Ursolic Acid Derivatives Down Regulate Inflammatory Mediators

Scherrer, Elaine C.; Valadares, Ydia M.; Alves, Caio C. S.; Carli, Alessandra P.; Fernandes, Bárbara G. R.; Carvalho, Paloma E.; Ramos, Karla A.; Salvador, Maiara R.; Silva, Jeferson G. da; Silva, Fernando S.; Denadai, Ângelo M. L.; Castro, Sandra B. R.

doi:10.21577/0103-5053.20230036

Elaine C. Scherrer

responsible for running the laboratory work

analysis of data

data curation

writing original draft

Instituto de Ciências da Vida, Universidade Federal de Juiz de Fora, 35010-180 Governador Valadares-MG, Brazil

Ydia M. Valadares

conceptualization

funding acquisition

in chemical synthesis

chemical analysis

writing original draft

Instituto de Ciências da Vida, Universidade Federal de Juiz de Fora, 35010-180 Governador Valadares-MG, Brazil

Caio C. S. Alves

conceptualization

funding acquisition

resources and writing original draft

writing - review and editing

Faculdade de Medicina, Universidade Federal dos Vales do Jequitinhonha e Mucuri, 39803-371 Teófilo Otoni-MG, Brazil

https://orcid.org/0000-0001-9765-8527

Alessandra P. Carli

biological analysis

critical review of the manuscript

Faculdade de Medicina, Universidade Federal dos Vales do Jequitinhonha e Mucuri, 39803-371 Teófilo Otoni-MG, Brazil

Bárbara G. R. Fernandes

running the laboratory work

supporting the analysis of data

data curation

Instituto de Ciências da Vida, Universidade Federal de Juiz de Fora, 35010-180 Governador Valadares-MG, Brazil

Paloma E. Carvalho

laboratory work

data analysis

Instituto de Ciências da Vida, Universidade Federal de Juiz de Fora, 35010-180 Governador Valadares-MG, Brazil

Karla A. Ramos

supporting the laboratory work

data analysis

Faculdade de Medicina, Universidade Federal dos Vales do Jequitinhonha e Mucuri, 39803-371 Teófilo Otoni-MG, Brazil

Maiara R. Salvador

laboratory work

data analysis

Instituto de Ciências da Vida, Universidade Federal de Juiz de Fora, 35010-180 Governador Valadares-MG, Brazil

Jeferson G. da Silva

chemical analysis

funding acquisition

writing original draft

Instituto de Ciências da Vida, Universidade Federal de Juiz de Fora, 35010-180 Governador Valadares-MG, Brazil

Fernando S. Silva

conceptualization

biological analysis

funding acquisition

writing-review and editing the manuscript

Instituto de Ciências da Vida, Universidade Federal de Juiz de Fora, 35010-180 Governador Valadares-MG, Brazil

Ângelo M. L. Denadai ^**e-mail: angelomld@gmail.com

funding acquisition

resources and the revision of the manuscript in this resubmission

Instituto de Ciências da Vida, Universidade Federal de Juiz de Fora, 35010-180 Governador Valadares-MG, Brazil

Sandra B. R. Castro

lead the conceptualization

project administration

funding acquisition

visualization and writing the original draft

Faculdade de Medicina, Universidade Federal dos Vales do Jequitinhonha e Mucuri, 39803-371 Teófilo Otoni-MG, Brazil

