急性重复低氧对小鼠脑组织血氧饱和度、线粒体功能以及ATP水平的影响

目的： 探讨急性重复低氧对脑组织血氧饱和度与线粒体功能的影响。方法: 将BALB/c小鼠置于低氧密闭罐中，通过小鼠呼吸消耗罐内氧造成罐内低氧，以小鼠出现喘呼吸为低氧耐受极限，然后将小鼠转到另一低氧密闭罐中，依此类推，连续进行5次低氧。记录小鼠每次的缺氧耐受时间、局部脑组织血氧饱和度，测定每次低氧暴露结束时的脑组织的线粒体复合体I活性和ATP含量。结果: 小鼠的缺氧耐受时间随缺氧暴露次数增加而显著延长。脑组织血氧饱和度在第1、2次缺氧暴露时急剧下降，但在第3、4、5低氧暴露时先小幅度下降再逐渐恢复至正常水平，然后再缓慢降低。脑组织线粒体复合体I的活性随着缺氧次数的增加逐渐被抑制，ATP含量在第1次低氧暴露结束时低于正常水平，在第3、5次低氧暴露结束时高于正常水平。结论: 急性重复低氧导致脑组织血氧饱和度降低的速度减慢、线粒体功能抑制以及脑组织ATP水平增高，后者很可能是动物脑组织耐缺氧能力增强的重要机制。     

Effect of rosuvastatin on plasma coenzyme Q10 in HIV-infected individuals on antiretroviral therapy

Background: Coenzyme Q10 (CoQ10) deficiency has been associated with statin-induced myopathy, and supplementation with CoQ10 may reduce inflammation markers. The effects of statins on CoQ10 and its anti-inflammatory properties have not been investigated in HIV-positive patients.

Objective: The objectives of this study were to examine the effect of rosuvastatin on CoQ10 and CoQ10/LDL ratio over 24-week SATURN-HIV trial, explore the associations between CoQ10 levels and markers of vascular disease, inflammation, and immune activation, and assess whether changes in CoQ10 affected the anti-inflammatory effects of statin therapy or were associated with myalgia symptoms.

Methods: This was a secondary analysis of the SATURN-HIV trial, a 96-week randomized clinical trial of 10 mg daily rosuvastatin vs. placebo in HIV-infected patients on antiretroviral therapy. We assessed the statin treatment effect on CoQ10 levels and CoQ10/LDL ratios and whether changes in these markers were related to myalgias. Relationships between CoQ10, subclinical vascular disease, and biomarkers of inflammation and immune activation were explored using Spearman correlations and multivariable regression models.

Results: Overall, 147 patients were included. Median age was 46 years; 78% were male and 68% African American. At baseline, CoQ10 levels and CoQ10/LDL ratio were modestly correlated with markers of HIV disease, immune activation, and carotid distensibility. After 24 weeks of statin therapy, CoQ10 levels decreased (p = 0.002 for between group difference) and CoQ10/LDL ratio increased (p = 0.036). In the statin treatment arm, we did not find evidence of a relationship between changes in CoQ10 or CoQ10/LDL ration and changes in markers of inflammation or immune activation. There was a borderline statistically significant association between changes in CoQ10 and myalgia symptoms [OR 4.0 per 0.1 mg/L decrease in CoQ10, p = 0.07].

Conclusion: Twenty-four weeks of 10 mg daily rosuvastatin decreases CoQ10 concentration and increases CoQ10/LDL ratio in HIV-infected patients on antiretroviral therapy.     

