Intermittent hypoxia training effectively protects against cognitive decline caused by acute hypoxia exposure.

Intermittent hypoxia training (IHT) is a promising approach that has been used to induce acclimatization to hypoxia and subsequently lower the risk of developing acute mountain sickness (AMS). However, the effects of IHT on cognitive and cerebrovascular function after acute hypoxia exposure have not been characterized. In the present study, we first confirmed that the simplified IHT paradigm was effective at relieving AMS at 4300 m. Second, we found that IHT improved participants' cognitive and neural alterations when they were exposed to hypoxia. Specifically, impaired working memory performance, decreased conflict control function, impaired cognitive control, and aggravated mental fatigue induced by acute hypoxia exposure were significantly alleviated in the IHT group. Furthermore, a reversal of brain swelling induced by acute hypoxia exposure was visualized in the IHT group using magnetic resonance imaging. An increase in cerebral blood flow (CBF) was observed in multiple brain regions of the IHT group after hypoxia exposure as compared with the control group. Based on these findings, the simplified IHT paradigm might facilitate hypoxia acclimatization, alleviate AMS symptoms, and increase CBF in multiple brain regions, thus ameliorating brain swelling and cognitive dysfunction.

Autophagy Is Essential for Neural Stem Cell Proliferation Promoted by Hypoxia.

Hypoxia as a microenvironment or niche stimulates proliferation of neural stem cells (NSCs). However, the underlying mechanisms remain elusive. Autophagy is a protective mechanism by which recycled cellular components and energy are rapidly supplied to the cell under stress. Whether autophagy mediates the proliferation of NSCs under hypoxia and how hypoxia induces autophagy remain unclear. Here, we report that hypoxia facilitates embryonic NSC proliferation through HIF-1/mTORC1 signaling pathway-mediated autophagy. Initially, we found that hypoxia greatly induced autophagy in NSCs, while inhibition of autophagy severely impeded the proliferation of NSCs in hypoxia conditions. Next, we demonstrated that the hypoxia core regulator HIF-1 was necessary and sufficient for autophagy induction in NSCs. Considering that mTORC1 is a key switch that suppresses autophagy, we subsequently analyzed the effect of HIF-1 on mTORC1 activity. Our results showed that the mTORC1 activity was negatively regulated by HIF-1. Finally, we provided evidence that HIF-1 regulated mTORC1 activity via its downstream target gene BNIP3. The increased expression of BNIP3 under hypoxia enhanced autophagy activity and proliferation of NSCs, which was mediated by repressing the activity of mTORC1. We further illustrated that BNIP3 can interact with Rheb, a canonical activator of mTORC1. Thus, we suppose that the interaction of BNIP3 with Rheb reduces the regulation of Rheb toward mTORC1 activity, which relieves the suppression of mTORC1 on autophagy, thereby promoting the rapid proliferation of NSCs. Altogether, this study identified a new HIF-1/BNIP3-Rheb/mTORC1 signaling axis, which regulates the NSC proliferation under hypoxia through induction of autophagy.

Activation of σ-1 receptor mitigates estrogen withdrawal-induced anxiety/depressive-like behavior in mice via restoration of GABA/glutamate signaling and neuroplasticity in the hippocampus.

Postpartum depression (PPD) is a significant contributor to maternal morbidity and mortality. The Sigma-1 (σ-1) receptor has received increasing attention in recent years because of its ability to link different signaling systems and exert its function in the brain through chaperone actions, especially in neuropsychiatric disorders. YL-0919, a novel σ-1 receptor agonist developed by our institute, has shown antidepressive and anxiolytic effects in a variety of animal models, but effects on PPD have not been revealed. In the present study, excitatory/inhibitory signaling in the hippocampus was reflected by GABA and glutamate and their associated excitatory-inhibitory receptor proteins, the HPA axis hormones in the hippocampus were assessed by ELISA. Finally, immunofluorescence for markers of newborn neuron were undertaken in the dentate gyri, along with dendritic spine staining and dendritic arborization tracing. YL-0919 rapidly improves anxiety and depressive-like behavior in PPD-like mice within one week, along with normalizing the excitation/inhibition signaling as well as the HPA axis activity. YL-0919 rescued the decrease in hippocampal dendritic complexity and spine density induced by estrogen withdrawal. The study results suggest that YL-0919 elicits a therapeutic effect on PPD-like mice; therefore, the σ-1 receptor may be a novel promising target for PPD treatment in the future.