https://orcid.org/0000-0002-5535-0919

*e-mail: angelomld@gmail.com

Editor handled this article: Brenno A. D. Neto

Compound^a a Compounds: ursolic acid (UA) and ursolic acid derivative (UAD);	NO production / µM
	15 µM^b b treatment concentration;	30 µM^b b treatment concentration;	60 µM^b b treatment concentration;	90 µM^b b treatment concentration;	IC₅₀ / µM
UA	9.65 ± 0.51^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	3.05 ± 1.16^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	1.99 ± 0.15^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	2.12 ± 0.83^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	17.06
UAD1	3.98 ± 0.44^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	4.69 ± 0.07^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	2.63 ± 0.37^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	1.66 ± 0.07^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	9.64
UAD2	8.05 ± 0.31^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	8.55 ± 0.47^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	6.69 ± 1.10^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	4.75 ± 0.61^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	> 90
UAD3	9.99 ± 1.85^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	9.13 ± 1.03^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	7.96 ± 1.33^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	6.10 ± 1.76^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	> 90
UAD4	14.32 ± 0.63	10.47 ± 0.93^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	8.05 ± 1.35^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	8.94 ± 0.27^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	> 90
UAD5	11.41 ± 1.33	8.39 ± 1.10^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	2.98 ± 0.38^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	4.56 ± 0.27^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	39.89
UAD6	10.72 ± 1.63^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	10.75 ± 0.19^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	4.08 ± 0.72^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	0.93 ± 0.21^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	74.62
UAD7	11.51 ± 2.40	8.18 ± 2.22^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	7.09 ± 0.99^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	5.83 ± 1.53^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	> 90
UAD8	10.79 ± 1.03^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	9.85 ± 0.60^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	3.63 ± 0.53^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	3.46 ± 0.70^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	47.25
UAD9	10.98 ± 1.75^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	10.87 ± 0.67^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	5.95 ± 0.30^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	5.51 ± 0.95^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	> 90
UAD10	12.19 ± 1.11	9.86 ± 0.87^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	5.96 ± 0.15^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	6.05 ± 2.12^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	> 90
UAD11	10.11 ± 2.37	10.28 ± 2.82	9.15 ± 0.08^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	9.89 ± 1.26^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	> 90
UAD12	21.06 ± 1.02	13.23 ± 1.55	12.77 ± 1.21	12.55 ± 0.54	88.76
UAD13	20.44 ± 3.29	15.32 ± 4.58	13.32 ± 1.35	8.57 ± 0.75^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	34.60
UAD14	16.33 ± 1.41	13.77 ± 1.89	10.98 ± 1.61	7.25 ± 1.92^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	> 90
UAD15	14.76 ± 0.34	17.34 ± 2.24	10.82 ± 1.70	10.59 ± 2.22	> 90
UAD16	13.59 ± 0.57	10.28 ± 4.06	9.02 ± 0.07^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	7.62 ± 1.83^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	24.60
UAD17	12.46 ± 2.61	10.45 ± 0.63^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	8.91 ± 1.26^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	6.01 ± 0.42^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	80.05
UAD18	12.46 ± 1.38	10.52 ± 1.35	8.58 ± 1.30^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	6.98 ± 0.56^c c p < 0.05 in relation to the nitric oxide (NO) production of the untreated stimulated RAW264.7 cells (14.77 ± 2.52). IC50: half maximal inhibitory concentration.	63.40

[1] *e-mail: angelomld@gmail.com

Brasil

Brasil

Ursolic Acid Derivatives Down Regulate Inflammatory Mediators

Compound^a a Compounds: ursolic acid (UA) and ursolic acid derivative (UAD);	NF-κB expression / %
	15 µM^b b treatment concentration;	30 µM^b b treatment concentration;	60 µM^b b treatment concentration;	90 µM^b b treatment concentration;
UA	13.59 ± 0.29^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	7.91 ± 0.11^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	8.15 ± 0.31^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	6.95 ± 0.20^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.
UAD1	12.77 ± 0.32^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	11.98 ± 0.51^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	9.65 ± 0.08^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	3.03 ± 0.11^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.
UAD2	15.11 ± 0.28^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	14.78 ± 0.19^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	11.27 ± 0.32^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	8.45 ± 0.08^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.
UAD3	15.06 ± 0.15^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	14.45 ± 0.09^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	10.43 ± 0.22^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	8.76 ± 0.20^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.
UAD4	9.77 ± 0.37^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	11.11 ± 0.20^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	9.17 ± 0.26^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	10.47 ± 0.16^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.
UAD5	15.42 ± 0.20^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	12.22 ± 0.23^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	12.75 ± 0.18^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	13.96 ± 0.24^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.
UAD6	12.08 ± 0.12^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	12.08 ± 0.06^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	13.97 ± 0.16^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	13.93 ± 0.27^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.
UAD7	12.09 ± 0.11^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	11.65 ± 0.16^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	11.10 ± 0.18^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	11.84 ± 0.14^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.
UAD8	13.64 ± 0.19^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	15.12 ± 0.16^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	14.96 ± 0.12^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	14.54 ± 0.15^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.
UAD9	16.15 ± 0.48	16.27 ± 0.19	11.75 ± 0.12^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	15.52 ± 0.24^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.
UAD10	14.66 ± 0.23^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	17.73 ± 0.29	16.67 ± 0.34^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	18.40 ± 0.35^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.
UAD11	12.71 ± 0.27^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	14.81 ± 0.29^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	15.26 ± 0.31^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	14.04 ± 0.17^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.
UAD12	9.04 ± 0.55^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	13.66 ± 0.54^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	11.29 ± 0.86^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	11.98 ± 0.11^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.
UAD13	9.64 ± 0.23^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	11.62 ± 0.24^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	11.21 ± 0.23^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	8.96 ± 0.09^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.
UAD14	11.07 ± 0.19^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	9.968 ± 0.06^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	11.79 ± 0.26^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	9.37 ± 0.28^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.
UAD15	10.08 ± 0.17^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	9.708 ± 0.19^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	10.36 ± 0.18^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	9.34 ± 0.19^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.
UAD16	22.69 ± 0.46	16.29 ± 0.21	15.66 ± 0.08	3.38 ± 0.11^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.
UAD17	17.20 ± 0.50	15.14 ± 0.23^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	15.12 ± 0.29^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	13.39 ± 0.10^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.
UAD18	11.27 ± 0.03^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	11.72 ± 0.19^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	12.12 ± 0.14^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.	11.49 ± 0.18^c c p < 0.05 NF-κB expression by RAW264.7 macrophages treated with UA or UADs versus RAW264.7 not treated (NF-κB expression control: 17.24 ± 0.41). NF-κB: nuclear factor kappa B.

