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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: Transcription Factor AP-1
Fulltext 15-Deoxy-Delta-12,14-prostaglandin J2 modulates pro-labour and pro-inflammatory responses in human myocytes, vaginal and amnion epithelial cells

Rasheed ZB, Lee YS, Kim SH, Teoh T, MacIntyre DA, Bennett PR, et al.

Front Endocrinol (Lausanne), 2022;13:983924.
PMID: 36213265 DOI: 10.3389/fendo.2022.983924

BACKGROUND: Prematurity is the leading cause of childhood death under the age of five. The aetiology of preterm birth is multifactorial; however, inflammation and infection are the most common causal factors, supporting a potential role for immunomodulation as a therapeutic strategy. 15-Deoxy-Delta-12,14-prostaglandin J2 (15dPGJ2) is an anti-inflammatory prostaglandin and has been shown to delay lipopolysaccharide (LPS) induced preterm labour in mice and improve pup survival. This study explores the immunomodulatory effect of 15dPGJ2 on the transcription factors NF-κB and AP-1, pro-inflammatory cytokines, and contraction associated proteins in human cultured myocytes, vaginal epithelial cell line (VECs) and primary amnion epithelial cells (AECs).
METHODS: Cells were pre-incubated with 32µM of 15dPGJ2 and stimulated with 1ng/mL of IL-1β as an in vitro model of inflammation. Western immunoblotting was used to detect phosphorylated p-65 and phosphorylated c-Jun as markers of NF-κB and AP-1 activation, respectively. mRNA expression of the pro-inflammatory cytokines IL-6, IL-8, and TNF-α was examined, and protein expression of COX-2 and PGE2 were detected by western immunoblotting and ELISA respectively. Myometrial contractility was examined ex-vivo using a myograph.
RESULTS: 15dPGJ2 inhibited IL-1β-induced activation of NF-κB and AP-1, and expression of IL-6, IL-8, TNF-α, COX-2 and PGE2 in myocytes, with no effect on myometrial contractility or cell viability. Despite inhibiting IL-1β-induced activation of NF-κB, expression of IL-6, TNF-α, and COX-2, 15dPGJ2 led to activation of AP-1, increased production of PGE2 and increased cell death in VECs and AECs.
CONCLUSION: We conclude that 15dPGJ2 has differential effects on inflammatory modulation depending on cell type and is therefore unlikely to be a useful therapeutic agent for the prevention of preterm birth.

Matched MeSH terms: Transcription Factor AP-1/metabolism; Transcription Factor AP-1/pharmacology; Transcription Factor AP-1/therapeutic use
Cancer chemopreventive activity of maslinic acid: suppression of COX-2 expression and inhibition of NF-κB and AP-1 activation in Raji cells

Hsum YW, Yew WT, Hong PL, Soo KK, Hoon LS, Chieng YC, et al.

Planta Med, 2011 Jan;77(2):152-7.
PMID: 20669087 DOI: 10.1055/s-0030-1250203

Chronic inflammation is one of the predisposing factors for neoplastic transformation. Targeting inflammation through suppression of the pro-inflammatory pathway by dietary phytochemicals provides an important strategy for cancer prevention. Maslinic acid is a novel natural triterpenoid known to inhibit proliferation and induce apoptosis in some tumor cell lines. Although maslinic acid has cytotoxic and pro-apoptotic effects on cancer cells, the underlying mechanisms of its effects on the inflammatory pathway have yet to be elucidated. It has been reported that abnormal expression of pro-inflammatory enzyme cyclooxygenase-2 (COX-2) causes promotion of cellular proliferation, suppression of apoptosis, enhancement of angiogenesis and invasiveness. In the present study, the suppressive effect of maslinic acid on COX-2 expression and the binding activity of upstream transcription factors NF- κB and AP-1, which are known to regulate COX-2 transcriptional activation, were assessed using Raji cells. The anti-inflammatory action of maslinic acid was benchmarked against oleanolic acid and other standard drugs. Western blot analysis and electrophoretic mobility shift assay (EMSA) were employed to analyze COX-2 expression as well as NF- κB and AP-1 binding activity. Our results showed that maslinic acid suppresses COX-2 expression in a concentration-dependent manner. Likewise, the constitutive nuclear NF- κB (p65) activity as well as phorbol 12-myristate 13-acetate (PMA)- and sodium N-butyrate (SnB)-induced AP-1 binding activity in Raji cells were significantly reduced following treatment with maslinic acid. Since maslinic acid suppresses COX-2 expression in Raji cells at concentrations that also lowered the NF- κB (p65) and AP-1 binding activity, it is possible that the suppression of COX-2 by this natural triterpenoid might be achieved, at least in part, via the NF- κB and AP-1 signaling pathways.

