缺氧诱导因子-1α参与肝纤维化形成机制研究进展

目的 肝纤维化是一种由于反复肝损伤而导致肝组织细胞外基质过多沉积导致的疾病。缺氧损伤为肝损伤的一部分,缺氧诱导因子-1α(HIF-1α)是响应缺氧应激的关键转录因子,在肝纤维化组织和活化的肝星状细胞(HSC)表达显著增加。目前,通过对大量HIF-1α依赖性基因和信号通路的研究,确认这些基因及其通路的变化参与肝纤维化发展过程,并可能在肝纤维化发生发展过程中起关键作用。本文综述了HIF-1α相关的信号通路参与肝纤维化发展的相关机制,并对上游影响HIF-1α合成和降解的相关信号通路进行了阐述,为其作为新型治疗靶点的可能潜力提供依据。     

张应力对小鼠蝶枕软骨联合细胞增殖及低氧诱导因子- 1α表达的影响

目的:了解循环张应力对小鼠颅底蝶枕软骨联合细胞(SOSCs)增殖及低氧诱导因子-1α表达的影响。方法:采集1 d龄小鼠的SOSCs进行体外培养,对第三代细胞加载牵张形变率分别为3%、6%、9%,频率为1 Hz,持续时间为1 h的循环张应力;用流式细胞术测算细胞增殖指数,用蛋白免疫印迹技术分析Hif-1α的表达水平。用按相同条件培养但不加力的细胞作为对照。结果:各实验组细胞的增殖指数和Hif-1α相对表达量都高于对照组(P<0.05);其中,6%牵张形变率组的细胞增殖指数和Hif-1α相对表达量较对照组增加最多。结论:适宜强度的循环张应力对体外培养小鼠SOSCs的增殖和Hif-1α表达具有促进作用。     

益气逐瘀方对缺氧诱导乳鼠心肌细胞凋亡及miR-24/Bim通路的影响

目的研究益气逐瘀方(参元丹)对缺氧诱导乳鼠心肌细胞凋亡及miR-24/Bim通路的影响。方法分离并培养乳鼠心肌细胞,建立心肌细胞缺氧模型,Lipofectamine2000转染miR-24 mimic/inhibitor至心肌细胞,实验分为正常组、缺氧组、参元丹组、参元丹+miR-24 mimic组、参元丹+miR-24 inhibitor组,治疗组予参元丹含药血清干预。比色法检测心肌细胞培养基上清液LDH、CPK活性,MTT法检测心肌细胞存活率,Annexin V/PI双染流式细胞术检测心肌细胞凋亡,qRT-PCR检测心肌细胞miR-24、Bim mRNA表达。结果与低氧组相比,参元丹组、参元丹+miR-24 mimic组、参元丹+miR-24 inhibitor组均能显著降低细胞培养基上清液LDH、CPK活性(P<0.05),提高心肌细胞存活率(P<0.05),降低心肌细胞凋亡(P<0.05),升高心肌细胞miR-24 mRNA表达(P<0.05),降低Bim mRNA表达(P<0.05);治疗组之间比较,参元丹+miR-24 mimic组作用更显著(P<0.05)。结论益气逐瘀方参元丹能够减轻缺氧诱导乳鼠心肌细胞损伤及细胞凋亡,其作用机制可能与其上调miR-24表达,同时抑制其靶基因Bim mRNA表达有关。     

Inhibition of Frizzled-2 by small interfering RNA protects rat hepatic BRL-3A cells against cytotoxicity and apoptosis induced by Hypoxia/Reoxygenation

Frizzled-2 plays an important role in maintaining normal hepatic cell functionality. This study aimed to investigate the role of inhibition of Frizzled-2 in protecting rat liver BRL-3A cells from Hypoxia/Reoxygenation (H/R). In vitro H/R hepatic cell model was established by culturing BRL-3A cells under H/R condition. Frizzled-2 siRNA was transfected into BRL-3A cells to inhibit Frizzled-2 signaling. Wnt5a and Frizzled-2 were significantly increased in BRL-3A cells upon H/R treatment. H/R treatment induced cell cytotoxicity, the early apoptosis rate and the intracellular Ca²⁺ level in BRL-3A cells while silencing frizzled-2 gene decreased the H/R induced cell cytotoxicity, apoptosis and intracellular Ca²⁺ level. In vivo mice study further showed the up-regulation of Frizzled-2/Wnt 5 pathway and cleaved Caspase-3 expression in liver tissues under ischemia and reperfusion injury (IRI). In summary, inhibition of Frizzled-2 by its siRNA may protects BRL-3A cells by attenuating the H/R induced cell cytotoxicity and apoptosis.     

Polyglobulie rare par mutation du gène EGLN1 : à propos d’un cas et revue de la littérature

IntroductionThe origin of polycythemia is often simple to detect. Sometimes it is necessary to look for hereditary forms, the decisive parameters being the dosage of erythropoietin and the measurement of the oxygen dissociation curve (P50). These rare diseases are related to high oxygen-affinity haemoglobins, abnormalities of the erythropoietin receptor or dysfunction of the HIF (hypoxia-inducible factor) pathway.Case reportWe report the case of a 56-year-old patient with unexplained polycythemia associated with normal serum erythropoietin and normal P50, in whom the never previously described mutation c.400C>T (p.Gln134*) on exon 1 in the EGLN1 gene (encoding PHD2) was found.ConclusionIn the face of an unexplained polycythemia a good cooperation between clinicians and biologists is necessary to be able to characterize rare hereditary pathologies.     

