原花青素对放射性心脏损伤大鼠血清cTn-Ⅰ、SOD、MDA、GSH-px的影响

目的:观察原花青素(proanthocyanidins)对放射性心脏损伤(radiation-induced heart damage,RIHD)大鼠血清肌钙蛋白Ⅰ(cardiac troponin Ⅰ,cTn-Ⅰ)、超氧化物歧化酶(superoxide dismutase,SOD)、丙二醛(malondialdehyde,MDA)、谷胱甘肽过氧化物酶(glutathione peroxidase,GSH-px)表达水平的影响,以及对RIHD大鼠的可能作用及作用机制.方法:60只雄性远交群(sprague dawley,SD)大鼠,随机数字表法分为6组,每组10只,分别为正常对照组、单纯照射组、OPC小剂量(50 mg/kg)组、OPC中剂量(100 mg/kg)组、OPC大剂量(150 mg/kg)组、蓝莓(200 mg/kg)组.除正常对照组外,其余各组大鼠给予6MVX线单次大剂量照射心脏,总剂量(total dose,Dt)20 Gy,OPC组和蓝莓组大鼠给予相应药物灌胃.放疗结束后4周,HE染色、Masson染色观察大鼠心肌组织病理改变,ELISA检测血清cTn-Ⅰ、SOD、MDA、GSH-px表达水平.结果:与正常对照组比较,单纯照射组、OPC组、蓝莓组病理评分和心肌胶原容积分数(collagen volume fraction,CVF)评分升高(P＜0.05);与单纯照射组比较,OPC组、蓝莓组病理评分和CVF评分升高(P＜0.05),差异均具有统计学意义.与正常对照组相比,单纯照射组、OPC组、蓝莓组cTn-Ⅰ、MDA表达水平升高,单纯照射组、OPC组、蓝莓组SOD、GSH-px表达水平下降;与单纯照射组相比,OPC组、蓝莓组cTn-Ⅰ、MDA表达水平升高,OPC组、蓝莓组SOD、GSH-px表达水平下降,差异均具有统计学意义(P＜0.05).结论:OPC可通过抑制氧化应激,下调RIHD大鼠血清cTn-Ⅰ、MDA表达水平,上调血清SOD、GSH-px表达水平,抑制RIHD大鼠心肌损伤,疗效优于蓝莓.     

原发性肝癌组织中PKM2、COX2及IAPs的表达及其与放疗敏感性的关系分析

目的 探究原发性肝癌患者癌组织中M2型丙酮酸激酶(PKM2)、环氧合酶2(COX2)及凋亡蛋白抑制因子(IAPs)的表达及其与放疗敏感性的关系.方法 选取接受三维适形放疗的原发性肝癌患者105例,经肝脏穿刺活检采集肝癌组织,采用免疫组化法检测肝癌组织中PKM2、COX2及IAPs家族[X关联凋亡抑制因子(XIAP)、细胞内凋亡抑制蛋白1(cIAP-1)]蛋白的表达,比较不同放疗效果和敏感性患者癌组织中PKM2、COX2、XIAP及cIAP-1蛋白表达的差异,并分析上述蛋白表达与患者预后的关系.结果 105例患者肝癌组织中PKM2、COX2、XIAP及cIAP-1蛋白表达阳性率分别为81.90％、74.28％、85.71％及82.86％;COX2、XIAP蛋白阳性表达者治疗有效率与阴性者比较,差异有统计学意义(P＜0.05);放疗敏感患者临床分期、分化程度、肿瘤直径、肝癌组织中PKM2、COX2、XIAP及cIAP-1蛋白表达情况与放疗不敏感者比较,差异有统计学意义(P＜0.05);高临床分期、低分化程度、COX2、XIAP阳性表达是患者放疗不敏感的独立危险因素(P＜0.05);XIAP阳性表达者复发率和转移率与阴性表达者比较,差异有统计学意义(P＜0.05).结论 原发性肝癌患者癌组织中PKM2、COX2、XI-AP及cIAP-1阳性率高,其中COX2、XIAP蛋白表达与患者放疗效果、敏感性密切相关,XIAP蛋白表达还与患者复发转移有关.     

