Fig 2: Inhibition of TAK1 activation blocks the HDAC6-induced activation of the TAK1–ADAM17 axis, release of sIL-6R and macrophage M2 polarization.A Western blot analysis of the phosphorylated and total protein expression of TAK1, ADAM17, and p38 in colon cancer cells treated with DMSO or Takinib (TAK1 selective inhibitor) after transfection with the empty vector or an HDAC6 overexpression plasmid. B Analysis of sIL-6R contents in the supernatants of HCT116 and HT29 cells in the indicated groups by ELISA. C Flow cytometry was used to evaluate the surface expression of CD11b, CD86, and CD206 of cocultured macrophages in the indicated groups. The statistical graphs (right) show the percentages of CD86+CD206- and CD86-CD206+ cells among CD11b+ cells. D QPCR detected the expression of M1 and M2 polarization related genes of cocultured macrophages in the indicated groups. Data were shown as the mean ± SD of three independent experiments, *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.

Fig 3: Simultaneous inhibition of p38 and ERK1/2 pathways decreases flagellin-induced inflammation and cell proliferation of KMM cells but has no obvious effect on MM cells. (A) MM and KMM cells were treated for 1 h with PBS, 10 µM p38 inhibitor (SB 203580), 10 µM ERK1/2 inhibitor (U0126), or a combination of 10 µM p38 inhibitor and 10 µM ERK1/2 inhibitor. Cells were then treated with PBS or 0.3 µg/ml flagellin for 1 h and analyzed for cytokines by qRT-PCR. (B) MM and KMM cells were treated for 1 h with PBS, 10 µM p38 inhibitor (SB 203580), 10 µM ERK1/2 inhibitor (U0126), or a combination of 10 µM p38 inhibitor and 10 µM ERK1/2 inhibitor. Cells were then treated with 1 µg/ml flagellin and examined for cell number at day 3 posttreatment. (C) Schematic illustration summarizing P. aeruginosa ligands, and their receptors and activated downstream pathways, that might enhance inflammation and cell proliferation of KSHV-transformed cells during P. aeruginosa infection. *, P = 0.05. NS, not significant.

Fig 4: E2 inhibited the leptin promoter activity and p38 phosphorylation stimulated by LPA(A) pGL4.17-LP1 transfected cells were treated as above, BBR as 2.5 µM, and E2 at a dose of 100 pM. The luminescence was set as 1 in the vehicle group treated with DMSO. Values are expressed as mean ± SEM, **p < 0.01 versus the LPA-stimulated group treated with DMSO. ##p < 0.01 versus the LPA-stimulated group treated with E2. (B) E2 (100 pM) inhibited LPA-induced p38 phosphorylation at Thr180/Tyr182. HepG2 cells were treated and western blot was conducted as described above. (C) Schematic diagram illustrates BBR restrained liver tumorigenesis through antagonizing the ATX-LPA-LPAR2-p38-leptin axis, and reducing LPA-stimulated abnormal leptin transcription in hepatoma cells.

Fig 5: Overexpression of miRNA-22 regulates p38 MAPK/NF-?B signaling in the in vitro stroke model. p-p38, NF-?B, COX-2 and iNOS protein expression was determined by western blotting and statistically analyzed. ##P<0.01 vs. control negative group. Control, control negative group; miRNA-22, overexpression of microRNA-22 group; MAPK, mitogen-activated protein kinase; NF, nuclear factor; p-, phosphorylated; COX, cyclooxygenase; iNOS, inducible NO synthase.