Displaying publications 1 - 20 of 151 in total

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  1. Curcumin Modulates Hepatocellular Carcinoma by Reducing UNC119 Expression
    Zhao Z, Malhotra A, Seng WY
    J Environ Pathol Toxicol Oncol, 2019;38(3):195-203.
    PMID: 31679307 DOI: 10.1615/JEnvironPatholToxicolOncol.2019029549
    UNCI 19 expression has been reported to be significantly higher in hepatic cancer cells (HCC). However, the clinical significance of modulating UNC119 expression in HCC is not well understood. The study described here aimed to explore the potential of curcumin in modulation of UNC119 expression in HCC by assessment with quantitative real-time PCR, western blot, and immune-histochemical analyses in HCC cell lines and tissues. The biological functions of UNC119 in the proliferation, growth, and cycle of tumor cells were analyzed both in vitro and in vivo. UNC119 expression was upregulated in HCC cell lines and tissues as indicated by comparison with normal liver cells and tissues. Cellular function assays showed that higher levels of UNC119 not only promoted proliferation but also enhanced HCC cell migration and invasion. UNC119 promoted progression of the cell cycle and significantly promoted HCC cell growth through the Wnt/β-catenin signal pathway, and enhanced tumor migration and invasion by the TGF-β/EMT pathway. Curcumin efficiently inhibited HCC cell proliferation by blocking the Wnt/β-catenin pathway and inhabited migration and invasion by blocking the TGF-p/EMT signal pathway. Curcumin not only was beneficial for tumor remission but also contributed to the long-term survival of HCC-bearing mice. UNC119 was significantly upregulated and promoted cell growth in hepatic cancer cells and tissues by the Wnt/β-catenin signal pathway and migration by TGF-β/EMT signal pathway. Curcumin treatment inhibited cell proliferation, growth, migration, and invasion by inhibition of those pathways.
    Matched MeSH terms: Curcumin/pharmacology*
  2. Cetyltrimethylammonium bromide-nanocrystalline cellulose (CTAB-NCC) based microemulsions for enhancement of topical delivery of curcumin
    Zainuddin N, Ahmad I, Zulfakar MH, Kargarzadeh H, Ramli S
    Carbohydr Polym, 2021 Feb 15;254:117401.
    PMID: 33357890 DOI: 10.1016/j.carbpol.2020.117401
    Low bioavailability and poor water solubility have limited the utilization of curcumin in conventional dosing methods. As an alternative, microemulsions as drug carrier can improve curcumin delivery. A cetyltrimethylammonium bromide-nanocrystalline cellulose (CTAB-NCC)-based microemulsion was developed and its potential use as a topical delivery method for curcumin was investigated. The effect of microemulsion's particle size and its microstructure as well as the presence of the CTAB-NCC nanoparticle on the topical delivery of curcumin was studied. In vitro permeation studies showed higher penetration rate of curcumin from the oil-in-water type-microemulsions. The skin permeation profile of curcumin followed Higuchi release kinetics. Furthermore, use of the (CTAB-NCC)-based microemulsion enhanced curcumin accumulation in the skin and these system showed non cytotoxicity effect on L929 cell line. These results showed the potential of (CTAB-NCC)-based microemulsions as controlled-release topical systems for the delivery of curcumin and potentially other lipophilic drugs.
    Matched MeSH terms: Curcumin
  3. Hydrophobic kenaf nanocrystalline cellulose for the binding of curcumin
    Zainuddin N, Ahmad I, Kargarzadeh H, Ramli S
    Carbohydr Polym, 2017 May 01;163:261-269.
    PMID: 28267505 DOI: 10.1016/j.carbpol.2017.01.036
    Nanocrystalline cellulose (NCC) extracted from lignocellulosic materials has been actively investigated as a drug delivery excipients due to its large surface area, high aspect ratio, and biodegradability. In this study, the hydrophobically modified NCC was used as a drug delivery excipient of hydrophobic drug curcumin. The modification of NCC with a cationic surfactant, cetyl trimethylammonium bromide (CTAB) was used to modulate the loading of hydrophobic drugs that would not normally bind to NCC. The FTIR, Elemental analysis, XRD, TGA, and TEM were used to confirm the modification of NCC with CTAB. The effect of concentration of CTAB on the binding efficiency of hydrophobic drug curcumin was investigated. The amounts of curcumin bound onto the CTAB-NCC nanoparticles were analyzed by UV-vis Spectrophotometric. The result showed that the modified CTAB-NCC bound a significant amount of curcumin, in a range from 80% to 96% curcumin added. Nevertheless, at higher concentration of CTAB resulted in lower binding efficiency.