Annexin-A1 tripeptide enhances functional recovery and mitigates brain damage in traumatic brain injury by inhibiting neuroinflammation and preventing ANXA1 nuclear translocation in mice.

This study explores the role and mechanism of Annexin-A1 Tripeptide (ANXA1sp) in mitigating neuronal damage and promoting functional recovery in a mouse model of traumatic brain injury (TBI). Our goal is to identify ANXA1sp as a potential therapeutic drug candidate for TBI treatment. Adult male C57BL/6J mice were subjected to controlled cortical impact (CCI) to simulate TBI, supplemented by an in vitro model of glutamate-induced TBI in HT22 cells.  We assessed neurological deficits using the Modified Neurological Severity Score (mNSS), tested sensorimotor functions with beam balance and rotarod tests, and evaluated cognitive performance via the Morris water maze. Neuronal damage was quantified using Nissl and TUNEL staining, while microglial activation and inflammatory responses were measured through immunostaining, quantitative PCR (qPCR), Western blotting, and ELISA. Additionally, we evaluated cell viability in response to glutamate toxicity using the Cell Counting Kit-8 (CCK-8) assay and lactate dehydrogenase (LDH) release. Intraperitoneal administration of ANXA1sp significantly enhanced neurological outcomes, markedly reducing sensorimotor and cognitive impairments caused by TBI. This treatment resulted in a significant reduction in lesion volume and decreased neuronal cell death in the ipsilateral cortex. Moreover, ANXA1sp effectively diminished microglial activation around the brain lesion and decreased the levels of pro-inflammatory markers such as IL-6, IL-1ß, TNF-α, and TGF-ß in the cortex, indicating a significant reduction in neuroinflammation post-TBI. ANXA1sp also offered protection against neuronal cell death induced by glutamate toxicity, primarily by inhibiting the nuclear translocation of ANXA1, highlighting its potential as a neuroprotective strategy in TBI management. Administration of ANXA1sp significantly reduced neuroinflammation and neuronal cell death, primarily by blocking the nuclear translocation of ANXA1. This treatment substantially reduced brain damage and improved neurological functional recovery after TBI. Consequently, ANXA1sp stands out as a promising neuroprotective agent for TBI therapy.

[Intermittent hypoxic preconditioning relieves fear and anxiety behavior in post-traumatic stress model mice].

Intermittent hypoxia (IH) has preventive and therapeutic effects on hypertension, myocardial infarction, cerebral ischemia and depression, but its effect on post-traumatic stress disorder (PTSD) has not been known. In this study, we used inescapable electric foot shock combined with context recapture to build PTSD mouse model. The levels of fear and anxiety were valued by the open field, the elevated plus maze (EPM) and the fear conditioning tests; the level of spatial memory was valued by Y maze test; the number of Fos positive neurons in hippocampus, amygdala and medial prefrontal cortex was valued by immunohistochemical staining; and the protein expressions of hypoxia inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) and brain derived neurotrophic factor (BDNF) in these brain area were valued by Western blot. The results showed that IH and model (foot shock) had an interaction on percentage of entering open arms (OE%) in EPM and freezing time and the number of fecal pellets in fear conditioning test. IH increased OE% in EPM and reduced the freezing time and the number of fecal pellets in fear conditioning test in PTSD model mice. At the same time, IH reduced the number of Fos positive neurons in the hippocampus, amygdala and medial prefrontal cortex of PTSD model mice, and increased the protein expression levels of HIF-1α, VEGF and BDNF in these brain tissues. In conclusion, IH pretreatment can relieve fear and anxiety behavior in post-traumatic stress model mice, suggesting that IH may be an effective means of preventing PTSD.

miR-210 protects renal cell against hypoxia-induced apoptosis by targeting HIF-1 alpha.

