Preclinical characterization of alginate‐poly‐L‐lysine encapsulated HepaRG for extracorporeal liver supply

We recently demonstrated that HepaRG cells encapsulated into 1.5% alginate beads are capable of self‐assembling into spheroids. They adequately differentiate into hepatocyte‐like cells, with hepatic features observed at Day 14 post‐encapsulation required for external bioartificial liver applications. Preliminary investigations performed within a bioreactor under shear stress conditions and using a culture medium mimicking acute liver failure (ALF) highlighted the need to reinforce beads with a polymer coating. We demonstrated in a first step that a poly‐l ‐lysine coating improved the mechanical stability, without altering the metabolic activities necessary for bioartificial liver applications (such as ammonia and lactate elimination). In a second step, we tested the optimized biomass in a newly designed perfused dynamic bioreactor, in the presence of the medium model for pathological plasma for 6 h. Performances of the biomass were enhanced as compared to the steady configuration, demonstrating its efficacy in decreasing the typical toxins of ALF. This type of bioreactor is easy to scale up as it relies on the number of micro‐encapsulated cells, and could provide an adequate hepatic biomass for liver supply. Its design allows it to be integrated into a hybrid artificial/bioartificial liver setup for further clinical studies regarding its impact on ALF animal models.     

Expression of ApoA5 and its function in the right ventricular failing and remodeling secondary to pulmonary hypertension

Right heart failure and right ventricular (RV) remodeling were the main reason for mortality of pulmonary hypertension (PH) patients. Apolipoprotein AV (ApoA5) is a key regulator of plasma triglyceride and have multifunction in several target organs. We detected decreased ApoA5 in serum of patients with PH and both in serum and RV of monocrotaline‐induced PH model. Exogenously, overexpression ApoA5 by adenovirus showed protective effects on RV failure and RV fibrosis secondary to PH. In addition, in vitro experiments showed ApoA5 attenuated the activation of fibroblast induced by transforming growth factor β1 and synthesis and secretion of extracellular matrix by inhibiting focal adhesion kinase‐c‐Jun N‐terminal kinase‐Smad3 pathway. Finally, we suggest that ApoA5 may potentially be a pivotal target for RV failure and fibrosis secondary of PH.     

Osthole interacts with an ER‐mitochondria axis and facilitates tumor suppression in ovarian cancer

Osthole is a natural coumarin found in a variety of plants and has been reported to have diverse biological functions, including antimicrobial, antiviral, immunomodulatory, and anticancer effects. Here, we investigated the natural derivative osthole as a promising anticancer compound against ovarian cancer and evaluated its ability to suppress and abrogate tumor progression. In addition, we found the endoplasmic reticulum‐mitochondrial axis‐mediated anticancer mechanisms of osthole against ES2 and OV90 ovarian cancer cells and demonstrated its calcium‐dependent pharmacological potential. Mechanistically, osthole was found to target the phosphatidylinositol 3‐kinase/mitogen‐activated protein kinase signaling pathway to facilitate tumor suppression in ovarian cancer. Furthermore, we identified the effects of osthole in a three‐dimensional tumor‐formation model using the zebrafish xenograft assay, providing convincing evidence of the pharmacological effects of osthole within the anchorage‐independent tumor microenvironment. These findings suggest that osthole has strong potential as a pharmacological agent for targeting ovarian cancer.     

糖-钠协同转运蛋白2抑制剂对心力衰竭合并糖尿病小鼠治疗效果及左心室重构影响的实验研究

摘要 目的：探究糖-钠协同转运蛋白2（Sodium-glucose cotransporter2,SGLT2）抑制剂对心力衰竭合并糖尿病小鼠治疗效果及左心室重构影响的实验研究。方法：选择4周龄雄性C57BL/6J小鼠,通过高脂饮食和免疫抑制剂他克莫司(Tacrolimus,TAC)诱导心力衰竭建立心衰合并糖尿病模型,分为三组：对照组（正常脂肪饮食）、模型组（高脂饮食第2周,TAC诱导心力衰竭）、SGLT2抑制剂组（高脂饮食+恩格列净灌胃第2周,同时TAC诱导心力衰竭）。治疗6周后,记录并比较各组小鼠死亡案例和生存率;酶联免疫吸附实验检测各组小鼠的白细胞介素-6(interleukin 6,IL-6)、IL-10、肿瘤坏死因子--α（tumor necrosis factor-α,TNF-α）的含量;50 MHz传感器耦合的Vevo 2100系统进行超声心动图评估;逆转录聚合酶链式反应(reverse transeription-polymerase chain reaction,RT-PCR)实时分析p53、p21和p16的mRNA表达;蛋白印迹分析组织因子血管细胞黏著因子(Vascular cell Adhesion Molecule-1,VCAM-1)、SGLT1、SGLT2、一氧化氮合酶(endothelial nitric oxide synthase,eNOS)蛋白表达。结果：10天内模型组较对照组和SGLT2抑制剂组生存率降低（P<0.05）,第20天、40天时模型组较对照组大鼠生存率降低,SGLT2抑制剂组较模型组的生存率升高（P<0.05）。模型组较对照组IL-6和TNF-α含量、右心室收缩压（right Ventricular Systolic Pre-ssure,RVSP）和平均肺动脉压（mean Pulmonary Artery Pressure,mPAP）水平、p53、p21和p16的mRNA表达量、VCAM-1、SGLT1、SGLT2的蛋白表达量以及左心室收缩末前后径(left ventricular end-systolic diameter,LVESD)、左心室舒张末前后径(left ventricular end-diastolic diameter,LVEDD)、左心室收缩末容量(left ventricular end-systolic volume,LVESV)均显著升高,IL-10含量、肺动脉血流加速时间(Pulmonary artery acceleration time,PAAT)水平、eNOS蛋白表达量以及左心室射血分数(left ventricular ejection fraction,LVEF)均显著降低（P<0.05）,SGLT2抑制剂组较对照组以上指标变化均与上述相反,且差异具有统计学意义（P<0.05）。结论：选择性SGLT2抑制剂恩格列净改善了心衰合并糖尿病小鼠的收缩压,心脏重塑和内皮功能障碍。促进心脏的保护作用,同时改善左心室重量和体积及后壁厚度。     

