Babao Dan attenuates acute ethanol-induced liver injury via Nrf2 activation and autophagy.

BACKGROUND: Babao Dan (BBD), a traditional Chinese medicine, has been used as a complementary and alternative medicine to treat multifarious liver diseases. In this study, we aimed to observe its protective effect on ethanol-induced liver injury and explore potential mechanisms. METHODS: Mice pretreated with BBD (0.125, 0.25 and 0.5 g/kg BW) were administrated by ethanol gavage (5 g/kg BW). Liver injury biomarkers and hepatic redox parameters were evaluated by histopathology as well as serum and hepatic content analysis. AML-12 cell was also utilized to determine the efficacy of BBD against ethanol-induced hepatotoxicity. RESULTS: Drunkenness experiment showed that the latency was significantly increased and the drunken sleep time was decreased in mice pretreated with BBD. We then found that BBD could reduce hepatic lipid peroxidation and steatosis induced by ethanol exposure. BBD could also suppress ethanol-induced depletion of hepatic antioxidant enzyme. Besides that, BBD treatment lessened the induction of hepatic cytochrome P450 2E1, a major contributor to ethanol-mediated oxidative stress, and up-regulated the expression of nuclear factor erythroid 2-related factor 2 and its two transcriptional targets hemeoxygenase-1 and glutamate-cysteine ligase catalytic subunit. Furthermore, autophagy induced by BBD contributed to hepatoprotection activity. CONCLUSIONS: Our results suggest that BBD can markedly dispel acute ethanol-induced hepatotoxicity through multiple pathways including attenuation of ethanol-mediated oxidative stress, enhancement of the oxidative defense systems and activation of autophagy.

TGF-ß in pancreatic cancer initiation and progression: two sides of the same coin.

Pancreatic cancer is highly lethal malignant tumor with characterised rapid progression, invasiveness and resistance to radiochemotherapy. Transforming growth factor-ß (TGF-ß) signaling plays a dual role in both pro-tumorigenic and tumor suppressive of pancreatic cancer, depending on tumor stage and microenvironment. TGF-ß signaling components alteration are common in pancreatic cancer, and its leading role in tumor formation and metastases has received increased attention. Many therapies have investigated to target TGF-ß signaling in the preclinical and clinical setting. In this review, we highlight the dual roles of TGF-ß and touch upon the perspectives on therapeutic target of TGF-ß signaling in pancreatic cancer.

Meta-analysis of oxaliplatin-based versus fluorouracil-based neoadjuvant chemoradiotherapy and adjuvant chemotherapy for locally advanced rectal cancer.

A meta-analysis was conducted to compare oxaliplatin-based with fluorouracil-based neoadjuvant chemoradiotherapy and adjuvant chemotherapy for locally advanced rectal cancer. MEDLINE, EMBASE and CENTRAL were systematically searched for relevant randomized controlled trials (RCTs) until January 31 2017. Review Manager (version 5.3) was used to analyze the data. Dichotomous data were calculated by odds ratio (OR) with 95% confidence intervals (CI). A total of 8 RCTs with 6103 stage II or III rectal cancer patients were analyzed, including 2887 patients with oxaliplatin+fluorouracil regimen and 3216 patients with fluorouracil alone regimen. Compared with fluorouracil-based regimen group, oxaliplatin-based regimen group attained higher pathologic complete response (OR = 1.29, 95% CI: 1.12-1.49, P = 0.0005) and 3-year disease-free survival (OR = 1.15, 95% CI: 0.93-1.42, P = 0.21), but suffered greater toxicity (OR = 2.07, 95% CI: 1.52-2.83, P < 0.00001). Also, there were no significant differences between two regimens in sphincter-sparing surgery rates (OR = 0.94, 95% CI: 0.83-1.06, P = 0.33), 5-year disease-free survival (OR = 1.15, 95% CI: 0.93-1.42, P = 0.21) and overall survival (3-year, OR = 1.14, 95% CI: 0.98-1.34, P = 0.09; 5-year, OR = 1.06, 95% CI: 0.78-1.44, P = 0.70). In conclusion, the benefits of adding oxaliplatin to fluorouracil-based neoadjuvant chemoradiotherapy and adjuvant chemotherapy for locally advanced rectal cancer remains controversial, and cannot be considered a standard approach.