The kidney is vulnerable to hypoxia-induced injury. One of the mechanisms underlying this phenomenon is cell apoptosis triggered by hypoxia-inducible factor-1-alpha (HIF-1α) activation. MicroRNA-210 (miR-210) is known to be induced by HIF-1α and can regulate various pathological processes, but its role in hypoxic kidney injury remains unclear. Here, in both kinds of rat systemic hypoxia and local kidney hypoxia models, we found miR-210 levels were upregulated significantly in injured kidney, especially in renal tubular cells. A similar increase was observed in hypoxia-treated human renal tubular HK-2 cells. We also verified that miR-210 can directly suppress HIF-1α expression by targeting the 3' untranslated region (UTR) of HIF-1α mRNA in HK-2 cells in severe hypoxia. Accordingly, miR-210 overexpression caused significant inhibition of the HIF-1α pathway and attenuated apoptosis caused by hypoxia, while miR-210 knockdown exerted the opposite effect. Taken together, our findings verify that miR-210 is involved in the molecular response in hypoxic kidney lesions in vivo and attenuates hypoxia-induced renal tubular cell apoptosis by targeting HIF-1α directly and suppressing HIF-1α pathway activation in vitro.

[Change of intracellular Ca2+ concentration and related signaling pathway in hippocampal cells after high-intensity sound exposure].

High-intensity sound often leads to the dysfunction and impairment of central nervous system (CNS), but the underlying mechanism is unclear. The present study was aimed to investigate the related mechanisms of CNS lesions in Bama miniature pig model treated with high-intensity sound. The pigs with normal hearing were divided into control and high-intensity sound (900 Hz-142 dB SPL, 15 min) groups. After the treatment, hippocampi were collected immediately. Fluo-4 was used to indicate intracellular Ca2+ concentration ([Ca2+]i) change. Real-time PCR and Western blot were used to detect mRNA and protein expressions of calcium-sensing receptor, L-Ca2+ channel α2/δ1 subunit, PKC and PI3K, respectively. DAPI staining was used to identify nuclear features. The result showed that high-intensity sound exposure resulted in significantly swollen cell nucleus and increased [Ca2+]i in hippocampal cells. Compared with control group, high-intensity sound group showed increased levels of PI3K, PKC and L-Ca2+ channel α2/δ1 subunit mRNA expressions, as well as up-regulated PKC and calcium-sensing receptor protein expressions. These results suggest that the high-intensity sound activates PKC signaling pathway and induces calcium overload, eventually leads to hippocampal injury, which would supply a novel strategy to prevent nervous system from high-intensity sound-induced injury.

[Establishment and evaluation of a murine model of brain injury induced by high altitude hypoxic inflammation].

The aim of this study was to develop a murine model of brain injury induced by high altitude hypoxic inflammation. In the study, we used a decompression chamber to mimic an acute hypobaric hypoxia, and 8-week-old male C57BL/6 mice were intraperitoneally injected with 5 mg/kg lipopolysaccharide (LPS) to induce inflammatory response. We determined the levels of pro-inflammatory factors (IL-6, TNF-α) and anti-inflammatory factor (IL-10) in mice serum using ELISA assays to confirm the high altitude hypoxic inflammation, and verified the brain injury after the inflammation using hematoxylin-eosin (HE) staining. The results showed that, among four experiment groups (ctrl, acute hypobaric hypoxia, LPS, and acute hypobaric hypoxia plus LPS groups), the acute hypobaric hypoxia plus LPS treatment group displayed the highest levels of IL-6, TNF-α, and IL-10. Meanwhile, the acute hypobaric hypoxia plus LPS treatment group showed the most severe cortex and hippocampus injuries, including cellular swelling, the widened pericellular spaces, angiogenesis, and shrunken neurons with darkly stained pyknotic nuclei, etc. Strikingly, nuclei ventrales posteriors thalami were found to be more sensitive to acute hypobaric hypoxia plus LPS treatment, and their destroy degrees were higher than those neurons in cortex and hippocampus. These results suggested that we established a reliable murine model of brain injury induced by high altitude hypoxic inflammation, and might be useful to the relevant studies.

