Non-alcoholic fatty liver disease (NAFLD) has become one of the most common diseases and severe problems worldwide because of the global increase in obesity, dyslipidemia, hypertension, and type 2 diabetes mellitus. NAFLD includes a wide spectrum of liver diseases, the histological forms of which range from non-alcoholic fatty liver (NAFL), which is generally nonprogressive, to non-alcoholic steatohepatitis (NASH), which can progress to chronic hepatitis, liver cirrhosis (LC), and sometimes hepatocellular carcinoma (HCC). Unlike NAFL, as the progressive form of NAFLD, NASH is characterized by the presence of inflammation with or without fibrosis in addition to hepatic steatosis. Although it is widely known and proved that persistent hepatic injury and chronic inflammation in the liver activate quiescent hepatic stellate cells (HSCs) and lead to hepatic fibrosis, the three-step process of “inflammation-fibrosis-carcinoma” in NAFLD has not been investigated and clarified clearly. In this process, the initiation of inflammation in the liver and the function of various liver inflammatory cells have been discussed regularly, while the activated HSCs, which constitute the principal cells responsible for fibrosis and their cross-talk with inflammation, seem not to be investigated specifically and frequently. Also, accumulated evidence suggests that HSCs can not only be activated by inflammation but also participate in the regulation of liver inflammation. Therefore, it is necessary to investigate the unique roles of HSCs in NAFLD from the perspective of inflammation and fibrosis. Here, we review the pivotal effects and mechanisms of HSCs and highlight the potential value of HSC-targeted treatment methods in NAFLD.

Introduction: Glucocorticoid (GC) therapy is the main treatment for systemic lupus erythematosus (SLE). However, some patients are resistant to these agents. Abnormalities of glucocorticoid receptor (GR) seem to be related to steroid resistance. This study evaluated GRs in T lymphocytes and monocytes of SLE patients by flow cytometry (FCM) using a monoclonal antibody (mAb) and FITC-Dex probes. Methods: Thirty-five patients with SLE before treatment and 27 age- and sex-matched normal controls were studied. Disease activity scores were determined before and after treatment and used to divide the patients into steroid-resistant (SR) and steroid-sensitive (SS) groups. GRs in T lymphocytes (CD3⁺) and monocytes (CD14⁺) were examined by FCM with GR-mAb and FITC-Dex probes before treatment. Peripheral blood mononuclear cells (PBMCs) were isolated for in vitro GCs sensitivity assays. The validity of FCM analysis of intracellular staining for GR with GR-mAb and FITC-Dex probes was evaluated through comparison with western blot and radioligand binding assay (RLBA) in U937 and K562 cells in vitro. One-way ANOVA, student's t test, linear regression and spearman correlation were performed. Results: A significant decrease in GR binding and the expression in K562 and U937 cells with 10^-6 M dexamethasone (Dex) was found compared with those without Dex. In addition, a positive correlation was found between FCM and RLBA as well as FCM and Western blot. The expression and binding of both CD3/GR and CD14/GR in SR patients with SLE, detected by FCM, were all lower than those in SS patients with SLE, whereas there was no significant difference in SS patients and controls. In vitro corticosteroid sensitivity assay indicated that PHA-stimulated tumour necrosis factor-α (TNF-α), IL-12 and interferon-γ (IFN-γ) secretion was significantly inhibited by 10^-6 M Dexamethasone in all controls and SS patients, compared with that in SR group, which confirms patient classification as SR and SS by disease activity index (SLEDAI) score. Conclusions: Abnormalities of expression and binding of the GR may be involved in tissue resistance to steroids in SLE patients. Determination of GR expression and binding by FCM may be useful in predicting the response to steroid treatment of SLE patients. Trial registration: Clinical trial registration number NCT00600652.

Oxidative stress, which occurs after ultraviolet (UV) radiation, usually results in Glucocorticoid (GC) resistance and the subsequent development of skin inflammation. One approach to protecting the skin against UV radiation is the use of antioxidants. The ginsenoside Rg1 is a novel natural antioxidant isolated from the medicinal plant Panax ginseng C.A. Mey. We demonstrated that UVB exposure exacerbated inflammation and reduced both the level of the glucocorticoid receptor (GR) and the efficacy of dexamethasone (Dex) in human keratinocytes (HaCaT cells). Pretreatment with Rg1 increased the expression of GR and restored Dex responsiveness to inflammation in UVB-irradiated HaCaT cells. Mechanistically, Rg1 rescued UVB-induced HDAC2 degradation. HDAC2 knockdown partially abolished the Rg1-induced up-regulation of GR and the enhancement of GC sensitivity. In addition, Rg1 reduced the production of reactive oxygen species (ROS), which preceded the up-regulation of HDAC2, and consequent sensitization of cells to Dex. Moreover, Rg1 treatment promoted the translocation and activation of Nrf2. Nrf2 knockdown partially abolished the Rg1-induced decrease of ROS production and increase of HDAC2. Rg1 also potentiated the anti-inflammatory effects of Dex in UVB-irradiated mouse skin. In conclusion, we demonstrated that Rg1 attenuated UVB-induced GC insensitivity. Notably, these effects were partially mediated by the Nrf2/HDAC2 pathway.