Meta-analysis of transcatheter arterial chemoembolization plus radiofrequency ablation versus transcatheter arterial chemoembolization alone for hepatocellular carcinoma.

This meta-analysis was conducted to compare transcatheter arterial chemoembolization (TACE) plus radiofrequency ablation (RFA) with TACE alone for hepatocellular carcinoma. We searched MEDLINE, EMBASE and CENTRAL for all relative randomized controlled trials (RCTs) and retrospective studies until October 31 2016. Tumor response, recurrence-free survival, overall survival and postoperative complications were the major evaluation indices. Review Manager (version 5.3) was used to analyze the data. Dichotomous data was calculated by odds ratio (OR) with 95% confidence intervals (CI). There were 1 RCT and 10 retrospective studies with 928 patients in this meta-analysis: 412 patients with TACE plus RFA and 516 patients with TACE alone. Compared with TACE alone group, TACE plus RFA group attained higher tumor response rates (OR = 6.08, 95% CI = 4.00 to 9.26, P < 0.00001), achieved longer recurrence-free survival rates (ORRFS = 3.78, 95% CI: 2.38 to 6.02, P < 0.00001) and overall survival rates (OR1-year = 3.92, 95% CI = 2.41-6.39, P < 0.00001; OR3-year = 2.56; 95% CI = 1.81-3.60; P < 0.00001; OR5-year = 2.78; 95% CI = 1.77-4.38; P < 0.0001). Serious postoperative complications were not observed, although complications were higher in TACE plus RFA group than that in TACE alone group (OR = 2.74, 95% CI = 1.07 to 7.07, P = 0.04). In conclusion, the use of TACE plus RFA for intermediate stage hepatocellular carcinoma can attain higher tumor response rates and improve survival rates than TACE alone.

Meta-analysis of laparoscopic versus open liver resection for colorectal liver metastases.

BACKGROUND: To compare surgical and oncological outcomes of laparoscopic versus open liver resection for colorectal liver metastases. RESULTS: A total of 14 retrospective studies with 1679 colorectal liver metastases patients were analyzed: 683 patients treated with laparoscopic liver resection and 996 patients with open liver resection. With respect to surgical outcomes, laparoscopic compared with open liver resection was associated with lower blood loss (MD, -216.7, 95% CI, -309.4 to -124.1; P < 0.00001), less requiring blood transfusion (OR, 0.36; 95% CI, 0.23 to 0.55; P < 0.00001), lower postoperative complication morbidity (OR, 0.61; 95% CI, 0.47 to 0.80; P = 0.003), and shorter hospitalization time (MD, -3.85, 95% CI, -5.00 to -2.71; P < 0.00001). However, operation time and postoperative mortality were no significant difference between the two approaches. With respect to oncological outcomes, laparoscopic liver resection group was prone to lower recurrence rate (OR, 0.78; 95% CI, 0.61-0.99; P = 0.04), but surgical margins R0, overall survival and disease-free survival were no significant difference. MATERIALS AND METHODS: We performed a systematic search in MEDLINE, EMBASE, and CENTRAL for all relevant studies. All statistical analysis was performed using Review Manager version 5.3. Dichotomous data were calculated by odds ratio (OR) and continuous data were calculated by mean difference (MD) with 95% confidence intervals (CI). CONCLUSIONS: Laparoscopic and open liver resection for colorectal liver metastases have the same effect on oncological outcomes, but laparoscopic liver resection achieves better surgical outcomes.

Meta-analysis of bariatric surgery versus non-surgical treatment for type 2 diabetes mellitus.

