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Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. Insulin resistance (IR) is important in the development and progression of NAFLD. Nuclear erythroid 2‑related factor 2 (Nrf2) has previously been reported to be a novel regulator in NAFLD. The present study determined that Nrf2 knockdown accelerated the onset of obesity and non‑alcoholic steatohepatitis (NASH), via the induction of hepatic IR in mice fed a high‑fat diet (HFD), which was confirmed by an increase in total and hepatic weight in Nrf2‑null‑HFD mice, in addition to marked structural disorder in liver tissues from the Nrf2‑null‑HFD group analyzed by histopathological examination. Subsequently, it was demonstrated that hepatic IR in Nrf2‑null‑HFD mice was influenced by oxidative stress; this was confirmed by an increase in malondialdehyde levels and a decrease in glutathione levels. In addition, it was determined that the induction of hepatic IR by Nrf2 knockdown in HFD-treated mice was regulated by activation of the nuclear factor‑κB (NF‑κB) signaling pathway, as detected by an increase in the expression levels of nuclear NF‑κB, and its downstream effectors interleukin‑6 and tumor necrosis factor‑α. The present study provides insight into the function of Nrf2 in NAFLD, indicating that Nrf2 deletion may lead to hepatic IR by activation of NF‑κB, which is often associated with oxidative stress. Therefore, activation of Nrf2 may limit disease progression and act as a therapeutic approach for the treatment of NASH.

The present study aimed to investigate the protective role of curcumin against oxidative stress in rat hepatic stellate cells (HSCs)-T6, and to determine the possible underlying mechanisms. HSC-T6 cells were divided into three groups: Negative control group, oxidant-treated group and curcumin-treated group. Flow cytometry and spectrophotometry were used to measure the production of reactive oxygen species (ROS), and the levels of malondialdehyde (MDA) and glutathione (GSH). Immunocytochemistry and a radioimmunoassay were used to determine the expression of smooth muscle α-actin (α-SMA) and the secretion of extracellular matrix (ECM) molecules. In addition, western blotting and immunocytochemistry were used to determine the expression levels of nuclear factor-erythroid 2-related factor (Nrf2). Treatment with glucose oxidase (GO) significantly stimulated the formation of ROS and increased the production of MDA, as compared with the control cells; however, the production of GSH was only slightly increased. In addition, treatment with GO significantly promoted the expression of α-SMA and the secretion of ECM molecules. Conversely, treatment with curcumin significantly decreased the levels of ROS and MDA, and significantly increased the levels of GSH. Curcumin significantly inhibited the expression of α-SMA and decreased the secretion of ECM molecules. Furthermore, treatment with curcumin significantly increased the nuclear expression levels of Nrf2. These results indicated that curcumin may protect rat HSCs against oxidative stress and inhibit the GO-induced activation and secretion of ECM molecules in vitro. These effects were mediated by the upregulation of Nrf2 nuclear translocation.

Background The SIP syncytium in the gut consists of smooth muscle cells, interstitial cells of Cajal, and PDGFRα+ cells. We studied the fate of SIP cells after blocking PDGFRα receptor to explore the roles of PDGFRα signaling in the postnatal development and functional maintenance of the SIP syncytium. Methods Crenolanib was administered to mice from P0, P10, or P50. The morphological changes in SIP cells were examined by immunofluorescence. Protein expression in SIP cells was detected by Western blotting. Moreover, colonic transit was analyzed by testing the colonic bead expulsion time. Key results A dose of 5 mg(kg•day)-1 crenolanib administered for 10 days beginning on P0 apparently hindered the development of PDGFRα+ cells in the colonic longitudinal muscularis and myenteric plexus without influencing their proliferative activity and apoptosis, but this result was not seen in the colonic circular muscularis. SMCs were also inhibited by crenolanib. A dose of 7.5 mg(kg•day)-1 crenolanib administered for 15 days beginning on P0 caused reductions in both PDGFRα+ cells and ICC in the longitudinal muscularis, myenteric plexus, and circular muscularis. However, when crenolanib was administered at a dose of 5 mg(kg•day)-1 beginning on P10 or P50, it only noticeably decreased the number of PDGFRα+ cells in the colonic longitudinal muscularis. Crenolanib also caused PDGFRα+ cells to transdifferentiate into SMC in adult mice. Colonic transit was delayed after administration of crenolanib. Conclusions & inferences Therefore, PDGFRα signaling is essential for the development and functional maintenance of the SIP cells, especially PDGFRα+ cells.