Anti-Inflammatory Activity of Oligomeric Proanthocyanidins Via Inhibition of NF-ΚB and MAPK in LPS-Stimulated MAC-T Cells = Anti-Inflammatory Activity of Oligomeric Proanthocyanidins Via Inhibition of NF-ΚB and MAPK in LPS-Stimulated MAC-T Cells

다국어 초록 (Multilingual Abstract)

Oligomeric proanthocyanidins (OPCs), classified as condensed tannins, have significant anti-oxidation, anti-inflammation and anti-cancer effects. This study was performed to investigate the anti-inflammatory effects of OPCs and the mechanism underlying these effects in lipopolysaccharide (LPS)-stimulated bovine mammary epithelial cells (MAC-T). Real-time PCR and ELISA assays indicated that OPC treatment at 1, 3 and 5 μg/ml significantly reduced the mRNA and protein, respectively, of oxidant indicators cyclooxygenase-2 (COX-2) (p < 0.05) and inducible nitric oxide synthase (iNOS) (p < 0.01) as well as inflammation cytokines interleukin (IL)-6 (p < 0.01), IL-1β (p < 0.01) and tumor necrosis factor-α (TNF-α) (p < 0.05) in LPS-induced MAC-T cells. Moreover, OPCs downregulated LPSinduced phosphorylation of p65 and inhibitor of nuclear factor kappa B (NF-κB) (IκB) in the NF-κB signaling pathway (p < 0.01), and they inhibited p65 translocation from the cytoplasm to the nucleus as revealed by immunofluorescence test and western blot. Additionally, OPCs decreased phosphorylation of p38, extracellular signal regulated kinase and c-jun NH₂-terminal kinase in the MAPK signaling pathway (p < 0.01). In conclusion, the anti-inflammatory and antioxidant activities of OPCs involve NF-κB and MAPK signaling pathways, thus inhibiting expression of pro-inflammatory factors and oxidation indicators. These findings provide novel experimental evidence for the further practical application of OPCs in prevention and treatment of bovine mastitis.

참고문헌 (Reference)

1 Cong L, "The research progress of extraction, separation and pharmacological effects of procyanidins" 39 : 285-288, 2017

2 Zhang H, "The protective effect of epicatechin on experimental ulcerative colitis in mice is mediated by increasing antioxidation and by the inhibition of NF-kappa B pathway" 68 : 514-520, 2016

3 Deorukhkar A, "Targeting inflammatory pathways for tumor radiosensitization" 80 : 1904-1914, 2010

4 Hsu LY, "Synthesis and protective effects of bis{4-[N, N-di-(carboxymethyl)amino]phenoxy}alkane derivatives on UVA-induced production of MMP-1 in human skin fibroblasts" 62 : 867-874, 2014

5 Gunther J, "Streptococcus uberis strains isolated from the bovine mammary gland evade immune recognition by mammary epithelial cells, but not of macrophages" 47 : 13-, 2016

6 Li DP, "Salidroside attenuates inflammatory responses by suppressing nuclear factor-kappa B and mitogen activated protein kinases activation in lipopolysaccharide-induced mastitis in mice" 62 : 9-15, 2013

7 Yu Q, "Resokaempferol-mediated anti-inflammatory effects on activated macrophages via the inhibition of JAK2/STAT3, NF-kappa B and JNK/p38 MAPK signaling pathways" 38 : 104-114, 2016

8 Sun SC, "Regulation of nuclear factor-kappa B in autoimmunity" 34 : 282-289, 2013

9 Zhang XJ, "Progress on epigenetic regulation of the pathogenesis of cow mastitis" 55 : 22-28, 2019

10 Huang J, "Proanthocyanidins promote osteogenic differentiation of human periodontal ligament fibroblasts in inflammatory environment via suppressing NF-kappaB signal pathway" 43 : 892-902, 2020

11 Sun WS, "Proanthocyanidins attenuation of H2O2-induced oxidative damage in tendon-derived stem cells via upregulating Nrf-2 signaling pathway" 8 : e7529104-, 2017

12 Yang LY, "Proanthocyanidins against oxidative stress : from molecular mechanisms to clinical applications" 11 : e8584136-, 2018

13 Xua Z, "Proanthocyanidins : oligomeric structures with unique biochemical properties and great therapeutic promise" 7 : 381-388, 2012

14 Jiang X, "Proanthocyanidin prevents lipopolysaccharide-induced depressive-like behavior in mice via neuroinflammatory pathway" 135 : 40-46, 2017

15 Ryu SJ, "Oleuropein suppresses LPS-induced inflammatory responses in RAW 264.7 cell and zebrafish" 63 : 2098-2105, 2015

16 Wu HC, "Nuciferine ameliorates inflammatory responses by inhibiting the TLR4-mediated pathway in lipopolysaccharide-induced acute lung injury" 8 : 10-, 2017

