Rakicidin J and K, two cytotoxic and antibacterial cyclic depsipeptides from the marine bacterium Micromonospora chalcea.

Rakicidin J (1) and rakicidin K (2), two new cyclic depsipeptides, were isolated from culture broth of Micromonospora chalcea FIM-R150103. Their structures were elucidated by extensive analysis of NMR, HR-ESI-MS, and electronic circular dichroism (ECD) data. The two compounds showed strong cytotoxic activity against human colon carcinoma HCT-8 and human pancreatic cancer PANC-1 cells under normoxic and hypoxic conditions in the range of IC50 values from 0.024 to 0.79 µg/mL. Moreover, compounds 1 and 2 also showed moderate antibacterial activity against ten Gram-positive bacterial strains with MIC values ranging from 4 to more than 32 µg/mL. Structure-activity relationship of these two compounds with a close analogue, rakicidin B1, is also discussed.

Meta-analysis of the timing of laparoscopic cholecystectomy after endoscopic retrograde cholangiopancreatography in patients with cholecystolithiasis and choledocholithiasis.

Endoscopic retrograde cholangiopancreatography (ERCP) combined with laparoscopic cholecystectomy plays an important role in the treatment of cholecystolithiasis combined with choledocholithiasis; however, there is no unified standard for the interval of ERCP before laparoscopic cholecystectomy. We conducted a literature search, data extraction and meta-analysis on this topic. Twelve articles with 1142 patients were included, including 567 patients in the E-laparoscopic cholecystectomy group (laparoscopic cholecystectomy performed within 72 h after ERCP) and 575 patients in the D-laparoscopic cholecystectomy group (laparoscopic cholecystectomy performed 72 h after ERCP). The results showed that: compared with the D-laparoscopic cholecystectomy group, the duration of cholecystectomy was shorter in the E-laparoscopic cholecystectomy group [weighted mean difference (WMD) = -16.18, 95% confidence interval (CI) (-22.27 to -10.08), P  < 0.00001], and the postoperative hospitalization was shorter [WMD = -1.24, 95% CI (-1.98 to -0.50), P  < 0.0001]. There were fewer complications [odds ratio (OR) = 0.25, 95% CI (0.39-0.62), P  < 0.0001], lower conversion rate [OR = 0.39, 95% CI (0.21-0.71), P  = 0.002], lower high sensitivity C-reactive protein at 3 days after surgery [WMD = -8.76, 95% CI (-12.59 to -4.93), P  < 0.00001], and fewer neutrophils in the ampulla of gallbladder specimen [WMD = -4.21, 95% CI (-4.55 to -3.88), P < 0.00001]. Therefore, in the treatment of cholecystolithiasis combined with choledocholithiasis by laparoscopic cholecystectomy within 72 h after ERCP, the degree of inflammation before and after surgery is less, the operation time and hospital stay are shortened, the postoperative complications and the conversion rate are reduced, which is a more appropriate time for surgery.

Transcytosable Peptide-Paclitaxel Prodrug Nanoparticle for Targeted Treatment of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is an extremely aggressive subtype associated with a poor prognosis. At present, the treatment for TNBC mainly relies on surgery and traditional chemotherapy. As a key component in the standard treatment of TNBC, paclitaxel (PTX) effectively inhibits the growth and proliferation of tumor cells. However, the application of PTX in clinical treatment is limited due to its inherent hydrophobicity, weak penetrability, nonspecific accumulation, and side effects. To counter these problems, we constructed a novel PTX conjugate based on the peptide-drug conjugates (PDCs) strategy. In this PTX conjugate, a novel fused peptide TAR consisting of a tumor-targeting peptide, A7R, and a cell-penetrating peptide, TAT, is used to modify PTX. After modification, this conjugate is named PTX-SM-TAR, which is expected to improve the specificity and penetrability of PTX at the tumor site. Depending on hydrophilic TAR peptide and hydrophobic PTX, PTX-SM-TAR can self-assemble into nanoparticles and improve the water solubility of PTX. In terms of linkage, the acid- and esterase-sensitive ester bond was used as the linking bond, with which PTX-SM-TAR NPs could remain stable in the physiological environment, whereas PTX-SM-TAR NPs could be broken and PTX be released at the tumor site. A cell uptake assay showed that PTX-SM-TAR NPs were receptor-targeting and could mediate endocytosis by binding to NRP-1. The vascular barrier, transcellular migration, and tumor spheroids experiments showed that PTX-SM-TAR NPs exhibit great transvascular transport and tumor penetration ability. In vivo experiments, PTX-SM-TAR NPs showed higher antitumor effects than PTX. As a result, PTX-SM-TAR NPs may overcome the shortcomings of PTX and present a new transcytosable and targeted delivery system for PTX in TNBC treatment.

