Fig 2: The protective effects of teneligliptin against OGD/R-induced reduction of ERK5 phosphorylation in HBMVECs. HBMVECs were exposed to hypoxic conditions for 6 h, followed by exposure to reperfusion media for different time points (24 h) in the presence or absence of teneligliptin (1, 3 μM). (A) Western blot analysis of phosphorylated and total ERK5 (****, P < 0.0001 vs. control group; ##, ###, P < 0.01, 0.001 vs. OGD/R group); (B and C). HBMVECs were exposed to hypoxic conditions for 6 h, followed by exposure to reperfusion media for different time points (24 h) in the presence or absence of teneligliptin (3 μM) or the ERK5 inhibitor XMD8-92 (100 nM). mRNA and Protein of KLF2 were measured; (D and E). HBMVECs were exposed to hypoxic conditions for 6 h, followed by exposure to reperfusion media for different time points (24 h) in the presence or absence of teneligliptin (3 μM) or the ERK5 inhibitor XMD8-92 (100 nM). mRNA and Protein of occludin was measured (****, P < 0.0001 vs. vehicle group; ####, P < 0.0001 vs. OGD/R group; $$$$, OGD/R+ teneligliptin group).

Fig 3: Diagrammatic representation of epigenetic and transcriptional control of hypertrophic signaling in heart. (A) Generally accepted protein pathways mediating cardiac hypertrophy. (B) Pathways targeted by quercetin in ZDF (Zucker Diabetic Fatty) rats. Quercetin attenuated expression of transcription factors MEF2, GATA4 and NFAT3 and downregulated upstream effectors HDAC4, calcineurin and Erk5.

Fig 4: Western blot analysis of relative protein expression of (A) total extracellular signal-regulated kinase 1/2 (Erk1/2), (B) Phospho Erk1/2 (Thr202/Tyr204), (C) Phospho Erk1/2 (Thr202/Tyr204)/total Erk1/2 ratio (D) extracellular signal-regulated kinase 5 (Erk5), (E) Protein Phosphatase 1 Catalytic Subunit Beta (PPP1CB), (F) Protein Phosphatase 2A C Subunit (PP2A), (G) calcium/calmodulin-dependent protein kinase II (CaMKII), (H) pThr286-CaMKII, (I) pThr286-CaMKII/CaMKII ratio, (J) pan-Akt (protein kinase B), (K) pThr308-Akt, (L) pThr308-Akt/pan Akt ratio, (M–O) Representative Western blots of detected proteins with estimated molecular weight (kDa) compared to total protein staining with Ponceau S. Data are presented as mean ± SEM and statistical differences as: *p < 0.05, **p < 0.01 (one-way ANOVA paired with Tukey´s multiple comparisons test).

Fig 5: Verify that glutamine metabolism acts on MEK5/ERK5 through the FGF17-FGFR4 axis to affect the oxidative stress level and apoptosis in NCI-H1299 cells. (A) Western blot analysis on the protein expression of E-cadherin, Vimentin, FGF17, FGFR4, p-MEK5, MEK5, p-ERK5, and ERK5 in NCI-H1299 cells (The blot for tubulin is shown once as it serves as the loading control for both GLUL and the above proteins, which were derived from the same cell samples); (B) Effect of FGF17 silencing and glutamine deprivation on ECAR and OCR in NCI-H1299 cells; (C) JC-1 mitochondrial membrane potential assay in NCI-H1299 (scale bar = 100 μm); (D) Quantitative results of the JC-1 mitochondrial membrane potential assay by ImageJ; (E) The effects of FGF17 silencing and glutamine deprivation on GSH/GSSG levels in NCI-H1299; (F) DCFH-DA assay to assess ROS level in NCI-H1299 (scale bar = 100 μm); (G) Quantitative results of the DCFH-DA assay by ImageJ. (Quantitative data are expressed as Mean ± SD, with three samples at least per group. For comparisons with Ctrl groups, ns, no significance; *p < 0.05, **p < 0.01, ***p < 0.001).