Effects of Intermittent Hypoxia Exposure on Symptoms of Chronic Fatigue Syndrome in Repeated Restraint Stress and Forced Swimming Induced-Mouse Model

Background: Chronic fatigue syndrome (CFS) shows as its main symptoms debilitating fatigue that is not relieved by physiological rest, depression, inflammation, learning disability and memory impairment. But, intermittent hypoxia, consisting of alternating exposure to hypoxia and normoxia, plays a very important role in improving CFS. However, the essential components for improving learning and memory in CFS patients as well as their mechanism are largely unknown. Objectives: This study aims to analyze the effects of 12% and 15% hypoxia on the expression of alpha tumor necrosis factor (TNF-α) and nuclear factor kappa B (NF-κB) in CFS induced-mouse model for clarifying the effects on the learning and memory function. Methods: A total of 48 type IC mice were used. The CFS mouse model was established using restrained stress and repeated forced swimming. Treatment of CFS was done by exposing CFS mice to intermittent hypoxia at 12% and 15%. The effects of intermittent hypoxia on learning and memory as well as its mechanism of action on inflammation were tested respectively with the Morris test, the SDS page, the immunohistochemistry technique and the Nissl staining. Results: We found that 12% and 15% intermittent hypoxia exposure improved learning capacity and memory of CFS induced-mice. SDS page showed that CFS caused higher TNF-α expression. By exposing CFS mice to 12% and 15% intermittent hypoxia, TNF-α expression decreased significantly, with a much better effect at 15%. Both TNF-α and NF-κB increased in CFS state and decreased after treatment with intermittent hypoxia. Conclusion: Intermittent hypoxia improves learning capacity and memory. It acted by decreasing NF-κB come to down-regulating TNF-α and ameliorates learning capacity and memory impairment in CFS mice.

Intermittent hypoxia attenuates ischemia/reperfusion induced apoptosis in cardiac myocytes via regulating Bcl-2/Bax expression

Intermittent hypoxia has been shown to provide myocardial protection against ishemia/reperfusion-induced injury.Cardiac myocyte loss through apoptosis has been reported in ischemia/reperfusion injury. Our aim was to investigate whether intermittent hypoxia could attenuate ischemia/reperfusion-induced apoptosis in cardiac myocytes and its potential mechanisms. Adult male Sprague-Dawley rats were exposed to hypoxia simulated 5000 m in a hypobaric chamber for 6 h/day, lasting 42 days. Normoxia group rats were kept under normoxic conditions. Isolated perfused hearts from both groups were subjected to 30 min of global ischemia followed by 60 min reperfusion.Incidence of apoptosis in cardiac myocytes was determined by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) and DNA agarose gel electrophoresis. Expressions of apoptosis related proteins,Bax and Bcl-2, in cytosolic and membrane fraction were detected by Western Blotting. After ischemia/reperfusion,enhanced recovery of cardiac function was observed in intermittent hypoxia hearts compared with normoxia group.Ischemia/reperfusion-induced apoptosis, as evidenced by TUNEL-positive nuclei and DNA fragmentation, was significantly reduced in intermittent hypoxia group compared with normoxia group. After ischemia/reperfusion,expression of Bax in both cytosolic and membrane fractions was decreased in intermittent hypoxia hearts compared with normoxia group. Although ischemia/reperfusion did not induce changes in the level of Bcl-2 expression in cytosolic fraction between intermittent hypoxia and normoxia groups, the expression of Bcl-2 in membrane fraction was upregulated in intermittent hypoxia group compared with normoxia group. These results indicated that the cardioprotection of intermittent hypoxia against ischemia/reperfusion injury appears to be in part due to reduce myocardial apoptosis. Intermittent hypoxia attenuated ischemia/reperfusion-induced apoptosis via increasing the ratio of Bcl-2/Bax, especially in membrane fraction.

