Soluble epoxide hydrolase deficiency promotes liver regeneration and ameliorates liver injury in mice by regulating angiocrine factors and angiogenesis.

BACKGROUND: Soluble epoxide hydrolase (sEH) is a key enzyme for the hydrolysis of epoxyeicosatrienoic acids (EETs) and has been implicated in the pathogenesis of hepatic inflammation, fibrosis, cancer, and nonalcoholic fatty liver disease. However, the role of sEH in liver regeneration and injury remains unclear. METHODS: This study used sEH-deficient (sEH-/-) mice and wild-type (WT) mice. Hepatocyte proliferation was assessed by immunohistochemical (IHC) staining for Ki67. Liver injury was evaluated by histological staining with hematoxylin and eosin (H&E), Masson's trichrome, and Sirius red, as well as IHC staining for α-SMA. Hepatic macrophage infiltration and angiogenesis were reflected by IHC staining for CD68 and CD31. Liver angiocrine levels were detected by ELISA. The mRNA levels of angiocrine or cell cycle-related genes were measured by quantitative real-time RT-PCR (qPCR). The protein levels of cell proliferation-related protein and phosphorylated signal transducer and activator of transcription 3 (STAT3) were detected by western blotting. RESULTS: sEH mRNA and protein levels were significantly upregulated in mice after 2/3 partial hepatectomy (PHx). Compared with WT mice, sEH-/- mice exhibited a higher liver/body weight ratio and more Ki67-positive cells on days 2 and 3 after PHx. The accelerated liver regeneration in sEH-/- mice was attributed to angiogenesis and endothelial-derived angiocrine (HGF) production. Subsequently, hepatic protein expression of cyclinD1 (CYCD1) and the downstream direct targets of the STAT3 pathway, such as c-fos, c-jun, and c-myc, were also suppressed post-PHx in sEH-/- compared to WT mice. Furthermore, sEH deficiency attenuated CCl4-induced acute liver injury and reduced fibrosis in both CCl4 and bile duct ligation (BDL)-induced liver fibrosis rodent models. Compared with WT mice, sEH-/- mice had slightly decreased hepatic macrophage infiltration and angiogenesis. Meanwhile, sEH-/- BDL mice had more Ki67-positive cells in the liver than WT BDL mice. CONCLUSIONS: sEH deficiency alters the angiocrine profile of liver endothelial to accelerate hepatocyte proliferation and liver regeneration, and blunts acute liver injury and fibrosis by inhibiting inflammation and angiogenesis. sEH inhibition is a promising target for liver diseases to improve liver regeneration and damage.

Apolipoprotein C1 (APOC1) promotes tumor progression via MAPK signaling pathways in colorectal cancer.

Aim: Identifying high-efficiency prognostic markers for colorectal cancer (CRC) is necessary for clinical practice. Increasing evidence demonstrates that apolipoprotein C1 (APOC1) promotes carcinogenesis in some human cancers. However, the expression status and biological function of APOC1 in CRC remain unclear. Materials and methods: We detected the association between APOC1 expression and clinicopathological features in 140 CRC patients by immunohistochemistry. Small interfering RNA (siRNA) technology was used to downregulate APOC1 expression in CRC cells. Cell proliferation was estimated by CCK8 and clonogenic assays. The cell cycle and apoptosis were analyzed by flow cytometry. Cell migration and invasion were examined by a transwell assay. Gene set enrichment analysis (GSEA) and protein expression of signaling pathways were used to suggest the possible APOC1-associated pathways in CRC. Results: APOC1 was highly expressed in CRC tissues. High immunohistochemistry (IHC) expression of APOC1 was correlated with the N stage, M stage and TNM stage. High IHC APOC1 expression in CRC tissues was associated with poor prognosis. Univariate and multivariate Cox regression analyses showed that APOC1 was an independent risk factor for OS. Cell proliferation of CRC cell lines was inhibited by the downregulation of APOC1. Moreover, si-APOC1 transfection induced cell cycle arrest but low apoptosis increases by regulating the expression of related proteins. Cell migration and invasion were also inhibited by the downregulation of APOC1. The Cancer Genome Atlas Colorectal Adenocarcinoma (TCGA COAD-READ) dataset analyzed by GSEA showed that APOC1 might be involved in the mitogen-activated protein kinase (MAPK) signaling pathway, which was further preliminarily confirmed by Western blotting. Conclusion: APOC1 was overexpressed in CRC tissues, and a high level of APOC1 contributed to a poor prognosis. APOC1 expression influenced the cell proliferation ability and motility capacity of CRC via the MAPK pathway. APOC1 could act as a novel prognostic biomarker in CRC.

