Activated pancreatic stellate cells can impair pancreatic islet function in mice

Background

Pancreatic or islet fibrosis is often associated with activated pancreatic stellate cells (PSCs). PSCs are considered not only to promote fibrosis, but also to be associated with glucose intolerance in some diseases. We therefore evaluated morphological and functional relationships between islets and PSCs in the normal mouse pancreas and transplanted islets.

Methods

Immunohistochemistry was used to map the presence of PSCs in the normal mouse pancreas and islets implanted under the renal capsule. We isolated and cultured mouse PSCs and characterized them morphologically by immunofluorescence staining. Furthermore, we measured their cytokine production and determined their effects on insulin release from simultaneously cultured islets.

Results

PSCs were scattered throughout the pancreas, with occasional cells within the islets, particularly in the islet capsule. In islet transplants they were found mainly in the graft periphery. Cultured PSCs became functionally activated and produced several cytokines. Throughout the culture period they linearly increased their production of interleukin-6 and mammalian keratinocyte-derived chemokine. PSC cytokine production was not affected by acute hyperglycemia. Syngeneic islets co-cultured with PSCs for 24–48 h increased their insulin release and lowered their insulin content. However, short-term insulin release in batch-type incubations was unaffected after 48 h of co-culture. Increased islet cell caspase-3 activation and a decreased islet cell replication were consistently observed after co-culture for 2 or 7 days.

Conclusion

Activated PSCs may contribute to impaired islet endocrine function seen in exocrine pancreatitis and in islet fibrosis associated with some cases of type 2 diabetes.     

下颌下入路手术治疗Hangman骨折的解剖与临床应用

目的：探讨下颌下入路手术的解剖要点及其治疗Hangman骨折的临床疗效。方法对5具成人新鲜尸体标本下颌下区的重要血管和神经进行解剖观察,并测量舌下神经与喉上神经内侧支之间纵向的最短距离;其中男3具、女2具,年龄39~62岁,均排除颈椎相关疾病病史。回顾分析2006年12月—2012年1月第二军医大学附属长征医院脊柱外科采用下颌下入路手术治疗21例Hangman骨折患者的临床资料,其中男14例、女7例,年龄27~59岁;根据Levine-Edward分型,Ⅱ型骨折18例,Ⅱa型骨折2例,Ⅲ型1例。结果下颌下入路的相关重要解剖结构在尸体解剖中得以充分显露,舌下神经与喉上神经内侧支之间纵向的最短距离为（21．7±3．1) mm,通过适当牵拉能够充分暴露C2、C3水平,满足Hangman骨折手术治疗操作要求。21例临床病例随访（21．3±8．1)个月,骨折愈合均良好,术后神经症状及颈肩部疼痛程度均较术前明显改善,JOA 改善率为64．9%。1例术中减压过程中出现脑脊液漏,术中行明胶海绵及Surgiflo填塞处理,术后常压引流3 d未引出脑脊液,引流拔除后手术切口愈合良好;1例术后出现声音嘶哑症状,2个月后自行恢复。结论下颌下入路可充分显露手术内固定治疗Hangman骨折所需的手术节段,手术疗效满意。熟知下颌下三角区域解剖结构、重要神经血管的走行是手术成功、减少手术并发症发生的关键因素。     

HPV-16 E6 promotes cell growth of esophageal cancer via downregulation of miR-125b and activation of Wnt/β-catenin signaling pathway

High-risk human papillomavirus (HPV) is a possible cause of esophageal cancer. However, the molecular pathogenesis of HPV-infected esophageal cancer remains unclear. The expression levels of some microRNAs including miR-125b have been negatively correlated with HPV infection, and miR-125b downregulation is associated with tumorigenesis. In addition, Wnt/β-catenin signaling pathway has been suggested to play an important role in esophageal cancer (EC). We examined miR-125b and Wnt/β-catenin signaling pathway in HPV-16 E6 promoted tumor progression in EC. HPV-16 E6 transfection decreased markedly the expression levels of miR-125b and promoted the colony formation in the Eca 109 and Kyse 150 cell lines, and restoration of miR-125b expression level antagonized the increased colony formation in HPV-16 E6 transfected cell lines. We also demonstrated that overexpression of E6 upregulated the Wnt/β-catenin signaling activity via modulating the multiple regulators including TLE1, GSK3β, and sFRP4. Overexpression of miR-125b restored the expression levels of these proteins. Expression of miR-125b was lower in HPV-16 E6 positive esophageal cancer tissues, and was negatively correlated with E6 mRNA levels. Our results indicate that HPV-16 E6 promotes tumorigenesis in EC via down-regulation of miR-125b, and this underlying mechanism may be involved in the activation of the Wnt/β-catenin signaling pathway.     