Combination therapy with metformin and coenzyme Q10 in murine experimental autoimmune arthritis

Metformin (Met) and coenzyme Q10 (CoQ10) are reported to have therapeutic functions in several inflammatory diseases. These drugs have shown anti-inflammatory effects and have been utilized in mouse models of rheumatoid arthritis (RA). However, there is no evidence of the additive effect of Met and CoQ10 in RA. Although Met and CoQ10 may be involved in the improvement of mitochondrial dysfunction, limited information is available regarding whether this effect can improve mitochondrial dysfunction in RA in particular. In this study, we sought to determine whether Met and CoQ10 attenuate the severity of collagen-induced arthritis (CIA) and show an additive effect in a mouse model. The combination of Met and CoQ10 improved CIA, reducing joint inflammation, Th17 differentiation and IgG production. In contrast, the combination of Met and CoQ10 induced Treg differentiation. Osteoclastogenesis was reduced by the combination of Met and CoQ10. The protein expression of interleukin-1β, interleukin-6 and tumor necrosis factor-alpha in mice splenocytes exposed to lipopolysaccharide decreased after drug combination therapy. We also found that the expression of JC-1 and COX IV were enhanced by treatment with the combination of Met and CoQ10. Moreover, the combination of Met and CoQ10 promoted mitochondrial O₂ consumption. These findings suggest that the combination of Met and CoQ10 reduced CIA severity, improving mitochondrial dysfunction compared to Met or CoQ10 alone. These results present a novel, significant preventive targets in RA and may enhance our understanding of its pathogenesis.     

Clk-1 deficiency induces apoptosis associated with mitochondrial dysfunction in mouse embryos

Clk-1 gene encodes demethoxyubiquinone hydroxylase that catalyzes the production of coenzyme Q (CoQ) in mitochondria. Clk-1-deficient mice that lack CoQ fail to survive beyond the embryonic day 10.5 (E10.5). However, the relationship between the clk-1-deficiency and embryonic lethality remains unclear. We show in this study that TUNEL-positive cells are frequently observed in whole bodies of clk-1-deficient mouse embryos at E10.5. In addition, dissociated cells from the embryos exhibited characteristic features of apoptosis, such as externalization of phosphatidylserine on the plasma membrane, caspase-3 activation, and the release of cytochrome c from mitochondria into the cytoplasm, as the first sign of mitochondria-mediated apoptosis. In embryonic cells, the mitochondrial functions such as maintenance of the mitochondrial membrane potential and intracellular ATP level were impaired. Since exogenous CoQ10 rescued the mitochondrial dysfunction and suppressed apoptosis in clk-1-deficent cells, we propose that clk-1-deficency induces apoptosis associated with mitochondrial dysfunction due to a lack of CoQ, which may lead to embryonic lethality in mice around E10.5.     

辅酶Q10与美满霉素联合干预1-甲基-4-苯基吡啶诱导的偏侧帕金森病大鼠模型研究（英文）

 目的：探讨辅酶Q10与美满霉素联合干预1-甲基-4-苯基吡啶（MPP+）帕金森病模型大鼠的效果。方法：采用MPP+黑质内注射建立帕金森病大鼠模型。小胶质细胞活化的程度用OX-42（小胶质细胞标志物）的免疫荧光强度测定。多巴胺能神经元由酪氨酸羟化酶（TH）阳性神经元的数目确定。大鼠行为学通过阿朴吗啡诱导的旋转行为、前肢跨步运动实验和触须引发的不对称放置实验进行评价。结果：辅酶Q10造模前给药与美满霉素造模后给药均可部分减轻MPP+诱导的帕金森模型鼠行为学缺陷,两者联合给药的效果优于任何一种单一给药方式（均P<0.01）,免疫组化分析表明,TH阳性神经元数量在联合给药组中较美满霉素干预组（P<0.01）及辅酶Q10干预组（P<0.01）均显著增多。结论：美满霉素与辅酶Q10联合给药较任何一种单一给药方式对MPP+帕金森病大鼠模型具有更好的神经保护作用,这种针对帕金森病发病过程中不同的病理环节所采取的联合给药方式可能对该病的治疗提供新的思路。     