Matched MeSH terms: Transcription Factor AP-1/drug effects*; Transcription Factor AP-1/metabolism
Fulltext Blockade of Eosinophil-Induced Bronchial Epithelial-Mesenchymal Transition with a Geranyl Acetophenone in a Coculture Model

Lee YZ, Yap HM, Shaari K, Tham CL, Sulaiman MR, Israf DA

Front Pharmacol, 2017;8:837.
PMID: 29201006 DOI: 10.3389/fphar.2017.00837

Epithelial-mesenchymal transition (EMT) is currently recognized as the main cellular event that contributes to airway remodeling. Eosinophils can induce EMT in airway epithelial cells via increased transforming growth factor (TGF)-β production. We assessed the effect of synthetic 2,4,6-trihydroxy-3-geranyl acetophenone (tHGA) upon eosinophil-induced EMT in a cellular model. The human eosinophil cell line EoL-1 was used to induce EMT in BEAS-2B human bronchial epithelial cells. The induction of EMT was dose-dependently suppressed following tHGA treatment in which the epithelial morphology and E-cadherin expression were not altered. Protein and mRNA expression of vimentin, collagen I and fibronectin in eosinophil-induced epithelial cells were also significantly suppressed by tHGA treatment. Following pathway analysis, we showed that tHGA suppressed eosinophil-induced activator protein-1-mediated TGF-β production by targeting c-Jun N-terminal kinase and phosphoinositide 3-kinase signaling pathways. These findings corroborated previous findings on the ability of tHGA to inhibit experimental murine airway remodeling.

Matched MeSH terms: Transcription Factor AP-1
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: Transcription Factor AP-1/metabolism
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: Transcription Factor AP-1/metabolism
Fulltext Steroid withdrawal or avoidance in renal transplant recipients

Chang, S.H., Tan, S.Y.

JUMMEC, 2006;9(1):2-6.
MyJurnal

Steroids remain an important component of maintenance immunosuppression after renal transplantation. Their anti-inflammatory action is partly due to the sequestration of CD4+ lymphocytes in the reticuloendothelial system. Steroids bind to intracellular receptors and the resulting steroid-receptor complex alters the transcription of cytokines by binding to glucocorticoid response elements on DNA. Transcription factors whose actions are altered by glucocorticoids include activating protein-1 (AP-1) and nuclear factor-B (NF-B). The main cytokines whose production by antigen-presenting cells is inhibited by steroids are interleukin-1 (IL-1), required for helper T-cell activation, and IL-6, required for B-cell activation. Other pro-inflammatory cytokines such as interferon gamma and tumour necrosis factor are also inhibited. This multiplicity of immunosuppressive actions is not fully replicated by other immunosuppressants. However, there are concerns about the long-term side effects of steroids. This review will examine the attempts at steroid withdrawal or steroid avoidance in renal transplant patients.

Matched MeSH terms: Transcription Factor AP-1
Fulltext BDMC33, A curcumin derivative suppresses inflammatory responses in macrophage-like cellular system: role of inhibition in NF-κB and MAPK signaling pathways

Lee KH, Chow YL, Sharmili V, Abas F, Alitheen NB, Shaari K, et al.

Int J Mol Sci, 2012;13(3):2985-3008.
PMID: 22489138 DOI: 10.3390/ijms13032985

Our preliminary screening has shown that curcumin derivative BDMC33 [2,6-bis(2,5-dimethoxybenzylidene)cyclohexanone] exerted promising nitric oxide inhibitory activity in activated macrophages. However, the molecular basis and mechanism for its pharmacological action is yet to be elucidated. The aim of this study was to investigate the anti-inflammatory properties of BDMC33 and elucidate its underlying mechanism action in macrophage cells. Our current study demonstrated that BDMC33 inhibits the secretion of major pro-inflammatory mediators in stimulated macrophages, and includes NO, TNF-α and IL-1β through interference in both nuclear factor kappaB (NF-κB) and mitogen activator protein kinase (MAPK) signaling cascade in IFN-γ/LPS-stimulated macrophages. Moreover, BDMC33 also interrupted LPS signaling through inhibiting the surface expression of CD-14 accessory molecules. In addition, the inhibitory action of BDMC33 not only restricted the macrophages cell (RAW264.7), but also inhibited the secretion of NO and TNF-α in IFN-γ/LPS-challenged microglial cells (BV-2). The experimental data suggests the inflammatory action of BDMC33 on activated macrophage-like cellular systems, which could be used as a future therapeutic agent in the management of chronic inflammatory diseases.

Matched MeSH terms: Transcription Factor AP-1/metabolism