Abstract Diabetic patients often experience delayed wound healing due to impaired functioning of human umbilical vein endothelial cells (HUVECs) under high glucose (HG) conditions. This is because HG conditions trigger uncontrolled lipid peroxidation, leading to iron‐dependent ferroptosis, which is caused by glucolipotoxicity. However, natural flavonoid compound Orientin (Ori) possesses anti‐inflammatory bioactive properties and is a promising treatment for a range of diseases. The current study aimed to investigate the function and mechanism of Ori in HG‐mediated ferroptosis. A diabetic wound model was established in mice by intraperitoneal injection of streptozotocin (STZ), and HUVECs were cultured under HG to create an in vitro diabetic environment. The results demonstrated that Ori inhibited HG‐mediated ferroptosis, reducing levels of malondialdehyde (MDA), lipid peroxidation, and mitochondrial reactive oxygen species (mtROS), while increasing decreased levels of malondialdehyde, lipid peroxidation, and mitochondrial reactive oxygen species, as well as increased levels of glutathione (GSH). Ori treatment also improved the wound expression of glutathione peroxidase 4 (GPX4) and angiogenesis markers, reversing the delayed wound healing caused by diabetes mellitus (DM). Additional investigations into the mechanism revealed that Ori may stimulate the nuclear factor‐erythroid 2‐related factor 2 (Nrf2)/GPX4 signaling pathway. Silencing Nrf2 in HG‐cultured HUVECs negated the beneficial impact mediated by Ori. By stimulating the Nrf2/GPX4 signaling pathway, Ori may expedite diabetic wound healing by decreasing ferroptosis.
To observe the effect of Tripterygium wilfordii polycoride (TWP) on ulcerative colitis (UC), and its intervention effect on toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88) signaling pathway, thus to investigate its possible mechanism.Trinitrobenzene sulfonic acid (TNBS)/ethanol enema method was used to set up the UC rat model. With random number table, 90 male Wistar rats were divided into normal control group, model group, TWP low, medium and high dose group (3, 6, 12 mg/kg, respectively) and azathioprine (AZA) group (6 mg/kg), with 15 rates in each group. Four days after enema, rates in each group were given corresponding drug lavage for 14 consecutive days. Disease activity index (DAI), colon gross morphological damage and histological grading of each group were observed. Using Western blot and reverse transcription (RT)-PCR method, the TLR4/MyD88 signaling pathway-related proteins in UC rat intestinal tissue were detected, namely TLR4, MyD88, tumor necrosis factor receptor related factor 6 (TRAF-6), nuclear factor kappa B (NF-κB), tumor necrosis factor alpha (TNF-α), and interleukin-1 beta (IL-1β).The DAI, colon gross morphological damage, and histological grading of the model group were significantly higher than that of the normal control group (all P<0.01), indicating successful establishment of UC model. The DAI, colon gross morphological damage and histological grading of the TWP high dose group were lower than those of the model group (0.87±0.25 vs 1.60±0.76, 3.93±1.94 vs 5.40±2.21, 5.45±2.73 vs 13.27±3.50, P<0.05). Compared with the normal control group, the mRNA and protein expressions of TLR4, MyD88, TRAF-6, NF-κB, TNF-α, and IL-1β in the model group rats were significantly increased (all P<0.01); which were significantly decreased in the TWP high dose group compared with model group rats (mRNA: 2.166±0.475 vs 5.647±0.275, 1.295±0.087 vs 3.774±0.418, 1.125±0.188 vs 2.535±0.320, 1.201±0.152 vs 2.082±0.077, 1.525±0.218 vs 3.094±0.022, 1.797±0.257 vs 17.152±0.145; protein: 0.252±0.010 vs 0.277±0.008, 0.172±0.002 vs 0.213±0.005, 0.233±0.006 vs 0.248±0.003, 0.099±0.003 vs 0.122±0.007, 0.238±0.002 vs 0.252±0.005, 0.235±0.003 vs 0.245±0.006, all P<0.05), also decreased in the AZA group (all P<0.01); and there were no significant differences between the TWP high dose group and the AZA group (all P>0.05).TWP can alleviate intestinal inflammation, promote healing of mucosa, showing a therapeutic effect for UC. One of its mechanisms may be through inhibiting the expression of TLR4, affecting the expression of TRAF-6, which is downstream to MyD66 signaling pathway, thus to suppress the activation of NF-κB and reduce the release of inflammatory factor such as TNF-α and IL-1β.
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