Compound^a a Compounds: ursolic acid (UA) and ursolic acid derivative (UAD);	TNF production / %
	15 µM^b b treatment concentration;	30 µM^b b treatment concentration;	60 µM^b b treatment concentration;	90 µM^b b treatment concentration;
UA	> 100	90.01 ± 8.08^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).	26.13 ± 5.98 ^c	23.98 ± 2.09^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).
UAD1	> 100	74.55 ± 9.52^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).	21.07 ± 0.33 ^c	17.98 ± 1.79^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).
UAD2	> 100	89.05 ± 6.69	31.73 ± 2.18 ^c	30.41 ± 1.36^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).
UAD3	> 100	> 100	33.48 ± 2.08 ^c	33.01 ± 2.72^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).
UAD4	> 100	91.13 ± 15.32	41.80 ± 2.78^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).	32.64 ± 4.11^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).
UAD5	> 100	> 100	48.02 ± 1.28^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).	32.38 ± 1.60^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).
UAD6	> 100	> 100	36.66 ± 2.82^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).	28.24 ± 1.03^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).
UAD7	67.02 ± 1.72^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).	37.97 ± 3.85^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).	15.78 ± 0.81^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).	14.82 ± 2.14^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).
UAD8	> 100	79.98 ± 12.35	19.55 ± 0.63^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).	14.43 ± 0.71^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).
UAD9	> 100	> 100	19.83 ± 0.63^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).	14.56 ± 1.83^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).
UAD10	84.01 ± 6.38	42.33 ± 0.96^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).	17.58 ± 1.13^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).	16.26 ± 0.69^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).
UAD11	77.09 ± 8.78	55.80 ± 3.63^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).	21.72 ± 1.52^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).	16.87 ± 0.56^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).
UAD12	49.87 ± 1.07^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).	19.48 ± 1.19^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).	6.50 ± 0.25^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).	4.71 ± 0.43^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).
UAD13	51.30 ± 2.07^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).	24.66 ± 1.48^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).	9.69 ± 0.55^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).	12.39 ± 1.03^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).
UAD14	53.41 ± 2.69^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).	16.34 ± 0.73^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).	10.92 ± 1.41^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).	10.81 ± 0.59^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).
UAD15	61.05 ± 3.85^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).	27.68 ± 2.01^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).	11.50 ± 1.14^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).	10.46 ± 0.60^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).
UAD16	93.81 ± 4.97	50.35 ± 1.39^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).	10.81 ± 0.92^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).	4.67 ± 0.46^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).
UAD17	> 100	> 100	74.88 ± 0.55^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).	40.87 ± 3.34^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).
UAD18	69.51 ± 1.20^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).	71.82 ± 4.95^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).	61.87 ± 4.40^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).	25.20 ± 2.09^c c p < 0.05 percentage of the tumor necrosis factor (TNF) production by RAW264.7 macrophages treated with UA and UADs versus RAW 264.7 not treated (100%).