Methylene Blue Reduces Acute Cerebral Ischemic Injury via the Induction of Mitophagy.

The treatment of stroke is limited by a short therapeutic window and a lack of effective clinical drugs. Methylene blue (MB) has been used in laboratories and clinics since the 1890s. Few studies have reported the neuroprotective role of MB in cerebral ischemia-reperfusion injury. However, whether and how MB protects against acute cerebral ischemia (ACI) injury was unclear. In this study, we investigated the effect of MB on this injury and revealed that MB protected against ACI injury by augmenting mitophagy. Using a rat middle cerebral artery occlusion (MCAO) model, we demonstrated that MB improved neurological function and reduced the infarct volume and necrosis after ACI injury. These improvements depended on the effect of MB on mitochondrial structure and function. ACI caused the disorder and disintegration of mitochondrial structure, while MB ameliorated the destruction of mitochondria. In addition, mitophagy was inhibited at 24 h after stroke and MB augmented mitophagy. In an oxygen-glucose deprivation (OGD) model in vitro, we further revealed that the elevation of mitochondrial membrane potential (MMP) by MB under OGD conditions mediated the augmented mitophagy. In contrast, exacerbating the decline of MMP during OGD abolished the MB-induced activation of mitophagy. Taken together, MB promotes mitophagy by maintaining the MMP at a relatively high level, which contributes to a decrease in necrosis and an improvement in neurological function, thereby protecting against ACI injury.

A review of methods for assessment of cognitive function in high-altitude hypoxic environments.

Hypoxic environments like those present at high altitudes may negatively affect brain function. Varying levels of hypoxia, whether acute or chronic, are previously shown to impair cognitive function in humans. Assessment and prevention of such cognitive impairment require detection of cognitive changes and impairment using specific cognitive function assessment tools. This paper summarizes the findings of previous research, outlines the methods for cognitive function assessment used at a high altitude, elaborates the need to develop standardized and systematic cognitive function assessment tools for high-altitude hypoxia environments.

Sigma-1 receptor agonist properties that mediate the fast-onset antidepressant effect of hypidone hydrochloride (YL-0919).

The most intriguing characteristic of the sigma-1 receptor is its ability to regulate multiple functional proteins directly via protein-protein interactions, giving the sigma-1 receptor the powerful ability to regulate several survival and metabolic functions in cells, fine tune neuronal excitability, and regulate the transmission of information within brain circuits. This characteristic makes sigma-1 receptors attractive candidates for the development of new drugs. Hypidone hydrochloride (YL-0919), a novel structured antidepressant candidate developed in our laboratory, possess a selective sigma-1 receptor agonist profile, as evidenced by molecular docking, radioligand receptor binding assays, and receptor functional experiments. In vivo studies have revealed that YL-0919 elicits a fast-onset antidepressant activity (within one week) that can be attenuated with pretreatment of the selective sigma-1 receptor antagonist, BD-1047. Taken together, the findings of the current study suggest that YL-0919 activates the sigma-1 receptor to partially mediate the rapid onset antidepressant effects of YL-0919. Thus, YL-0919 is a promising candidate as a fast-onset antidepressant that targets the sigma-1 receptor.

Efficient gene transfer into neonatal mouse brain using electroporation.

In vivo electroporation works as an effective method to transfer exogenous genes into postnatal rodent forebrain. Nevertheless, two deficiencies were found in the reported methods. First, surgical operation brings unnecessary trauma to newborn pups. Second, the procedure was complicated and the transfection efficiency was relatively low. Here we improved the previous electroporation method and make it more simple and efficient. The pulse voltage was decreased to 90 v. DNA injection into one pup's forebrain could be completed within 30 s without any surgical operation. More than 94% of injected neonates survived. Almost 100% of the survivors expressed the introduced gene and the expression persists as long as 20 days after injection. Thus, this method offers a powerful new way for gene function study in postnatal neurogenesis and neural development.

