Salvianolic acid B suppresses hepatic fibrosis by inhibiting ceramide glucosyltransferase in hepatic stellate cells.

UDP-glucose ceramide glucosyltransferase (UGCG) is the first key enzyme in glycosphingolipid (GSL) metabolism that produces glucosylceramide (GlcCer). Increased UGCG synthesis is associated with cell proliferation, invasion and multidrug resistance in human cancers. In this study we investigated the role of UGCG in the pathogenesis of hepatic fibrosis. We first found that UGCG was over-expressed in fibrotic livers and activated hepatic stellate cells (HSCs). In human HSC-LX2 cells, inhibition of UGCG with PDMP or knockdown of UGCG suppressed the expression of the biomarkers of HSC activation (α-SMA and collagen I). Furthermore, pretreatment with PDMP (40 µM) impaired lysosomal homeostasis and blocked the process of autophagy, leading to activation of retinoic acid signaling pathway and accumulation of lipid droplets. After exploring the structure and key catalytic residues of UGCG in the activation of HSCs, we conducted virtual screening, molecular interaction and molecular docking experiments, and demonstrated salvianolic acid B (SAB) from the traditional Chinese medicine Salvia miltiorrhiza as an UGCG inhibitor with an IC50 value of 159 µM. In CCl4-induced mouse liver fibrosis, intraperitoneal administration of SAB (30 mg · kg-1 · d-1, for 4 weeks) significantly alleviated hepatic fibrogenesis by inhibiting the activation of HSCs and collagen deposition. In addition, SAB displayed better anti-inflammatory effects in CCl4-induced liver fibrosis. These results suggest that UGCG may represent a therapeutic target for liver fibrosis; SAB could act as an inhibitor of UGCG, which is expected to be a candidate drug for the treatment of liver fibrosis.

Predictors of difficult endoscopic resection of submucosal tumors originating from the muscularis propria layer at the esophagogastric junction.

BACKGROUND: Endoscopic resection approaches, including endoscopic submucosal dissection (ESD), submucosal tunneling endoscopic resection (STER) and endoscopic full-thickness resection (EFTR), have been widely used for the treatment of submucosal tumors (SMTs) located in the upper gastrointestinal tract. However, compared to SMTs located in the esophagus or stomach, endoscopic resection of SMTs from the esophagogastric junction (EGJ) is much more difficult because of the sharp angle and narrow lumen of the EGJ. SMTs originating from the muscularis propria (MP) in the EGJ, especially those that grow extraluminally and adhere closely to the serosa, make endoscopic resection even more difficult. AIM: To investigate the predictors of difficult endoscopic resection for SMTs from the MP layer at the EGJ. METHODS: A total of 90 patients with SMTs from the MP layer at the EGJ were included in the present study. The difficulty of endoscopic resection was defined as a long procedure time, failure of en bloc resection and intraoperative bleeding. Clinicopathological, endoscopic and follow-up data were collected and analyzed. Statistical analysis of independent risks for piecemeal resection, long operative time, and intraoperative bleeding were assessed using univariate and multivariate analyses. RESULTS: According to the location and growth pattern of the tumor, 44 patients underwent STER, 14 patients underwent EFTR, and the remaining 32 patients received a standard ESD procedure. The tumor size was 20.0 mm (range 5.0-100.0 mm). Fourty-seven out of 90 lesions (52.2%) were regularly shaped. The overall en bloc resection rate was 84.4%. The operation time was 43 min (range 16-126 min). The intraoperative bleeding rate was 18.9%. There were no adverse events that required therapeutic intervention during or after the procedures. The surgical approach had no significant correlation with en bloc resection, long operative time or intraoperative bleeding. Large tumor size (≥ 30 mm) and irregular tumor shape were independent predictors for piecemeal resection (OR: 7.346, P = 0.032 and OR: 18.004, P = 0.029, respectively), long operative time (≥ 60 min) (OR: 47.330, P = 0.000 and OR: 6.863, P = 0.034, respectively) and intraoperative bleeding (OR: 20.631, P = 0.002 and OR: 19.020, P = 0.021, respectively). CONCLUSION: Endoscopic resection is an effective treatment for SMTs in the MP layer at the EGJ. Tumors with large size and irregular shape were independent predictors for difficult endoscopic resection.

Positive feedback loop of IL-1ß/Akt/RARα/Akt signaling mediates oncogenic property of RARα in gastric carcinoma.

Abnormal expression and function of retinoic acid receptor α (RARα) have been reported to be associated with various cancers including acute promyelocytic leukemia and hepatocellular carcinoma. However, the role and the mechanism of RARα in gastric carcinoma (GC) were unknown. Here, the expression of RARα was frequently elevated in human GC tissues and cell lines, and its overexpression was closely correlated with tumor size, lymph node metastasis and clinical stages in GC patients. Moreover, RARα overexpression was related with pathological differentiation. Functionally, RARα knockdown inhibited the proliferation and metastasis of GC cells, as well as enhanced drug susceptibility both in vitro and in vivo. Additionally, RARα knockdown suppressed GC progression through regulating the expression of cell proliferation, cell cycle, invasion and drug resistance associated proteins, such as PCNA, CyclinB1, CyclinD2, CyclinE, p21, MMP9 and MDR1. Mechanistically, the above oncogenic properties of RARα in GC were closely associated with Akt signaling activation. Moreover, overexpression of RARα was induced by IL-1ß/Akt signaling activation, which suggested a positive feedback loop of IL-1ß/Akt/RARα/Akt signaling in GC. Taken together, we demonstrated that RARα was frequently elevated in GC and exerted oncogenic properties. It might be a potential molecular target for GC treatment.

