MicroRNA-24 regulates cardiac fibrosis after myocardial infarction

Cardiac fibrosis after myocardial infarction (MI) has been identified as a key factor in the development of heart failure. Although dysregulation of microRNA (miRNA) is involved in various pathophysiological processes in the heart, the role of miRNA in fibrosis regulation after MI is not clear. Previously we observed the correlation between fibrosis and the miR-24 expression in hypertrophic hearts, herein we assessed how miR-24 regulates fibrosis after MI. Using qRT-PCR, we showed that miR-24 was down-regulated in the MI heart; the change in miR-24 expression was closely related to extracellular matrix (ECM) remodelling. In vivo, miR-24 could improve heart function and attenuate fibrosis in the infarct border zone of the heart two weeks after MI through intramyocardial injection of Lentiviruses. Moreover, in vitro experiments suggested that up-regulation of miR-24 by synthetic miR-24 precursors could reduce fibrosis and also decrease the differentiation and migration of cardiac fibroblasts (CFs). TGF-β (a pathological mediator of fibrotic disease) increased miR-24 expression, overexpression of miR-24 reduced TGF-β secretion and Smad2/3 phosphorylation in CFs. By performing microarray analyses and bioinformatics analyses, we found furin to be a potential target for miR-24 in fibrosis (furin is a protease which controls latent TGF-β activation processing). Finally, we demonstrated that protein and mRNA levels of furin were regulated by miR-24 in CFs. These findings suggest that miR-24 has a critical role in CF function and cardiac fibrosis after MI through a furin-TGF-β pathway. Thus, miR-24 may be used as a target for treatment of MI and other fibrotic heart diseases.     

Body mass index and depressive symptoms: instrumental‐variables regression with genetic risk score

The causal role of obesity in the development of depression remains uncertain. We applied instrumental‐variables regression (Mendelian randomization) to examine the association of adolescent and adult body mass index (BMI) with adult depressive symptoms. Participants were from the Young Finns prospective cohort study (n = 1731 persons, 2844 person‐observations), with repeated measurements of BMI and depressive symptoms (modified Beck's Depression Inventory). Genetic risk score of 31 single nucleotide polymorphisms previously identified as robust genetic markers of body weight was used as a proxy for variation in BMI. In standard linear regression analysis, higher adult depressive symptoms were predicted by higher adolescent BMI (B = 0.33, CI = 0.06–0.60, P = 0.017) and adult BMI (B = 0.47, CI = 0.32–0.63, P < 0.001). These associations were replicated in instrumental‐variables analysis with genetic risk score as instrument (B = 1.96, CI = 0.03–3.90, P = 0.047 for adolescent BMI; B = 1.08, CI = 0.11–2.04, P = 0.030 for adult BMI). The association for adolescent BMI was significantly stronger in the instrumented analysis compared to standard regression (P = 0.04). These findings provide additional evidence to support a causal role for high BMI in increasing symptoms of depression. However, the present analysis also demonstrates potential limitations of applying Mendelian randomization when using complex phenotypes.     

多层螺旋CT 对腹膜后纤维化的诊断价值

目的:评价MSCT对腹膜后纤维化的诊断价值。方法:回顾性分析经临床及手术、活检病理证实9例腹膜后纤维化患者的MSCT影像资料,分别由两名副主任医师采用盲法对RPF病变发生部位、病变范围、病灶形态、密度及与周围组织的解剖关系显示情况进行分析,所有病例均进行平扫及三期增强扫描,并进行平扫及增强后病变CT值测定。采用多平面重建(MPR)、曲面重建(CMPR)、容积重建(VR)及CT尿路造影(CTU)技术进行分析。结果:所有患者CT平扫表现为腹膜后不规则近似于肌肉密度的软组织病变,6例病灶边界清晰,3例边界不清。9例均不同程度包绕腹膜后大血管,8例始于肾门下方,一例累及十二指肠上动脉。9例均不同程度累及一侧或双侧输尿管,造成输尿管及肾盂扩张积水,输尿管管壁增厚。增强扫描7例有轻中度强化,2例强化不明显。结论:MSCT可以显示腹膜后纤维化的特征,MPR、CMPR、VR及CTU技术综合应用有利于明确病变部位、形态、范围及与周围组织的解剖关系,有利于提高该病的诊断准确率。     