Diagnostic model constructed by nine inflammation-related genes for diagnosing ischemic stroke and reflecting the condition of immune-related cells.

Background: Ischemic cerebral infarction is the most common type of stroke with high rates of mortality, disability, and recurrence. However, the known diagnostic biomarkers and therapeutic targets for ischemic stroke (IS) are limited. In the current study, we aimed to identify novel inflammation-related biomarkers for IS using machine learning analysis and to explore their relationship with the levels of immune-related cells in whole blood samples. Methods: Gene expression profiles of healthy controls and patients with IS were download from the Gene Expression Omnibus. Analysis of differentially expressed genes (DEGs) was performed in healthy controls and patients with IS. Single-sample gene set enrichment analysis was performed to calculate inflammation scores, and weighted gene co-expression network analysis was used to analyze genes in significant modules associated with inflammation scores. Key DEGs in significant modules were then analyzed using LASSO regression analysis for constructing a diagnostic model. The effectiveness and specificity of the diagnostic model was verified in healthy controls and patients with IS and with cerebral hemorrhage (CH) using qRT-PCR. The relationship between diagnostic score and the levels of immune-related cells in whole blood were analyzed using Pearson correlations. Results: A total of 831 DEGs were identified. Both chronic and acute inflammation scores were higher in patients with IS, while 54 DEGs were also clustered in the gene modules associated with chronic and acute inflammation scores. Among them, a total of 9 genes were selected to construct a diagnostic model. Interestingly, RT-qPCR showed that the diagnostic model had better diagnostic value for IS but not for CH. The levels of lymphocytes were lower in blood of patients with IS, while the levels of monocytes and neutrophils were increased. The diagnostic score of the model was negatively associated with the levels of lymphocytes and positively associated with levels of monocytes and neutrophils. Conclusions: Taken together, the diagnostic model constructed using the inflammation-related genes TNFSF10, ID1, PAQR8, OSR2, PDK4, PEX11B, TNIP1, FFAR2, and JUN exhibited high and specific diagnostic value for IS and reflected the condition of lymphocytes, monocytes, and neutrophils in the blood. The diagnostic model may contribute to the diagnosis of IS.

BNIP3 phosphorylation by JNK1/2 promotes mitophagy via enhancing its stability under hypoxia.

Mitophagy is an important metabolic mechanism that modulates mitochondrial quality and quantity by selectively removing damaged or unwanted mitochondria. BNIP3 (BCL2/adenovirus e1B 19 kDa protein interacting protein 3), a mitochondrial outer membrane protein, is a mitophagy receptor that mediates mitophagy under various stresses, particularly hypoxia, since BNIP3 is a hypoxia-responsive protein. However, the underlying mechanisms that regulate BNIP3 and thus mediate mitophagy under hypoxic conditions remain elusive. Here, we demonstrate that in hypoxia JNK1/2 (c-Jun N-terminal kinase 1/2) phosphorylates BNIP3 at Ser 60/Thr 66, which hampers proteasomal degradation of BNIP3 and drives mitophagy by facilitating the direct binding of BNIP3 to LC3 (microtubule-associated protein 1 light chain 3), while PP1/2A (protein phosphatase 1/2A) represses mitophagy by dephosphorylating BNIP3 and triggering its proteasomal degradation. These findings reveal the intrinsic mechanisms cells use to regulate mitophagy via the JNK1/2-BNIP3 pathway in response to hypoxia. Thus, the JNK1/2-BNIP3 signaling pathway strongly links mitophagy to hypoxia and may be a promising therapeutic target for hypoxia-related diseases.

A novel low-cost electrode for recording the local field potential of freely moving rat's brain.

