A role for heme oxygenase‐1 (HO‐1) induction in providing the beneficial effects of caffeic acid phenethyl ester (CAPE) in vivo

Abstract Objectives Caffeic acid phenethyl ester (CAPE), an active component of propolis from honeybee hives, is well studied for its beneficial effects on cancer, inflammation and diabetes. There are however limited studies investigating the effects of CAPE on obesity. Currently, several natural products are under investigation for their effects on adipocyte life cycle. A multi-targeted approach for prevention and treatment of obesity includes targeting adipocytes at all the stages of life cycle by decreasing adipocyte differentiation, inducing lipolysis and/or by inducing adipocyte apoptosis. In this study, we examined the effects of CAPE on preadipocyte viability, adipogenesis and lipolysis. Earlier reports on CAPE indicate that CAPE is liable to enzymatic hydrolysis in vivo making this compound unstable for therapeutic applications. In the current study, we compared the anti-adipogenic effects of CAPE with its novel fluorinated derivative (FCAPE), a more stable compound. Methods 3T3-L1 pre-adipocytes were differentiated using a cocktail consisting of insulin, dexamethasone, and isobutyl methyl xanthine in DMEM supplemented with 10% FBS following adipogeneic differentiation. Pre- and mature adipocytes were incubated with CAPE or FCAPE for 24–48 hours and their effects on viability, lipolysis, and adipogenesis was tested using Prestoblue, Lipolysis assay (Zen-Bio) and AdipoRed assay respectively. Results Our results indicate that neither CAPE nor FCAPE significantly altered preadipocyte viability within the tested dose range. Although both CAPE and FCAPE significantly decreased adipogenesis compared to control, FCAPE decreased lipid content by 73.6 ± 1.6% while CAPE reduced lipid content by only 36.8 ± 9.1% at 25 μM concentration. In contrast to adipogenesis data, our preliminary results with lipolysis assay indicate that only CAPE, but not FCAPE induces lipolysis in mature adipocytes. Conclusions These findings suggest that both CAPE and FCAPE possess anti-adipogenic properties. Further studies are needed to elucidate their differential effects on adipogenesis and lipolysis. Funding Sources This study was funded by the Department of Research, PCOM.

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Cytoprotection of human endothelial cells from menadione cytotoxicity by caffeic acid phenethyl ester: The role of heme oxygenase-1

European Journal of Pharmacology ◽

10.1016/j.ejphar.2008.06.017 ◽

2008 ◽

Vol 591 (1-3) ◽

pp. 28-35 ◽

Cited By ~ 28

Author(s):

Xinyu Wang ◽

Salomon Stavchansky ◽

Baiteng Zhao ◽

James A. Bynum ◽

Sean M. Kerwin ◽

...

Keyword(s):

Endothelial Cells ◽

Caffeic Acid ◽

Heme Oxygenase ◽

Caffeic Acid Phenethyl Ester ◽

Heme Oxygenase 1 ◽

Human Endothelial Cells

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Correction to “Caffeic Acid Phenethyl Ester and Curcumin: A Novel Class of Heme Oxygenase-1 Inducers”

Molecular Pharmacology ◽

10.1124/mol.61.5.1264 ◽

2002 ◽

Vol 61 (5) ◽

pp. 1264-1264 ◽

Cited By ~ 1

Keyword(s):

Caffeic Acid ◽

Heme Oxygenase ◽

Caffeic Acid Phenethyl Ester ◽

Heme Oxygenase 1

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Structure–activity relationships in the cytoprotective effect of caffeic acid phenethyl ester (CAPE) and fluorinated derivatives: Effects on heme oxygenase-1 induction and antioxidant activities

European Journal of Pharmacology ◽

10.1016/j.ejphar.2010.02.034 ◽

2010 ◽

Vol 635 (1-3) ◽

pp. 16-22 ◽

Cited By ~ 28

Author(s):

Xinyu Wang ◽

Salomon Stavchansky ◽

Sean M. Kerwin ◽

Phillip D. Bowman

Keyword(s):

Caffeic Acid ◽

Heme Oxygenase ◽

Antioxidant Activities ◽

Caffeic Acid Phenethyl Ester ◽

Heme Oxygenase 1 ◽

Cytoprotective Effect ◽

Structure Activity Relationships ◽

Structure Activity ◽

Fluorinated Derivatives

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Caffeic Acid Phenethyl Ester Inhibits PDGF-Induced Proliferation of Vascular Smooth Muscle Cells via Activation of p38 MAPK, HIF-1α, and Heme Oxygenase-1

Journal of Natural Products ◽

10.1021/np100724f ◽

2011 ◽

Vol 74 (3) ◽

pp. 352-356 ◽

Cited By ~ 25

Author(s):

Thomas U. Roos ◽

Elke H. Heiss ◽

Andrea V. Schwaiberger ◽

Daniel Schachner ◽

Irene M. Sroka ◽

...

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Caffeic Acid ◽

P38 Mapk ◽

Vascular Smooth Muscle Cells ◽

Heme Oxygenase ◽

Muscle Cells ◽

Caffeic Acid Phenethyl Ester ◽

Heme Oxygenase 1

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Heme Oxygenase-1 Induction in Human BeWo Trophoblast Cells Decreases Toxoplasma gondii Proliferation in Association With the Upregulation of p38 MAPK Phosphorylation and IL-6 Production

Frontiers in Microbiology ◽

10.3389/fmicb.2021.659028 ◽

2021 ◽

Vol 12 ◽

Author(s):

Marcos Paulo Oliveira Almeida ◽

Caroline Martins Mota ◽

Tiago Wilson Patriarca Mineo ◽

Eloisa Amália Vieira Ferro ◽

Bellisa Freitas Barbosa ◽

...

Keyword(s):

Toxoplasma Gondii ◽

P38 Mapk ◽

Heme Oxygenase ◽

Heme Oxygenase 1 ◽

Trophoblast Cells ◽

Human Trophoblast ◽

Mapk Phosphorylation ◽

Beneficial Effects ◽

Bewo Cells

Heme oxygenase-1 (HO-1) enzyme exerts beneficial effects at the maternal-fetal interface, especially in trophoblasts, being involved in survival and maturation of these cell phenotypes. Trophoblast cells play essential roles throughout pregnancy, being the gateway for pathogens vertically transmitted, such as Toxoplasma gondii. It was previously shown that HO-1 activity was involved in the control of T. gondii infection in vivo; however, its contribution in trophoblast cells during T. gondii infection, remain undefined. Thus, this study aimed to investigate the influence of HO-1 in T. gondii-infected BeWo and HTR-8/SVneo human trophoblast cells. For this purpose, trophoblast cells were infected and the HO-1 expression was evaluated. T. gondii-infected BeWo cells were treated with hemin or CoPPIX, as inducers of HO-1, or with bilirubin, an end-product of HO-1, and the parasitism was quantified. The involvement of p38 MAPK, a regulator of HO-1, and the cytokine production, were also evaluated. It was found that T. gondii decreased the HO-1 expression in BeWo but not in HTR-8/SVneo cells. When treated with the HO-1 inducers or bilirubin, BeWo cells reduced the parasite proliferation. T. gondii also decreased the p38 MAPK phosphorylation in BeWo cells; on the other hand, HO-1 induction sustained its activation. Finally, the IL-6 production was upregulated by HO-1 induction in T. gondii-infected cells, which was associated with the control of infection.

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