特发性腹膜后纤维化误诊为输尿管癌1 例报告并文献复习

目的:分析并掌握腹膜后纤维化的诊疗特点,避免对该病的误诊误治。方法:回顾性分析1例腹膜后纤维化患者分别因两侧肾积水先后两次住院并最终确诊的诊疗过程中的临床资料,包括临床表现、影像特点、病理结果、治疗方法及预后等,并结合相关文献进行复习。结果:患者因右肾积水首次入院诊断为右输尿管癌而行右侧肾输尿管切除术,后患者因左肾积水来我院住院诊断为腹膜后纤维化,行腹腔镜输尿管松解+腹腔内置术,术后长期随访疗效满意。结论:腹膜后纤维化作为一种少见病,缺乏对其认识极易导致误诊误治,掌握该疾病的临床特点及选择适宜的治疗方案,对本病的诊疗具有重要意义。     

超声弹性成像评价肝纤维化程度的探讨

目的:运用实时组织弹性成像(RTE)对肝脏弹性图像进行评分,并通过与实验室指标的比较,探讨RTE评分诊断肝纤维化程度的可行性与准确性。方法:选取我院收治的慢性病毒性肝炎患者90例作为研究对象,行RTE以及肝功能、血常规和凝血五项等实验室检查,随后肝活检获得病理学证据。比较RTE评分与实验室指标诊断肝纤维化程度的准确性。结果:90例患者中,S0期21例,S1期31例,S2期31例,S3期20例,S4期7例。RTE评分与肝纤维化程度呈正相关(r=0.79,P<0.05)。同样,门冬氨酸氨基转移酶/血小板比例指数(APRI)与肝纤维化程度也呈正相关(r=0.57,P<0.05)。RTE评分只与APRI呈相关性(r=0.667,P=0.000)。RTE评分诊断明显肝纤维化的敏感度为94.31%、特异度为78.65%、准确率为85.22%、阳性预测值为76.63%、阴性预测值为94.58%,均高于APRI。结论:实时组织弹性成像技术在诊断肝纤维化方面有广泛的临床研究价值和前景。     

扶正化瘀胶囊对鼠血吸虫肝纤维化的作用及机制探讨

目的:研究扶正化瘀胶囊对实验性血吸虫病肝纤维化的影响,探讨其相关作用机制。方法:70只昆明小鼠分为正常对照组(A)、模型组(B)、吡喹酮组(C)、INF-γ组(D)、扶正化瘀胶囊低剂量组(E)、中剂量组(F)、高剂量组(G),采用日本血吸虫尾蚴30条/只攻击感染小鼠建立血吸虫性肝纤维化模型。第6周用吡喹酮驱虫治疗后予扶正化瘀胶囊干预,第14周末观察血清透明质酸、层粘连蛋白、III型前胶原、IV型胶原水平,HE染色观察肝脏病理改变及虫卵结节变化,免疫组化检测PDGF-BB和I、III型胶原的表达。结果:扶正化瘀胶囊各剂量组肝脏病理损伤减轻,虫卵肉芽肿面积和数量明显减小;血清HA、LN、PC-III、C-IV水平显著下降(P<0.05);肝组织I、III型胶原和PDGF-BB表达明显低于模型组(P<0.05)。结论:扶正化瘀胶囊具有抗血吸虫性肝纤维化作用,降低肝组织PDGF-BB的表达可能是其抗纤维化作用机制之一。     

Positional dependence of non-native polar mutations on folding of CFTR helical hairpins

Mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) cause CF disease by altering the biosynthesis, maturation, folding and ion conductance of this protein. Our laboratory has focused on expression and structural analysis of the CFTR transmembrane (TM) domains using two-TM segments (i.e., helix-loop-helix constructs) which we term ‘helical hairpins’; these represent the minimal model of tertiary contacts between two helices in a membrane. Previous studies on a library of TM3/4 hairpins of the first CFTR TM domain suggested that introduction of non-native polar residues into TM4 can compromise CFTR function through side chain-side chain H-bonding interactions with native Q207 in TM3 [Choi, M. Y., Cardarelli, L., Therien, A. G., and Deber, C. M. Non-native interhelical hydrogen bonds in the cystic fibrosis transmembrane conductance regulator domain modulated by polar mutations, Biochemistry 43 (2004) 8077-8083]. In the present work, we combine gel shift assays with a series of NMR experiments for comparative structural characterization of the wild type TM3/4 hairpin and its mutants V232D, I231D, Q207N/V232E. Over 95% of the backbone resonances of a ¹⁵N,¹³C-labelled V232D-TM3/4 construct in the membrane-mimetic environment of perfluorooctanoate (PFO) micelles were successfully assigned, and the presence and boundaries of helical segments within TM3 and TM4 were defined under these conditions. Comparative analysis of ¹⁵N and ¹H chemical shift variations among HSQC spectra of WT-, V232D-, I231D- and Q207N/V232E-TM3/4 indicated that hairpin conformations vary with the position of a polar mutation (i.e., V232D and I231D vs. WT), but remain similar when hairpins with identically-positioned polar partners are compared (i.e., V232D vs. Q207N-V232E). The overall findings suggest that a polar mutation in a TM helix can potentially distort native interfacial packing determinants in membrane proteins such as CFTR, with consequences that may lead to disease.     

Scotin: A new p63 target gene expressed during epidermal differentiation

Accumulating evidence indicates that bacteria and bacterial products promote hepatic fibrogenesis. The activation of hepatic stellate cells (HSC) plays a central role in hepatic fibrosis. Here, we demonstrate that HSC express toll-like receptor 9 (TLR9), a pattern recognition receptor that is activated by CpG motifs present specifically in bacterial DNA. Upon CpG stimulation human as well as murine HSC isolated from wild-type (TLR9+/+) mice express increased levels of the profibrogenic chemokine monocyte chemotactic protein 1 (MCP-1). In contrast, HSC isolated from TLR9 deficient (TLR9−/−) mice lacked CpG motif induced MCP-1 expression indicating the functionality of TLR9 in HSC. Bile duct ligation revealed significantly lower hepatic MCP-1 and collagen expression and less hepatic fibrosis in TLR9−/− compared to TLR9+/+ mice. In addition, the expression of hepatic α-smooth-muscle actin, a known marker for HSC activation, was reduced in TLR9−/− mice indicating that bacterial DNA induces the activation of HSC and therefore promotes hepatic fibrosis.     

Characterisation of electrogenic nutrient absorption in the <Emphasis Type="Italic">Cftr</Emphasis><Superscript><Emphasis Type="Italic">TgH(neoim)Hgu</Emphasis></Superscript> mouse model

Most cystic fibrosis (CF) patients show an exocrine pancreatic insufficiency that results in lower enzyme and bicarbonate secretion. To test whether an altered function of nutrient transporters might additionally attribute to the lower bodyweight of CF patients we investigated electrogenic absorption of alanine, glycyl-glutamine, glucose and the effect of pH on nutrient absorption by Ussing chambers in a CF mouse model carrying the Cftr TgH(neoim)Hgu mutation. The electrogenic transport of all three nutrients was similar between the D2.129P2(CF/3)-Cftr TgH(neoim)Hgu congenic strain and DBA/2J mice as well as between the B6.129P2(CF/3)-Cftr TgH(neoim)Hgu congenic strain and C57BL/6J mice. This indicates that the Cftr TgH(neoim)Hgu mutation does not affect the electrogenic absorption of alanine, glycyl-glutamine and glucose. In contrast, electrogenic nutrient absorption was reduced in the CF/1-Cftr TgH(neoim)Hgu and CF/3-Cftr TgH(neoim)Hgu inbred strains compared to the HsdOla:MF1, D2.129P2(CF/3)-Cftr TgH(neoim)Hgu and B6.129P2(CF/3)-Cftr TgH(neoim)Hgu strains, whereas no difference was found among the wild-type strains. This indicates that not the Cftr TgH(neoim)Hgu mutation but differences in the genetic background of the CF/1-Cftr TgH(neoim)Hgu and CF/3-Cftr TgH(neoim)Hgu strains compared to HsdOla:MF1, D2.129P2(CF/3)-Cftr TgH(neoim)Hgu and B6.129P2(CF/3)-Cftr TgH(neoim)Hgu strains are associated with the differences in electrogenic nutrient absorption. The electrogenic absorption of alanine, glycyl-glutamine and glucose was not influenced by an acidic pH (5.4) compared to absorption at pH 7.4.