Treatment with sorafenib remains the first-line therapy for patients with advanced stage hepatocellular carcinoma (HCC), however, it has limited effect due to the acquired resistance of HCC. Elucidating the potential mechanism can assist in developing promising strategies to overcome this resistance. In the present study, a sorafenib-refractory HCC cell was established from the Huh7 parental cell line, which was resistant to sorafenib mediated-cytotoxicity in vitro. The cell inhibition rate and apoptosis of cells were determined by MTT assay and flow cytometry, respectively. Electronic microscopy was used to detect autophagy in cells. The expression levels of endoplasmic reticulum stress (ERS)-related protein, apoptosis-related protein and cFLIP were examined by western blot analysis. Co-immunoprecipitation was used to examine the ubiquitination of cFLIP. It was found that sustained exposure to sorafenib activated ERS in the HCC cells. The ERS inhibitor partly increased sorafenib-induced cell death in these cells. In addition, ERS-induced autophagy was important in resistance to sorafenib, as inhibiting autophagy led to the resistant HCC cells becoming more sensitive to sorafenib. However, ERS-induced apoptosis did not differ between sorafenib-sensitive HCC cells and sorafenib-refractory HCC cells. The knockdown of cFLIP reversed the acquired sorafenib resistance by activating caspase-8 and inhibiting activated ERS in the sorafenib-resistant HCC cells. Mechanistically, a sustained increased in cFLIP was found to be dependent on USP2-induced deubiquitination. In conclusion, cFLIP was identified as a potential target for overcoming the acquired sorafenib resistance in HCC. These effects occurred partially through reducing ERS-related autophagy in HCC.

Postsurgical recurrence within 2 years is the major cause of poor survival of hepatocellular carcinoma (HCC) patients. However, the molecular mechanism underlying HCC recurrence remains unclear. Here, we distinguish the function and mechanism of Sec62 in promoting HCC recurrence. The correlation between Sec62 and early recurrence was demonstrated in 60 HCC samples from a prospective study. HCC cells with Sec62 knockdown (Sec62^KD) or overexpression (Sec62^OE) were used to determine the potential of Sec62 in cell migration in vitro. Microarray analysis comparing Sec62^KD or Sec62^OE to their control counterparts was used to explore the mechanisms of Sec62-induced recurrence. A luciferase-labelled orthotopic nude mouse model of HCC with Sec62^KD or Sec62^OE was used to validate the potential of Sec62 in early HCC recurrence in vivo. We found that high expression of Sec62 was positively correlated with surgical recurrence in clinical HCC samples. Multivariate analysis revealed that Sec62 was an independent prognostic factor for early recurrence in postoperative HCC patients. Moreover, Sec62 promoted migration and invasion of HCC cells in vitro and postsurgical recurrence in vivo. Mechanically, integrinα/CAV1 signalling was identified as one of the targets of Sec62 in cell movement. Overexpression of integrin α partially rescued the Sec62 knockdown-induced inhibition of cell migration. Sec62 is a potentially prognostic factor for early recurrence in postoperative HCC patients and promotes HCC metastasis through integrinα/CAV1 signalling. Sec62 might be an attractive drug target for combating HCC postsurgical recurrence.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. In China, traditional Chinese herb medicine has been widely used in the treatment of HCC. Jiedu Recipe (JR) is a common used prescription which has shown good results against HCC. However, the exact mechanisms of JR are still unknown. Therefore, we investigated the efficacy of JR on HCC in the current study. JR inhibited the cell viability of both SMMC‐7721 and Huh7 cells in both time‐ and dose‐dependent manners. Transwell assay revealed that JR decreased the number of migrated cells of SMMC‐7721 cells. JR treatment increased the E‐cadherin expression level and decreased the levels of p‐Smad2/3 and Smad2/3. Further study showed that JR reversed the effect of TGFβ1 on the expression of E‐cadherin, vimentin, N‐cadherin, and MMP2/9. JR also significantly inhibited TGFβ1‐induced migration and invasion of SMMC‐7721 and Huh7 cells determined by wound healing assay and transwell assay. TGFβ1 treatment increased the phosphorylation of Smad2/3, p38 MAPK, JNK, ERK1/2, and Akt in SMMC‐7721 cells and pretreatment with JR blocked TGFβ1‐induced activation of Smad2/3 and Akt and MAPKs. In conclusion, JR inhibits liver cancer cells migration and invasion through epithelial mesenchymal transition (EMT) inhibition via Smad2/3 dependent and independent pathways, suggesting it is an effective therapeutic strategy against HCC metastasis.