辅酶Q10对大鼠再生肝细胞线粒体通透性转换的影响

目的 了解辅酶Q₁₀（CoQ₁₀）对大鼠再生肝细胞线粒体通透性转换（MPT）的影响。方法 雌性SD大鼠120只,用不同剂量CoQ₁₀灌胃后行部分肝切除术（PH）,于术后不同时间取肝组织分离线粒体,分光光度计法测定线粒体悬液的A540nm值,之后再加入钙离子诱导并检测A540nm值。结果 PH后6~48h,高剂量（60mg/kg）CoQ₁₀处理组的再生肝线粒体通透性明显低于对照组,而低剂量（6mg/kg）处理组只在48h明显低于对照组,其他时间均无显著差异。用钙离子诱导后,各组各时间点的线粒体通透性随时间延长而不同程度的增强,但PH后6~48 h的CoQ₁₀处理组的再生肝线粒体通透性稍小于对照组。结论 一定剂量的CoQ₁₀能降低大鼠再生肝线粒体通透性,作用主要体现在肝再生的细胞增殖阶段。     

The coenzyme Q10 status of the brain regions of Parkinson's disease patients

There is increasing evidence that impairment of mitochondrial function and oxidative damage are contributing factors to the pathophysiology of Parkinson's disease (PD). Studies have reported decreased levels of the mitochondrial electron transport chain carrier, coenzyme Q(10) (CoQ(10)) in plasma and platelets from PD patients. Although a deficit in peripheral CoQ(10) has been reported no studies have assessed the CoQ(10) status of the PD brain. In this study we investigated the CoQ(10) status of the substantia nigra, cerebellum, cortex and striatum brain regions of both PD patients and age-matched controls. The results of this study indicate a significant reduction (p=0.007) in CoQ(10) concentration in the cortex region of the brain. In conclusion, the results of this study indicate evidence of a deficit in brain CoQ(10) status may be involved in the pathophysiology of PD.     

A metabolism chamber for measuring oxygen consumption in the laboratory rat and mouse

Details are given for the construction and use of an inexpensive metabolism chamber to measure oxygen consumption in a relatively large group of laboratory rodents in a brief time. Metabolic rates (MR) were measured regularly in male and female Sprague Dawley rats, 11–114 days old, and mice, 100 days old. Adult mice had higher MR than rats of approximately the same age. Female rats and mice had higher MR than males at all times. To demonstrate the versatility of the metabolism chambers adult rats were injected once or for 9 consecutive days with 6-n-propyl-2-thiouracil (PTU) to inhibit thyroid function and reduce MR, or with the carboxymethyl-cellulose (CMC) vehicle. PTU failed to lower MR in the animals most probably because CMC vehicle tended to increase MR, an effect more prominent in males than females.     

Mathematical models of the spatial distribution of retinal oxygen tension and consumption,including changes upon illumination

To better understand oxygen utilization by the retina, a mathematical model of oxygen diffusion and consumption in the cat outer, avascular retina was developed by analyzing previously recorded profiles of oxygen tension (PO₂) as a function of retinal depth. Simple diffusion modelling of the oxygen distribution through the outer retina is possible because the PO₂ depends only on diffusion from the choroidal and retinal circulations and on consumption within the tissue. Several different models were evaluated in order to determine the best one from the standpoints of their ability to represent the data and to agree with physiological reality. For the steady state one-dimensional diffusion model adopted (the special three-layer diffusion model), oxygen consumption was constant through the middle layer and zero in the layers near the choroid and near the inner retina. On the average, the oxygen consuming layer, as found by nonlinear regression for each profile, extended from about 75% to 85% of the retinal depth from the vitreous. This is a narrow band through the mid-region of the photoreceptors. Oxygen consumption of the entire avascular retina, determined from fitting eight PO₂ profiles measured in light-adapted retinas, averaged 2.7 ml O₂(STP)/(100 g tissue · min), while the value determined from fitting thirty-two PO₂ profiles measured in dark-adapted retinas averaged 4.4 ml O₂(STP)/(100 g tissue · min). Consumption in the light was thus only 60% of that in the dark. This suggests that the outer retina is at greater risk of hypoxic injury in the dark than in the light, a fuinding of considerable clinical significance.     

