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Effect of Aryl-Cyclohexanones and their Derivatives on Macrophage Polarization In Vitro

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Abstract

Macrophages are critical in both tissue homeostasis and inflammation, and shifts in their polarization have been indicated as pivotal for the resolution of inflammatory processes. Inflammation is a complex and necessary component of the immune response to stimuli that are harmful to host homeostasis and is regulated by cellular and molecular events that remain a source of ongoing investigation. Among the compounds studied that have potential against autoimmune and inflammatory diseases, cannabinoids are currently highlighted. In this work, nineteen aryl-cyclohexanones diesters and their derivatives were synthesized based on the aryl-cyclohexane skeleton of phytocannabinoids, such as cannabidiol (CBD), and were evaluated for their anti-inflammatory and macrophage polarization potential. The results showed that Compound 4 inhibited the production of nitric oxide in RAW 264.7 macrophages. Furthermore, it reduced the levels of pro-inflammatory cytokines IL-12p70, TNF-α, IFN-γ, MCP-1, and IL-6 while, at the same time, was able to increase the production of anti-inflammatory cytokines IL-4, IL-10, and IL-13. Compound 4 also reduced macrophage apoptosis, increased the expression of the CD206 (mannose receptor) and at the same time, decreased the expression of CD284 (TLR-4 receptor) on the surface of these cells. Finally, it increased the phagocytic capacity and inhibited the phosphorylation of the p65 of NF-kβ. In conclusion, Compound 4, identified as diethyl-4-hydroxy-2-(4-methoxyphenyl)-4-methyl-6-oxocyclohexane-1–3-dicarboxylate, showed significant anti-inflammatory effect, while demonstrating the ability to transform phenotypically macrophages from the M1 phenotype (pro-inflammatory) to the M2 phenotype (anti-inflammatory). This led us to hypothesize that the main mechanism of anti-inflammatory effect of this molecule is linked to its immune modulation capacity.

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Acknowledgements

The students (TLL, ETBM, JSR, LAE) received scholarships from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil) and the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Brazil).

Funding

This work received support from the Coordination for the Improvement of Higher Education Personnel (CAPES) and the National Council for Scientific and Technological Development (CNPq) for its development.

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Author notes

  1. Tainá L. Lubschinski and Luiz A. E. Pollo both authors contributed equally to the development of this study.

Authors and Affiliations

  1. Department of Clinical Analysis, Center of Health Sciences, Federal University of Santa Catarina, Florianópolis, Santa Catarina, 88040-970, Brazil

    Tainá L. Lubschinski, Eduarda T. B. Mohr, Julia S. da Rosa & Eduardo M. Dalmarco

  2. Department of Pharmaceutical Sciences, Center of Health Sciences, Federal University of Santa Catarina, Florianópolis, Santa Catarina, 88040-970, Brazil

    Luiz A. E. Pollo, Luigi A. Nardino & Maique W. Biavatti

  3. Department of Chemistry, CFM, Federal University of Santa Catarina, Florianópolis, Santa Catarina, 88040-970, Brazil

    Louis P. Sandjo

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Contributions

TLL, ETBM, and JSR carried out the experimental work and performed the statistical analyses. LAE and LPS synthesized and supplied the studied molecules. EMD designed and supervised the study, helped in the statistical analysis, and corrected the manuscript. All authors read and approved the final manuscript.

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Correspondence to Eduardo M. Dalmarco.

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Lubschinski, T.L., Pollo, L.A.E., Mohr, E.T.B. et al. Effect of Aryl-Cyclohexanones and their Derivatives on Macrophage Polarization In Vitro. Inflammation 45, 1612–1630 (2022). https://doi.org/10.1007/s10753-022-01646-9

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