Deperitoneum biological mesh repair for abdominal wall hernia: a novel wound healing promotion idea.

PURPOSE: Nowadays, biological matrix has become more widely applied than synthetic mesh for the surgical management of ventral hernia. Conventionally, such biodegradable matrix is commonly placed in an intraperitoneal or extraperitoneal position to reinforce the abdominal wall during surgery. Herein, we introduce our novel idea to deliver such biological material. MATERIAL AND METHODS: After contrast-enhanced CT-scan via lateral decubitus confirmed the position of ventral hernias, 11 patients underwent deperitoneum biological mesh repair by open or laparoscopic approach. During surgery, biological material was placed in preperitoneal position with elimination of matrix-covered peritoneum meanwhile. No bridge repair was allowed for this technique. Postoperative complications were prospectively documented. RESULTS: Laparoscopic and open repair were performed in six and five patients, respectively. The mean operative time was 115 min, with no significant difference between the two procedures. All patients had quick recovery and returned to their normal life, with median five days (range, 3-12 days) of hospital stay after surgery. Although wound dehiscence and chronic pain occurred in three (27.3%) patients, no additional surgery was required. No recurrence case was observed within the one-year follow-up period. CONCLUSION: This novel approach could be safely performed in ventral hernia patients. Early evaluation of this surgical technique demonstrates quick recovery and minimal complications.

High expression of SLC17A9 correlates with poor prognosis in colorectal cancer.

Solute carrier family 17 member 9 (SLC17A9) is a member of the family of transmembrane proteins that are involved in the transport of small molecules. The role of SLC17A9 in colorectal cancer (CRC) remains poorly understood. The present study aimed to demonstrate the clinicopathological significance and prognostic role of SLC17A9 in CRC. Here, we firstly analyzed the data from The Cancer Genome Atlas on SLC17A9 expression in CRC data sets and detected SLC17A9 expression level in 8 pairs of fresh CRC tissues and adjacent nontumorous tissues by quantitative real-time reverse-transcription polymerase chain reaction and Western blotting assays. Immunohistochemical staining was used to detect SLC17A9 protein expression in 144 CRC patients in our center. The bioinformatic analysis, Western blotting, and immunohistochemical analyses revealed that SLC17A9 was significantly up-regulated in CRC specimens compared with adjacent nontumorous tissues. SLC17A9 overexpression was significantly correlated with several clinicopathological features, such as advanced T stage (P < .001), N stage (P < .001), M stage (P < .001), TNM stage (P < .001), and tumor location (P = .01). A Kaplan-Meier survival curve suggested that higher SLC17A9 expression was statistically correlated with poor overall survival and disease-free survival in patients with CRC. Univariate and multivariate Cox regression analyses demonstrated that SLC17A9 was an independent prognostic predictor for survival of CRC patients. Therefore, our data suggested that SLC17A9 may play an important role in the progression of CRC and may potentially be used as an independent biomarker for prognostic evaluation of CRC.

Laparoscopic right hemicolectomy oriented by superior mesenteric artery for right colon cancer: efficacy evaluation with a match-controlled analysis.

BACKGROUND: Laparoscopic right hemicolectomy (LRC) with a principle of D3 lymphadenectomy seems to be appropriate in treatment of right-sided colon cancer (RCC). This study aimed to evaluate clinical efficacy of superior mesenteric artery (SMA)-guided LRC (SLRC) for RCC patients. PATIENTS AND METHODS: Data for RCC patients with radical resection were retrieved from our database and electronic medical records (January 2010 to December 2014). Patients undergoing SLRC procedure were compared with those undergoing conventional laparoscopic right hemi-colectomy (CLRC), with a match ratio of 1:2 for group balance. Perioperative and long-term outcomes were compared between two groups. RESULTS: In sum, 102 matched patients were selected, with a median follow-up of 32 (range, 3-68) months. The mean operative time was significantly reduced in the SLRC group compared to the CLRC group (206.9 vs 240.0 minutes, P=0.007), with increased incidence of postoperative complications observed (14.7% vs 8.8%, P=0.499). Average length of stay after surgery (7.4 vs 8.0 days), estimated blood loss (85.3 vs 105.4 mL), number of harvested (28.4 vs 28.2) and positive (0.6 vs 0.9) lymph nodes, and overall costs ($4826.9 vs $4874.6) were comparable between two groups (P>0.05). The 3-year disease-free survival rate (89.4% vs 92.1%, P=0.840) and overall survival rate (93.0% vs 83.1%, P=0.273) were similar in both groups. Older age (≥65 years, P=0.049) and advanced tumor stage (≥II, P=0.009) were independent risk factors of recurrence. CONCLUSION: The perioperative and oncologic outcomes of SLRC were not superior, but comparable to CLRC. SMA-guided dissection was a feasible surgical approach in treatment of RCC.