Normobaric hypoxia training causes more weight loss than normoxia training after a 4-week residential camp for obese young adults

Background

Intermittent normobaric hypoxia training, an alternative to altitude training for athletes, may be beneficial to treat overweight and obesity. The purpose of this study is to investigate whether normobaric hypoxia training combined with low-caloric diet has the additive effect on weight loss compared with normoxia training in obese young adults.

Methods

Twenty-two subjects (age 17–25 years, body mass index >27.5 kg/m²) were recruited for a 4-week residential camp of weight loss with low caloric intake, and trained at 60–70 % maximal heart rate of aerobics and 40–50 % of maximal strength of training. They were randomly assigned to either a normobaric hypoxia (HT, FiO₂?=?16.4–14.5 %) or normoxia training group (NT, FiO₂?=?21 %), and subjects in HT and NT groups experienced weekly 16-h normoxia and 6-h hypoxia or 22-h normoxia training, respectively. Body composition, resting blood pressure (BP) and brachial-ankle pulse wave velocity (baPWV) were determined before and after the intervention.

Results

Weight loss was found in HT (?6.9 kg or ?7.0 %, p?p?p?<?0.01). Hypoxia training improved systolic BP (?7.6 %) and mean BP (?7.1 %) significantly (p?<?0.05) despite having no effect on baPWV.

Conclusion

Four weeks of normobaric hypoxia residential training with low caloric diet has an additive improvement on weight loss. It seems that normobaric hypoxia training might be a promising method to treat obesity.     

Label‐free molecular probe based on G‐quadruplex and strand displacement for sensitive and selective detection and naked eye discrimination of exon 2 deletion of AIMP2

Exon 2 deletion of aminoacyl tRNA synthetase complex‐interacting multifunctional protein 2 (AIMP2) is a genetic deletion related to various cancers, for instance ovarian and lung cancers. It can be worked as an indicator of cancer for diagnosis of diseases. Here, we developed a label‐free method based on the formation of split G‐quadruplex in the presence of target DNA combined with strand displacement to detect exon 2 deletion of AIMP2 (DE2) sensitively and selectively. This method is easy‐operating and cost‐saving. Moreover, it has observed discrimination of gene deletion from wild‐types by naked eyes. The results demonstrate that this strategy can be further used for the detection of different gene deletions to achieve early diagnosis of diseases and allow better prognosis.     

CD137-CD137配体对巨噬细胞基质金属蛋白酶9及血管平滑肌细胞钙化形成的影响

目的探讨CD137-CD137配体(CD137L)信号是否通过调控巨噬细胞基质金属蛋白酶9(MMP-9)的表达影响血管平滑肌细胞(VSMC)钙化形成。方法采用巯基乙酸盐腹腔灌洗法获取C57BL/6J小鼠腹腔巨噬细胞(PM),采用组织块贴壁法取3~6代胸主动脉VSMC分为对照组、共培养组、CD137激动组和MMP-9抑制组(n=3)。对照组用重组CD137L蛋白干预VSMC,共培养组用PM和VSMC共培养,CD137激动组和MMP-9抑制组分别用重组CD137L蛋白和MMP-9抑制剂干预PM后,与VSMC共培养,再加入重组CD137蛋白(10μg/ml)干预。采用Western blot检测各组钙化相关的骨桥蛋白(OPN)、Runt相关转录因子2(Runx-2)表达,微板法检测钙离子浓度和碱性磷酸酶(ALP)活性,Von Kossa和茜素红染色检测各组细胞钙化程度。结果CD137激动组VSMC中OPN和Runx-2蛋白表达、钙离子浓度及ALP活性明显高于共培养组(P<0.01),而MMP-9抑制组VSMC中OPN和Runx-2蛋白表达、钙离子浓度及ALP活性明显低于CD137激动组,差异有统计学意义[0.25±0.27 vs 2.12±0.34,0.30±0.32 vs 2.63±0.41,(1.92±0.09)mmol/g vs(4.99±0.37)mmol/g,(1.11±0.50)KU/g vs(2.63±0.04)KU/g,P<0.01]。共培养组VSMC中OPN和Runx-2蛋白表达、钙离子浓度及ALP活性与对照组比较,无统计学意义(P>0.05)。CD137激动组茜素红染色红色颗粒物质沉积和Von Kossa染色黑色颗粒物质沉积明显多于对照组和共培养组;MMP-9抑制组钙化程度显著降低;对照组和共培养组钙化程度则无明显差异。结论CD137-CD137L信号可能通过调控巨噬细胞MMP-9表达影响VSMC钙化形成。     

