 0.04 µm) and highly endothelium dependent in pulmonary artery but weak on intact aorta (EC40 = 1.8 µm). Activity profiles suggest actions through additional cell pathways for promoting vasorelaxation. CONCLUSIONS: Curcumin analogues are potential leads for developing efficacious and selective PDE5 inhibitors and other pathologies of pulmonary hypertension.


Subject(s)
Curcumin/analogs & derivatives , Phosphodiesterase 5 Inhibitors/pharmacology , Pulmonary Artery/drug effects , Vasodilator Agents/pharmacology , Animals , Dose-Response Relationship, Drug , Endothelium, Vascular/metabolism , Phosphodiesterase 5 Inhibitors/chemistry , Rats , Structure-Activity Relationship , Vasodilation/drug effects
12.
Mol Pharmacol ; 87(3): 451-64, 2015.
Article in English | MEDLINE | ID: mdl-25527638

ABSTRACT

We have previously reported that curcumin analogs with a C7 linker bearing a C4-C5 olefinic linker with a single keto group at C3 (enone linker) display midnanomolar activity against the bloodstream form of Trypanosoma brucei. However, no clear indication of their mechanism of action or superior antiparasitic activity relative to analogs with the original di-ketone curcumin linker was apparent. To further investigate their utility as antiparasitic agents, we compare the cellular effects of curcumin and the enone linker lead compound 1,7-bis(4-hydroxy-3-methoxyphenyl)hept-4-en-3-one (AS-HK014) here. An AS-HK014-resitant line, trypanosomes adapted to AS-HK014 (TA014), was developed by in vitro exposure to the drug. Metabolomic analysis revealed that exposure to AS-HK014, but not curcumin, rapidly depleted glutathione and trypanothione in the wild-type line, although almost all other metabolites were unchanged relative to control. In TA014 cells, thiol levels were similar to untreated wild-type cells and not significantly depleted by AS-HK014. Adducts of AS-HK014 with both glutathione and trypanothione were identified in AS-HK014-exposed wild-type cells and reproduced by chemical reaction. However, adduct accumulation in sensitive cells was much lower than in resistant cells. TA014 cells did not exhibit any changes in sequence or protein levels of glutathione synthetase and γ-glutamylcysteine synthetase relative to wild-type cells. We conclude that monoenone curcuminoids have a different mode of action than curcumin, rapidly and specifically depleting thiol levels in trypanosomes by forming an adduct. This adduct may ultimately be responsible for the highly potent trypanocidal and antiparasitic activity of the monoenone curcuminoids.


Subject(s)
Curcumin/analogs & derivatives , Curcumin/metabolism , Glutathione/analogs & derivatives , Spermidine/analogs & derivatives , Trypanocidal Agents/metabolism , Trypanosoma brucei brucei/drug effects , Trypanosoma brucei brucei/metabolism , Cell Survival/drug effects , Cell Survival/physiology , Curcumin/pharmacology , Glutathione/metabolism , Humans , Spermidine/metabolism , Trypanocidal Agents/pharmacology
13.
Bioorg Med Chem Lett ; 24(22): 5242-6, 2014 Nov 15.
Article in English | MEDLINE | ID: mdl-25305686

ABSTRACT

The length of telomeres controls the life span of eukaryotic cells. Telomerase maintains the length of telomeres in certain eukaryotic cells, such as germline cells and stem cells, and allows these cells to evade replicative senescence. Here, we report for the first time a number of curcuminoid derivatives that enhance telomerase activity in an in vitro TRAP assay. A preliminary analysis of structure-activity relationships found that the minimal requirement for this enhanced telomerase activity is a curcuminoid core with at least one n-pentylpyridine side chain, while curcuminoids with two such side chains exhibit even greater activity. The finding here might lead to a new class of telomerase activators that act directly or indirectly on telomerase, rather than through the reactivation of the telomerase reverse transcriptase (TERT) gene associated with other telomerase activators found in the literature.