Two new rakicidin derivatives from marine Micromonospora chalcea FIM-R160609.

The establishment of structure activity relationship (SAR) for rakicidin derivatives is pretty vital to develop rakicidins as a new type of anti-cancer agents. Herein, two novel rakicidin derivatives, compounds B1-1 (1) and B1-2 (2), a cyclic depsipeptide and a chain lipopeptide, respectively, were isolated from culture broth of Micromonospora chalcea FIM-R160609, and their structures were elucidated clearly by extensive NMR and HR-ESI-MS analyses. Following, their cytotoxic activities were evaluated against HCT-8 and PANC-1 human cancer cell lines under hypoxic and normoxic conditions. Their activities were significantly decreased when compared with that of rakicidin B1. These results demonstrated that the double bond located on the position 9 and 10 of conjugated diene unit and cycle-type structure plays an important role in keeping the biological activity of rakicidins. Furthermore, the positive effect of double bond and cycle form on the anti-bacterial activities were also confirmed by testing their inhibitory activities against gram positive bacteria. This work will definitely diversify the SAR of rakicidins and provide the guidance for the design of new potent rakicidin analogues.

Protective effects of melatonin in cisplatin-induced cardiac toxicity: possible role of BDNF-TNF-α signaling pathway.

PURPOSE: The present study explored the role of melatonin in cisplatin-induced cardiac injury along with the possible role of brain-derived neurotrophic factor (BDNF) in melatonin-mediated effects. METHODS: Wistar rats were administered cisplatin (10 mg/kg), and cardiac injury was assessed by measuring the levels of cardiac troponin (cTnT) and lactate dehydrogenase (LDH-1).The extent of apoptosis was measured by measuring caspase-3 (pro-apoptotic) and Bcl-2 (anti-apoptotic) in hearts. The levels of BDNF, tumour necrosis factor α (TNF-α) and reduced glutathione were measured in heart. Melatonin (5 and 10 mg/kg) was administered for 15 days, and the role of BDNF was identified by co-administering BDNF inhibitor, ANA-12 (0.25 and 0.5 mg/kg). RESULTS: Melatonin attenuated cTnT and LDH-1 levels along with reduction in caspase-3 and increase in Bcl-2. It also increased cisplatin-induced decrease in BDNF, increase in TNF-α and decrease in reduced glutathione levels. Moreover, ANA-12 abolished the cardioprotective effects, anti-inflammatory and antioxidant effects of melatonin suggesting the role of BDNF in melatonin-mediated effects in cisplatin-induced cardiac injury. CONCLUSIONS: Melatonin is useful in cisplatin-induced cardiac injury, which may be due to an increase in BDNF, decrease in inflammation and increase in antioxidant activities.

Protective effects of melatonin in cisplatin-induced cardiac toxicity: possible role of BDNF-TNF-α signaling pathway

Purpose: The present study explored the role of melatonin in cisplatin-induced cardiac injury along with the possible role of brain-derived neurotrophic factor (BDNF) in melatonin-mediated effects. Methods: Wistar rats were administered cisplatin (10 mg/kg), and cardiac injury was assessed by measuring the levels of cardiac troponin (cTnT) and lactate dehydrogenase (LDH-1).The extent of apoptosis was measured by measuring caspase-3 (pro-apoptotic) and Bcl-2 (anti-apoptotic) in hearts. The levels of BDNF, tumour necrosis factor α (TNF-α) and reduced glutathione were measured in heart. Melatonin (5 and 10 mg/kg) was administered for 15 days, and the role of BDNF was identified by co-administering BDNF inhibitor, ANA-12 (0.25 and 0.5 mg/kg). Results: Melatonin attenuated cTnT and LDH-1 levels along with reduction in caspase-3 and increase in Bcl-2. It also increased cisplatin-induced decrease in BDNF, increase in TNF-α and decrease in reduced glutathione levels. Moreover, ANA-12 abolished the cardioprotective effects, anti-inflammatory and antioxidant effects of melatonin suggesting the role of BDNF in melatonin-mediated effects in cisplatin-induced cardiac injury. Conclusions: Melatonin is useful in cisplatin-induced cardiac injury, which may be due to an increase in BDNF, decrease in inflammation and increase in antioxidant activities.