    Matched MeSH terms: Curcumin/chemistry*
  4. Curcumin as an anti-arthritic agent in collagen-induced arthritic Sprague-Dawley rats
    Zahidah A, Faizah O, Nur Aqilah K, Taty Anna K
    Sains Malaysiana, 2012;41:591-595.
    Curcuma longa or turmeric has long been used in traditional medicine by the local population in Malaysia as an antiinflammatory agent. It has been proven to contain natural antiarthritic compound called curcumin. Joints abnormality and destruction have been implicated in the pathogenesis of rheumatoid arthritis (RA) due to inflammatory reactions. In this study, collagen-induced arthritis (CIA) model was utilized to study the effects of curcumin on joint inflammation in Sprague-Dawley rats. Body weight measurement, arthritis score assessment and radiology score assessment were carried out at specific intervals throughout this study. The results showed that the mean arthritis and radiology scores for animal groups designated as CIA CurcuminC and CIA CurcuminT were significantly lower compared with the negative control (CIA OV) group respectively. The mean arthritis scores for CIA CurcuminC group is significantly lower compared with CIA CurcuminT group but there is no significant difference in the mean radiology scores between the CIA CurcuminC and CIA CurcuminT groups. In conclusion, the oral supplementation of curcumin at the dose of 110 mg/mL/kg/day has a potential to delay and improve joint abnormality and injury in Sprague-Dawley rats with CIA.
    Matched MeSH terms: Curcumin
  5. Fulltext Immunomodulatory Effects and Mechanisms of Curcuma Species and Their Bioactive Compounds: A Review
    Yuandani, Jantan I, Rohani AS, Sumantri IB
    Front Pharmacol, 2021;12:643119.
    PMID: 33995049 DOI: 10.3389/fphar.2021.643119
    Curcuma species (family: Zingiberaceae) are widely utilized in traditional medicine to treat diverse immune-related disorders. There have been many scientific studies on their immunomodulating effects to support their ethnopharmacological uses. In this review, the efficacy of six Curcuma species, namely, C. longa L., C. zanthorrhiza Roxb., C. mangga Valeton & Zijp, C. aeruginosa Roxb. C. zedoaria (Christm.) Roscoe, and C. amada Roxb., and their bioactive metabolites to modulate the immune system, their mechanistic effects, and their potential to be developed into effective and safe immunomodulatory agents are highlighted. Literature search has been carried out extensively to gather significant findings on immunomodulating activities of these plants. The immunomodulatory effects of Curcuma species were critically analyzed, and future research strategies and appropriate perspectives on the plants as source of new immunomodulators were discussed. Most of the pharmacological investigations to evaluate their immunomodulatory effects were in vivo and in vitro experiments on the crude extracts of the plants. The extracts were not chemically characterized or standardized. Of all the Curcuma species investigated, the immunomodulatory effects of C. longa were the most studied. Most of the bioactive metabolites responsible for the immunomodulating activities were not determined, and mechanistic studies to understand the underlying mechanisms were scanty. There are limited clinical studies to confirm their efficacy in human. Of all the bioactive metabolites, only curcumin is undergoing extensive clinical trials based on its anti-inflammatory properties and main use as an adjuvant for the treatment of cancer. More in-depth studies to understand the underlying mechanisms using experimental in vivo animal models of immune-related disorders and elaborate bioavailability, preclinical pharmacokinetics, and toxicity studies are required before clinical trials can be pursued for development into immunomodulatory agents.
    Matched MeSH terms: Curcumin
  6. Docking Studies of Curcumin and Analogues with Various Phosphodiesterase 4 Subtypes
    Yi YX, Gaurav A, Akowuah GA
    Curr Drug Discov Technol, 2020;17(2):248-260.
    PMID: 30332967 DOI: 10.2174/1570163815666181017091655
    INTRODUCTION: The primary aim of this study is to understand the binding of curcumin and its analogues to different PDE4 subtypes and identify the role of PDE4 subtype inhibition in the anti-inflammatory property of curcumin. Docking analysis has been used to acquire the above mentioned structural information and this has been further used for designing of curcumin derivatives with better anti-inflammatory activity.