Subject(s)
Curcumin/chemistry , Curcumin/pharmacology , Telomerase/metabolism , Astragalus propinquus/enzymology , Curcumin/metabolism , Enzyme Activation/drug effects , Nucleic Acid Amplification Techniques , Oligonucleotides/chemistry , Oligonucleotides/metabolism , Structure-Activity Relationship , Telomerase/chemistry
14.
Bioorg Med Chem Lett ; 24(13): 2839-44, 2014 Jul 01.
Article in English | MEDLINE | ID: mdl-24857542

ABSTRACT

A general method for the synthesis of substituted (1E,4E,6E)-1,7-diphenylhepta-1,4,6-trien-3-ones, based on the aldol condensations of substituted 4-phenylbut-3-en-2-ones and substituted 3-phenylacrylaldehydes, was achieved. The natural trienones 4 and 5 have been synthesized by this method, together with the trienone analogues 9-20. These analogues were evaluated for their cytotoxic activity against human oral cancer KB cell line. The structure-activity relationship study has indicated that the analogues with the 1,4,6-trien-3-one function are more potent than the curcuminoid-type function. Analogues with meta-oxygen function on the aromatic rings are more potent than those in the ortho- and para-positions. Free phenolic hydroxy group is more potent than the corresponding methyl ether analogues. Among the potent trienones, compounds 11, 18 and 20 were more active than the anticancer drug ellipticine. All compounds were also evaluated against the non-cancerous Vero cells and it was found that compounds 11, 12 and 17 were much less toxic than curcumin (1); they showed high selectivity indices of 35.46, 33.46 and 31.68, respectively. These analogues are regarded as the potent trienones for anti-oral cancer study.


Subject(s)
Antineoplastic Agents/pharmacology , Curcumin/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Chlorocebus aethiops , Curcumin/analogs & derivatives , Curcumin/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , KB Cells , Molecular Structure , Structure-Activity Relationship , Vero Cells
15.
Asian Pac J Cancer Prev ; 15(4): 1807-10, 2014.
Article in English | MEDLINE | ID: mdl-24641413

ABSTRACT

BACKGROUND: It is known that inducible nitric oxide synthase (iNOS)/nitric oxide (NO) plays an integral role during intestinal inflammation, an important factor for colon cancer development. Natural compounds from Curcuma longa L. (Zingiberaceae) have long been a potential source of bioactive materials with various beneficial biological functions. Among them, a major active curcuminoid, demethoxycurcumin (DMC) has been shown to possess anti-inflammatory properties in lipopolysaccharide (LPS)-activated macrophages or microglia cells. However, the role of DMC on iNOS expression and NO production in an in vitro inflamed human intestinal mucosa model has not yet been elucidated. This study concerned inhibitory effects on iNOS expression and NO production of DMC in inflamed human intestinal Caco-2 cells. An in vitro model was generated and inhibitory effects on NO production of DMC at 65 µM for 24-96 h were assessed by monitoring nitrite levels. Expression of iNOS mRNA and protein was also investigated. DMC significantly decreased NO secretion by 35-41% in our inflamed cell model. Decrease in NO production by DMC was concomitant with down-regulation of iNOS at mRNA and protein levels compared to proinflammatory cytokine cocktail and LPS-treated controls. Mechanism of action of DMC may be partly due to its potent inhibition of the iNOS pathway. Our findings suggest that DMC may have potential as a therapeutic agent against inflammation-related diseases, especially in the gut.


Subject(s)
Curcumin/analogs & derivatives , Inflammation/drug therapy , Intestinal Mucosa/pathology , Nitric Oxide Synthase Type II/antagonists & inhibitors , Anti-Inflammatory Agents/pharmacology , Caco-2 Cells , Cell Line, Tumor , Curcuma/metabolism , Curcumin/pharmacology , Diarylheptanoids , Humans , Inflammation/immunology , Intestinal Mucosa/immunology , Lipopolysaccharides , Nitric Oxide/biosynthesis , Nitric Oxide Synthase Type II/genetics , Plant Preparations/pharmacology , RNA, Messenger/biosynthesis
16.
Ann Hematol ; 92(3): 379-86, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23079892

ABSTRACT

Thalassemia is an inherited disorder of hemoglobin molecules that is characterized by an imbalance of α- and ß-globin chain synthesis. Accumulation of unbound α-globin chains in erythroid cells is the major cause of pathology in ß-thalassemia. Stimulation of γ-globin production can ameliorate disease severity as it combines with the α-globin to form fetal hemoglobin. We examined γ-globin-inducing effect of curcuminoids extracted from Curcuma longa L. and their metabolite reduced forms in erythroid leukemia K562 and human primary erythroid precursor cells. The results showed that curcuminoid compounds, especially bisdemethoxycurcumin are potential γ-globin enhancers. We also demonstrated that its reduced analog, hexahydrobisdemethoxycurcumin (HHBDMC), is most effective and leads to induction of γ-globin mRNA and HbF in primary erythroid precursor cells for 3.6 ± 0.4- and 2.0 ± 0.4-folds, respectively. This suggested that HHBDMC is the potential agent to be developed as a new therapeutic drug for ß-thalassemia and related ß-hemoglobinopathies.