Expression of RUNX2 and MDM21 in rats with periodontitis under chronic intermittent hypoxia

Objective: To discuss the expression of RUNX2 and MDM21 in rats with periodontitis under the chronic intermittent hypoxia. Methods: A total of 32 SD healthy rats were randomly divided into four groups, with 8 rats in each group. The molecular biological techniques of immunohistochemistry, RT-PCR and Western blotting were employed to detect the effect of different hypoxia time(0, 6, 12, 24 and 48 h) and different concentrations of hypoxia(0.000, 0.001, 0.010, 0.060 and 0.100 ppm) on the expression of RUNX2 and MDM21 in rats of four groups. Results: The expression of RUNX2 and MDM21 in each group was significantly higher than the one at other concentrations when the concentration was 0.010 ppm, with the statistical difference(P<0.05). The expression of RUNX2 and MDM21 was that normoxic control group > periodontitis group> chronic intermittent hypoxia group > compound group under the action with the concentration of 0.010 ppm for 12 h, but there was no significant difference for the comparison among groups(P>0.05). Conclusions: The condition of chronic intermittent hypoxia can reduce the expression of RUNX2 and MDM21 in rats with periodontitis and aggravate the damage of periodontal bone.

Shengmaisan combined with Liuwei Dihuang Decoction alleviates chronic intermittent hypoxia-induced cognitive impairment by activating the EPO/EPOR/JAK2 signaling pathway

Chronic intermittent hypoxia(CIH),a principal pathophysiological aspect of obstructive sleep apnea(OSA),is associated with cognitive deficits.Clinical evidence suggests that a combination of Shengmaisan and Liuwei Dihuang Decoctions(SMS-LD)can enhance cognitive function by nourishing yin and strengthening the kidneys.This study aimed to assess the efficacy and underlying mechanisms of SMS-LD in addressing cognitive impairments induced by CIH.We exposed C57BL/6N mice to CIH for five weeks(20%-5%O_(2),5 min/cycle,8 h/day)and administered SMS-LD intragastrically(15.0 or 30 g·kg^(-1)·day)30 min before each CIH session.Additionally,AG490,a JJanus kinase 2(JAK2)inhibitor,was administered via intracerebroventricular injection.Cognitive function was evaluated using the Morris water maze,while synaptic and mitochondrial structures were examined by transmission electron microscopy.Oxidative stress levels were determined using DHE staining,and the activation of the erythropoietin(ER)/ER receptor(EPOR)/JAK2 signaling pathway was analyzed through immunohistochemistry and Western blotting.To further investigate molecular mechanisms,HT22 cells were treated in vitro with either SMS-LD medicated serum alone or in combination with AG490 and then exposed to CIH for 48 h.Our results indicate that SMS-LD significantly mitigated CIH-induced cognitive impairments in mice.Specifically,SMS-LD treatment enhanced dendritic spine density,ameliorated mitochondrial dysfunction,reduced oxidative stress,and activated the EPO/EPOR/JAK2 signaling pathway.Conversely,AG490 negated SMS-LD’s neuroprotective and cognitive improvement effects under CIH conditions.These findings suggest that SMS-LD’s beneficial impact on cognitive impairment and synaptic and mitochondrial integrity under CIH conditions may predominantly be attributed to the activation of the EPO/EPOR/JAK2 signaling pathway.

Atorvastatin Attenuates Myocardial Hypertrophy Induced by Chronic Intermittent Hypoxia In Vitro Partly through miR-31/PKCε Pathway

Atorvastatin is proven to ameliorate cardiac hypertrophy induced by chronic intermittent hypoxia （CIH）. However, little is known about the mechanism by which atorvastatin modulates CIH-induced cardiac hypertrophy, and whether specific hypertrophyrelated microRNAs are involved in the modulation. MiR-31 plays key roles in the development of cardiac hypertrophy induced by ischemia/hypoxia. This study examined whether miR-31 was involved in the protective role of atorvastatin against CIH-induced myocardial hypertrophy. H9c2 cells were subjected to 8-h intermittent hypoxia per day in the presence or absence of atorvastatin for 5 days. The size of cardiomyocytes, and the expression of caspase 3 and miR-31 were determined by Western blotting and RT-PCR, respectively. MiR-31 mimic or Ro 31-8220, a specific inhibitor of protein kinase C epsilon （PKCε）, was used to determine the role of miR-31 in the anti-hypertrophic effect of atorvastatin on cardiomyocytes. PKCε in the cardiomyocytes with miR-31 upregulation or downregulation was detected using RT-PCR and Western blotting. The results showed that CIH induced obvious enlargement of cardiomyocytes, which was paralleled with increased atrial natriuretic peptide （ANP）, brain natriuretic peptide （BNP）, and slow/beta cardiac myosin heavy-chain （MYHT） mRNA levels. All these changes were reversed by the treatment with atorvastatin. Meanwhile, miR-31 was increased by CIH in vitro. Of note, the atorvastatin pretreatment significantly increased the mRNA and protein expression of PKCε and decreased that of miR-31. Moreover, overexpression of miR-31 abolished the anti-hypertrophic effect of atorvastatin on cardiomyocytes. Upregulation and downregulation of miR-31 respectively decreased and increased the mRNA and protein expression of PKCε. These results suggest that atorvastatin provides the cardioprotective effects against CIH probably via up-regulating PKCε and down-regulating miR-31.