    MATERIALS AND METHODS: Curcumin and its analogues were subjected to docking using PDE4A, PDE4B, PDE4C and PDE4D as the targets. A data set comprising 18 analogues of curcumin, was used as ligands for docking of PDE4 subtypes. Curcumin was used as the standard for comparison. Docking was performed using AutoDock Vina 1.1.2 software integrated in LigandScout 4.1. During this process water molecules were removed from proteins, charges were added and receptor structures were minimised by applying suitable force fields. The docking scores were compared, and the selectivity of compounds for PDE4B over PDE4D was calculated as well.

    RESULTS: All curcumin analogues used in the study showed good binding affinity with all PDE4 subtypes, with evident selectivity towards PDE4B subtype. Analogue A11 provides the highest binding affinity among all ligands.

    CONCLUSION: Curcumin and analogues have moderate to strong affinity towards all PDE4 subtypes and have evident selectivity towards PDE4B. The Oxygen atom of the methoxy group plays a key role in PDE4B binding and any alterations could interfere with the binding. Tetrahydropyran side chain and heterocyclic rings are also suggested to be helpful in PDE4B binding.

    Matched MeSH terms: Curcumin/analogs & derivatives; Curcumin/pharmacology*; Curcumin/chemistry
  7. Fulltext Low dose triterpene-quinone fraction from Ardisia crispa root precludes chemical-induced mouse skin tumor promotion
    Yeong LT, Abdul Hamid R, Saiful Yazan L, Khaza'ai H, Mohtarrudin N
    BMC Complement Altern Med, 2015;15(1):431.
    PMID: 26638207 DOI: 10.1186/s12906-015-0954-3
    Drastic increment of skin cancer incidence has driven natural product-based chemoprevention as a promising approach in anticancer drug development. Apart from its traditional usages against various ailments, Ardisia crispa (Family: Myrsinaceae) specifically its triterpene-quinone fraction (TQF) which was isolated from the root hexane extract (ACRH) was recently reported to exert antitumor promoting activity in vitro. This study aimed at determining chemopreventive effect of TQF against chemically-induced mouse skin tumorigenesis as well as elucidating its possible pathway(s).
    Matched MeSH terms: Curcumin/administration & dosage
  8. Synergistic action of compounds isolated from the hexane extract of Ardisia crispa root against tumour-promoting effect, in vitro
    Yeong LT, Abdul Hamid R, Saiful Yazan L, Khaza'ai H, Awang Hamsin DE
    Nat Prod Res, 2014;28(22):2026-30.
    PMID: 24836304 DOI: 10.1080/14786419.2014.917415
    An isomeric mixture of α,β-amyrin (triterpene) and 2-methoxy-6-undecyl-1,4-benzoquinone (quinone) isolated from the Ardisia crispa root hexane (ACRH) extract was reported to possess anti-inflammatory properties in vivo. Considering the close association between inflammation and cancer, on top of the lack of antitumour study on those compounds, this study aimed to determine the potential of both compounds against tumour promotion in vitro, either as single agent or in combination. Triterpene and quinone compounds, as well as triterpene-quinone fraction (TQF) and ACRH were subjected to inhibition of Epstein-Barr virus-early antigen (EBV-EA) activation assay for that purpose. Compared with curcumin (positive control), inhibition against EBV-EA activation occurred in the order: ACRH>TQF ≥ curcumin>α,β-amyrin ≥ 2-methoxy-6-undecyl-1,4-benzoquinone. These findings reported, for the first time, the antitumor-promoting effect of α,β-amyrin and 2-methoxy-6-undecyl-1,4-benzoquinone from the roots of A. crispa, which was enhanced when both compounds act in synergy.
    Matched MeSH terms: Curcumin
  9. Fulltext Induction of Apoptosis and Regulation of MicroRNA Expression by (2E,6E)-2,6-bis-(4-hydroxy-3-methoxybenzylidene)-cyclohexanone (BHMC) Treatment on MCF-7 Breast Cancer Cells
    Yeap SK, Mohd Ali N, Akhtar MN, Razak NA, Chong ZX, Ho WY, et al.
    Molecules, 2021 Feb 26;26(5).
