Chalcone Derivatives: Anti-inflammatory Potential and Molecular Targets Perspectives

Chalcone or (E)-1,3-diphenyl-2-propene-1-one scaffold has gained considerable scientific interest in medicinal chemistry owing to its simple chemistry, ease in synthesizing a variety of derivatives and exhibiting a broad range of promising pharmacological activities by modulating several molecular targets. A number of natural and (semi-) synthetic chalcone derivatives have demonstrated admirable anti-inflammatory activity due to their inhibitory potential against various therapeutic targets like Cyclooxygenase (COX), Lipooxygenase (LOX), Interleukins (IL), Prostaglandins (PGs), Nitric Oxide Synthase (NOS), Leukotriene D4 (LTD4), Nuclear Factor-κB (NF- κB), Intracellular Cell Adhesion Molecule-1 (ICAM-1), Vascular Cell Adhesion Molecule-1 (VCAM-1), Monocyte Chemoattractant Protein-1 (MCP-1) and TLR4/MD-2, etc. The chalcone scaffold with hydroxyl, methoxyl, carboxyl, prenyl group and/or heterocyclic ring substitution like thiophene/furan/indole showed promising anti-inflammatory activity. In this review, a comprehensive study (from the year 1991 to 2016) on multi-targets of inflammatory interest, related inflammation reactions and their treatment by chalcone-based inhibitors acting on various molecular targets entailed in inflammation, Structure-Activity Relationships (SARs), Mechanism of Actions (MOAs), and patents are highlighted.

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Erythromycin exerts in vivo anti-inflammatory activity downregulating cell adhesion molecule expression

British Journal of Pharmacology ◽

10.1038/sj.bjp.0706021 ◽

2005 ◽

Vol 144 (2) ◽

pp. 190-201 ◽

Cited By ~ 26

Author(s):

María-Jesús Sanz ◽

Yafa Naim Abu Nabah ◽

Miguel Cerdá-Nicolás ◽

José-Enrique O'Connor ◽

Andrew C Issekutz ◽

...

Keyword(s):

Cell Adhesion ◽

Adhesion Molecule ◽

Cell Adhesion Molecule ◽

Inflammatory Activity ◽

Adhesion Molecule Expression ◽

Anti Inflammatory

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Magnolol Reduced TNF-α-Induced Vascular Cell Adhesion Molecule-1 Expression in Endothelial Cells via JNK/p38 and NF-κB Signaling Pathways

The American Journal of Chinese Medicine ◽

10.1142/s0192415x14500402 ◽

2014 ◽

Vol 42 (03) ◽

pp. 619-637 ◽

Cited By ~ 18

Author(s):

Chan-Jung Liang ◽

Chiang-Wen Lee ◽

Hsin-Ching Sung ◽

Yung-Hsiang Chen ◽

Shu-Huei Wang ◽

...

Keyword(s):

Endothelial Cells ◽

Cell Adhesion ◽

Adhesion Molecule ◽

Cell Adhesion Molecule ◽

Vascular Cell Adhesion ◽

Vascular Cell ◽

Vascular Cell Adhesion Molecule ◽

Tnf Α ◽

Anti Inflammatory ◽

Cell Adhesion Molecule 1

Expression of cell adhesion molecules by the endothelium and the attachment of leukocytes to these cells play major roles in inflammation and cardiovascular disorders. Magnolol, a major active component of Magnolia officinalis, has antioxidative and anti-inflammatory properties. In the present study, the effects of magnolol on the expression of vascular cell adhesion molecule-1 (VCAM-1) in human aortic endothelial cells (HAECs) and the related mechanisms were investigated. TNF-α induced VCAM-1 protein expression and mRNA stability were significantly decreased in HAECs pre-treated with magnolol. Magnolol significantly reduced the phosphorylation of ERK, JNK, and p38 in TNF-α-treated HAECs. The decrease in VCAM-1 expression in response to TNF-α treatment was affected by JNK and p38 inhibitors, not by an ERK inhibitor. Magnolol also attenuates NF-κB activation and the translocation of HuR (an RNA binding protein) in TNF-α-stimulated HAECs. The VCAM-1 expression was weaker in the aortas of TNF-α-treated apo-E deficient mice with magnolol treatment. These data demonstrate that magnolol inhibits TNF-α-induced JNK/p38 phosphorylation, HuR translocation, NF-κB activation, and thereby suppresses VCAM-1 expression resulting in reduced leukocyte adhesion. Taken together, these results suggest that magnolol has an anti-inflammatory property and may play an important role in the prevention of atherosclerosis and inflammatory responses.