Local field potentials (LFPs) are involved in almost all cognitive activities of animals. Several kinds of recording electrodes are used for recording LFPs in freely moving animals, including commercial and homemade electrodes. However, commercial recording electrodes are expensive, and their relatively fixed size often causes a steric hindrance effect, especially when combining deep brain stimulation (DBS) with LFP recording, which may not always satisfy the aim of researchers. Currently, an increasing number of researchers are designing their own recording electrodes to lower research costs. Nevertheless, there is no simple universal method to produce low-cost recording electrodes with a specific size according to the target brain area. Thus, we developed a simple method for quickly producing low-cost multiple-channel recording electrodes. To inspect the effectiveness of our self-designed electrode, LFPs were recorded in a Parkinson's disease (PD) rat model, and an electrical stimulation electrode was implanted into the subthalamic nucleus to verify the space-saving ability of the self-designed recording electrode. The results showed that <30 min was needed to prepare an electrode and that the electrode materials cost <5 dollars. Further investigations showed that our electrode successfully recorded the beta oscillations (12-40 Hz) in the PD rat model. Thus, this method will greatly reduce the cost of recording electrodes and save time for researchers. Additionally, the small size of the electrode will further facilitate DBS research.

[Effects of acute high altitude hypoxia on EEG power in different emotional states].

Objective: To investigate the effects of acute high altitude hypoxia on EEG power in different emotional states. Methods: This study was two-factor within-subject design (2 levels of oxygen environment ×4 levels of emotion type). Twelve male subjects aged between 20 and 25 years old were induced to produce four different types of emotions by emotional picture evoked paradigm: low valence and low arousal(LVLA), high valence and low arousal(HVLA), low valence and high arousal(LVHA), high valence and high arousal(HVHA). Brain Products 32 was used to collect EEG signals under different emotional states. The next day, a constant depressed oxygen chamber was used to simulate a 4 300 m plateau hypoxia environment, and the same group of subjects used the same experimental paradigm to collect EEG signals 10h after hypoxia. The collected EEG signals were analyzed by power spectrum (FFT), and the five frequency bands (Delta, Theta, Alpha, beta, gamma) of the frontal lobe (F3\Fz\F4) were analyzed by variance analysis of two-factor repeated measurements. Results: FFT analysis found that before and after acute hypoxia, the whole brain distribution of alpha wave in four emotional states was mainly concentrated in frontal and parietal leaves; the distribution of alpha wave in the whole brain was the least in relaxed emotional state. The results of the two-factor repeated measurement ANOVA showed that: ①the power of delta\ beta band was significantly affected by the oxygen environment(P＜0.05), and the power was enhanced under hypoxia. ②The power index of theta\ alpha band showed a significant interaction between the oxygen environment and emotional types(P＜0.05). Except for the HVLA emotional state, the power of theta alpha band was significantly enhanced under hypoxia. ③ The two factors had no significant influence on the gamma band(P＞0.05). Conclusion: Under the four kinds of emotional states, the difference of the influence of oxygen environment on brain activity was mainly in the frontal lobe, parietal lobe and part of temporal lobe. Of the four types of emotions, the oxygen environment had the least significant effect on brain activity in HVLA emotional states, while the rest showed significant differences.

Quinacrine protects neuronal cells against heat-induced injury.

The effects of quinacrine (QA) on heat-induced neuronal injury have been explored, with the intention of understanding the mechanisms of QA protection. Primary cultivated striatum neurons from newborn rats were treated with QA 1h before heat treatment at 43 degrees C which lasted for another 1h, and necrosis and apoptosis were detected by Annexin-V-FITC and propidium iodide (PI) double staining. Neuronal apoptosis was determined using terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) techniques. Cell membrane fluidity, activity of cytosolic phospholipase A(2) (cPLA(2)) and the level of arachidonic acid (AA) were also examined. Membrane surface ultrastructure of striatum neurons was investigated by atomic force microscopy (AFM). Results showed that heat treatment induced great striatum neurons death, with many dying neurons undergoing necrosis rather than apoptosis. QA alone had little effect on the survival of striatum neurons, while QA pretreatment before heat treatment decreased necrosis. Heat treatment also resulted in decreased membrane fluidity and increased cPLA(2) activity as well as arachidonic acid level; these effects were reversed by QA pretreatment. QA pretreatment also significantly prevented damage to the membrane surface ultrastructure of heat-treated neurons. These results suggest that QA protects striatum neurons against heat-induced neuronal necrosis, and also demonstrate that inhibition of cPLA(2) activity and stabilization of membranes may contribute to protective effect of quinacrine.