Both mTORC1 and mTORC2 are involved in the regulation of cell adhesion

mTOR is a central controller for cell growth/proliferation and survival. Recent studies have shown that mTOR also regulates cell adhesion, yet the underlying mechanism is not known. Here we found that inhibition of mTOR by rapamycin reduced the basal or type I insulin-like growth factor (IGF-1)-stimulated adhesion of cancer cells. Further research revealed that both mTORC1 and mTORC2 were involved in the regulation of cell adhesion, as silencing expression of raptor or rictor inhibited cell adhesion. Also, PP242, an mTORC1/2 kinase inhibitor, inhibited cell adhesion more potently than rapamycin (mTORC1 inhibitor). Of interest, ectopic expression of constitutively active and rapamycin-resistant mutant of p70 kinase 1 (S6K1) or downregulation of eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) conferred resistance to rapamycin inhibition of cell adhesion, whereas expression of constitutively hypophosphorylated 4E-BP1 (4EBP1-5A) or downregulation of S6K1 suppressed cell adhesion. In contrast, neither genetic manipulation of Akt activity nor pharmacological inhibition of Akt affected cell adhesion. The results suggest that both mTORC1 and mTORC2 are involved in the regulation of cell adhesion; and mTORC1 regulates cell adhesion through S6K1 and 4E-BP1 pathways, but mTORC2 regulates cell adhesion via Akt-independent mechanism.     

Enhanced tryptophan-kynurenine metabolism via indoleamine 2,3-dioxygenase 1 induction in dermatomyositis

Clinical Rheumatology - Extrahepatic tryptophan (Trp)-kynurenine (Kyn) metabolism via indoleamine 2,3-dioxygenase 1 (IDO1) induction was found to be associated with intrinsic immune regulation....     

Circulating microRNAs,potential biomarkers for drug-induced liver injury

Drug-induced liver injury is a frequent side effect of many drugs, constitutes a significant threat to patient health and has an enormous economic impact on health care expenditures. Numerous efforts have been made to identify reliable and predictive markers to detect the early signs of drug-induced injury to the liver, one of the most vulnerable organs in the body. These studies have, however, not delivered any more informative candidates than the serum aminotransferase markers that have been available for ≈30 years. Using acetaminophen overdose-induced liver injury in the mouse as a model system, we have observed highly significant differences in the spectrum and levels of microRNAs in both liver tissues and in plasma between control and overdosed animals. Based on our survey of microRNA expression among normal tissues, some of the microRNAs, like messenger RNAs, display restricted tissue distributions. A number of elevated circulating microRNAs in plasma collected from acetaminophen-overdosed animals are highly expressed in the liver. We have demonstrated that specific microRNA species, such as mir-122 and mir-192, both are enriched in the liver tissue and exhibit dose- and exposure duration-dependent changes in the plasma that parallel serum aminotransferase levels and the histopathology of liver degeneration, but their changes can be detected significantly earlier. These findings suggest the potential of using specific circulating microRNAs as sensitive and informative biomarkers for drug-induced liver injury.     

Parallel group ICA+ICA: Joint estimation of linked functional network variability and structural covariation with application to schizophrenia

There is growing evidence that rather than using a single brain imaging modality to study its association with physiological or symptomatic features, the field is paying more attention to fusion of multimodal information. However, most current multimodal fusion approaches that incorporate functional magnetic resonance imaging (fMRI) are restricted to second‐level 3D features, rather than the original 4D fMRI data. This trade‐off is that the valuable temporal information is not utilized during the fusion step. Here we are motivated to propose a novel approach called “parallel group ICA+ICA” that incorporates temporal fMRI information from group independent component analysis (GICA) into a parallel independent component analysis (ICA) framework, aiming to enable direct fusion of first‐level fMRI features with other modalities (e.g., structural MRI), which thus can detect linked functional network variability and structural covariations. Simulation results show that the proposed method yields accurate intermodality linkage detection regardless of whether it is strong or weak. When applied to real data, we identified one pair of significantly associated fMRI‐sMRI components that show group difference between schizophrenia and controls in both modalities, and this linkage can be replicated in an independent cohort. Finally, multiple cognitive domain scores can be predicted by the features identified in the linked component pair by our proposed method. We also show these multimodal brain features can predict multiple cognitive scores in an independent cohort. Overall, results demonstrate the ability of parallel GICA+ICA to estimate joint information from 4D and 3D data without discarding much of the available information up front, and the potential for using this approach to identify imaging biomarkers to study brain disorders.     

Effect of herpes simplex virus on spermatogenesis

To investigate the effect of Herpes Simplex virus (HSV) on spermatogenesis, HSV in ejaculate was detected by a rapid cultural method in 268 infertile males and 47 healthy ones. The number of mobile spermatozoa in HSV infected samples was less than in non-infected samples (21 mln/mlversus 40 mln/ml, p = 0.0001). The relative number of morphologically normal gametes was 13% versus 19% (p = 0.002), respectively. The quantitative karyological test discovered that males with HSV-infected ejaculate have more degenerating sex cells while in high virus contamination (more than 10 virus particles in 1 ml) the number of spermatides and spermatocytes of the 1 order at diploten stage is low. Organic testicular culture was used for more detailed study of pathogenetic mechanisms of HSV impact on spermatogenesis. Testicular explants infection was associated with reduction in the number of spermatogones, spermatocytes and spermatides on culturing week 2. The above findings reveal some pathogenetic mechanisms underling fertility disorders in males with HSV infection: a gametotoxic effect of the virus reducing populations of spermatogones, spermatocytes and spermatide; affected mobility and morphological characteristics of spermatozoa. Detection of the mechanisms of HSV action on spermatogenesis opens a perspective of antivirus drug administration in combined treatment of male infertility.     