Influence of chronic intermittent hypoxia on growth associated protein 43 expression in the hippocampus of young rats

This study aimed to explore the pathological change to hippocampal neurons and the expression of growth associated protein 43 in 21-day-old young rats following chronic intermittent hypoxia. Hematoxylin-eosin staining results showed varying degrees of degeneration and necrosis in hippocampal neurons depending on the modeling time. Immunohistochemistry revealed that growth associated protein 43 expression in young rats following chronic intermittent hypoxia decreased, but that levels were still higher than those of normal rats at each time point, especially 4 weeks after modeling. During 1 5 weeks after modeling, a slow growth in rat weight was observed. Experimental findings indicate that chronic intermittent hypoxia may induce growth dysfunction and necrosis of hippocampal neurons, as well as increase the expression of growth associated protein 43 in young rats.

Intermittent hypoxia is involved in gut microbial dysbiosis in type 2 diabetes mellitus and obstructive sleep apnea-hypopnea syndrome

BACKGROUND Obstructive sleep apnea(OSA)-hypopnea syndrome(OSAHS)has been recognized as a comorbidity of type 2 diabetes mellitus(T2DM);more than half of T2DM patients suffer from OSAHS.Intermittent hypoxia(IH)plays an important role in metabolic diseases,such as obesity and OSAHS,through various mechanisms,including altering the gut microecological composition and function.Therefore,it is important to study the role of gut microbiota in T2DM patients with OSAHS,which has a high incidence and is prone to several complications.AIM To assess whether IH is involved in altering the fecal microbiome in T2DM patients with OSAHS.METHODS Seventy-eight participants were enrolled from Henan Province People’s Hospital and divided into healthy control(HC,n=26),T2DM(n=25),and T2DM+OSA(n=27)groups based on their conditions.The fecal bacterial DNA of the research participants was extracted and subjected to 16S ribosomal RNA sequencing.The clinical indices,such as insulin resistance index,homocysteine(HCY)concentration,and the concentrations of inflammatory factors in the peripheral blood,were assessed and recorded.RESULTS Group T2DM+OSA had the highest apnea-hypopnea index(AHI)(2.3 vs 3.7 vs 13.7),oxygen desaturation index(0.65 vs 2.2 vs 9.1),HCY concentration(9.6μmol/L vs 10.3μmol/L vs 13.81μmol/L)and C-reactive protein(CRP)concentrations(0.3 mg/L vs 1.43 mg/L vs 2.11 mg/L),and lowest mean oxygen saturation(97.05%vs 96.6%vs 94.7%)among the three groups.Twelve and fifteen key differences in amplicon sequence variants were identified when comparing group T2DM+OSA with groups T2DM and HC,respectively.We found progressively decreased levels of Faecalibacterium,Eubacterium,and Lachnospiraceae,and an increase in the level of Actinomyces,which strongly correlated with the HCY,CRP,fasting plasma glucose,and hemoglobin A1c concentrations,AHI,mean oxygen saturation,and insulin resistance index in group T2DM+OSA(P<0.05).CONCLUSION For T2DM patients with OSAHS,IH may be involved in selective alterations of the gut microbiota,which may affect the pathophysiological development of T2DM and DM-related complications.

Chronic intermittent hypoxia induces cardiac inflammation and dysfunction in a rat obstructive sleep apnea model