BACKGROUND: To compare short-term and long-term results of bariatric surgery vs non-surgical treatment for type 2 diabetes mellitus (T2DM). METHODS: A systematic search was conducted in the PubMed, Embase, and Cochrane Library databases for randomized controlled trials (RCTs). All statistical analysis was performed using Review Manager version 5.3. The dichotomous data was calculated using risk ratio (RR) and continuous data was using mean differences (MD) along with 95% confidence intervals (CI). RESULTS: A total of 8 RCTs with 619 T2DM patients were analyzed. Compared with non-surgical treatment group, bariatric surgery group was associated with higher rate T2DM remission (RR = 5.76, 95%CI:3.15-10.55, P < 0.00001), more reduction HbA1C (MD = 1.29, 95%CI: -1.70 to -0.87, P < 0.00001), more decrease fasting plasma glucose (MD = -36.38, 95%CI: -51.76 to -21.01, P < 0.00001), greater loss body weight (MD = -16.93, 95%CI: 19.78 to -14.08, P < 0.00001), more reduction body mass index (MD = -5.80, 95%CI: -6.95 to -4.64, P < 0.00001), more decrease triglyceride concentrations (MD = -51.27, 95%CI: -74.13 to -28.41, P < 0.0001), and higher increase density lipoprotein cholesterol (MD = 9.10, 95%CI: 7.99 to 10.21; P < 0.00001). But total and low density lipoprotein cholesterol were no significant changes. CONCLUSION: Bariatric surgery for T2DM is efficacious and improves short- and long-term outcomes as compared with non-surgical treatment.

Mesenchymal stem cells promote pancreatic adenocarcinoma cells invasion by transforming growth factor-ß1 induced epithelial-mesenchymal transition.

Mesenchymal stem cells (MSCs) could be ideal delivery vehicles for antitumor biological agents in pancreatic adenocarcinoma (PA). While the role of MSCs in tumor growth is elusive. Inflammation is an important feature of PA. In this study, we reported that MSCs pre-stimulated with the combination of TNF-α and IFN-γ promote PA cells invasion. The invasion of PA cell lines were evaluate by wound healing assay and transwell assay in vitro and liver metastasis in nude mice. We observed MSCs pre-stimulated with the combination of TNF-α and IFN-γ promoted PA cells invasion in vitro and in vivo. Consistent with MSCs promoting PA cells invasion, PA cells were found undergo epithelial-mesenchymal transition (EMT). We demonstrated that MSCs pre-stimulated with both of TNF-α and IFN-γ provoked expression transforming growth factor-ß1 (TGF-ß1). MSCs promoting EMT-mediated PA cells invasion could be reversed by short interfering RNA of TGF-ß1. Our results suggest that MSCs could promote PA cells invasion in inflammation microenvironment and should be cautious as delivery vehicles in molecular target therapy.

Surgical approach does not influence the outcome of incidental gallbladder carcinoma.

UNLABELLED: Several reports claim that there is a risk that laparoscopic cholecystectomy (LC) might worsen the prognosis of unsuspected gallbladder cancer. The aim of this study was to evaluate whether the surgical approach influence the outcome in patients with incidental gallbladder carcinoma. METHODS: A retrospective study was done of 28 patients who were diagnosed with unsuspected gallbladder carcinoma who had undergone cholecystectomy for benign gallbladder disease at our institution between 1999 and 2007. 20 patients (4 men and 16 women, aged from 37 to 81 years) undergoing LC (group A) and 8 patients (6 men and 2 women, aged from 43 to 88 years) undergoing open cholecystectomy (OC) (group B) with incidental diagnosed GC. We evaluated the outcome in the two groups correlating the cumulative survival rates with tumor stage and surgical technique (LC or OC), time of diagnosis (after or during cholecystectomy). RESULTS: nine patients (69.2 %) in group A and four patients (30.8%) in group B had recurrence. Survival rate was statistically correlated to tumor stage (P<0.0001) Survival rate was statistically correlated with tumor stage but neither with the surgical approach used to perform cholecystectomy, nor with time of diagnosis (intra- or post-operatively). CONCLUSION: These results would seem to lend support to the opinion that LC does not worsen the prognosis for incidental GC, regardless of whether the tumor was detected during or after cholecystectomy.

