Adenovirus-mediated siRNA targeting Bcl-xL inhibits proliferation, reduces invasion and enhances radiosensitivity of human colorectal cancer cells

<p>Abstract</p> <p>Introduction</p> <p>Bcl-xL, an important member of anti-apoptotic Bcl-2 family, plays critical roles in tumor progression and development. Previously, we have reported that overexpression of Bcl-xL was correlated with prognosis of colorectal cancer (CRC) patients. The aim of this study was to investigate the association of Bcl-xL expression with invasion and radiosensitivity of human CRC cells.</p> <p>Methods</p> <p>RT-PCR and Western blot assays were performed to determine the expression of Bcl-xL mRNA and protein in CRC cells and normal human intestinal epithelial cell line. Then, adenovirus-mediated RNA interference technique was employed to inhibit the expression of Bcl-xL gene in CRC cells. The proliferation of CRC cells was analyzed by MTT and colony formation assay. The migration and invasion of CRC cells was determined by wound-healing and tranwell invasion assays. Additionally, the in vitro and in vivo radiosensitivity of CRC cells was determined by clonogenic cell survival assay and murine xnograft model, respectively.</p> <p>Results</p> <p>The levels of Bcl-xL mRNA and protein expression were significantly higher in human CRC cells than in normal human intestinal epithelial cell line. Ad/shBcl-xL could significantly reduce the expression of Bcl-xL protein in CRC cells. Also, we showed that adenovirus-mediated siRNA targeting Bcl-xL could significantly inhibit proliferation and colony formation of CRC cells. Ad/shBcl-xL could significantly suppress migration and invasion of CRC cells. Moreover, Ad/shBcl-xL could enhance in vitro and in vivo radiosensitivity of CRC cells by increasing caspase-dependent apoptosis.</p> <p>Conclusions</p> <p>Targeting Bcl-xL will be a promising strategy to inhibit the metastatic potential and reverse the radioresistance of human CRC.</p

A systematic review of maggot debridement therapy for chronically infected wounds and ulcers

SummaryObjectiveThis study aimed to systematically evaluate maggot debridement therapy (MDT) in the treatment of chronically infected wounds and ulcers.MethodsWe performed a meta-analysis referring to the PRISMA statement (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). We searched for published articles in the following databases: PubMed, Web of Science, Embase, Wanfang (Chinese), and the China National Knowledge Infrastructure (CNKI). The latest search was updated on March 14, 2014. For dichotomous outcomes, the effects of MDT were expressed as the relative risk (RR) and 95% confidence interval (CI). For continuous outcomes with different measurement scales, we calculated the standardized mean difference (SMD). The pooled effects were estimated using a fixed effect model or random effect model based on the heterogeneity test. Subgroup analyses were performed according to the types of wounds or ulcers.ResultsMDT had a significantly increased positive effect on wound healing compared with conventional therapies, with a pooled RR of 1.80 (95% CI 1.24–2.60). The subgroup analysis revealed that the combined RRs were 1.79 (95% CI 0.95–3.38) for patients with diabetic foot ulcers (DFU) and 1.70 (95% CI 1.28–2.27) for patients with other types of ulcers. The time to healing of the ulcers was significantly shorter among patients treated with MDT, with a pooled SMD of −0.95 (95% CI −1.24, −0.65). For patients with DFU, the SMD was −0.79 (95% CI −1.18, −0.41), and for patients with other types of ulcers, the SMD was −1.16 (95% CI −1.63, −0.69).ConclusionMDT not only shortened the healing time but also improved the healing rate of chronic ulcers. Therefore, MDT may be a feasible alternative in the treatment of chronic ulcers

Multifactor dimensionality reduction analysis of syndrome characteristics of chronic persistent asthma