    PMID: 33652854 DOI: 10.3390/molecules26051277
    (2E,6E)-2,6-bis-(4-hydroxy-3-methoxybenzylidene)-cyclohexanone (BHMC) is a synthetic curcumin analogue, which has been reported to possess anti-tumor, anti-metastatic, and anti-invasion properties on estrogen receptor (ER) negative breast cancer cells in vitro and in vivo. However, the cytotoxic effects of BHMC on ER positive breast cancer cells were not widely reported. This study was aimed to investigate the cytotoxic potential of BHMC on MCF-7 cells using cell viability, cell cycle, and apoptotic assays. Besides, microarray and quantitative polymerase chain reaction (qPCR) were performed to identify the list of miRNAs and genes, which could be dysregulated following BHMC treatment. The current study discovered that BHMC exhibits selective cytotoxic effects on ER positive MCF-7 cells as compared to ER negative MDA-MB-231 cells and normal breast cells, MCF-10A. BHMC was shown to promote G2/M cell cycle arrest and apoptosis in MCF-7 cells. Microarray and qPCR analysis demonstrated that BHMC treatment would upregulate several miRNAs like miR-3195 and miR-30a-3p and downregulate miRNAs such as miR-6813-5p and miR-6132 in MCF-7 cells. Besides, BHMC administration was also found to downregulate few tumor-promoting genes like VEGF and SNAIL in MCF-7. In conclusion, BHMC induced apoptosis in the MCF-7 cells by altering the expressions of apoptotic-regulating miRNAs and associated genes.
    Matched MeSH terms: Curcumin/analogs & derivatives; Curcumin/pharmacology
  10. Fulltext Fluorine-19 Magnetic Resonance Imaging for Detection of Amyloid β Oligomers Using a Keto Form of Curcumin Derivative in a Mouse Model of Alzheimer's Disease
    Yanagisawa D, Ibrahim NF, Taguchi H, Morikawa S, Tomiyama T, Tooyama I
    Molecules, 2021 Mar 04;26(5).
    PMID: 33806326 DOI: 10.3390/molecules26051362
    Recent evidence suggests that the formation of soluble amyloid β (Aβ) aggregates with high toxicity, such as oligomers and protofibrils, is a key event that causes Alzheimer's disease (AD). However, understanding the pathophysiological role of such soluble Aβ aggregates in the brain in vivo could be difficult due to the lack of a clinically available method to detect, visualize, and quantify soluble Aβ aggregates in the brain. We had synthesized a novel fluorinated curcumin derivative with a fixed keto form, named as Shiga-Y51, which exhibited high selectivity to Aβ oligomers in vitro. In this study, we investigated the in vivo detection of Aβ oligomers by fluorine-19 (19F) magnetic resonance imaging (MRI) using Shiga-Y51 in an APP/PS1 double transgenic mouse model of AD. Significantly high levels of 19F signals were detected in the upper forebrain region of APP/PS1 mice compared with wild-type mice. Moreover, the highest levels of Aβ oligomers were detected in the upper forebrain region of APP/PS1 mice in enzyme-linked immunosorbent assay. These findings suggested that 19F-MRI using Shiga-Y51 detected Aβ oligomers in the in vivo brain. Therefore, 19F-MRI using Shiga-Y51 with a 7 T MR scanner could be a powerful tool for imaging Aβ oligomers in the brain.
    Matched MeSH terms: Curcumin/metabolism*; Curcumin/chemistry
  11. Curcumin-loaded liposomes prepared from bovine milk and krill phospholipids: Effects of chemical composition on storage stability, in-vitro digestibility and anti-hyperglycemic properties
    Wu Y, Mou B, Song S, Tan CP, Lai OM, Shen C, et al.
    Food Res Int, 2020 10;136:109301.
    PMID: 32846513 DOI: 10.1016/j.foodres.2020.109301
    Present study prepared curcumin liposomes with high encapsulation efficiency (>70%) using bovine milk and krill phospholipids; and investigated the effects of phospholipids composition on storage stability, in-vitro bioavailability, antioxidative and anti-hyperglycemic properties of the curcumin liposomes. Curcumin liposomes prepared from bovine milk phospholipids have smaller particle sizes (163.1 ± 6.42 nm) and greater negative zeta potentials (-26.7 mv) as compared to that prepared from krill phospholipids (particle size: 212.2 ± 4.1 nm, zeta potential: -15.23 mv). In addition, curcumin liposomes from bovine milk phospholipids demonstrated better stability under harsh storage conditions (alkaline conditions, oxygen, high temperature and relative humidity). Nevertheless, curcumin-loaded liposomes prepared from bovine milk phospholipids have inferior bioavailability compared to that prepared from krill phospholipids. No significant differences can be observed in terms of anti-oxidative and anti-hyperglycemic properties of liposomes prepared from both bovine milk and krill phospholipids. Findings from present study will open up new opportunities for development of stable curcumin liposomes with good functional properties (high digestibility, bioavailability and pharmacological effects).