Chronic intermittent hypoxia is considered to play an important role in cardiovascular pathogenesis during the development of obstructive sleep apnea（OSA）.We used a well-described OSA rat model induced with simultaneous intermittent hypoxia.Male Sprague Dawley rats were individually placed into plexiglass chambers with air pressure and components were electronically controlled.The rats were exposed to intermittent hypoxia 8 hours daily for 5weeks.The changes of cardiac structure and function were examined by ultrasound.The cardiac pathology,apoptosis,and fibrosis were analyzed by H＆E staining,TUNNEL assay,and picosirius staining,respectively.The expression of inflammation and fibrosis marker genes was analyzed by quantitative real-time PCR and Western blot.Chronic intermittent hypoxia/low pressure resulted in significant increase of left ventricular internal diameters（LVIDs）,endsystolic volume（ESV）,end-diastolic volume（EDV）,and blood lactate level and marked reduction in ejection fraction and fractional shortening.Chronic intermittent hypoxia increased TUNNEL-positive myocytes,disrupted normal arrangement of cardiac fibers,and increased Sirius stained collagen fibers.The expression levels of hypoxia induced factor（HIF）-l α,NF-κB,IL-6,and matrix metallopeptidase 2（MMP-2） were significantly increased in the heart of rats exposed to chronic intermittent hypoxia.In conclusion,the left ventricular function was adversely affected by chronic intermittent hypoxia,which is associated with increased expression of HIF-lα and NF-κB signaling molecules and development of cardiac inflammation,apoptosis and fibrosis.

Effect of NADPH Oxidase Inhibitor Apocynin on the Expression of Hypoxia-induced Factor-1α and Endothelin-1 in Rat Carotid Body Exposed to Chronic Intermittent Hypoxia

The effects of nicotinamide adenine dinucleotide phosphate （NADPH） oxidase inhibitor apocynin on the enhanced hypoxia induced factor-let （HIF-lct） and endothelin-1 （ET-1） expression, elevated systolic blood pressure under chronic intermittent hypoxia （CIH） condition and its action mechanism were investigated. Thirty healthy 8-week old Sprague-Dawley （SD） male rats were randomly divided into three groups （n=10 each）： sham group, CIH group, and apocynin-treated CIH group. Tail artery systolic blood pressure was measured by tail-cuff method. Real-time fluorescence quantitative polymerase chain reaction （PCR） was used to detect the mRNA expression of HIF-lu and ET-1 in the carotid body, and the HIF-1a protein expression was examined by using Western blotting. The levels of malondialdehyde （MDA） and superoxide dismutase （SOD） were determined by using colorimetric method. In addition, the plasma ET-1 and HIF-1a levels were measured by using enzyme-linked immunosorbent assay. It was found that CIH exposure was associated with increased MDA levels, and apo- cynin-treated CIH animals showed reduction in MDA levels. Apocynin treatment prevented CIH-induced hypertension as well as CIH-induced decrease in SOD. The increases of HIF-1a and ET-1 mRNA along with HIF-la protein expression in the carotid body, and elevated circulating HIF-1a and ET-1 levels were observed in CIH-exposed animals. Treatment with apocynin significantly decreased the ET-1 mRNA, HIF-lct protein expression and circulating HIF-la level in CIH-exposed animals, and there was no statistically significant difference in the HIF-lu mRNA expression between CIH group and apo- cynin-treated group. These results indicated that apocynin alleviated CIH-induced hypertension by inhibiting NADPH oxidase, further leading to the reduced vasoconstrictor ET-1 level and oxidative stress. HIF-1a/ET-1 system signal pathway may interact with CIH-induced NADPH oxidase-dependent oxidative stress. Inhibition of NADPH oxidase activity may hopefully serve as a useful strategy for prevention and treatment of obstructive sleep apnea hypopnea syndrome-induced hypertension.

Relationship between Occurrence and Progression of Lung Cancer and Nocturnal Intermittent Hypoxia, Apnea and Daytime Sleepiness