Subject(s)
Curcumin/analogs & derivatives , Curcumin/pharmacology , Fetal Hemoglobin/biosynthesis , Cell Differentiation/drug effects , Cell Differentiation/physiology , Cells, Cultured , Curcumin/chemistry , Diarylheptanoids , Erythroid Cells/drug effects , Erythroid Cells/metabolism , Fetal Hemoglobin/agonists , Humans , K562 Cells , gamma-Globins/agonists , gamma-Globins/biosynthesis
17.
J Nat Med ; 66(2): 400-5, 2012 Apr.
Article in English | MEDLINE | ID: mdl-21993909

ABSTRACT

The chemically modified analogs, the demethylated analogs 4-6, the tetrahydro analogs 7-9 and the hexahydro analogs 10-12, of curcumin (1), demethoxycurcumin (2) and bisdemethoxycurcumin (3) were evaluated for their inhibitory activity on lipopolysaccharide activated nitric oxide (NO) production in HAPI microglial cells. Di-O-demethylcurcumin (5) and O-demethyldemethoxycurcumin (6) are the two most potent compounds that inhibited NO production. The analogs 5 and 6 were twofold and almost twofold more active than the parent curcuminoids 1 and 2, respectively. Moreover, the mRNA expression level of inducible NO synthase was inhibited by these two compounds. The strong neuroprotective activity of analogs 5 and 6 provide potential alternative compounds to be developed as therapeutics for neurological disorders associated with activated microglia.


Subject(s)
Lipopolysaccharides/pharmacology , Microglia/drug effects , Microglia/metabolism , Nitric Oxide/biosynthesis , Animals , Cell Line , Curcumin/analogs & derivatives , Curcumin/chemistry , Curcumin/pharmacology , Diarylheptanoids , Nitric Oxide Synthase Type II/metabolism , Rats
18.
Eur J Med Chem ; 45(10): 4446-57, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20691508

ABSTRACT

Curcumin (1), demethoxycurcumin (2) and bisdemethoxycurcumin (3), the curcuminoid constituents of the medicinal plant Curcuma longa L., have been structurally modified to 55 analogs and antimycobacterial activity against Mycobacterium tuberculosis has been evaluated. Among the highly active curcuminoids, the isoxazole analogs are the most active group, with mono-O-methylcurcumin isoxazole (53) being the most active compound (MIC 0.09 microg/mL). It was 1131-fold more active than curcumin (1), the parent compound, and was approximately 18 and 2-fold more active than the standard drugs kanamycin and isoniazid, respectively. Compound 53 also exhibited high activity against the multidrug-resistant M. tuberculosis clinical isolates, with the MICs of 0.195-3.125 microg/mL. The structural requirements for a curcuminoid analog to exhibit antimycobacterial activity are the presence of an isoxazole ring and two unsaturated bonds on the heptyl chain. The presence of a suitable para-alkoxyl group on the aromatic ring which is attached in close proximity to the nitrogen function of the isoxazole ring and a free para-hydroxyl group on another aromatic ring enhances the biological activity.


Subject(s)
Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Curcuma/chemistry , Curcumin/chemistry , Curcumin/pharmacology , Isoxazoles/chemistry , Isoxazoles/pharmacology , Mycobacterium tuberculosis/drug effects , Antitubercular Agents/chemical synthesis , Curcumin/chemical synthesis , Humans , Isoxazoles/chemical synthesis , Microbial Sensitivity Tests , Tuberculosis/drug therapy
19.
Eur J Med Chem ; 45(3): 941-56, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20004045