    Matched MeSH terms: Curcumin/administration & dosage*; Curcumin/metabolism; Curcumin/pharmacokinetics
  12. Selective antibacterial activities and storage stability of curcumin-loaded nanoliposomes prepared from bovine milk phospholipid and cholesterol
    Wu Y, Wang K, Liu Q, Liu X, Mou B, Lai OM, et al.
    Food Chem, 2022 Jan 15;367:130700.
    PMID: 34352694 DOI: 10.1016/j.foodchem.2021.130700
    Present study prepared curcumin-loaded nanoliposomes using bovine milk, krill phospholipids and cholesterol; and investigated the effects of cholesterol on membrane characteristics, storage stability and antibacterial properties of the curcumin nanoliposomes. Bovine milk phospholipids which have higher saturation than krill phospholipids resulted in formation of curcumin-loaded nanoliposomes with higher encapsulation efficiency (84.78%), larger absolute value of zeta potential and vesicle size (size: 159.15 ± 5.27 nm, zeta potential: -28.3 ± 0.62 mV). Cholesterol helps to formation of a more hydrophobic, compact and tighter bilayer membrane structure which improved the storage stability of nanoliposomes under alkaline (66.25 ± 0.46%), heat (43.25 ± 0.69%) and sunlight (49.44 ± 1.78%) conditions. In addition, curcumin-loaded nanoliposomes can effectively target infectious bacteria which secrete pore-forming toxins such as Staphylococcus aureus by causing the bacterial cell wall to lysis. Findings from present work can guide future development of novel antibacterial agents for use in food preservation.
    Matched MeSH terms: Curcumin*
  13. Fulltext Anticancer Mechanism of Curcumin on Human Glioblastoma
    Wong SC, Kamarudin MNA, Naidu R
    Nutrients, 2021 Mar 16;13(3).
    PMID: 33809462 DOI: 10.3390/nu13030950
    Glioblastoma (GBM) is the most malignant brain tumor and accounts for most adult brain tumors. Current available treatment options for GBM are multimodal, which include surgical resection, radiation, and chemotherapy. Despite the significant advances in diagnostic and therapeutic approaches, GBM remains largely resistant to treatment, with a poor median survival rate between 12 and 18 months. With increasing drug resistance, the introduction of phytochemicals into current GBM treatment has become a potential strategy to combat GBM. Phytochemicals possess multifarious bioactivities with multitarget sites and comparatively marginal toxicity. Among them, curcumin is the most studied compound described as a potential anticancer agent due to its multi-targeted signaling/molecular pathways properties. Curcumin possesses the ability to modulate the core pathways involved in GBM cell proliferation, apoptosis, cell cycle arrest, autophagy, paraptosis, oxidative stress, and tumor cell motility. This review discusses curcumin's anticancer mechanism through modulation of Rb, p53, MAPK, P13K/Akt, JAK/STAT, Shh, and NF-κB pathways, which are commonly involved and dysregulated in preclinical and clinical GBM models. In addition, limitation issues such as bioavailability, pharmacokinetics perspectives strategies, and clinical trials were discussed.
    Matched MeSH terms: Curcumin/therapeutic use*
  14. Fulltext Curcumin Nanoformulations for Colorectal Cancer: A Review
    Wong KE, Ngai SC, Chan KG, Lee LH, Goh BH, Chuah LH
    Front Pharmacol, 2019;10:152.
