Fig 2: IOE-mediated anti-neurodegenerative effects. Oxidative stress in brain tissue has been considered as a major cause of neurodegenerative diseases. TMT and glutamate can induce the phosphorylation of MAPKs in the brain, and elevated phosphorylation of MAPKs attenuate the expression of Nrf2 and Heme oxygenase-1 (HO-1), resulting in oxidative stress in the brain. Our study suggested that oral administration of IOE ameliorates oxidative stress-mediated neurodegeneration through regulating the MAPK/Nrf2/HO-1 antioxidant pathways.

Fig 3: FXR deficiency exacerbates cisplatin-induced renal injury and ferroptotic response in a mouse model of the AKI.The WT and FXR knockout mice were intraperitoneally injected with cisplatin (20 mg/kg) or vehicle control (saline). After 48 h of cisplatin injection, the serum and the kidneys were collected. (A) BUN, sCr, and neutrophil gelatinase-associated lipocalin (NGAL) levels were measured in the serum. MDA and iron levels and GSH/GSSG ratio were measured in the kidney tissue (n = 6–7). (B) Protein levels of GPX4, HMOX1, ACSL4, and FTH1 were detected by immunoblotting. The relative protein levels are shown. The values for the WT control group were set to 1 (n = 4). (C) The mRNA levels of the indicated genes were measured by qRT-PCR. The values for the control group are set to 1. (D) Representative images of H&E and PAS staining to examine histology. Paraffin-embedded kidney tissue sections were stained with antibodies against 3-NT and 4-HNE (scale bar 100 μm). Computer-based morphometric analysis is shown (right bar graph, n = 7–8 in each group). All values are presented as the mean ± SD. Statistical significance was measured using one-way ANOVA with Bonferroni post hoc-test. *P < 0.05, **P < 0.005.

Fig 4: Adiponectin affects the release of HO-1/HMGB1 via AdipoR1/APPL1. (A) Relative expression of HO-1 in the different groups was detected using western blot analysis. Relative expression of HMGB1 in the different groups was detected using western blot analysis. ***P<0.001 vs. control; ###P<0.001 vs. D-gal + Ov-NC; $P<0.05, $$$P<0.001 vs. D-gal + Ov-adiponectin + negative-NC. Adiponectin/AdipoR1/APPL1 inhibits oxidative stress via HO-1/HMGB1. (B) H9C2 cells overexpressing adiponectin were treated with HO-1 inhibitor.; the relative expression of ROS in the different groups was detected using a ROS Assay kit. ***P<0.001 vs. control; ###P<0.001 vs. D-gal + Ov-adiponectin group. (C) ROS production in H9c2 cells in the different groups was detected using a ROS Assay kit. DCF fluorescence staining of the cells is indicated by arrows in the figure, the intensity of staining can reflect the level of ROS (magnification, ×200). (D) Relative expression of MDA in the different groups was detected using a Lipid Peroxidation MDA Assay kit. ***P<0.001 vs. control; ###P<0.001 vs. D-gal + Ov-adiponectin group. AdipoR1, adiponectin receptor 1; ROS, reactive oxygen species; HO-1, heme oxygenase 1; HMGB1, high mobility group box 1; APPL1, adaptor protein phosphotyrosine interacting with PH domain and leucine zipper 1; NC, negative control; Ov-, overexpression; si-, small interfering RNA; D-gal, D-galactose; MDA, malondialdehyde.

Fig 5: Overexpression of KNG1 notably restores the regulatory effects of sufentanil on NF-κB and Nrf2/HO-1 signaling. Western blot analysis was performed to detect the protein expression levels of (A) p-NF-κB and NF-κB, and (B) Nrf2 and HO-1 in LPS-stimulated alveolar epithelial type II cells. ***P<0.001 vs. control; ##P<0.01, ###P<0.001 vs. LPS; ΔP<0.05 vs. LPS + 40 µM sufentanil + Oe-NC. KNG1, kininogen-1; NF-κB, nuclear factor-κB; Nrf2, nuclear factor erythroid 2-related factor 2; HO-1, heme oxygenase-1; LPS, lipopolysaccharide; Oe, overexpression; NC, negative control; p-, phosphorylated.