颅内动脉瘤破裂出血术后血清HIF-1α、miR-210表达与脑血管痉挛的关系

目的检测颅内动脉瘤破裂出血术后血清缺氧诱导因子1α（HIF-1α）、miR-210表达情况，并探讨其与脑血管痉挛（CVS）的关系。 方法选取禹城市人民医院神经外科自2015年1月至2018年12月收治的87例颅内动脉瘤破裂急诊自发性蛛网膜下腔出血（SAH）并接受介入栓塞或开颅夹闭治疗的患者为研究对象，采用头颅X线、CT及全脑数字减影血管造影（DSA）检查判断CVS的发生情况，并评估其严重程度。术后3、7 d采用ELISA法检测血清HIF-1α表达情况，采用qRT-PCR法检测血清miR-210表达情况。分析颅内动脉瘤破裂出血患者术后血清HIF-1α、miR-210表达的关系，采用ROC曲线分析颅内动脉瘤破裂出血患者术后3 d血清HIF-1α、miR-210水平对CVS的诊断价值。 结果87例颅内动脉瘤破裂出血患者出现术后CVS者37例（42.53%），其中轻度CVS 10例（11.49%），中度19例（21.84%），重度8例（90.20%）；术后3、7 d，与无CVS组患者相比，不同程度CVS患者血清中的HIF-1α、miR-210水平均显著升高（P<0.05），且CVS程度越重，血清HIF-1α、miR-210表达水平越高，不同程度CVS患者术后3、7 d时血清HIF-1α、miR-210水平均显著高于术前（P<0.05），术后7 d时血清HIF-1α、miR-210水平均显著低于术后3 d，差异有统计学意义（P<0.05）；颅内动脉瘤破裂出血术后3、7 d患者血清HIF-1α水平与miR-210水平均呈正相关（r=0.381、0.631，P<0.05）；术后3 d血清HIF-1α、miR-210水平及HIF-1α+miR-210联合诊断颅内动脉瘤破裂出血患者CVS的曲线下面积分别为0.834、0.769、0.900，二者联合诊断CVS的敏感度为93.06%，准确度为87.36%，均高于单项指标检测。 结论颅内动脉瘤破裂出血术后血清HIF-1α、miR-210水平可有效预示CVS的发生，二者可能成为CVS发生、发展的重要生物学指标。     

Acute psycho-physiological responses to perceptually regulated hypoxic and normoxic interval walks in overweight-to-obese adults

ObjectivesWe investigated psycho-physiological responses to perceptually regulated interval walks in hypoxia versus normoxia in obese individuals.DesignWithin-participants repeated measures.MethodsTen obese adults (BMI = 32 ± 3 kg/m^?2) completed a 60-min interval session (15 × 2 min walking at a rating of perceived exertion of 14 on the 6–20 Borg scale with 2 min of rest) either in hypoxia (FiO₂ = 13.0%, HYP) or normoxia (NOR). A third trial replicating the HYP speed pattern was carried out in normoxia as a control (CON). Exercise responses were analysed comparing the average of 1st to 3rd exercise bouts to those of the 4th–6th, 7th–9th, 10th–12th and 13th–15th exercise bouts (block 1 versus 2, 3, 4 and 5).ResultsTreadmill speed was slower during block 4 (6.14 ± 0.67 versus 6.24 ± 0.73 km/h^?1) and block 5 (6.12 ± 0.64 versus 6.25 ± 0.75 km/h^?1) in HYP compared to NOR or CON (p = 0.009). Compared to NOR and CON, heart rate was +6–10% higher (p = 0.001), whilst arterial oxygen saturation (?12–13%) was lower (p < 0.001) in HYP. Perceived limb discomfort was lower in HYP and CON versus NOR (?21 ± 4% and ?34 ± 6%; p = 0.004).ConclusionsIn overweight-to-obese adults, perceptually regulated interval walks in hypoxia versus normoxia leads to progressively slower speeds along with lower limb discomfort and larger physiological stress than normoxia. Walking at the speed adopted in hypoxia produces similar psycho-physiological responses at the same absolute intensity in normoxia.     

Diagnostic approaches to respiratory abnormalities in craniofacial syndromes

Craniofacial syndromes are a complex cluster of genetic conditions characterized by embryonic perturbations in the developmental trajectory of the upper airway and related structures. The presence of reduced airway size and maladaptive neuromuscular responses, particularly during sleep, leads to significant alterations in sleep architecture and overall detrimental gas exchange abnormalities that can be life-threatening. The common need for multi-stage therapeutic interventions for these craniofacial problems requires careful titration of anatomy and function, and the latter is currently evaluated by overnight polysomnography in sleep laboratories. The cost, inconvenience, and scarcity of pediatric sleep laboratories preclude the frequent evaluations that could optimize the overall process of treatment and corresponding outcomes. Here, we critically examine reductionist approaches to polysomnography in children to establish the parallel approximation of such techniques to infant with craniofacial disorders. The need for prospective longitudinal multicenter studies with side-by-side comparisons aimed at identifying an optimal diagnostic and long-term monitoring paradigm for these potentially life-threatening conditions is emphasized.