    PMID: 30890933 DOI: 10.3389/fphar.2019.00152
    Colorectal cancer (CRC) is the third most prevalent form of cancer, after lung cancer and breast cancer, with the second highest death incidence. Over the years, natural compounds have been explored as an alternative to conventional cancer therapies such as surgery, radiotherapy, and chemotherapy. Curcumin, an active constituent of turmeric has been associated with various health benefits. It has gained much attention as an anticancer agent due to its ability to regulate multiple cell signaling pathways, including NF-κB, STAT3, activated protein-1 (AP-1), epidermal growth response-1 (Egr-1), and p53, which are crucial in cancer development and progression. Nevertheless, the clinical application of curcumin is greatly restricted because of its low water solubility, poor oral absorption, and rapid metabolism. These issues have led to the development of curcumin nanoformulations to overcome the limitations of the compound. Nanotechnology-based delivery systems have been widely used in improving the delivery of poorly-water soluble drugs. Besides, these systems also come with the added benefits of possible cellular targeting and improvement in cellular uptake. An ideal improved formulation should display a greater anticancer activity compared to free curcumin, and at the same time be non-toxic to the normal cells. In this review, we focus on the design and development of various nanoformulations to deliver curcumin for use in CRC such as liposomes, micelles, polymer nanoparticles, nanogels, cyclodextrin complexes, solid lipid nanoparticles (SLN), phytosomes, and gold nanoparticles. We also discuss the current pre-clinical and clinical evidences of curcumin nanoformulations in CRC therapy, analyse the research gap, and address the future direction of this research area.
    Matched MeSH terms: Curcumin
  15. Fulltext Molecular Mechanisms of Antiproliferative and Apoptosis Activity by 1,5-Bis(4-Hydroxy-3-Methoxyphenyl)1,4-Pentadiene-3-one (MS13) on Human Non-Small Cell Lung Cancer Cells
    Wan Mohd Tajuddin WNB, Abas F, Othman I, Naidu R
    Int J Mol Sci, 2021 Jul 10;22(14).
    PMID: 34299042 DOI: 10.3390/ijms22147424
    Diarylpentanoid (DAP), an analog that was structurally modified from a naturally occurring curcumin, has shown to enhance anticancer efficacy compared to its parent compound in various cancers. This study aims to determine the cytotoxicity, antiproliferative, and apoptotic activity of diarylpentanoid MS13 on two subtypes of non-small cell lung cancer (NSCLC) cells: squamous cell carcinoma (NCI-H520) and adenocarcinoma (NCI-H23). Gene expression analysis was performed using Nanostring PanCancer Pathways Panel to determine significant signaling pathways and targeted genes in these treated cells. Cytotoxicity screening revealed that MS13 exhibited greater inhibitory effect in NCI-H520 and NCI-H23 cells compared to curcumin. MS13 induced anti-proliferative activity in both cells in a dose- and time-dependent manner. Morphological analysis revealed that a significant number of MS13-treated cells exhibited apoptosis. A significant increase in caspase-3 activity and decrease in Bcl-2 protein concentration was noted in both MS13-treated cells in a time- and dose-dependent manner. A total of 77 and 47 differential expressed genes (DEGs) were regulated in MS13 treated-NCI-H520 and NCI-H23 cells, respectively. Among the DEGs, 22 were mutually expressed in both NCI-H520 and NCI-H23 cells in response to MS13 treatment. The top DEGs modulated by MS13 in NCI-H520-DUSP4, CDKN1A, GADD45G, NGFR, and EPHA2-and NCI-H23 cells-HGF, MET, COL5A2, MCM7, and GNG4-were highly associated with PI3K, cell cycle-apoptosis, and MAPK signaling pathways. In conclusion, MS13 may induce antiproliferation and apoptosis activity in squamous cell carcinoma and adenocarcinoma of NSCLC cells by modulating DEGs associated with PI3K-AKT, cell cycle-apoptosis, and MAPK pathways. Therefore, our present findings could provide an insight into the anticancer activity of MS13 and merits further investigation as a potential anticancer agent for NSCLC cancer therapy.
    Matched MeSH terms: Curcumin/analogs & derivatives*; Curcumin/pharmacology; Curcumin/chemistry
  16. Fulltext Mechanistic Understanding of Curcumin's Therapeutic Effects in Lung Cancer
    Wan Mohd Tajuddin WNB, Lajis NH, Abas F, Othman I, Naidu R
    Nutrients, 2019 Dec 06;11(12).