Evaluation of the associations of body height with blood pressure and early‐stage atherosclerosis in Chinese adults

Body height has been recently related to the risk of coronary heart disease and metabolic risk factors. However, data are scarce regarding the relationship between body height and early‐stage atherosclerotic changes, especially in Chinese individuals. In this study, we aimed to comprehensively examine the associations of body height with early‐stage atherosclerosis and blood pressure in Chinese adults. Carotid‐femoral pulse wave velocity (cfPWV), carotid‐radial pulse wave velocity (crPWV), carotid artery‐dorsalis pedis pulse wave velocity (cdPWV), and body height were measured in 5098 men and women. All samples were obtained from a community‐based health examination survey in central China. After adjusting for sex, age, weight, fasting glucose level, lipid level, creatinine, and heart rate, low body heights were significantly associated with higher cfPWV, crPWV, and blood pressure (all P for trend <.01), whereas no significant association was found between body height and cdPWV. In addition, we found a significant interaction between prehypertension status and body height in relation to cfPWV, after adjusting for covariates (P for interaction = .0024). The associations were stronger in participants with prehypertension than in those with normal blood pressure. Compared to the group with the tallest stature and normal blood pressure, individuals in the group with the shortest stature and prehypertension had nearly a 2.5 m/s higher cfPWV. These results indicate that short body height was associated with an increased risk of early‐stage atherosclerosis in Chinese adults, independent of traditional cardiometabolic risk factors. Prehypertension might modify the association between body height and cfPWV.     

Traditional uses,phytochemistry, pharmacology and toxicology of Lamiophlomis rotata (Benth.) Kudo: a review

Lamiophlomis rotata (Benth.) Kudo is a herbaceous plant of the family Lamiaceae, subfamily Lamioideae. Approximately, 127 chemical constituents have been isolated and identified from L. rotata, including iridoids, flavonoids, phenylethanoid glycosides, polysaccharides, and organic acids. These chemical constituents have extensive pharmacological properties, which include anti-nociceptive, haemostatic, anti-inflammatory, anti-tumour, immunomodulatory, antioxidant, and cardio-protective activities. Documentation of its historical use in traditional medicine and contemporary phytochemical and pharmacological research indicate that L. rotata has significant potential in therapeutic and health care applications. Both whole extracts and individual chemical components isolated from this plant exhibit a wide range of biological activities that warrant further investigation. These investigations can be assisted by careful review of existing traditional knowledge from diverse cultural backgrounds. A new search for chemical and biological markers and reinforced protection of the germplasm resources of L. rotata are also important to ensure targeted and sustainable use of this medicinal resource. The aim of this review was to provide comprehensive information on the botanical characteristics, traditional uses, ethnopharmacology, chemical and pharmacological properties, toxicity profile, and conservation status of L. rotata, to improve understanding of its mechanisms of action so that novel therapeutic agents may be developed from this plant.

The useful information of Lamiophlomis rotata (Benth.) Kudo was summarized, which provided a basis for the development of new therapeutic drugs for this plant.     

Interspecies prediction of pharmacokinetics and tissue distribution of doxorubicin by physiologically-based pharmacokinetic modeling

The aim of the study was to develop a physiologically-based pharmacokinetic (PBPK) model to describe and predict whole-body disposition of doxorubicin following intravenous administration. The PBPK model was established using previously published data in mice and included 10 tissue compartments: lungs, heart, brain, muscle, kidneys, pancreas, intestine, liver, spleen, adipose tissue, and plasma. Individual tissues were described by either perfusion-limited or permeability-limited models. All parameters were simultaneously estimated and the final model was able to describe murine data with good precision. The model was used for predicting doxorubicin disposition in rats, rabbits, dogs, and humans using interspecies scaling approaches and was qualified using plasma and tissue observed data. Reasonable prediction of the plasma pharmacokinetics and tissue distribution was achieved across all species. In conclusion, the PBPK model developed based on a rich dataset obtained from mice, was able to reasonably predict the disposition of doxorubicin in other preclinical species and humans. Applicability of the model for special populations, such as patients with hepatic impairment, was also demonstrated. The proposed model will be a valuable tool for optimization of exposure profiles of doxorubicin in human patients.