The possible relationship between lung cancer and nocturnal intermittent hypoxia,apnea and daytime sleepiness,especially the possible relationship between the occurrence and progression of lung cancer and obstructive sleep apnea syndrome (OSAS) was explored.Forty-five cases of primary lung cancer suitable for surgical resection at the Third Affiliated Hospital of Kunming Medical University between January 2017 and December 2017 were recruited (lung cancer group),and there were 45 patients in the control group who had no significant differences in age,sex and other general data from lung cancer group.The analyzed covariates included general situation,snore score,the Epworth Sleeping Scale (ESS),Pittsburgh Sleep Quality Index (PSQI),apnea and hypopneas index (AHI),oxygen desaturation index 4 (ODk),lowest arterial oxygen saturation [LSpCh (%)],oxygen below 90% of the time [T90%(min)],the percentage of the total recorded time spend below 90% oxygen saturation (TS90%),to explore the possible relationship between lung cancer and above indicators.The participants were followed up for one year.The results showed that:(1) There was significant difference in body mass index (BMI),ESS,AHI,T90%(min),TS90%,ODh,snore score and LSpCh (%) between lung cancer group and control group (P<0.05).There was no statistically significant difference in age,gender,PSQI score,incidence of concurrent hypertension,diabetes and coronary heart disease (CHD),and smoking history between the two groups (P>0.05);(2) Patients in the lung cancer group were divided into OSAS subgroup and non- OSAS subgroup according to the international standard for the diagnosis of OSAS.There was significant difference in BMI,age,staging,incidence of concurrent hypertension and concurrent CHD,snore score,ESS score,T90%(min),TS90%,ODh and LSpCh (%) between OSAS subgroup and non-OSAS subgroup (P<0.05).There was no statistically significant difference in gender,PSQI score,incidence of concurrent diabetes,smoking history and lung cancer type between the two groups (P>0.05);(3) AHI was strongly negatively correlated with the LSpCh (%) and positively with ESS,staging,snoring score,T90%(min),TS90%,ODh and BMI (P<0.05);(4) There were 3 deaths,5 cases of recurrence,and 4 cases of metastasis in OSAS subgroup;and there was 1 death,4 cases of recurrence and 2 cases of metastasis in non-OSAS subgroup during the follow-up period of one year,respectively.There was no significant difference in mortality,recurrence rate and metastasis rate between the two subgroups,and the total rate of deterioration in OSAS subgroup was significantly increased compared to the non-OSAS subgroup (P<0.05).It was concluded that the patients with lung cancer are prone to nocturnal hypoxemia,apnea,snoring and daytime sleepiness compared to control group.The incidence of OSAS in patients with lung cancer was higher,and the difference in the hypoxemia-related indicators was statistically significant.The mortality,recurrence rate,and metastasis rate increases in lung cancer patients with OSAS during the one-year follow-up period,suggesting that OSAS may be a contributing factor to the occurrence and progression of lung cancer.

Impairment of cognitive function and reduced hippocampal cholinergic activity in a rat model of chronic intermittent hypoxia

The present study established a rat model of chronic intermittent hypoxia （CIH） to simulate obstructive sleep apnea syndrome. CIH rats were evaluated for cognitive function using the Morris water maze, and neuronal pathology in the hippocampus was observed using hematoxylin-eosin staining. In addition, hippocampal choline acetyl transferase （CHAT） and nicotinic acetylcholine receptor （nAChR） expression was determined by immunohistochemistry. Our results revealed necrotic hippocampal neurons, decreased ChAT and nAChR expression, as well as cognitive impairment in CIH rats. These results suggest that hippocampal neuronal necrosis and decreased cholinerqic activity may be involved in CIH-induced cognitive impairment in rats.

Adiponectin Ameliorated Pancreatic Islet Injury Induced by Chronic Intermittent Hypoxia through Inhibiting the Imbalance in Mitochondrial Fusion and Division

Objective This study aimed to assess the protective value of adiponectin(APN)in pancreatic islet injury induced by chronic intermittent hypoxia(CIH).Methods Sixty rats were randomly divided into three groups:normal control(NC)group,CIH group,and CIH with APN supplement(CIH+APN)group.After 5 weeks of CIH exposure,we conducted oral glucose tolerance tests(OGTT)and insulin released test(IRT),examined and compared the adenosine triphosphate(ATP)levels,mitochondrial membrane potential(MMP)levels,reactive oxygen species(ROS)levels,enzymes gene expression levels of Ant1,Cs,Hmox1,and Cox4 i1 which represented mitochondrial tricarboxylic acid cycle function,the protein and gene expression levels of DRP1,FIS1,MFN1,and OPA1 which represented mitochondrial fusion and division,and the protein expression levels of BAX,BCL-2,cleaved Caspase-3,and cleaved PARP which represented mitochondrial associated apoptosis pathway of pancreatic islet.Results OGTT and IRT showed blood glucose and insulin levels had no differences among the NC,CIH and CIH+APN groups(both P>0.05)at 0 min,20 min,30 min,60 min,120 min.However,we found that compared to NC group,CIH increased the ROS level,reduced ATP level and MMP level.The islets of CIH exposed rats showed reduced gene expression levels of Ant1,Cs,Hmox1,and Cox4 i1,decreased protein and gene expression levels of MFN1 and OPA1,increased protein and gene expression levels of DRP1 and FIS1,increased protein expression levels of cleaved Caspase-3 and cleaved PARP,with lower ratio of BCL-2/BAX at protein expression level.All the differences among three groups were statistically significant.APN treated CIH rats showed mitigated changes in the above measurements associated with islet injuries.Conclusion APN may ameliorate the pancreatic islet injury induced by CIH via inhibiting the imbalance in mitochondrial fusion and division.

