Evaluation of hypoxia inducible factor targeting pharmacological drugs as antileishmanial agents

Objective:To evaluate whether hypoxia inducible factor(HIF-1α) targeting pharmacological drugs,echinomycin,resveratrol and CdCl_2 which inhibit HIF-1α stimulation,and mimosine,which enhances the stability of HIF-1α present antileishmanial properties.Methods:The leishmanicidal effect of drugs was evaluated in mouse macrophages and Balb/c mouse model for cutaneous leishmaniosis.Results:Resveratrol and CdCl_2 reduced the parasite load [IC50,(27.3±2.25) μM and(24.8±0.95) μM,respectively].The IC50 value of echinomycin was(22.7±7.36) nM and mimosine did not alter the parasite load in primary macrophages.The macrophage viability IC50 values for resveratrol,echinomycin and CdCl_2 and mimosine were 40 μM,100 nM, 200 μM and2 000 μM,respectively.In vivo no differences between cutaneous lesions from control,resveratrol-and echinomycin-treated Balb/c mice were detected.Conclusions:Resveratrol,echinomycin and CdCl_2 reduce parasite survival in vitro.The HIF-1α targeting pharmacological drugs require further study to more fully determine their anti-Leishmania potential and their role in therapeutic strategies.     

阻塞性睡眠呼吸暂停患者肺动脉僵硬度的评价及其与低氧的关系

目的:旨在研究阻塞性睡眠呼吸暂停患者(OSA)夜间间歇性缺氧程度对肺动脉僵硬度(PAS)和右心室功能的影响。方法:对可疑OSA的患者进行多导睡眠图(PSG)和经胸超声心动图检查(n=376)。按夜间最低脉搏血氧饱和度(SpO2)分为三组(对照组:Sp O2≥90%,轻中度低氧组:80%≤SpO2<90%,重度低氧组:SpO2<80%)。比较三组患者的PAS和右心室功能,并进一步分析其相关影响因素。结果:最终本研究对278例患者进行分析。重度低氧组PAS显著升高(P=0.003),与平均肺动脉压(mPAP)有良好的相关性(r=0.780,P<0.001),而mPAP在不同组间差异无统计学意义(P>0.05)。各组间右心室功能相关参数,差异无统计学意义(P>0.05)。单因素和多因素Logistic分析表明,只有夜间最低SpO2(OR=1.807,P=0.001)是PAS升高的相关因素。结论:在重度低氧血症的OSA患者中PAS增加,仅夜间最低SpO2是其相关因素。     

报告基因成像评价Ghrelin对骨髓间充质干细胞的缺氧保护作用

目的通过报告基因成像评价Ghrelin对骨髓间充质干细胞(MSCs)的缺氧保护作用。方法采用密度梯度离心法分离稳定表达萤火虫荧光素酶(Fluc)的MSCs,随机分为对照组、缺氧复氧组和10~(-9)、10~(-8)、10~(-7) Ghrelin组,后3组分别加入10~(-9)、10~(-8)、10~(-7)mol/L Ghrelin培养。运用Fluc报告基因成像、MTT法对MSCs的生物学活性进行定量评价,Western blot和ELISA法检测MSCs的作用机制。结果 MSCs稳定表达报告基因Fluc,其光学信号强度与细胞数量呈正相关(r~2=0.96)。缺氧复氧组MSCs生存活力较对照组显著下降;与缺氧复氧组比较,10~(-8)、10~(-7) Ghrelin组MSCs生存率和VEGF分泌水平明显升高,10~(-8) Ghrelin组磷酸化Akt表达明显升高(P<0.05)。结论 Ghrelin能够显著提高缺氧复氧后MSCs的存活能力,可能是MSCs的保护性因素。     

血液病与缺氧

大气中的氧气随呼吸进入肺泡 ,并弥散入肺泡周围毛细血管 ,与血红蛋白 (Ｈｂ)结合后随血液循环输送到全身 ,最后被组织细胞摄取利用。上述任何环节发生障碍都可引起缺氧 ,其中Ｈｂ数量的减少或性质的改变可使血氧含量[Ｃａ(Ｏ2 ) ]降低或Ｈｂ与氧分子 (Ｏ2 )结合力异常 ,导致组织缺氧 ,称为血液性缺氧 (ｈｅｍｉｃｈｙｐｏｘｉｎ) [1] 。血液性缺氧时 ,由于肺的呼吸功能正常 ,动脉血氧分压 [Ｐａ(Ｏ2 ) ]和饱和度[Ｓａ(Ｏ2 ) ]也相应正常 ,但因Ｈｂ数量或性质的改变 ,出现Ｃａ(Ｏ2 )下降 ,动静脉氧含量差 (Ｃａ -ｖＯ2 )小于正常 ;在少部分…     