The Optimal Application of Transrectal Ultrasound in Staging of Rectal Cancer Following Neoadjuvant Therapy: A Pragmatic Study for Accuracy Investigation.

Background: Transrectal ultrasound (TRUS) is a cost-effective test for preoperative assessment of rectal cancer. However, whether the accuracy of TRUS staging is correlated with tumor location remains obscured. This study is designed to explore their relationship and confirm an optimal application of TRUS in rectal cancer restaging. Methods: From 2005 to 2011, rectal cancer patients with TRUS data were retrospectively reviewed. Patients were divided into five groups according to tumor-involved rectal segment (SEG) above the anal verge: SEG I 1-3cm, II 3-6cm, III 6-9cm, IV 9-12cm, and V 12-16cm. The accuracy and long-term outcomes of tumor staging were compared between ultrasonographic and pathological stages. Results: 219 patients were included, with 55 (25.1%) in SEG I, 123 (56.2%) in SEG II, 32 (14.6%) in SEG III, 4 (1.8%) in SEG IV and 5 (2.3%) in SEG V. The overall accuracy of TRUS staging was remarkably superior to clinical staging by CT (64.8% vs. 34.7%, P<0.001), with 70.3% and 82.2% for ultrasonographic T and N stages respectively. The accuracy of TRUS reached its peak value when tumors were located in SEG II. The 5-year overall survival had no significant difference between TRUS and pathology staging for all stages. A cox regression analysis indicated that high levels of CEA and tumor location were risk factors of inaccurate staging. Conclusions: TRUS is still a valuable examination for restaging of rectal cancer after neoadjuvant therapy. The application of TRUS would be optimal for rectal cancer located 3-6cm above the anal verge.

The macrophage C-type lectin receptor CLEC5A (MDL-1) expression is associated with early plaque progression and promotes macrophage survival.

BACKGROUND: Biomarkers of early plaque progression are still elusive. Myeloid DAP12-associating lectin-1 (MDL-1), also called CLEC5A, is a C-type lectin receptor implicated in the progression of multiple acute and chronic inflammatory diseases. However, the relationship between its level and atherosclerosis is unknown. In this study, we aimed to investigate the correlation between macrophage MDL-1 expression and early atherosclerosis progression. METHODS: Immunofluorescence staining, real-time PCR and western blot were performed to analyze MDL-1 expression in aorta or mice macrophages. The role of MDL-1 in macrophage survival was further investigated by adenovirus infection and TUNEL assay. RESULTS: Significant MDL-1 expression was found in advanced human and apoE-/- mice atherosclerotic plaques, especially in lesional macrophages. In the model of atherosclerosis regression, we found MDL-1 expression was highly downregulated in lesional macrophages from ldlr-/- mouse regressive plaques, coincident with a reduction in lesional macrophage content and marker of M1 proinflammatory macrophages. Furthermore, we found MDL-1 was significantly expressed in inflammatory M1 subtype polarized bone marrow-derived macrophages. In vitro experiments, the level of MDL-1 was remarkably elevated in macrophages treated with pathophysiological drivers of plaque progression, such as oxidized low-density lipoprotein (ox-LDL) and hypoxia. Mechanistically, we demonstrated that MDL-1 overexpression notably promoted macrophage survival and decreased cleaved caspase-3 expression under ox-LDL stimulation, which suggested that it could maintain lesional macrophage survival and cause its accumulation. CONCLUSIONS: This study firstly demonstrated that MDL-1 is mainly expressed in atherosclerotic lesional macrophages and increased macrophage MDL-1 expression is associated with early plaque progression and promotes macrophage survival.

The anti-inflammatory vasostatin-2 attenuates atherosclerosis in ApoE-/- mice and inhibits monocyte/macrophage recruitment.