Cryptotanshinone inhibits lymphatic endothelial cell tube formation by suppressing VEGFR-3/ERK and small GTPase pathways

Cryptotanshinone (CPT), isolated from the plant Salvia miltiorrhiza Bunge, is a potential anticancer agent. However, the underlying mechanism remains to be defined. Here, we show that CPT inhibited lymphangiogenesis in an in vitro model (tube formation). This effect was partly attributed to inhibiting expression of VEGF receptor 3 (VEGFR-3) in murine lymphatic endothelial cells (LEC), as overexpression of VEGFR-3 conferred resistance to CPT inhibition of the tube formation, whereas downregulation of VEGFR-3 mimicked the effect of CPT, blocking the tube formation. Furthermore, CPT inhibited phosphorylation of the extracellular signal-related kinase 1/2 (ERK1/2). Overexpression of VEGFR-3 attenuated CPT inhibition of ERK1/2 phosphorylation, whereas downregulation of VEGFR-3 inhibited ERK1/2 phosphorylation in LECs. Expression of constitutively active MKK1 resulted in activation of ERK1/2 and partially prevented CPT inhibition of LEC tube formation. In addition, CPT also inhibited protein expression and activities of Rac1 and Cdc42 but not RhoA. Expression of constitutively active Rac1 and Cdc42 concurrently, but not Rac1 or Cdc42 alone, conferred resistance to CPT inhibition of LEC tube formation. Taken together, the results suggest that CPT inhibits LEC tube formation, in part, by inhibiting VEGFR-3-mediated ERK1/2 phosphorylation and, in part, by inhibiting expression of the small GTPases.     

与成人型多囊肾病基因位点1连锁的微卫星的遗传多态性研究

目的探讨广泛应用于高加索人多囊肾病（ＰＫＤ１）基因诊断的两个微卫星在中国汉族及壮族人群中的多态性及其等位基因频率是否存在群体差异。方法用聚合酶链反应（ＰＣＲ）扩增与ＰＫＤ１连锁的两个微卫星，１０％非变性聚丙烯酰胺凝胶电泳结合ＤＮＡ序列测定检测ＰＣＲ产物。结果ＡＣ２．５和ＳＭ７两个微卫星：（１）在汉族中分别观察到１０和１１个等位基因，期望杂合度分别为６８．４％及７７．４％，多态信息含量（ＰＩＣ）分别为０．６８及０．７７；（２）在壮族中分别观察到８及９个等位基因，期望杂合度分别６７．１％及５７．５％，ＰＩＣ分别为０．６７及０．５７；（３）６个ＡＣ２．５等位基因的频率及８个ＳＭ７等位基因的频率存在群体差异（Ｐ＜０．０５）。结论ＡＣ２．５和ＳＭ７在汉族和壮族中均高度多态（ＳＭ７在壮族中稍差），可用于汉、壮族人ＰＫＤ１基因诊断。同时，这两个微卫星的等位基因频率分布具有群体差异，在应用它们进行基因诊断和疾病关联性研究时应引起注意。     

Analysis of Hymenoptera stings reported to the Illinois Poison Center

Although there is some detailed research on anaphylactic reactions to Hymenoptera venom, there continues to be little epidemiological data about the distribution, trend, and factors associated with the occurrence of Hymenoptera envenomations in humans. We describe characteristics of persons suffering Hymenoptera stings from bees, wasps, and hornets as reported to the Illinois Poison Center, and assess seasonal, climatologic, and time trends of calls for envenomations between 2002 and 2007. Mean daily temperature and mean daily atmospheric pressure were positively associated with envenomations, whereas wind speed was negatively associated with envenomations. We also observed a significant increase in calls for envenomations on summer holidays (P < 0.001). In addition, our findings showed that the number of calls for envenomations declined by nearly half after 2005 (P < 0.001) compared with previous years. Our findings indicate that the decline in bees, wasps, and hornets may be widespread, affecting both wild and commercial populations, and that the decline appears to have been rapid and sustained in recent years. Poison center data are a valuable resource for the surveillance of poisoning in humans, but our findings show that the data can be used to monitor changes in nonhuman species.