Hyperventilation-induced cerebral hypoxia

Acute respiratory alkalosis decreases cerebral blood flow, increases the affinity of hemoglobin for oxygen, and can result in cerebral hypoxia. This experiment was designed to study this phenomenon in dogs, and to demonstrate the effect of an increased concentration of inspired oxygen. Seven mongrel dogs were anesthetized with pentobarbital and ventilated with a constant volume respirator. A Telfon-coated stainless steel catheter was placed through a craniotomy into the parietal lobe and advanced through the corona radiata to monitor cerebral PO2 and PCO2 with a mass spectrometer. Steady state cerebral and arterial gas tensions were recorded during eucapnic ventilation with air, eucapnic ventilation with 100% oxygen, hypocapnic ventilation with air, and hypocapnic ventilation with 100% oxygen. Decreased cerebral tissue oxygen tension was demonstrated in hypocapnic dogs ventilated with air. When the concentration of inspired oxygen was increased, the relatively small increase in artrial oxygen content was associated with a marked increase in PO2 at the cerebral tissue level. This may be of clinical importance in therapeutic or centrally mediated hyperventilation.     

慢性间断缺氧小鼠缺氧诱导因子1α的研究

目的　探索睡眠呼吸暂停综合征(SAS)的慢性间断性缺氧(CIH)对心血管损害的可能机制。方法　制作CIH小鼠模型。将30只ICR小鼠均分为实验组、空气模拟对照组及空白对照组。免疫组织化学方法检测实验小鼠心肌细胞缺氧诱导因子1α(HIF1α)及诱导型一氧化氮合成酶(NOS2)的表达。酶联免疫吸附测定(ELISA)方法检测小鼠血浆血管内皮生长因子(VEGF)及内皮素1(ET1)的浓度。结果　实验组心肌细胞HIF1α表达高于空白对照组(t=354,P<005)及空气模拟对照组(t=292,P<005);空白对照组HIF1α表达与空气模拟对照组比较差异无统计学意义(P>005)。实验组血浆VEGF浓度[(957±141)ng/ml]高于空白对照组[(810±062)ng/ml,q=427,P<005]及空气模拟对照组[(832±099)ng/ml,q=364,P<005];空白对照组血浆VEGF浓度与空气模拟对照组比较差异无统计学意义(P>005)。实验组血浆ET1浓度[(331±081)ng/ml]高于空白对照组[(250±072)ng/ml,q=364,P<005];空气模拟对照组血浆ET1浓度[(269±043)ng/ml]与实验组及空白对照组[(331±081)、(250±072)ng/ml]比较差异均无统计学意义(P均>005)。小鼠心肌细胞NOS2表达在各组间比较差异均无统计学意义(P均>005)。结论　CIH可引起小鼠HIF1α表达增加,并可促进HIF1α目的基因产物VEGF、ET1的表达。这可能     

一氧化碳中毒与缺氧

一氧化碳 (ＣａｒｂｏｎｍｏｎｏｘｉｄｅＣＯ)为无色、无味、无刺激性的气体。大气中ＣＯ含量甚微 ,仅有 0 0 4× 10 6。空气混合爆炸极限为 12 5 %～ 74%。当吸入气中ＣＯ含量超过 5× 10 -4 (即 0 0 5 % )或 30ｍｇ/ｍ3 时 ,就可使人中毒 ;当空气中含量超过 12 5× 10 -3 (12 5 % )时 ,有爆炸的危险。ＣＯ在红外线波段区吸收电磁辐射 ,主要吸收带为 4 6 μｍ ,利用这个性质可测定空气中的ＣＯ浓度。1　中毒原因环境中ＣＯ主要来源有职业性和生活性两大类 ,也偶有意外情况。凡含碳的物质燃烧不完全时 ,都可产生ＣＯ气体。在工业生产中…     

Intermittent high altitude hypoxia

The effect of intermittent high altitude (IHA) hypoxia on the myocardium and lesser circulation was investigated in adult male Wistar rats. IHA can induce intermittent pulmonary hypertension and right ventricular hypertrophy in a relatively short time. Even marked pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular changes can be normalized when rats are removed from the hypoxic atmosphere. At the beginning of the exposure to IHA acute myocardial necrotic changes were found; prolongation of IHA did not lead to further acute lesions. Experimentally induced CO polycythemia leads to mild pulmonary hypertension; IHA-induced pulmonary hypertension may, thus, be partly due to polycythemia. Beta blocking agents are able to decrease chronic hypoxic pulmonary hypertension, hypertensive changes in the pulmonary circulation, the degree of right ventricular hypertrophy, and necrotic myocardial changes.     