Curdlan sulfate/O-linked quaternized chitosan nanoparticles acting as potential adjuvants promote multiple arms of immune responses.

Nasal immunization to prevent and treat diseases caused by infection through the respiratory tract cannot be actualized because of the lack of effective adjuvants. We have proven that compared with antigens loaded on CS or O-HTCC alone in nasal vaccination, antigens loaded on the nanoparticles of curdlan sulfate/O-(2-hydroxyl) propyl-3-trimethyl ammonium chitosan chloride (CS/O-HTCC) can induce stronger systemic and mucosal immune responses. In this study, we evaluated the immunostimulatory activity and mechanisms of CS/O-HTCC nanoparticles. The results showed that CS/O-HTCC nanoparticles can improve the activation of antigen-presenting cells, upregulate the production of inflammatory factors and cytokines, induce cross-presentation, and simultaneously activate type I interferon-related genes. CS/O-HTCC nanoparticles also activated the PI3K/AKT and MAPK pathways and significantly promoted IL-2 transcription to induce the proliferation of lymphocytes. The results revealed that CS/O-HTCC nanoparticles as a type of multifunctional adjuvant can improve multiple arms of immune responses.

Efficacy of fast track surgery in laparoscopic radical gastrectomy for gastric cancer:a meta-analysis of randomized controlled trials.

OBJECTIVE: To conduct a systematic review of efficacy and security of fast track surgery (FTS) in laparoscopic radical gastrectomy for gastric cancer. METHODS: We searched PubMed, Embase, and Cochrane Library Databases and supplemented by other searches to collect randomized controlled trials (RCTs) on the comparison of fast track surgery combined with laparoscopy versus laparoscopy separately used in radical gastrectomy for gastric cancer before December 2016. After screening for inclusion, data extraction, and quality assessment, meta-analysis was conducted by the Review Manager 5.3 software. RESULTS: A total of 6 RCTs, involving 464 patients, were included. There were 232 patients in the FTS group and conventional care group separately. Compared with the conventional care group, patients of FTS group had shorter postoperative hospital stay [WMD = -1.85, 95%CI: (-2.60, -1.11), P < .00001], earlier first flatus [WMD = -9.33, 95%CI: (-13.74, -4.91), P < .0001], lower level of C-reactive protein (CRP) at postoperative day 4 [WMD = -13.94, 95%CI: (-22.74, -5.15), P = .002], and less hospitalization fees [SMD = -1.12, 95%CI: (-2.07, -0.18), P = .02]. There were no significant differences in operation time, intraoperative blood loss, and postoperative complications between the two groups. CONCLUSION: Based on current evidence, the FTS protocol is safe and effective in laparoscopic radical gastrectomy for gastric cancer. Due to the limitations of our study, further larger and multicenter studies are needed to validate our findings.

Effect of gum chewing on ameliorating ileus following colorectal surgery: A meta-analysis of 18 randomized controlled trials.

BACKGROUND AND OBJECTIVE: Chewing gum, as an alternative to sham feeding, had been shown to hasten the recovery of gut function following abdominal surgery. However, conclusions remained contradictory. We sought to conduct an updated meta-analysis to evaluate the efficacy of gum chewing in alleviating ileus following colorectal surgery. METHODS: We searched PubMed, EMBASE, and Cochrane Library Databases through February 2017 to identify randomized controlled trials (RCTs) evaluating the efficacy of the additional use of chewing gum following colorectal surgery. After screening for inclusion, data extraction, and quality assessment, meta-analysis was conducted by the Review Manager 5.3 software. The outcomes of interest were the time to first flatus, time to first bowel movement, length of hospital stay, and some clinically relevant parameters. We also performed subgroup analyses according to the type of surgical approaches or on trials that adopted enhanced recovery after surgery (ERAS) protocol or sugared gum. RESULTS: A total of 18 RCTs, involving 1736 patients, were included. Compared with standardized postoperative care, Chewing gum resulted in a shorter passage to first flatus [WMD = -8.81, 95%CI: (-13.45, -4.17), P = 0.0002], earlier recovery of bowel movement [WMD = -16.43, 95%CI: (-22.68, -10.19), P < 0.00001], and a reduction in length of hospital stay [WMD = -0.89, 95%CI: (-1.72, -0.07), P = 0.03]. Chewing gum was also associated with a lower risk of postoperative ileus [OR = 0.41, 95%CI: (0.23, 0.73), P = 0.003]. No evidence of significant advantages in overall postoperative complication, nausea, vomiting, bloating, readmission and reoperation towards the addition of chewing gum was observed. Subgroup analyses all favored gum chewing. However, the findings are hampered by the significant heterogeneity between trials. CONCLUSIONS: Based on current evidence, chewing gum offers an inexpensive, well-tolerated, safe and effective method to ameliorate ileus following colorectal surgery. However, tightly controlled, randomized and considerably larger multicenter trials are warranted to further validate our findings.