Impact of the number of resected lymph nodes on survival after preoperative radiotherapy for esophageal cancer.

To assess the impact of the number of resected lymph nodes (RLNs) for survival in esophageal cancer (EC) patients treated with preoperative radiotherapy and cancer-directed surgery. The Surveillance Epidemiology and End Results (SEER) database was queried to identify EC patients treated from 1988 to 2012 who had complete data on the number of positive lymph nodes and number of RLNs. Kaplan-Meier survival analysis and Cox regression proportional hazard methods were used to determine factors that significantly impact cause-specific survival (CSS) and overall survival (OS). There were a total of 3,159 patients who received preoperative radiotherapy and cancer-directed surgery. The median number of RLNs was 10 in both patients who received and did not receive preoperative radiotherapy (P = 0.332). Cox regression univariate and multivariate analysis showed that RLN count was a significant prognostic factor for CSS and OS. Patients with 11-71 RLNs had better CSS (hazard ratio [HR] = 0.694, 95% confidence interval [CI]: 0.603-0.799, P < 0.001) and OS (HR = 0.724, 95% CI: 0.636-0.824, P < 0.001) than patients with 1-10 RLNs. The 5-year CSS rates were 39.1% and 44.8% in patients with 1-10 RLNs and 11-71 RLNs, respectively (P < 0.001). The 5-year OS rates were 33.7% and 39.9% in patients with 1-10 RLNs and 11-71 RLNs, respectively (P < 0.001). A higher number of RLNs was associated with better survival by tumor stage and nodal stage (all P < 0.05). RLN count is an independent prognostic factor in EC patients who undergo preoperative radiotherapy and cancer-directed surgery.

Effect of postoperative radiotherapy for squamous cell cancer of the breast in a surveillance epidemiology and end results population-based study.

The therapeutic value of postoperative radiotherapy (RT) for squamous cell cancer of the breast (SCCB) is unclear. This retrospective study used a population-based national registry to determine the impact of postoperative RT on survival of women with SCCB. The Surveillance Epidemiology and End Results (SEER) database was used to identify females with SCCB who underwent primary surgical resection from 1973 to 2012. Kaplan-Meier survival analysis and Cox regression proportional hazard methods were used to determine the impact of RT following resection associated with cause-specific survival (CSS) and overall survival (OS). A total of 523 patients met the eligibility criteria. The median follow-up time was 55 months, the 10-year CSS and OS rates were 65.6%, and 46.0%, respectively. A total of 167 patients (31.9%) received postoperative RT. Multivariate analysis indicated that advanced pT and pN stage, and no postoperative RT were independently associated with poor OS; advanced pT and pN stage were independently associated with poor CSS. Postoperative RT was significantly associated with improved 10-year OS (54.5% vs. 42.0%, P =.001), but had no effect on CSS (P =.217). Analysis of patients with different stages of SCCB indicated that RT was associated with improved CSS (P =.047) and OS (P <.001) in those with stage II cancer and improved OS in patients with stage pN0 cancer (P <.001). Postoperative RT improved the survival of SCCB patients, especially in those with stage II and stage pN0 cancer.

IL-1ß induced RXRα overexpression through activation of NF-κB signaling in gastric carcinoma.

BACKGROUND: Abnormal expression of Retinoid X Receptor α (RXRα) seems to be a frequent incident in a variety of cancers. However, the expression pattern and the mechanisms in gastric carcinoma (GC) remain unclear. METHODS: In GC tissues and cell lines, the expression levels of RXRα mRNA and protein were detected by Q-PCR and Western blot, respectively; the localization of RXRα was evaluated by immunohistochemistry (IHC) or immunocytochemistry (ICC). The effect of IL-1ß on RXRα expression and localization was detected by Western blot and ICC. Nuclear factor-κB (NF-κB) pathway was assessed via Western blot. RESULTS: RXRα expression was markedly elevated at both mRNA and protein levels in GC tissues and cell lines (all P<0.05). The abnormal overexpression of RXRα was predominantly visualized in cytoplasm. IL-1ß significantly induced cytoplasmic expression of RXRα in a time-dependent manner. Co-incubation with IL-1ß enhanced phospho-IKKα (p-IKKα) expression and this effect could be inhibited by the specific inhibitor for NF-κB (all P<0.01). CONCLUSIONS: IL-1ß upregulated RXRα through activation of NF-κB signaling and these suggested a possible clinic significance of retinoid receptor expression in the diagnosis and treatment of GC.