A 10-year experience with hepatic trauma in a Chinese level one trauma center.

OBJECTIVES: To analyze strategies of operative management (OM) and non-operative management (NOM), mortality, and morbidity of hepatic trauma patients. METHODS: We retrospectively reviewed 296 consecutive patients with hepatic trauma at the Department of Hepatobiliary Surgery, 101st Hospital of PLA, Wuxi, Jiangsu, China a single level one trauma center between January 2003 and December 2012. Data on demographics, mechanism of trauma, American Association for the Surgery of Trauma grade, initial management, and outcome were collected for this study. RESULTS: A total of 101 (34%) patients were of low-grade, while 195 (66%) were of high-grade. Hepatic trauma with associated injury of other organs was noted in 205 (69.3%) patients. The initial management was OM for 119 (40.2%) and NOM for 177 (59.8%), 12 patients later required laparotomy. Surgical intervention included perihepatic packing in 6, liver parenchyma suturing in 29, liver parenchyma suturing and hemostasis in 50, segmental resection in 19, and right hepatectomy in 2. The overall mortality rate was 9.1%, and the mortality rate of 8.4% was due to hepatic injuries. CONCLUSION: All hemodynamically stable patients can be managed by NOM with excellent results, while high-grade hepatic injuries require OM due to hemodynamic instability, or concomitant injuries.

Increased of serum high-mobility group box chromosomal protein 1 correlated with intestinal mucosal barrier injury in patients with severe acute pancreatitis.

BACKGROUND: Secondary infections are the leading cause of death in patients with severe acute pancreatitis (SAP). The gut represents the main source of pancreatic contamination and related septic complications. High-mobility group box chromosomal protein 1 (HMGB1) was recently identified to play an important role in the SAP intestinal mucosal barrier dysfunction. OBJECTIVE: To investigate the correlation of high-mobility group box 1 (HMGB1) with intestinal barrier injury and infections in patients with severe acute pancreatitis (SAP). METHODS: The serum levels of HMGB1, amylase, lipase, and biochemical indicators were measured in 80 patients with SAP at the time of admission. Furthermore, relationship between their serum HMGB1 levels and intestinal barrier injury, infection and other clinical factors were analyzed. RESULTS: The mean value of serum HMGB1 levels was significantly higher in patients with SAP (6.02 ± 2.42 ng/mL) than that in healthy volunteers (1.87 ± 0.63 ng/mL). Serum HMGB1 levels were significantly positively correlated with the Ranson score. The HMGB1 levels were higher in patients with infection during the clinical course, the HMGB1 levels in non-survivors were higher than those in survivors, and positively correlated with DAO activity, L/M ratio, the concentration of endotoxin (R = 0.484, P <0.01). CONCLUSIONS: HMGBl level of patients with severe acute pancreatitis was significantly increased, and can be used as an important indicator to determine the intestinal barrier dysfunction and infection.

Looped host defense peptide CLP-19 binds to microtubules and inhibits surface expression of TLR4 on mouse macrophages.

The looped host defense peptide CLP-19 is derived from a highly functional core region of the Limulus anti-LPS factor and exerts robust anti-LPS activity by directly interacting with LPS in the extracellular space. We previously showed that prophylactic administration of CLP-19 even 20 h prior to LPS challenge might significantly increase the survival rate in a lethal endotoxin shock mouse model. Such an effect may be associated with immune regulation of CLP-19. To investigate the underlying mechanisms, peptide affinity chromatography, immunofluorescence, and Western blotting procedures were used to identify α- and ß-tubulin as direct and specific binding partners of CLP-19 in the mouse macrophage cell line RAW 264.7. Bioinformatic analysis using the AutoDock Vina molecular docking and PyMOL molecular graphics system predicted that CLP-19 would bind to the functional residues of both α- and ß-tubulin and would be located within the groove of microtubules. Tubulin polymerization assay revealed that CLP-19 might induce polymerization of microtubules and prevent depolymerization. The immunoregulatory effect of CLP-19 involving microtubules was investigated by flow cytometry, immunofluorescence, and Western blotting, which showed that CLP-19 prophylactic treatment of RAW 264.7 cells significantly inhibited LPS-induced surface expression of TLR4. Taken together, these results suggest that CLP-19 binding to microtubules disrupts the dynamic equilibrium of microtubules, reducing the efficacy of microtubule-dependent vesicular transport that would otherwise translocate TLR4 from the endoplasmic reticulum to the cell surface.