Eupafolin Exhibits Potent Anti-Angiogenic and Antitumor Activity in Hepatocellular Carcinoma.

Eupafolin is a flavonoid extracted from the common sage herb which has been used in China as traditional medicine. Previous studies had reported that eupafolin had antioxidative, anti-inflammatory and antitumor effects. However, the function and the mechanism of eupafolin to exert its antitumor activity, especially its effect on tumor angiogenesis, have not been elucidated. Herein, we showed that eupafolin significantly inhibited vascular endothelial growth factor (VEGF)-induced cell proliferation, migration and tube formation of human umbilical vascular endothelial cells (HUVECs) in a dose-dependent manner. Meanwhile, the new blood microvessels induced by VEGF in the matrigel plug were also substantially suppressed by eupafolin. The results of HCC xenograft experiments demonstrated eupafolin remarkably inhibited tumor growth and tumor angiogenesis in vivo, suggesting the antitumor activity exerted by eupafolin was closely correlated with its potency on tumor angiogenesis. Mechanism investigations revealed that eupafolin significantly blocked VEGF-induced activation of VEGFR2 in HUVEC cells as well as its downstream signaling pathway. In addition to the effect on endothelial cells, through inhibiting Akt activity in tumor cells, VEGF secretion in HepG2 was dramatically decreased after eupafolin treatment. Our study was the first to report the activity of eupafolin against tumor angiogenesis as well as the underlying mechanism by which eupafolin to exert its anti-angiogenic activity.

Chrysin inhibited tumor glycolysis and induced apoptosis in hepatocellular carcinoma by targeting hexokinase-2.

BACKGROUND: Hexokinase-2(HK-2) plays dual roles in glucose metabolism and mediation of cell apoptosis, making it an attractive target for cancer therapy. Chrysin is a natural flavone found in plant extracts which are widely used as herb medicine in China. In the present study, we investigated the antitumor activity of chrysin against hepatocellular carcinoma (HCC) and the role of HK-2 played for chrysin to exert its function. METHODS: The expression of HK-2 in HCC cell line and tumor tissue was examined by western blotting and immunohistochemistry staining. The activities of chrysin against HCC cell proliferation and tumor glycolysis were investigated. Chrysin-induced apoptosis was analyzed by flow cytometry. The effect of chrysin on HK-2 expression and the underlying mechanisms by which induced HCC cell apoptosis were studied. In HK-2 exogenous overexpression cell, the changes of chrysin-induced cell apoptosis and glycolysis suppression were investigated. HCC cell xenograft model was used to confirm the antitumor activity of chrysin in vivo and the effect on HK-2 was tested in chrysin-treated tumor tissue. RESULTS: In contrast with normal cell lines and tissue, HK-2 expression was substantially elevated in the majority of tested HCC cell lines and tumor tissue. Owing to the decrease of HK-2 expression, glucose uptake and lactate production in HCC cells were substantially inhibited after exposure to chrysin. After chrysin treatment, HK-2 which combined with VDAC-1 on mitochondria was significantly declined, resulting in the transfer of Bax from cytoplasm to mitochondria and induction of cell apoptosis. Chrysin-mediated cell apoptosis and glycolysis suppression were dramatically impaired in HK-2 exogenous overexpression cells. Tumor growth in HCC xenograft models was significantly restrained after chrysin treatment and significant decrease of HK-2 expression was observed in chrysin-treated tumor tissue. CONCLUSION: Through suppressing glycolysis and inducing apoptosis in HCC, chrysin, or its derivative has a promising potential to be a novel therapeutic for HCC management, especially for those patients with high HK-2 expression.

Transcription Factor MafB Promotes Hepatocellular Carcinoma Cell Proliferation through Up-Regulation of Cyclin D1.