AbstractObjectiveTo analyze the syndrome characteristics in patients with chronic persistent asthma.Methods365 patients (121 males, 244 females, 60.8 ± 29.1 years old) with chronic persistent asthma were enrolled in this cross-sectional study. The information of syndrome, symptoms, signs, tongue coating and pulse were collected from all patients. The syndrome characteristics of chronic persistent asthma were examined through the multifactor dimensionality reduction (MDR) analysis and the results were verified by the Chi-square test.ResultsThe results of the MDR analysis and the Chi-square test showed the following positive correlation of the interaction among: the deficiency syndrome of the lung and spleen and deep pulse, disinclination to talk due to lack of qi, fatigue, lassitude and thick tongue coating; the deficiency syndrome of the lung and kidney and dizziness and disinclination to talk due to lack of qi, fatigue, lassitude and pallid complexion; the syndrome of phlegm-heat obstructing the lung and rapid pulse, abdominal distension, disinclination to talk due to lack of qi, frequent urination and lassitude; the syndrome of phlegm-dampness obstructing the lung and disinclination to talk due to lack of qi, greasy coating, fatigue and lassitude. (P < .05 for all).ConclusionThe syndrome of chronic persistent asthma is characterized by fatigue and lassitude due to dysfunction of the lung, spleen and kidney

Effects of a novel pH-sensitive liposome with cleavable esterase-catalyzed and pH-responsive double smart mPEG lipid derivative on ABC phenomenon

Daquan Chen1,2, Wanhui Liu1,2, Yan Shen3, Hongjie Mu1,2, Yanchun Zhang4 , Rongcai Liang1,2, Aiping Wang1,2, Kaoxiang Sun1,2, Fenghua Fu1,2 1School of Pharmacy, Yantai University, Yantai, People&amp;rsquo;s Republic of China; 2State Key Laboratory of Long-acting and Targeting Drug Delivery System, Yantai, People&amp;rsquo;s Republic of China; 3College of Pharmacy, China Pharmaceutical University, Nanjing, People&amp;rsquo;s Republic of China; 4College of Pharmacy, Anhui University of Traditional Chinese Medicine, Hefei, People&amp;rsquo;s Republic of China Background: The ABC phenomenon is described as a syndrome of accelerated clearance of polyethylene glycol (PEG)-modified liposomes from the bloodstream when repeatedly injected, with their increased accumulation in the liver and spleen. Methods: To clarify this immune response phenomenon, we evaluated a novel modified pH-sensitive liposome with a cleavable double smart PEG-lipid derivative (mPEG-Hz-CHEMS). Results: The ABC phenomenon in mice was brought about by repeated injection of conventional PEG-PE liposomes and was accompanied by a greatly increased uptake in the liver. However, a slight ABC phenomenon was brought about by repeated injection of mPEG-CHEMS liposomes and was accompanied by only a slightly increased uptake in the liver, and repeated injection of mPEG-Hz-CHEMS liposomes did not induce the ABC phenomenon and there was no increase in liver accumulation. This finding indicates that the cleavable mPEG-Hz-CHEMS derivative could lessen or eliminate the ABC phenomenon induced by repeated injection of PEGylated liposomes. Conclusion: This research has shed some light on a solution to the ABC phenomenon using a cleavable PEG-Hz-CHEMS derivative encapsulated in nanoparticles. Keywords: accelerated blood clearance, double smart, cleavable, mPEG-lipid derivates, pH-sensitive liposom

P2X7 Integrates PI3K/AKT and AMPK-PRAS40-mTOR Signaling Pathways to Mediate Tumor Cell Death

Background: Extracellular adenosine triphosphate (ATP) functions as a novel danger signal that boosts antitumor immunity and can also directly kill tumor cells. We have previously reported that chronic exposure of tumor cells to ATP provokes P2X7-mediated tumor cell death, by as yet incompletely defined molecular mechanisms. Methodology/Principal Findings Here, we show that acute exposure of tumor cells to ATP results in rapid cytotoxic effects impacting several aspects of cell growth/survival, leading to inhibition of tumor growth in vitro and in vivo. Using agonist and antagonist studies together with generation of P2X7 deficient tumor cell lines by lentiviral shRNA delivery system, we confirm P2X7 to be the central control node transmitting extracellular ATP signals. We identify that downstream intracellular signaling regulatory networks implicate two signaling pathways: the known P2X7-PI3K/AKT axis and remarkably a novel P2X7-AMPK-PRAS40-mTOR axis. When exposed to high levels of extracellular ATP, these two signaling axes perturb the balance between growth and autophagy, thereby promoting tumor cell death. Conclusions: Our study defines novel molecular mechanisms underpinning the antitumor actions of P2X7 and provides a further rationale for purine-based drugs in targeted cancer therapy