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Anti-Atherogenic Effects of Orlistat on Obesity-Induced Vascular Oxidative Stress Rat Model

Antioxidants ◽

10.3390/antiox10020251 ◽

2021 ◽

Vol 10 (2) ◽

pp. 251

Author(s):

Zaidatul Akmal Othman ◽

Zaida Zakaria ◽

Joseph Bagi Suleiman ◽

Wan Syaheedah Wan Ghazali ◽

Mahaneem Mohamed

Keyword(s):

Oxidative Stress ◽

Cell Adhesion ◽

Adhesion Molecule ◽

Cell Adhesion Molecule ◽

Inflammatory Marker ◽

Density Lipoprotein ◽

Normal Group ◽

Anti Inflammatory ◽

Cell Adhesion Molecule 1 ◽

Vascular Oxidative Stress

Obesity is typically linked to oxidative stress and inflammation, which lead to vascular damage and initiate the progression of atherosclerosis. The aim of this study was to determine the anti-atherosclerotic effect of orlistat on obesity-induced vascular oxidative stress in obese male rats. Twenty-four male Sprague–Dawley rats were categorized into two groups: normal (Normal group, n = 6) and high-fat diet (HFD group, n = 12). After six weeks, obese rats in the HFD group were administered either with distilled water (OB group) or orlistat 10 mg/kg/day (OB/OR group) for another six weeks. The OB group had a significant increase in lipid profiles (total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL)) and decrease in high-density lipoprotein (HDL) level compared to the Normal group. The aortic antioxidants enzymes activities (superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST), and catalase (CAT)) as well as total glutathione (GSH) and total antioxidant capacity (TAC) of the OB group were significantly decreased compared to the Normal group. Furthermore, pro-inflammatory atherosclerotic markers (tumour necrosis factor-alpha (TNF-α), vascular cell adhesion molecule-1 (VCAM-1), and intercellular cell adhesion molecule-1 (ICAM-1)) expressions were increased significantly, and anti-inflammatory marker (interleukin-10 (IL-10)) was decreased significantly in the OB group compared to the Normal group. Treatment with orlistat significantly improved lipid profile, increased antioxidant enzymes and expression of anti-inflammatory markers, and decreased the expression of the pro-inflammatory marker compared to the OB group. These findings may suggest the therapeutic effect of orlistat in attenuating the progression of the atherosclerotic stage in obesity.

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Calpain inhibitor I attenuates atherosclerosis and inflammation in atherosclerotic rats through eNOS/NO/NF-κB pathway

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2016-0652 ◽

2018 ◽

Vol 96 (1) ◽

pp. 60-67 ◽

Cited By ~ 8

Author(s):

Lan Yu ◽

Meihui Yin ◽

Xueyan Yang ◽

Meili Lu ◽

Futian Tang ◽

...

Keyword(s):