    PMID: 31817718 DOI: 10.3390/nu11122989
    Lung cancer is among the most common cancers with a high mortality rate worldwide. Despite the significant advances in diagnostic and therapeutic approaches, lung cancer prognoses and survival rates remain poor due to late diagnosis, drug resistance, and adverse effects. Therefore, new intervention therapies, such as the use of natural compounds with decreased toxicities, have been considered in lung cancer therapy. Curcumin, a natural occurring polyphenol derived from turmeric (Curcuma longa) has been studied extensively in recent years for its therapeutic effects. It has been shown that curcumin demonstrates anti-cancer effects in lung cancer through various mechanisms, including inhibition of cell proliferation, invasion, and metastasis, induction of apoptosis, epigenetic alterations, and regulation of microRNA expression. Several invitro and invivo studies have shown that these mechanisms are modulated by multiple molecular targets such as STAT3, EGFR, FOXO3a, TGF-β, eIF2α, COX-2, Bcl-2, PI3KAkt/mTOR, ROS, Fas/FasL, Cdc42, E-cadherin, MMPs, and adiponectin. In addition, limitations, strategies to overcome curcumin bioavailability, and potential side effects as well as clinical trials were also reviewed.
    Matched MeSH terms: Curcumin/adverse effects; Curcumin/pharmacokinetics; Curcumin/pharmacology*; Curcumin/therapeutic use
  17. Zebrafish phenotypic screen identifies novel Notch antagonists
    Velaithan V, Okuda KS, Ng MF, Samat N, Leong SW, Faudzi SM, et al.
    Invest New Drugs, 2017 04;35(2):166-179.
    PMID: 28058624 DOI: 10.1007/s10637-016-0423-y
    Zebrafish represents a powerful in vivo model for phenotype-based drug discovery to identify clinically relevant small molecules. By utilizing this model, we evaluated natural product derived compounds that could potentially modulate Notch signaling that is important in both zebrafish embryogenesis and pathogenic in human cancers. A total of 234 compounds were screened using zebrafish embryos and 3 were identified to be conferring phenotypic alterations similar to embryos treated with known Notch inhibitors. Subsequent secondary screens using HEK293T cells overexpressing truncated Notch1 (HEK293TΔE) identified 2 compounds, EDD3 and 3H4MB, to be potential Notch antagonists. Both compounds reduced protein expression of NOTCH1, Notch intracellular domain (NICD) and hairy and enhancer of split-1 (HES1) in HEK293TΔE and downregulated Notch target genes. Importantly, EDD3 treatment of human oral cancer cell lines demonstrated reduction of Notch target proteins and genes. EDD3 also inhibited proliferation and induced G0/G1 cell cycle arrest of ORL-150 cells through inducing p27KIP1. Our data demonstrates the utility of the zebrafish phenotypic screen and identifying EDD3 as a promising Notch antagonist for further development as a novel therapeutic agent.
    Matched MeSH terms: Curcumin/analogs & derivatives*; Curcumin/pharmacology*
  18. The synthetic curcuminoid BHMC restores endotoxin-stimulated HUVEC dysfunction:Specific disruption on enzymatic activity of p38 MAPK
    Tham CL, Hazeera Harith H, Wai Lam K, Joong Chong Y, Singh Cheema M, Roslan Sulaiman M, et al.
    Eur J Pharmacol, 2015 Feb 15;749:1-11.
    PMID: 25560198 DOI: 10.1016/j.ejphar.2014.12.015
    2,6-bis-(4-hydroxyl-3-methoxybenzylidine)cyclohexanone (BHMC) has been proven to selectively inhibit the synthesis of proinflammatory mediators in lipopolysaccharide-induced U937 monocytes through specific interruption of p38 Mitogen-Activated Protein Kinase enzymatic activity and improves the survival rate in a murine lethal sepsis model. The present study addressed the effects of BHMC upon lipopolysaccharide-induced endothelial dysfunction in human umbilical vein endothelial cells to determine the underlying mechanisms. The cytotoxicity effect of BHMC on HUVEC were determined by MTT assay. The effects of BHMC on endothelial dysfunction induced by lipopolysaccharide such as endothelial hyperpermeability, monocyte-endothelial adhesion, transendothelial migration, up-regulation of adhesion molecules and chemokines were evaluated. The effects of BHMC at transcriptional and post-translational levels were determined by Reverse Transcriptase-Polymerase Chain Reaction and Western Blots. The mode of action of BHMC was dissected by looking into the activation of Nuclear Factor-kappa B and Mitogen-Activated Protein Kinases. BHMC concentration-dependently reduced endothelial hyperpermeability, leukocyte-endothelial cell adhesion and monocyte transendothelial migration through inhibition of the protein expression of adhesion molecules (Intercellular Adhesion Molecule-1 and Vascular Cell Adhesion Molecule-1) and secretion of chemokines (Monocyte Chemotactic Protein-1) at the transcriptional level. BHMC restored endothelial dysfunction via selective inhibition of p38 Mitogen-Activated Protein Kinase enzymatic activity which indirectly prevents the activation of Nuclear Factor-kappaB and Activator Protein-1 transcription factors. These findings further support earlier observations on the inhibition of BHMC on inflammatory events through specific disruption of p38 Mitogen-Activated Protein Kinase enzymatic activity and provide new insights into the inhibitory effects of BHMC on lipopolysaccharide-induced endothelial dysfunction.