Cooling of the brain through oxygen flushing of the nasal cavities in intubated rats: an alternative model for treatment of brain injury

Local cooling of the brain by respiration has been found in several animal species with a rete mirabile in the carotid artery/cavernous sinus complex. The present experiment was made to investigate whether a similar cooling could be found in the rat, which does not have a rete. Eleven rats were anesthetized and intubated. Three thermoprobes were inserted into the brain (two probes) and rectum, and the temperatures measured continuously. The nasal cavities were flushed with oxygen (250-1000 ml/min) during 15-min periods, interrupted by 15-min control periods. The mean brain temperature decreased by 0.43 +/- 0.03 degree C (n = 86, P < 0.005) with individual values up to 1.11 degrees C during the flushing periods. The decrease was oxygen-flow dependent, but not correlated to the rectal temperature. It is concluded that even an animal species without a rete mirabile is able to decrease the brain temperature through nasal cooling. The cooling was probably connected to the blood flow. If the results can be extrapolated to man (no rete mirabile), brain temperature can be decreased by nasal flushing with air or oxygen in intubated patients with hyperthermia. We also suggest that this simple treatment will reduce the infarct volume after head injury, trauma, or brain ischemia.     

Direct determination of local oxygen consumption of the brain cortex in vivo

Summary A method is described to determine local oxygen consumption quantitatively in the brain cortex under in vivo conditions. Local oxygen consumption is calculated from the slope of local tissue P_{O 2} decrease during a few seconds of total ischemia of the brain for each second after the stop of circulation. The decrease of tissue P_{O 2} is recorded simultaneously at several measuring sites. To be independent of oxygen chemically bound to hemoglobin, tissue P_{O 2} values are raised above 100 Torr. The calculation of local oxygen consumption for each second during the short period of ischemia showed that the O₂ consumption remains constant only for a few seconds ranging from 5 to maximally 15 s at different locations. Then O₂ consumption decreases continuously although the tissue P_{O 2} values are still above the full saturation of hemoglobin. The rate of local oxygen consumption varies considerably at different measuring sites of the superficial layers of the brain cortex (cat). The mean value amounts to 3±1.5 ml O₂/100 g tissue and minute.     

High oxygen extraction combined with extensive oxygen consumption in the rat liver perfused with fluosol-DAR,a new perfluoro compound emulsion

Different O₂ values of the perfused rat liver and the metabolic turnover of urea and glucose, with and without substrate loads, were measured in a hemodiluted control group and in a group perfused with the perfluoro compound emulsion (PFC) Fluosol-DA^{R 1}. The following results were obtained. The basal O₂ consumption with PFC was 6.42 and 6.51 ml O₂/(min·100 g liver), respectively, both being higher than in the control group, despite the fact that the latter revealed values of a good oxidative metabolism compatible with that found for larger species in situ. With substrate loads the values increased to a mean of 8.62 ml O₂/(min·100 g) for periods of 20 min and more. Also O₂ extractions of 95% could be found like otherwise mostly in cases with severely reduced O₂ supply and under diminished O₂ consumption. This seems to be due to the increased surface area of the O₂ transporting particles with a mean diameter of 0.1 m. Furthermore, the linear O₂ delivery of physically dissolved oxygen from PFC enables a higher O₂ pressure to remain in the outflowing perfusate after the same amount of oxygen is consumed, provided sufficiently high arterial O₂ pressures are used. Finally, an increase of intracellular O₂ concentration rather than O₂ tension by incorporated PFC particles might play a role.—The substrate turnover values were compared with those in the literature; they are within the normal range.Supported by a grant from the DFG     

Mitochondrial oxygen consumption, lipid peroxidation and antioxidant enzyme systems in skeletal muscle of senile dystrophic mice