17 Chen XX, "Nuciferine alleviates LPS-induced mastitis in mice via suppressing the TLR4-NFκB signaling pathway" 67 : 903-911, 2018

18 Liu T, "NF-kappaB signaling in inflammation" 2 : 17023-, 2017

19 Zhang HS, "NF-kappa B in inflammation and renal diseases" 5 : 12-, 2015

20 Cheng WN, "Moringa extract attenuates inflammatory responses and increases gene expression of casein in bovine mammary epithelial cells" 9 : 391-, 2019

21 Wang JJ, "Morin suppresses inflammatory cytokine expression by downregulation of nuclear factor-kappa B and mitogen-activated protein kinase(MAPK)signaling pathways in lipopolysaccharidestimulated primary bovine mammary epithelial cells" 99 : 3016-3022, 2016

22 Hamza AA, "Molecular characterization of the grape seeds extract's effect against chemically induced liver cancer : in vivo and in vitro analyses" 8 : 16-, 2018

23 Prince PD, "LPS-induced renal inflammation is prevented by(–)–epicatechin in rats" 11 : 342-349, 2017

24 Kim JY, "Isoliquiritigenin isolated from the roots of glycyrrhiza uralensis inhibits LPS-induced NOS and COX-2 expression via the attenuation of NF-kappa B in RAW 264. 7 macrophages. Eur. J" 584-, 2008

25 이재은, "Inhibition of inflammatory responses in lipopolysaccharide-induced RAW 264.7 cells by Pinus densiflora root extract" 한국응용생명화학회 61 (61): 275-281, 2018

26 Wang RH, "Inhibition of PHLDA2 transcription by DNA methylation and YY1 in goat placenta" 739 : 144512-, 2020

27 Wu H, "IFN-τ alleviates lipopolysaccharide-induced inflammation by suppressing NF-κB and MAPKs pathway activation in mice" 39 : 1141-1150, 2016

28 Naigang Wang, "Hesperetin ameliorates lipopolysaccharide-induced acute lung injury in mice through regulating the TLR4–MyD88–NF-kB signaling pathway" 대한약학회 42 (42): 1063-1070, 2019

29 Sang-Hyon Kim, "Grape seed proanthocyanidin extract ameliorates murine autoimmune arthritis through regulation of TLR4/MyD88/NF-κB signaling pathway" 대한내과학회 33 (33): 612-621, 2018

30 Fu YH, "Glycyrrhizin inhibits the inflammatory response in mouse mammary epithelial cells and a mouse mastitis model" 281 : 2543-2557, 2014

31 Hu XL, "Effects of trichostatin A on the expressions of inflammatory cytokines and Toll-like receptor 4 and the acetylation of nuclear factor-κB induced by lipopolysaccharide in macrophage" 64 : 651-656, 2012

32 Chin-Hee Song, "Effects of 17β-Estradiol on Colonic Permeability and Inflammation in an Azoxymethane/Dextran Sulfate Sodium-Induced Colitis Mouse Model" 거트앤리버 소화기연관학회협의회 12 (12): 682-693, 2018

33 Pinedo PJ, "Dynamics of culling risk with disposal codes reported by dairy herd improvement dairy herds" 93 : 2250-2261, 2010

34 Gomes F, "Control of bovine mastitis : old and recent therapeutic approaches" 72 : 377-382, 2016

35 Borbon TY, "Coinfection with leishmania major and Staphylococcus aureus enhances the pathologic responses to both microbes through a pathway involving IL-17A" 13 : e0007247-, 2019

36 Nakanishi T, "Catechins inhibit vascular endothelial growth factor production and cyclooxygenase-2 expression in human dental pulp cells" 48 : 277-282, 2015

37 Jedrzejczak M, "Bovine mammary epithelial cell cultures for the study of mammary gland functions" 50 : 389-398, 2014

38 Liu J, "Anti-tumor effect of Pinus massoniana bark proanthocyanidins on ovarian cancer through induction of cell apoptosis and inhibition of cell migration" 10 : e0142157-, 2015

39 Pornngarm Limtrakul, "Anti-inflammatory effects of proanthocyanidin-rich red rice extract via suppression of MAPK, AP-1 and NF-κB pathways in Raw 264.7 macrophages" 한국영양학회 10 (10): 251-258, 2016

40 Nan B, "Acrylamide induced the activation of NLRP3 inflammasome via ROS-MAPKs pathways in Kupffer cells" 31 : 45-62, 2020

41 Hussein SSS, "(+)-Catechin attenuates NF-kappa B activation through regulation of akt, MAPK, and AMPK signaling pathways in LPS-induced BV-2 microglial cells" 43 : 927-952, 2015