Stem cell therapy for heart failure:Medical breakthrough,or dead end?

Heart failure continues to be one of the leading causes of morbidity and mortality worldwide.Myocardial infarction is the primary causative agent of chronic heart failure resulting in cardiomyocyte necrosis and the subsequent formation of fibrotic scar tissue.Current pharmacological and non-pharmacological therapies focus on managing symptoms of heart failure yet remain unable to reverse the underlying pathology.Heart transplantation usually cannot be relied on,as there is a major discrepancy between the availability of donors and recipients.As a result,heart failure carries a poor prognosis and high mortality rate.As the heart lacks significant endogenous regeneration potential,novel therapeutic approaches have incorporated the use of stem cells as a vehicle to treat heart failure as they possess the ability to self-renew and differentiate into multiple cell lineages and tissues.This review will discuss past,present,and future clinical trials,factors that influence stem cell therapy outcomes as well as ethical and safety considerations.Preclinical and clinical studies have shown a wide spectrum of outcomes when applying stem cells to improve cardiac function.This may reflect the infancy of clinical trials and the limited knowledge on the optimal cell type,dosing,route of administration,patient parameters and other important variables that contribute to successful stem cell therapy.Nonetheless,the field of stem cell therapeutics continues to advance at an unprecedented pace.We remain cautiously optimistic that stem cells will play a role in heart failure management in years to come.     

腹腔镜手术联合药物治疗卵巢子宫内膜异位症疗效分析

目的探讨腹腔镜手术联合孕三烯酮治疗卵巢子宫内膜异位症的远期疗效及安全性。方法回顾性分析我院2008年8月-2009年12月收治的经腹腔镜手术的卵巢子宫内膜异位症患者78例,将术后给予孕三烯酮治疗的39例设为治疗组,单纯开腹手术治疗组39例设为对照组。所有患者随访1年以上,评价两组临床治疗效果。结果 LO组手术情况39例EM患者均成功完成手术。无一例转开腹手术。其手术时间、出血量、平均住院时间等与AO组相比差异有显著性（P〈0.05）,复发率分别为17.95%和20.51%,两者相比无统计学意义（P〉0.05）。结论腹腔镜术后联合孕三烯酮治疗卵巢子宫内膜异位症疗效确切,能降低复发率,提高受孕,且副反应小。     

呼吸机的故障分析及管理措施

统计了2009-2010年本院40台呼吸机机械通气时的故障的类型及各种类型故障所占的百分比。分析了故障产生的原因,提出如何从管理措施方面着手,以达到降低故障率,提高设备寿命为目的。     

Hydraulic failure and tree dieback are associated with high wood density in a temperate forest under extreme drought

Catastrophic hydraulic failure will likely be an important mechanism contributing to large‐scale tree dieback caused by increased frequency and intensity of droughts under global climate change. To compare the susceptibility of 22 temperate deciduous tree and shrub species to hydraulic failure during a record drought in the southeastern USA, we quantified leaf desiccation, native embolism, wood density, stomatal conductance and predawn and midday leaf water potential at four sites with varying drought intensities. At the two driest sites, there was widespread leaf wilting and desiccation, and most species exhibited predawn leaf water potentials of ≤3 MPa and >60% loss of xylem conductivity in branches. Although species with high wood density were more resistant to cavitation, they had higher levels of native embolism and greater canopy dieback than species with low wood density. This unexpected result can be explained by the failure of species with dense wood to avert a decline in water potential to dangerous levels during the drought. Leaf water potential was negatively correlated with wood density, and the relationship was strongest under conditions of severe water deficit. Species with low wood density avoided catastrophic embolism by relying on an avoidance strategy that involves partial drought deciduousness, higher sensitivity of stomata to leaf water potential and perhaps greater rooting depth. These species therefore maintained water potential at levels that ensured a greater margin of safety against embolism. These differences among species may mediate rapid shifts in species composition of temperate forests if droughts intensify due to climate change.