BACKGROUND/AIMS: MafB, a member of the Maf transcription factor family, plays a key role in the regulation of pancreatic alpha and beta cell differentiation. However, its function in the control of cancer cell proliferation remains unknown. METHODS: The mRNA and protein expression levels of MafB in hepatocellular carcinoma tissues and adjacent non-tumor normal specimens were determined by real-time RT-PCR and Western blot, respectively. Report assay was performed to determine whether the regulation of Cyclin D1 by MafB is at the transcriptional level. The binding of MafB to the Cyclin D1 promoter was determined by Chromatin Immunoprecipitation (ChIP) assays. To determine the potential oncogenic effects of MafB in vivo, HepG2 cells transfected with adenovirus containing empty vector or MafB were injected subcutaneously to the skin under the front legs of the nude mice. RESULTS: In the current study, we showed that MafB was markedly up-regulated in hepatocellular carcinoma (HCC) tissues and cells. Enforced overexpression of MafB enhanced, while its deficiency inhibited HCC cell proliferation. Mechanistically, Cyclin D1, an important regulator of cell cycle progression, was identified as a direct transcriptional target of MafB. Consistently, knockdown of Cyclin D1 largely attenuated the proliferative roles of MafB in HCC cells. Importantly, MafB overexpression significantly promoted cancer cell growth in mice. CONCLUSIONS: Collectively, our results identified a novel HCC regulatory pathway involving MafB and Cyclin D1, the dysfunction of which drives proliferative character in HCC.

A canine model of osteonecrosis of the femoral head induced by MRI guided argon helium cryotherapy system.

OBJECTIVE: This study is to identify the reliability of osteonecrosis of the femoral head (ONFH) modeling established by MRI guided argon helium cryotherapy system in beagles. METHODS: A total of 15 beagles were used to establish the ONFH model. The left femoral heads of the beagles received two cycles of argon helium freezing-thawing under MRI guidance and were considered as experimental group while the right femoral heads received only one cycle of argon helium freezing-thawing and were considered as the control group. X-ray, MRI, general shape and histological examinations were performed so as to identify the effect of modeling. RESULTS: At 4 week after modeling, MRI showed obvious bilateral hip joint effusion and marked femoral head bone marrow high signal. At 8 week after surgery, abnormal signal appeared in bilateral femoral heads. T1WI showed irregular patchy low signal, T2WI showed irregular mixed signals and the joint capsule effusion showed long T1 and T2 changes. Twelve weeks after operation, T1WI showed a low signal strip with clear boundary and T2WI showed intermediate signal. The changes of the left femoral heads were significant while compared with those of the right sides. The lacunae rates of femoral heads in the experimental group at 4, 8, and 12 week after surgery (40.75 ± 3.77, 57.46 ± 4.01, 50.27 ± 2.98) were higher than those in control group (30.08 ± 3.61, 49.43 ± 2.82, 40.56 ± 2.73). CONCLUSION: Canine model of ONFH was successfully established using an argon helium cryotherapy system.

DAX-1 inhibits hepatocellular carcinoma proliferation by inhibiting ß-catenin transcriptional activity.

BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) represents the most common type of liver cancer. DAX1 (dosage-sensitive sex reversal adrenal hypoplasia congenital critical region on X chromosome, gene 1), an atypical member of the nuclear receptor family due to lack of classical DNA-binding domains, has been known for its fundamental roles in the development, especially in the sex determination and steroidogenesis. Previous studies also showed that DAX-1 played a critical role in endocrine and sex steroid-dependent neoplasms such as adrenocortical, pituitary, endometrial, and ovarian tumors. However, its biological roles in the development of HCC remain largely unexplored. METHODS: Real-time PCR and Western blot were used to detect the expression of DAX-1 in HCC tissues and cell lines. Immunoprecipitation (IP) assay was used to show the interaction between DAX-1 and ß-Catenin. Small interfering RNA (siRNA) was used to silence the expression of DAX-1. BrdU incorporation and Cell-cycle assays were used to detect the role of DAX-1 in HCC cells proliferation. Migration and invasion assays were carried out to test the metastasis ability of DAX-1 in HCC cells. RESULTS: In the present study, we found that mRNA and protein levels of DAX-1 were down-regulated in HCC tissues and cell lines. Furthermore, overexpression of DAX-1 could inhibit while its knockdown using small interfering RNA promoted cell proliferation in several HCC cell lines. At the molecular level, we demonstrated that DAX-1 could interact with ß-Catenin and attenuate its transcriptional activity. CONCLUSION: Therefore, our results suggest a previously unknown DAX-1/ß-Catenin molecular network controlling HCC development.