We showed previously that reduced level of vasostatin-2 (VS-2) correlates to the presence and severity of coronary artery disease. In this study, we aimed to figure out the role of chromogranin A (CGA) derived VS-2 in the development of atherosclerosis and monocyte/macrophage recruitment. Apolipoprotein E-deficient (ApoE-/-) mice fed a high-fat diet exhibited attenuated lesion size by 65 % and 41 % in En face and aortic root Oil red O staining, MOMA-2 positive area by 64 %, respectively, in VS-2 treatment group compared with PBS group. Proinflammatory cytokines tumour necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1) were all remarkably reduced in aortic tissues after VS-2 treatment. Mechanistically, in adhesion assay using intravital microscopy in vivo, VS-2 suppressed the number of leukocytes adhering to the wall of apoE-/- mice mesenteric arteries. In chemotactic assay, flow cytometry analysis of peritoneal lavage exudate from C57BL/6 mice showed VS-2 significantly decreased the recruiment number of inflammatory monocytes/macrophages in a thioglycollate-induced peritonitis model. Furthermore, fewer fluorescent latex beads labelled Ly-6Chi monocytes accumulated in aortic sinus lesions of apoE-/- mice after VS-2 treatment. In addition, according to the microarray of human monocyte/macrophage, we found VS-2 stimulation caused a dose-dependent decrease of Rac1 expression and inactivation of Pak1 in mice primary monocytes as well as THP-1 cells and inhibited MCP-1/CCL-5 induced transmigration in vitro. In conclusion, the Chromogranin A-derived VS-2 attenuates atherosclerosis in apoE-/- mice and, in addition to its anti-inflammatory property, also acts as an inhibitor in monocyte/macrophage recruitment.

Association of decreased serum sTREM-1 level with the severity of coronary artery disease: Inhibitory effect of sTREM-1 on TNF-α- and oxLDL-induced inflammatory reactions in endothelial cells.

Soluble triggering receptor expressed on myeloid cells 1 (sTREM-1) is closely involved in autoimmune diseases and inflammatory reactions. We aimed to investigate whether serum sTREM-1 is related to coronary artery disease (CAD) and to evaluate the biological effects of sTREM-1 in cell experiments.This cross-sectional study included 263 consecutive patients with angiographically documented CAD, who were admitted for diagnosis and interventional treatment of CAD (CAD group), with 162 participants without CAD serving as controls (control group). Serum levels of sTREM-1 and high sensitivity C reactive protein (hsCRP) were determined in all participants. In cell experiments, the influence of sTREM-1 on tumor necrosis factor-α (TNF-α)- or oxidized low-density lipoprotein (oxLDL)-induced inflammatory reactions was evaluated in human umbilical vein endothelial cells (HUVECs).Serum level of sTREM-1 was significantly lower in CAD patients than in controls (P < 0.001). sTREM-1 values were related to the number of diseased coronary arteries (Spearman r = -0.413, P < 0.001) and the severity represented by Gensini score (Pearson r = -0.336, P < 0.001). Multivariable logistic regression analysis revealed that decreased sTREM-1 were independent determinants of CAD (OR = 0.428, P < 0.001). In cell experiments, recombinant sTREM-1 protein concentration-dependently inhibited the expression of IL-1ß, IL-6, TNF-α, VCAM-1, and ICAM-1 induced by TNF-α or oxLDL in HUVECs.This study demonstrates that decreased serum sTREM-1 level is significantly associated with the presence and severity of CAD. sTREM-1 restrains inflammatory reaction in endothelial cells, suggesting that it might be a potential vascular protective factor.

Clinical utility of the ratio between circulating fibrinogen and fibrin (ogen) degradation products for evaluating coronary artery disease in type 2 diabetic patients.

BACKGROUND: We investigated whether and to what extent the ratio between circulating fibrinogen (Fg) and its degradation products (FDP) reflects the severity of coronary artery disease (CAD) in type 2 diabetic patients. METHODS: Plasma levels of Fg and FDP were determined, and Fg/FDP ratio was calculated in 344 consecutive patients with type 2 diabetes and chest pain on exertion undergoing coronary angiography. The severity of CAD was evaluated by the number of significant CAD (>50% luminal diameter narrowing) and Gensini score. RESULTS: Plasma Fg was higher, but Fg/FDP ratio was lower in patients with significant CAD (n = 255) compared with those without (n = 89), due to a disproportionate increase in FDP. Fg and FDP correlated positively, while Fg/FDP ratio negatively, with the number of diseased coronary arteries and the tertile of Gensini score (all P values for trend < 0.01). After adjusting for age, sex, risk factors for CAD, lipid profiles, glycosylated hemoglobin A1c, creatinine, leukocyte count, and high-sensitivity C-reactive protein, Fg/FDP ratio remained an independent determinant for multivessel coronary disease (MVD) (odds ratio [OR], 0.869; 95% confidence interval [CI], 0.788-0.958, P = 0.005) and high tertile of Gensini score (OR, 0.797, 95% CI, 0.682-0.930, P = 0.004). The area under the curve of Fg/FDP ratio was larger than that of Fg for predicting the presence of MVD (0.647 vs. 0.563, P = 0.048) and Gensini score ≥ 30 (0.656 vs. 0.538, P = 0.026). CONCLUSIONS: Elevated plasma Fg and FDP level and reduced Fg/FDP ratio are associated with presence of CAD, and Fg/FDP ratio is superior to Fg in reflecting severe coronary atherosclerosis for patients with type 2 diabetes.