Cell Adhesion ◽

Protein Expression ◽

Adhesion Molecule ◽

Cell Adhesion Molecule ◽

Nuclear Factor Κb ◽

High Cholesterol Diet ◽

Aortic Tissue ◽

Calpain Inhibitor ◽

Monocyte Chemoattractant Protein 1 ◽

Cell Adhesion Molecule 1

We previously reported that calpain, the Ca2+-sensitive cysteine protease, gets involved in atherogenesis. This study aimed to investigate the effects of calpain inhibitor I (CAI, 5 mg/kg per day) with or without NG-nitro-l-arginine-methyl ester (l-NAME) (100 mg/kg per day), the inhibitor of nitric oxide synthase (NOS), on atherosclerosis and inflammation in a rat model induced by high-cholesterol diet (HCD). The results demonstrated HCD increased protein expression of calpain-1 but not calpain-2 in aortic tissue. In addition, CAI reduced the thickness of atherosclerotic intima compared with HCD group, which was weakened by the l-NAME combination. CAI with or without l-NAME decreased the activity of calpain in the aorta. Also, CAI decreased the expressions of vascular cell adhesion molecule-1 (VCAM-1), intracellular cell adhesion molecule-1 (ICAM-1), and monocyte chemoattractant protein-1 (MCP-1) in the aorta at the levels of both mRNA and protein. Furthermore, CAI increased the activity and the protein expression of endothelial NOS (eNOS) accompanied by increased content of NO and downregulated the protein expression of nuclear factor κB (NF-κB) of the nucleus in the aorta. However, the abovementioned effects were at least partly cancelled by l-NAME except for the protein expression of eNOS. The results suggested that CAI attenuated atherosclerosis and inflammation through eNOS/NO/NF-κB pathway.

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Proteinase 3 Enhances Endothelial Monocyte Chemoattractant Protein-1 Production and Induces Increased Adhesion of Neutrophils to Endothelial Cells by Upregulating Intercellular Cell Adhesion Molecule-1

Journal of the American Society of Nephrology ◽

10.1681/asn.v125932 ◽

2001 ◽

Vol 12 (5) ◽

pp. 932-940

Author(s):

MIRIAM E. J. TAEKEMA-ROELVINK ◽

CEES VAN KOOTEN ◽

SANDRA VAN DER KOOIJ ◽

EVERT HEEMSKERK ◽

MOHAMED R. DAHA

Keyword(s):

Endothelial Cells ◽

Cell Adhesion ◽

Adhesion Molecule ◽

Cell Adhesion Molecule ◽

Time Dependent ◽

Proteinase 3 ◽

Monocyte Chemoattractant Protein 1 ◽

Monocyte Chemoattractant ◽

Monocyte Chemoattractant Protein ◽

Cell Adhesion Molecule 1

Abstract. Wegener's granulomatosis is an autoimmune disease that is characterized by systemic vasculitis and granuloma formation. Early influx of polymorphonuclear neutrophils (PMN), followed at a later stage by mononuclear cells, contributes to the granulomatous inflammation. Previous studies have shown that proteinase 3 (PR3), the major autoantigen in Wegener's granulomatosis, specifically binds to endothelial cells and plays a possible role in activation of these cells by enhancing interleukin-8 production, thus providing a chemotactic and activating stimulus for PMN. The present study demonstrated that PR3 enhances the production of monocyte chemoattractant protein-1 (MCP-1) by human umbilical vein endothelial cells (HUVEC) in a dose- and time-dependent manner. The PR3-induced increase in MCP-1 production was demonstrated at both the protein and the mRNA levels and was chemotactic for monocytes. In addition, it was demonstrated that PR3 induces a dose- and time-dependent increase in the expression of intercellular adhesion molecule-1 (ICAM-1) as determined by fluorescence-activated cell sorter analysis. The PR3-induced increase in expression of ICAM-1 was also demonstrated at the mRNA level. PR3 induced a slight increase in vascular cell adhesion molecule-1 expression and had no effect on the expression of both P- and E-selectin. Incubation of HUVEC for 24 h in the presence of PR3 resulted in a significant increase in adhesion of PMN, which was reduced to baseline levels in the presence of blocking monoclonal antibody anti—ICAM-1 or anti-CD18 or a combination of both. Monocytes showed a slight but statistically not significant increase in adhesion. Incubation of HUVEC with PR3 for 4 h did not result in enhanced adhesion of either PMN or monocytes. It was hypothesized that PR3, which may be released locally at inflammatory sites after activation of cytokineprimed PMN, plays a role in endothelial cell activation by enhancing both interleukin-8 and MCP-1 production, thus providing a chemotactic and activating stimulus for both PMN and monocytes. In addition, PR3 may contribute to the ongoing inflammation by enhancing the adhesion of PMN to endothelial cells by upregulating ICAM-1 expression.

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