 To evaluate age-dependent abnormalities in mitochondrial redox metabolism specifically in dystrophic skeletal muscle, oxygen consumption, thiobarbituric acid reactivity (TBARS), free-radical scavengers and oxidative marker enzymes were measured in the skeletal muscle from adult and senile control (C57BL/10) and dystrophic (mdx/+) mice. Mitochondrial oxygen consumption in state 3 was significantly lowered with age in the senile dystrophic (–52%) and less markedly in the senile control (–30%) skeletal muscle. Compared with adult muscle, mitochondrial concentration of TBARS and cellular concentration of lipofuscin were significantly increased in senile control and dystrophic muscle. Enzymatic activity of glutathione peroxidase (GSH-Px) and concentration of α-tocopherol were significantly increased in the senile control (GSH-Px 43±5.7 vs 53±8.7 U/g protein, α-tocopherol 0.19±0.09 vs 0.29±0.14 μmol/g total lipids), but significantly decreased in the senile dystrophic (GSH-Px 80±8.0 vs 53±12 U/g protein, α-tocopherol 0.45±0.13 vs 0.19±0.03 μmol/g total lipids) muscle. Selenium content was significantly decreased only in senile dystrophic muscle (1.37±0.42 vs 0.78±0.21 nmol/g wet muscle). In conclusion, the enzymatic adaptation to reactive oxygen species was limited in the dystrophic skeletal muscle, suggesting a higher need for antioxidants, especially α-tocopherol. Received: 3 June 1998 / Received after revision: 11 September 1998 / Accepted: 14 September 1998     

Expression of apoptosis-inducing factor (AIF) in the aged rat brain

The mitochondrial flavoprotein apoptosis-inducing factor (AIF) promotes cell death upon nuclear translocation or by impinging on mitochondrial respiratory complex-I activity. Because decreased complex-I activity is associated with brain aging, we investigated the expression and distribution of AIF in frontal cortex, hippocampus and striatum of aged Long-Evans rat brains. We found that AIF was: (i) more abundantly expressed in striatum than in the other two brain regions, (ii) enriched in deep layers of frontal cortex and in the pyramidal cell layer of hippocampus, and (iii) overall mainly localized to mitochondria, but significantly more translocated to the nucleus in the deep layers of frontal cortex. Altogether, our data point to a difference in regionl AIF expression patterns, and provide evidence for the involvement of AIF in the cell death of a subpopulation of cortical neurons in aged animals.     

Numerical studies on the effect of lowering temperature on the oxygen transport during brain hypothermia resuscitation

There have been arguments about the advantage and shortcoming of hypothermia on the brain resuscitation during circulation arrest. People usually accepted that hypothermia may decrease the cerebral oxygen demands, which is beneficial for the patient to sustain longer time when subjected to a hypoxia. However, there are also quite a few disputes claiming that the blood viscosity would increase with the reduction of temperature, which may lead to an increase of cerebral vascular resistance and thus worsen the hypoxia state. To resolve this critical issue, a heat transfer model was established to characterize the thermal response of brain tissue during hypothermia resuscitation. Combined with this model, a compartmental model taking account of the temperature effect was further developed to analyze the transient oxygen partial pressure (PO₂) distribution over the successive branches of the vascular network during circulation arrest. Using the morphological and physiological data of a sheep brain, effects of lowering temperature on the oxygen consumption dynamics were studied. Calculations indicated that the lower the temperature, the slower the decreasing rate for the PO₂. Although immediately lowering the brain temperature may induce an evident increase in blood viscosity and subsequently a decrease in blood flow rate, which is responsible for oxygen delivery, it seems to always result in a monotonic increase of PO₂. The results show a good qualitative accord with the experimental data. They also present better understanding on the transient oxygen transport in brain hypothermia during circulation arrest.     