[Epigenetics in cancer stem cells].

According to the types of stem cells and considering tumor evolution, one of the most significant theories about stem cells is derived from cancer stem cells (CSCs), which, similar to normal adult stem cells, possess the capacity of self-renewal and potential of differentiation. Over the past few years, compelling evidence has emerged in support of the CSC model for many tumors. The CSCs are posited to be responsible not only for tumor initiation but also for tumor metastasis, relapse and therapyresistance. Thus, understanding the mechanisms that govern the generation and maintenance of this special population of cells is of great importance. Despite the current progress in basic genetic research, the latest work implies that epigenetic mechanisms, from DNA methylation, histone modifications and chromatin-remodeling to the wide discovered miRNAs, play critical roles in the regulation of CSC features. This review focuses on the key epigenetic mechanisms that regulate and define the unique CSC properties.

Cyclic Limulus anti-lipopolysaccharide (LPS) factor-derived peptide CLP-19 antagonizes LPS function by blocking binding to LPS binding protein.

Inflammation and septic shock due to endotoxins from Gram-negative bacteria infection continue to pose significant challenges to human healthcare. It is, therefore, necessary to develop therapeutic strategies targeting endotoxins, such as lipopolysaccharide (LPS), to prevent their potentially systemic effects. Pathogenesis due to Gram-negative bacteria involves LPS binding to the host LPS-binding protein (LBP), causing detrimental downstream signaling cascades. Our previous study showed that CLP-19, a synthetic peptide derived from the Limulus anti-LPS factor (LALF), could effectively neutralize LPS toxicity; however, the detailed mechanisms underlying this anti-LPS effect remained unexplained. Thus, we carried out investigations to determine how the CLP-19 neutralizes LPS toxicity. CLP-19 was found to block LPS binding to LBP in a dose-dependent manner, as evidenced by competitive enzyme-linked immunosorbent assay (ELISA). In peripheral blood mononuclear cells, CLP-19 blocked LPS-induced phosphorylation of mitogen activated protein kinase (MAPK) signaling proteins p38, extracellular signal-regulating kinase (ERK)1/2 and c-Jun N-terminal kinase (JNK)1/2. Furthermore, CLP-19 potency in LPS antagonism in vitro and in vivo was directly associated with its ability to block the LPS-LBP interaction. Taken together, the results suggested that CLP-19's inhibitory effect on LPS-LBP binding and on the subsequent MAPK pathway signaling may be responsible for its anti-LPS mechanism. This peptide appears to represent a potential therapeutic agent for clinical treatment of sepsis.

FSCB phosphorylation in mouse spermatozoa capacitation.

It is generally accepted that spermatozoa capacitation is associated with protein kinase A-mediated tyrosine phosphorylation. In our previous study, we identified the fibrous sheath CABYR binding protein (FSCB), which was phosphorylated by PKA. However, the phosphorylation status of FSCB protein during spermatozoa capacitation should be further investigated. To this aim, in this study, we found that phosphorylation of this 270-kDa protein occurred as early as 1 min after mouse spermatozoa capacitation, which increased over time and remained stable after 60 min. Immunoprecipitation assays demonstrated that the tyrosine and Ser/Thr phosphorylation of FSCB occurred during spermatozoa capacitation. The extent of phosphorylation and was closely associated with the PKA activity and spermatozoa motility characteristics. FSCB phosphorylation could be induced by PKA agonist DB-cAMP, but was blocked by PKA antagonist H-89.Therefore, FSCB contributes to spermatozoa capacitation in a tyrosine-phosphorylated format, which may help in further elucidating the molecular mechanism of spermatozoa capacitation.