Effect of hypoxia and hypoxia/reoxygenation on proteoglycan metabolism by vascular smooth muscle cells

Hypoxia and hypoxia/reoxygenation are known to affect vascular smooth muscle cell physiology. In this study, we first investigated proteoglycan synthesis by human aortic smooth muscle cells exposed to normoxia, hypoxia, or hypoxia/reoxygenation. We then compared the newly synthesized proteoglycans from normoxic and hypoxic-reoxygenation cultures for their ability to bind low density lipoprotein (LDL). Confluent smooth muscle cells under normoxia, hypoxia, or hypoxia/reoxygenation were pulsed with [35S]sulfate, and secreted and cell-associated proteoglycans were analyzed. Secreted proteoglycans in cultures exposed to hypoxia (4 h)/reoxygenation (19 h) increased 28% over those of cells continuously exposed to normoxia. Cell-associated proteoglycans did not differ significantly between the two groups. In contrast, hypoxia (4 h) followed by a 30-min reoxygenation produced a 37% decrease in newly synthesized proteoglycans. Hypoxia alone also resulted in a 24% decrease in secreted proteoglycans and a 20% decrease in cell-associated proteoglycans. Proteoglycans newly synthesized by smooth muscle cells exposed to normoxia and hypoxia/reoxygenation did not differ in their charge densities and molecular size but did differ in glycosaminoglycan composition. Exposure of smooth muscle cells to hypoxia/reoxygenation produced a 60% increase in a proteoglycan subfraction that bound LDL with very high affinity. The incorporation of [3H]leucine into total cellular protein decreased significantly following exposure of smooth muscle cells to hypoxia as well as hypoxia/reoxygenation. These results indicate that hypoxia and hypoxia/reoxygenation cause major alterations in proteoglycan metabolism by vascular smooth muscle cells.     

Prolonged lobar hypoxia in vivo enhances the responsivity of isolated pulmonary veins to hypoxia.

The hypoxic response of pulmonary vessels isolated from eight sheep whose right apical lobes (RAL) had inspired 100% N2 for 20 h was studied. The RAL of these conscious sheep inspired hypoxic gas and the remainder of the lung inspired air. During hypoxia, RAL perfusion was 33 +/- 3% of its air value, carotid arterial PO2 averaged 86 +/- 3 mm Hg and pulmonary perfusion pressure was not significantly different from the initial control period when the RAL inspired air. At the end of the hypoxic exposure, the sheep were killed, and pulmonary artery and vein rings (0.5 to 2 mm inner diameter) were isolated from both the RAL and the right cardiac lobe, which served as the control lobe (CL). Arteries from the RAL and CL did not contract in response to 6% O2/6% CO2/88% N2 (hypoxia). In contrast, RAL veins did contract vigorously in response to hypoxia, whereas CL veins did not contract or contracted only minimally. Rubbing of the endothelium or prior incubation of RAL veins with catalase (1,200 units/ml), indomethacin (10(-5) M), or the thromboxane A2/prostaglandin H2 (TxA2/PGH2) receptor antagonist, SQ 29,548 (3 X 10(-6) M) each significantly reduced the response to hypoxia. RAL veins were also found to be more reactive than CL veins to the prostaglandin endoperoxide analogue U46619. We conclude that prolonged lobar hypoxia in vivo increases the responsivity of isolated pulmonary veins to hypoxia. These contractions may result from an increase in reactive O2 species, which in turn modify production of, metabolism of, and/or tissue responsivity to TxA2/PGH2.     

Thresholds of hypoxia for marine biodiversity

Hypoxia is a mounting problem affecting the world's coastal waters, with severe consequences for marine life, including death and catastrophic changes. Hypoxia is forecast to increase owing to the combined effects of the continued spread of coastal eutrophication and global warming. A broad comparative analysis across a range of contrasting marine benthic organisms showed that hypoxia thresholds vary greatly across marine benthic organisms and that the conventional definition of 2 mg O(2)/liter to designate waters as hypoxic is below the empirical sublethal and lethal O(2) thresholds for half of the species tested. These results imply that the number and area of coastal ecosystems affected by hypoxia and the future extent of hypoxia impacts on marine life have been generally underestimated.