Short-term Chronic Intermittent Hypobaric Hypoxia Alters Gut Microbiota Composition in Rats

Chronic intermittent hypobaric hypoxia (CIHH) is a treatment of moderate hypoxia that simulates high altitude interrupted by normoxia. Growing evidence shows that CIHH has multiple beneficial effects on

Beneficial effects of intermittent hypobaric hypoxia on the body

Myocardial ischemia and reperfusion(I/R) is a common problem in clinic and there is no satisfactory method for prevention or treatment of I/R injury so far.Chronic intermittent hypobaric hypoxia(CIHH),similar to the concept of ischemia preconditioning(IPC)or altitude hypoxia adaptation(AHA),has been recognized to confer a protective effect on heart against I/R injury with a longer protective effect than IPC and a less adverse effect than AHA.It has been proved that CIHH increases myocardial tolerance to ischemia or hypoxia,reserving cardiac function and preventing arrhythmia during I/R.Multiple mechanisms or pathway underlying the cardiac protection of CIHH have been proposed,such as induction of heatshock protein,enhancement of myocardial antioxidation capacity,increase of coronary flow and myocardial capillary angiogenesis,activation of adenosine triphosphate(ATP)-sensitive potassium channels,inhibition of mitochondrial permeability transition pores,and activation of protein kinase C(PKC) and induced nitric oxide synthase(iNOS).In addition,CIHH has been found having many beneficial effects on the body,such as promotion of health,increase of oxygen utilization,and prevention or treatment for some diseases.The beneficial effects of CIHH and potential mechanisms are reviewed mainly based on the researches performed by our group.

半夏厚朴汤通过抑制炎症反应改善CIH小鼠肺脏损伤的机制研究

目的本研究旨在观察半夏厚朴汤(Banxia houpu decoction,BHD)对慢性间歇性低氧(Chronic intermittent hypoxia,CIH)暴露小鼠肺脏损伤的改善作用,并探讨其可能的分子机制。方法将30只健康的6-8周龄雄性C57BL/6小鼠随机分成:常氧组(CON)、慢性间歇性低氧暴露组(CIH)、慢性间歇性低氧+半夏厚朴汤组(CIH+BHD)。CON组暴露于常氧环境,CIH组与CIH+BHD组暴露于间歇性低氧的环境中。其中,CIH+BHD组于每日放入低氧舱前30 min给予半夏厚朴汤灌胃(7 g·kg^(-1)·d^(-1)),而CIH组与CON组给予同等体积生理盐水。造模5周结束后取材,应用HE染色观察各组小鼠肺脏的病理学改变;免疫组化方法检测各组小鼠NF-κB、IL-6、TNF-α的蛋白表达情况;Westernblot检测NLRP3炎性小体(包括NLRP3、ASC、caspase-1)、IL-6、TNF-α、TLR4/MyD88/NF-κB、TXNIP和IL-18的蛋白表达。结果CIH处理后,小鼠肺组织病理学改变为肺泡壁增厚、炎性细胞浸润;免疫组化结果显示CIH暴露后NF-κB、IL-6、TNF-α蛋白表达升高;Western blot检测CIH暴露后NLRP3炎性小体(包括NLRP3、ASC、caspase-1)、IL-6、TNF-α、TLR4/MyD88/NF-κB、TXNIP和IL-18的蛋白表达升高。与CIH组相比,CIH+BHD组小鼠肺脏病理切片可见肺泡壁厚度大致正常,炎性细胞浸润情况改善;免疫组化和Western blot中检测的相关指标均有下降的表现。结论半夏厚朴汤可能是通过抑制炎症反应改善CIH暴露后小鼠肺脏损伤。