ABSTRACT

The natural curcuminoids curcumin (1), demethoxycurcumin (2) and bisdemethoxycurcumin (3) have been chemically modified to give 46 analogs and 8 pairs of 1:1 mixture of curcuminoid analogs and these parent curcuminoids and their analogs were assessed against protozoa of the Trypanosoma and Leishmania species. The parent curcuminoids exhibited low antitrypanosomal activity (EC(50) for our drug-sensitive Trypanosoma brucei brucei line (WT) of compounds 1, 2 and 3 are 2.5, 4.6 and 7.7 microM, respectively). Among 43 curcuminoid analogs and 8 pairs of 1:1 mixture of curcuminoid analogs tested, 8 pure analogs and 5 isomeric mixtures of analogs exhibited high antitrypanosomal activity in submicromolar order of magnitude. Among these highly active analogs, 1,7-bis(4-hydroxy-3-methoxyphenyl)hept-4-en-3-one (40) was the most active compound, with an EC(50) value of 0.053+/-0.007 microM; it was about 2-fold more active than the standard veterinary drug diminazene aceturate (EC(50) 0.12+/-0.01 microM). Using a previously characterized diminazene-resistant T. b. brucei (TbAT1-KO) and a derived multi-drug resistant line (B48), no cross-resistance of curcuminoids was observed to the diamidine and melaminophenyl arsenical drugs that are the current treatments. Indeed, curcuminoids carrying a conjugated keto (enone) motif, including 40, were significantly more active against T. b. brucei B48. This enone motif was found to contribute to particularly high trypanocidal activity against all Trypanosoma species and strains tested. The parent curcuminoids showed low antileishmanial activity (EC(50) values of compounds 1 and 2 for Leishmania mexicana amastigotes are 16+/-3 and 37+/-6 microM, respectively) while the control drug, pentamidine, displayed an EC(50) of 16+/-2 microM. Among the active curcuminoid analogs, four compounds exhibited EC(50) values of less than 5 microM against Leishmania major promastigotes and four against L. mexicana amastigotes. No significant difference in sensitivity to curcuminoids between L. major promastigotes and L. mexicana amastigotes was observed. The parent curcuminoids and most of their analogs were also tested for their toxicity against human embryonic kidney (HEK) cells. All the curcuminoids exhibited lower toxicity to HEK cells than to T. b. brucei bloodstream forms and only one of the tested compounds showed significantly higher activity against HEK cells than curcumin (1). The selectivity index for T. b. brucei ranged from 3-fold to 1500-fold. The selectivity index for the most active analog, the enone 40, was 453-fold.


Subject(s)
Curcumin/analogs & derivatives , Leishmania/drug effects , Trypanosoma/drug effects , Antimalarials/chemical synthesis , Antimalarials/chemistry , Antimalarials/pharmacology , Cell Line , Curcumin/chemical synthesis , Curcumin/chemistry , Curcumin/pharmacology , Diarylheptanoids , Humans , Inhibitory Concentration 50 , Molecular Structure , Trypanocidal Agents/chemical synthesis , Trypanocidal Agents/chemistry , Trypanocidal Agents/pharmacology
20.
World J Gastroenterol ; 14(13): 2003-9, 2008 Apr 07.
Article in English | MEDLINE | ID: mdl-18395899

ABSTRACT

AIM: To determine the effect of tetrahydrocurcumin (THC) on tumor angiogenesis compared with curcumin (CUR) by using both in vitro and in vivo models of human hepatocellular carcinoma cell line (HepG2). METHODS: The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay was used for testing the anti-proliferating activities of CUR and THC. In male BALB/c nude mice, 2 multiply 10(6) human HepG2 cells were inoculated onto a dorsal skin-fold chamber. One day after HepG2 inoculation, the experimental groups were fed oral daily with CUR or THC (300 mg/kg or 3000 mg/kg). On d 7, 14 and 21, the tumor microvasculature was observed using fluorescence videomicroscopy and capillary vascularity (CV) was measured. RESULTS: Pathological angiogenic features including microvascular dilatation, tortuosity, and hyper-permeability were observed. CUR and THC could attenuate these pathologic features. In HepG2-groups, the CV were significantly increased on d 7 (52.43%), 14 (69.17%), and 21 (74.08%), as compared to controls (33.04%, P < 0.001). Treatment with CUR and THC resulted in significant decrease in the CV (P < 0.005 and P < 0.001, respectively). In particular, the anti-angiogenic effects of CUR and THC were dose-dependent manner. However, the beneficial effect of THC treatment than CUR was observed, in particular, from the 21 d CV (44.96% and 52.86%, P < 0.05). CONCLUSION: THC expressed its anti-angiogenesis without any cytotoxic activities to HepG2 cells even at the highest doses. It is suggested that anti-angiogenic properties of CUR and THC represent a common potential mechanism for their anti-cancer actions.


Subject(s)
Angiogenesis Inhibitors/pharmacology , Antineoplastic Agents/pharmacology , Carcinoma, Hepatocellular/drug therapy , Curcumin/analogs & derivatives , Curcumin/pharmacology , Liver Neoplasms/drug therapy , Animals , Cell Line, Tumor , Dose-Response Relationship, Drug , Humans , Inhibitory Concentration 50 , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasm Transplantation
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