Construction of tissue-engineered bone using a bioreactor and platelet-rich plasma.

The aim of the present study was to construct tissue-engineered bone using a bioreactor and platelet-rich plasma (PRP). Bone marrow mesenchymal stem cells (BMSCs) and ß-tricalcium phosphate (ß-TCP) were cultured in a perfusion bioreactor with PRP-containing medium for 21 days to form a BMSC-TCP composite. Rabbits were then implanted with the BMSC-TCP composite. The morphology of the implanted BMSC-TCP composite was observed three months after surgery by scanning electron microscopy and hematoxylin and eosin (H&E) staining. In addition, the expression of cluster of differentiation (CD)31 and von Willebrand factor (WF) in the implanted BMSC-TCP composite was detected using immunohistochemistry. Bone formation was determined by comprehensive testing Following culture in a perfusion bioreactor and PRP, the BMSCs adhered to the ß-TCP scaffold and the secretion of extracellular matrix was observed. The spreading and proliferation of cells was found to be enhanced on the scaffold. Furthermore, the vascular endothelial cell markers CD31 and VEF, were positively expressed. Therefore, these results suggest that tissue-engineered bone may be constructed using a bioreactor and PRP. PRP, which contains multiple growth factors, may promote vascularization of tissue-engineered bone.

A novel animal model of osteonecrosis of the femoral head induced using a magnetic resonance imaging-guided argon-helium cryotherapy system.

The aim of the present study was to establish a novel animal model of osteonecrosis of the femoral head (ONFH) using a magnetic resonance imaging (MRI)-guided argon-helium cryotherapy system. A total of 48 rabbits were used to generate the ONFH models. In group I, the left femoral head of the rabbits received two cycles of argon-helium freezing-thawing under MRI guidance, while in group II, the right femoral head of each rabbit received only one cycle of argon-helium freezing-thawing. X-ray and histological examinations were performed. The percentages of lacunae in the femoral heads of group I at weeks 4, 8 and 12 following surgery (49.75±3.17, 62.06±4.12 and 48.25±2.76%, respectively) were higher than those in group II (39.13±4.48, 50.69±3.84 and 37.50±3.86%, respectively). In addition, the percentage of empty lacunae in group I was 62.06% at week 8 following surgery. Therefore, an animal model of ONFH was successfully established using an argon-helium cryotherapy system. The percentage of empty lacunae in group I was higher than that in group II at weeks 4, 8 and 12 after surgery.

MicroRNA-195 regulates steroid receptor coactivator-3 protein expression in hepatocellular carcinoma cells.

Multiple studies have shown that steroid receptor coactivator-3 (SRC-3) is upregulated and promotes cell proliferation in several human cancers, including breast, lung, and prostate carcinoma. However, its molecular determinants remain largely unexplored. In the current study, by way of informatics software, we found that MicroRNA-195 (miR-195) could negatively regulate protein levels of SRC-3 through targeting its 3'-untranslated region (3'-UTR) in hepatocellular carcinoma (HCC) cells. As a result, miR-195 mimics inhibited while its antisense enhanced SRC-3 protein levels. Furthermore, miR-195 could modulate cell proliferation and tumor growth in vivo and in vitro. Therefore, our results demonstrate a novel molecular mechanism for the dysregulated expression of SRC-3 in hepatocellular carcinoma.

Capsaicin mediates cell cycle arrest and apoptosis in human colon cancer cells via stabilizing and activating p53.

Capsaicin is the major pungent ingredient in red peppers which is world widely consumed. Except its potent pain relieving efficacy as reported, capsaicin also exerted its antitumor activity in several tumor models. Here, we reported that capsaicin had a profound anti-proliferative effect on human colon cancer cells via inducing cell cycle G0/G1 phase arrest and apoptosis, which was associated with an increase of p21, Bax and cleaved PARP. The underlying mechanism of capsaicin's antitumor potency was mainly attributed to the stabilization and activation of p53. Capsaicin substantially prolonged the half-life of p53 and significantly elevated the transcriptional activity of p53. Through suppressing the interaction between p53 and MDM2, MDM2-mediated p53 ubiquitination was remarkably decreased after capsaicin treatment, which resulted in the stabilization and accumulation of p53. The results of p53-shRNA experiment further demonstrated that p53 knockdown severely impaired the sensitivity of tested cells to capsaicin, G0/G1 phase arrest and the apoptosis induced by capsaicin in p53-knockdown cells was also dramatically decreased, implicating the important role of p53 played in capsaicin's antitumor activity. In summary, our data suggested that capsaicin, or a related analogue, may have a role in the management of human colon cancer.