阻塞性睡眠呼吸暂停综合征患者多导睡眠监测性别差异的研究

目的评估阻塞性睡眠呼吸暂停综合征(OSAS)患者多导睡眠监测(PSG)结果中呼吸事件和睡眠结构的性别差异。方法回顾性分析2023年1~8月因睡眠打鼾就诊于北京同仁医院,完成整夜PSG,呼吸暂停低通气指数(AHI)≥5次/h均诊断为OSAS的成年人患者。比较男性和女性OSAS患者的基本特征、呼吸事件和睡眠结构。结果共纳入380例OSAS患者,其中男293例(77.1%),女87例(22.9%)。年龄22~78(44.4±11.5)岁,体重指数(BMI)为15.8~39.9(26.5±3.9)kg/m^(2),AHI为5.0~115.8(34.9±24.8)次/h,最低血氧饱和度(lowest oxygen saturation,LSpO_(2))为43%~97%(80.7±11.6)%。男性和女性OSAS患者比较,AHI值男性高于女性[(37.9±24.8)次/h vs.(24.5±21.7)次/h,P=0.000],REM期AHI值男性高于女性[(36.7±23.2)次/h vs.(30.9±22.8)次/h,P=0.040],LSpO_(2)男性低于女性[(79.2±12.0)%vs.(85.7±8.3)%,P=0.000];觉醒指数、睡眠有效率、一期睡眠占总睡眠时间百分比和三期睡眠占总睡眠时间百分比,差异比较均有统计学意义。50岁以上男性和女性OSAS患者,AHI值男性高于女性[(39.3±21.4)次/h vs.(30.5±23.0)次/h,P=0.029],LSpO_(2)、REM期AHI值差异无显著性。睡眠结构性别间的差异与研究对象总体一致。结论男性OSAS患者AHI值、LSpO_(2)较女性患者严重,慢波睡眠减少更为明显;女性更年期后病情加重,突出表现为REM期呼吸事件增多、LSpO_(2)下降更严重。女性激素对OSAS的保护作用主要是减轻REM期呼吸事件和低氧损伤,而不是通过改善睡眠结构。

黄芪甲苷对慢性间歇性缺氧诱导的遗尿症大鼠TLR4-p38 MAPK通路的影响

目的 探讨黄芪甲苷对慢性间歇性缺氧诱导的遗尿症大鼠Toll样受体4(Toll-like receptor-4,TLR4)/p38丝裂原活化蛋白激酶(p38 mitogen-activated protein kinase, p38 MAPK)信号通路的影响。方法 将SD大鼠随机分为对照组、模型组、黄芪甲苷低剂量组、黄芪甲苷中剂量组、黄芪甲苷高剂量组、去氨加压素组、脂多糖组、黄芪甲苷高剂量+脂多糖(Lipopolysaccharide, LPS)组,每组12只。除对照组外,其他组均需采用慢性间歇性缺氧诱导的方法构建遗尿症大鼠模型,各组大鼠每天于进入动物舱前1 h进行给药处理,1次/d,持续4周。末次处理24 h后,检测各组大鼠24 h排尿量及膀胱漏尿点压(bladder leak point pressures, BLPP)值的变化;ELISA法检测大鼠血清中抗利尿激素(antidiuretic hormone, ADH)含量;HE染色检测大鼠膀胱组织病理变化;比色法检测大鼠膀胱组织中超氧化物歧化酶(superoxide dismutase, SOD)活性、丙二醛(malonic dialdehyde, MDA)含量;Western blot检测大鼠膀胱组织中P2X3、TLR4、p-p38蛋白表达。结果 与对照组比较,模型组大鼠膀胱组织病理损伤严重,24 h排尿量增多,BLPP值变小,ADH含量、SOD活性降低,MDA含量和P2X3、TLR4、p-p38蛋白表达升高(P<0.05);与模型组比较,黄芪甲苷低剂量组、黄芪甲苷中剂量组、黄芪甲苷高剂量组、去氨加压素组大鼠膀胱组织病理损伤减轻,24 h排尿量减少,BLPP值变大,ADH含量、SOD活性升高,MDA含量和P2X3、TLR4、p-p38蛋白表达降低,LPS组大鼠膀胱组织病理损伤加剧,24 h排尿量增多,BLPP值变小,ADH含量、SOD活性降低,MDA含量和P2X3、TLR4、p-p38蛋白表达升高(P<0.05);与黄芪甲苷高剂量组比较,黄芪甲苷高剂量+LPS组大鼠膀胱组织病理损伤严重,24 h排尿量增多,BLPP值变小,ADH含量、SOD活性降低,MDA含量和P2X3、TLR4、p-p38蛋白表达升高(P<0.05)。结论 黄芪甲苷可能通过抑制TLR4/p38MAPK信号通路改善慢性间歇性缺氧诱导的大鼠遗尿症。