大鼠30 min全脑缺血再灌注肾脏损伤及其机制研究

目的: 从血栓素(TXA₂)与前列环素(PGI₂)平衡失调和肿瘤坏死因子(TNF-α)的变化方面探讨老龄大鼠脑缺血再灌注肾脏损伤的发生机制。方法: 青年(5月龄)和老龄(20月龄以上)大鼠均分为模型组和正常对照组, 观察大鼠全脑缺血30 min再灌注60 min后肾脏组织形态、肾内及血浆TXB₂、6-Keto-PGF_1α和肾内TNF-α含量的变化。结果: 青年和老龄模型组大鼠肾脏组织形态均出现明显的病理改变, 且老龄较青年更为严重。青年模型组血浆TXB₂/6-Keto-PGF_1α高于青年对照组和老龄模型组, 老龄对照组高于青年对照组。青年对照组肾脏组织TXB₂/6-Keto-PGF_1α低于老龄对照组和青年模型组, 老龄模型组高于青年模型组。老龄模型组肾组织TNF水平高于老龄对照组和青年模型组。结论: 以TXA₂占优势的TXA₂与PGI₂的平衡失调及TNF的增高与大鼠脑缺血再灌注肾脏损伤有关, 老龄大鼠脑缺血再灌注肾脏损伤的病理变化更明显。     

Effect of short-term energy intake level and exercise on oxygen consumption in men

Summary The influence of short-term energy intake and cycle exercise on oxygen consumption in response to a 1.5 MJ test meal was investigated in ten young, adult men. On the morning after a previous day's low-energy intake (LE regimen) of 4.5 MJ, the mean resting oxygen consumption increased by 0.7 ml · kg^–1 · min^–1 after the test meal (P<0.025). After a high-energy intake (HE regimen) of 18.1 MJ, the resting measurement was unchanged (+0.4 ml · kg^–1 · min^–1) after the meal (n.s.). These trends are the reverse of what would be expected if oxygen consumption in response to feeding is a factor in the acute control of body weight. The mean fasting oxygen consumption during cycle exercise at 56% of (constant work) for both LE and HE prior intakes was not different at 31.1 ml · kg^–1 · min^–1. Oxygen consumption during exercise increased after feeding by 0.5 ml · kg^–1 · min^–1 on the LE regimen (n.s.) and decreased by 1.2 ml · kg^–1 · min^–1 on the HE regimen (n.s.). These results are also the reverse of what would be expected if oxygen consumption in response to exercise is related to short-term energy intake.     

Increase in oxygen consumption induced by selective spinal cord cooling in the exercising pigeon

Six domestic pigeons with chronically implanted spinal thermodes were exercised on a treadmill at neutral ambient temperature. During the exercise the spinal cord was cooled to 34.7±0.4°C (mean±S.E.M.). Oxygen consumption of the pigeons increased from 28.3 ±2.1 to 61.2±3.7 ml·min^–1·kg^–1 due to exercise per se, and superimposed cooling of the spinal cord during exercise induced an additional increase in oxygen consumption to 84.9±4.5 ml·min^–1·kg^–1. The result demonstrates that cooling of the spinal cord elicits shivering in exercising pigeons at thermoneutral conditions.     

心宁胶囊对犬心脏血流动力学及心肌耗氧量的影响

目的：研究心宁胶囊对麻醉开胸犬心脏血流动力学及心肌耗氧量的影响,探索其对心脏功能的药理作用及作用机制。方法：将20只犬随即分成模型组、阳性药物组、心宁胶囊高、低剂量组,观察麻醉犬冠状动脉血流量、心肌耗氧量和心率等指标的变化。结果：与模型组比较,心宁胶囊具有增加冠脉血流量、降低心肌耗氧量等作用（P〈0.05）。结论：心宁胶囊对犬心脏血流动力学及心肌耗氧量有调整和改善作用。     

Plasma and tissue concentrations of coenzyme Q10 in the rat after its oral administration

Coenzyme Q10 (CoQ10) kinetics was investigated in rat tissues after oral treatment. CoQ10 passes quickly from plasma into the tissue examined, reaching levels higher than physiological ones; the liver shows the maximal CoQ10 concentrations. Our results indicate that oral treatment makes it possible to obtain good tissue levels of CoQ10 that might be of clinical value against endogenous CoQ10 insufficiencies due either to pathological alterations and/or to drug administration.