Significant association between XRCC3 C241T polymorphism and increased risk of hepatocellular carcinoma: a meta-analysis.

Many studies were published to examine the association between XRCC3 C241T polymorphism and hepatocellular carcinoma risk, but their results were inconsistent. To assess the association between XRCC3 C241T polymorphism and hepatocellular carcinoma risk more precisely, a meta-analysis was performed. PubMed, Embase and Wanfang databases were searched for relevant case-control studies. Data were extracted, and the pooled odds ratios (OR) with 95 % confidence intervals (95% CI) were calculated. Finally, seven studies comprising 2,288 cases with hepatocellular carcinoma and 3,249 controls were included into the meta-analysis. Overall, there was an obvious association between XRCC3 C241T polymorphism and increased risk of hepatocellular carcinoma (TT versus CC: OR = 3.31, 95% CI 1.52-7.19, P = 0.003; TT versus CC/CT: OR = 3.31, 95% CI 1.81-6.06, P < 0.001). After adjusting for heterogeneity, there was still an obvious association between XRCC3 C241T polymorphism and increased risk of hepatocellular carcinoma (TT versus CC: OR = 1.92, 95 % CI 1.13-3.26, P = 0.016; TT versus CC/CT: OR = 2.10, 95% CI 1.25-3.55, P = 0.005). Overall, there is a significant association between XRCC3 C241T polymorphism and increased risk of hepatocellular carcinoma. Further studies are needed to further assess the association in Caucasians.

Association between XRCC1 Arg399Gln polymorphism and hepatitis virus-related hepatocellular carcinoma risk in Asian population.

To investigate the association between X-ray repair cross-complementing group 1 (XRCC1) Arg399Gln polymorphism and hepatitis virus-related hepatocellular carcinoma risk, we performed a systematic meta-analysis of eligible case-control studies. Eligible studies were identified from the PubMed, Embase, and Chinese National Knowledge Infrastructure databases up to March 2013. The odds ratios (ORs) and corresponding 95 % confidence interval (95 % CI) of XRCC1 Arg399Gln polymorphism in hepatitis virus-related hepatocellular carcinoma cases compared with those in controls were calculated. The meta-analysis was performed using fixed-effect or random-effect methods according to the absence or presence of heterogeneity. This meta-analysis included 1,558 cases with hepatitis virus-related hepatocellular carcinoma and 1,338 controls. Meta-analysis of available data showed that there was no association between XRCC1 Arg399Gln polymorphism and risk of hepatitis virus-related hepatocellular carcinoma under all contrast models (Gln vs. Arg: fixed-effect OR = 0.92, 95 % CI 0.82-1.04, P = 0.18; GlnGln vs. ArgArg: random-effect OR = 0.79, 95 % CI 0.50-1.25, P = 0.32; GlnGln/ArgGln vs. ArgArg: fixed-effect OR = 0.92, 95 % CI 0.79-1.07, P = 0.28; and GlnGln vs. ArgArg/ArgGln: random-effect OR = 0.83, 95 % CI 0.52-1.34, P = 0.45). Sensitivity analysis further showed that there was no association between XRCC1 Arg399Gln polymorphism and risk of hepatitis B-related hepatocellular carcinoma under all contrast models (Gln vs. Arg: fixed-effect OR = 0.93, 95 % CI 0.82-1.05, P = 0.25; GlnGln vs. ArgArg: fixed-effect OR = 0.86, 95 % CI 0.64-1.16, P = 0.32; GlnGln/ArgGln vs. ArgArg: fixed-effect OR = 0.93, 95 % CI 0.80-1.10, P = 0.41; and GlnGln vs. ArgArg/ArgGln: fixed-effect OR = 0.85, 95 % CI 0.63-1.13, P = 0.26). Our meta-analysis of the available data did not find an obvious effect of XRCC1 Arg399Gln polymorphism on hepatitis-related hepatocellular carcinoma. More well-designed studies with large sample are needed to further verify the effect.