    Matched MeSH terms: Curcumin/analogs & derivatives*; Curcumin/pharmacology
  19. The effects of a synthetic curcuminoid analogue, 2,6-bis-(4-hydroxyl-3-methoxybenzylidine)cyclohexanone on proinflammatory signaling pathways and CLP-induced lethal sepsis in mice
    Tham CL, Lam KW, Rajajendram R, Cheah YK, Sulaiman MR, Lajis NH, et al.
    Eur J Pharmacol, 2011 Feb 10;652(1-3):136-44.
    PMID: 21114991 DOI: 10.1016/j.ejphar.2010.10.092
    We previously showed that 2,6-bis-(4-hydroxyl-3-methoxybenzylidine)cyclohexanone (BHMC), suppressed the synthesis of various proinflammatory mediators. In this study we explain the mechanism of action of BHMC in lipopolysaccharide (LPS)-induced U937 monocytes and further show that BHMC prevents lethality of CLP-induced sepsis. BHMC showed dose-dependent inhibitory effects on p38, JNK and ERK 1/2 activity as determined by inhibition of phosphorylation of downstream transcription factors ATF-2, c-Jun and Elk-1 respectively. Inhibition of these transcription factors subsequently caused total abolishment of AP-1-DNA binding. BHMC inhibited p65 NF-κB nuclear translocation and DNA binding of p65 NF-κB only at the highest concentration used (12.5μM) but failed to alter phosphorylation of JNK, ERK1/2 and STAT-1. Since the inhibition of p38 activity was more pronounced we evaluated the possibility that BHMC may bind to p38. Molecular docking experiments confirmed that BHMC fits well in the highly conserved hydrophobic pocket of p38 MAP kinase. We also show that BHMC was able to improve survival from lethal sepsis in a murine caecal-ligation and puncture (CLP) model.
    Matched MeSH terms: Curcumin/analogs & derivatives*; Curcumin/chemical synthesis; Curcumin/pharmacology; Curcumin/chemistry
  20. A synthetic curcuminoid derivative inhibits nitric oxide and proinflammatory cytokine synthesis
    Tham CL, Liew CY, Lam KW, Mohamad AS, Kim MK, Cheah YK, et al.
    Eur J Pharmacol, 2010 Feb 25;628(1-3):247-54.
    PMID: 19958764 DOI: 10.1016/j.ejphar.2009.11.053
    Curcumin is a highly pleiotropic molecule with significant regulatory effects upon inflammation and inflammatory related diseases. However curcumin has one major important limitation in which it has poor bioavailability. Design of synthetic structural derivatives of curcumin is but one approach that has been used to overcome its poor bioavailability while retaining, or further enhancing, its drug-like effects. We have synthesized a series of curcumin analogues and describe the effects of 2,6-bis-4-(hydroxyl-3-methoxy-benzylidine)-cyclohexanone or BHMC upon nitric oxide and cytokine synthesis in cellular models of inflammation. BHMC showed a significant dose-response inhibitory action upon the synthesis of NO and we have shown that this effect was due to suppression of both iNOS gene and enzyme expression without any effects upon scavenging of nitrite. We also demonstrated that BHMC has a very minimal effect upon iNOS activity with no effect at all upon the secretion of PGE(2) but has a strong inhibitory effect upon MCP-1 and IL-10 secretion and gene expression. Secretion and gene expression of TNF-alpha and IL-6 were moderately inhibited whereas IL-8 and IL-1beta were not altered. We conclude that BHMC selectively inhibits the synthesis of several inflammatory mediators. BHMC should be considered a promising drug lead for preclinical and further pharmacological studies.
    Matched MeSH terms: Curcumin/analogs & derivatives*; Curcumin/chemical synthesis; Curcumin/pharmacology*
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