大鼠颈上神经节中Ⅰ组代谢型谷氨酸受体表达及慢性间歇性低氧对其的影响

目的观察Ⅰ组代谢型谷氨酸受体(mGluR1/5)在大鼠颈上神经节(SCG)组织的表达、定位,及慢性间歇性低氧(CIH)对mGluR1/5蛋白水平的影响。方法12只雄性SD大鼠随机分为对照组(Ctrl)和CIH组(CIH),每组6只,模型制作6周。Western blotting检测CIH对mGluR1/5蛋白水平的影响,免疫组织化学法和免疫荧光共定位染色检测大鼠SCG中mGluR1/5的表达及分布。结果mGluR1/5表达于大鼠SCG,mGluR1分布于神经元和小强荧光(SIF)细胞,而在卫星胶质细胞(SGCs)、神经纤维和血管不表达;mGluR5主要分布于神经纤维,少量分布于神经元,而在SIF细胞、SGCs及血管不表达;CIH上调mGluR1/5的蛋白水平(P<0.01)。结论mGluR1和mGluR5均表达于大鼠SCG,但其表达部位有所不同,两者蛋白水平的升高可能参与了CIH诱导的血压升高。

复氧改善间歇性缺氧所致的肥胖大鼠下丘脑瘦素反应性降低

目的使用饮食诱导肥胖(DIO)大鼠模型,探索间歇性缺氧-复氧(IHR)对肥胖大鼠体质量、食水摄入量、循环代谢因子和中枢瘦素注射反应的影响。方法通过12周高脂饮食(HFD)喂养建立DIO大鼠模型,将其随机分为3组并继续HFD喂养:常氧组(NM,n=15)、间歇性缺氧组(IH:6%O2,30周期/h,8 h/d,4周,n=15),IHR组(缺氧2周后复氧2周,n=15)。记录大鼠体质量、饮食饮水情况,检测循环瘦素、IL-6、Ang-II含量。IHR干预结束后,大鼠接受4μg瘦素侧脑室注射,1 h后处死取材下丘脑及肝脏。通过免疫组化观察下丘脑POMC、FRA-1、FRA-2表达,Western blotting检测下丘脑POMC、pSTAT3、LepR表达,RT-PCR检测下丘脑和肝脏中LepR mRNA含量,对比各组大鼠下丘脑瘦素受体(LepR)及下游通路蛋白的变化。结果IH暴露导致DIO大鼠体质量(P=0.001)和摄食量(P=0.001)增加,全身炎症因子升高(瘦素P=0.004;IL-6 P=0.008;Ang-II P<0.001)。IH抑制下丘脑食欲抑制肽POMC表达(P<0.001 vs NM组),降低反映瘦素反应性神经元活性的FRA-1表达(P<0.001 vs NM组),抑制对瘦素响应的pSTAT3表达(瘦素+vs瘦素-,P=0.241),降低对外源性瘦素给药的反应性(P<0.001 vs NM组),并下调下丘脑和肝脏LepR mRNA含量(P<0.001 vs NM组)。经过2周的复氧治疗后,IH加剧的体质量增加和代谢紊乱能够得到改善,下丘脑瘦素反应性也有所提高。结论IH可能通过下调LepR表达损害下丘脑瘦素信号传导,从而促进肥胖大鼠增重,这可以通过复氧治疗得到改善。

瞬时受体电位通道5对间歇性低氧致心肌焦亡的影响

目的探讨瞬时受体电位通道5(TRPC5)对间歇性低氧致心肌焦亡的影响。方法TRPC5^(-/-)大鼠及SD大鼠各12只,两种大鼠分别随机分为慢性间歇性低氧组(CIH组)和常氧组(Control组),即WT-Control组、WT-CIH组、TRPC5^(-/-)-Control组、TRPC5^(-/-)-CIH组,每组6只。通过Masson染色观察大鼠心肌纤维化情况,ELISA检测血清炎症因子水平,Western blot检测TRPC5及焦亡相关蛋白相对表达水平。结果Masson染色显示,TRPC5^(-/-)-CIH组胶原容积分数高于TRPC5^(-/-)-Control组,低于WT-CIH组。ELISA结果显示,TRPC5^(-/-)-CIH组血清IL-1、IL-6、TGF-β水平高于TRPC5^(-/-)-Control组,低于WT-CIH组。Western Blot结果显示,TRPC5^(-/-)-CIH组焦亡相关蛋白Caspase-1、NLRP3、GSDMD、GSDMD-N相对表达量高于TRPC5^(-/-)-Control组、低于WT-CIH组。结论TRPC5缺乏减轻间歇性低氧导致的心肌焦亡,并改善心肌纤维化。