[Effects of simulated high-altitude hypobaric hypoxia on cardiac structure and function in rats].

OBJECTIVE: To investigate the effects of simulated hypobaric hypoxia environment at 7 000 m above sea level on cardiac structure and function in rats. METHODS: A total of 96 male SD rats were randomly divided into high-altitude hypobaric hypoxia group (hypoxia group) and normobaric normoxia group (control group). Rats of hypoxia group were placed in a large cabin simulated 7 000 m high-altitude hypobaric hypoxia environment. Operating time 23 h / d, the control circadian ratio of approximately 12 h:12 h. The rats in control group were bred under normobaric normoxia. The hypoxic group was divided into 3 d, 7 d, 14 d, 28 d groups according to hypoxic time, 12 rats in each group. Changes of structure and function of heart due to hypoxia were evaluated by echocardiography and electrocardiogram. Myocardial pathological changes were analyzed by hematoxylin-eosin staining(HE). RESULTS: Compared with the control group at the same time point ①With prolonged exposure to hypobaric hypoxia, the growth ratio of body mass in rats is slower. Arterial oxygen saturation was significantly lower in both 14 d and 28 d (P＜0.05). ② Left ventricular end-diastolic anterior wall thickness (LVAWD) and left ventricular end-diastolic posterior wall thickness (LVPWD) of rats in 28 d were increased significantly (P＜0.05). Left ventricular end-diastolic diameter (LVIDD) and left ventricular internal dimension systole (LVIDS) of rats in 28 d were decreased significantly (P＜0.05, P＜0.01). Left ventricular ejection fraction (EF), fractional shortening of left ventricle (FS), pulmonary vein (PV) peak velocity and PV peak gradient of rats in 7 d were decreased significantly (P＜0.05, P＜0.01). ③The QRS and QT interval period were significantly prolonged in 14 d and 28 d (P＜0.05, P＜0.01). The ST was significantly lower in 3 d and 7 d (P＜0.05, P＜0.01). The amplitude of R wave gradually shifted downward in 7 d, 14 d, 28 d (P＜0.05, P＜0.01). ④The red blood cell (RBC), hemoglobin (HGB), red blood cell distribution width (RDW) in hypoxic group were increased significantly (P＜0.01). The platelet count (PLT) count was decreased significantly in 14 d and 28 d (P＜0.01). The serum creatinine (CR) was increased significantly in 14 d and 28 d (P＜0.05). ⑤Pathological changes such as myocardial edema, sarcolemma condensate, focal degeneration and necrosis with inflammatory cell infiltration could be found at early stage of hypoxia. Myocardial compensatory repair such as myocardial fibroblasts proliferation was significant at end stage of hypoxia. CONCLUSION: Left ventricular systolic functions of rats were decreased significantly after exposure to high altitude hypoxia hypobaric. The left ventricular systolic functions would recovery compensatory after one week exposed to high altitude hypoxia hypobaric.

Quinacrine pretreatment reduces microwave-induced neuronal damage by stabilizing the cell membrane.

Quinacrine, widely used to treat parasitic diseases, binds to cell membranes. We previously found that quinacrine pretreatment reduced microwave radiation damage in rat hippocampal neurons, but the molecular mechanism remains poorly understood. Considering the thermal effects of microwave radiation and the protective effects of quinacrine on heat damage in cells, we hypothesized that quinacrine would prevent microwave radiation damage to cells in a mechanism associated with cell membrane stability. To test this, we used retinoic acid to induce PC12 cells to differentiate into neuron-like cells. We then pretreated the neurons with quinacrine (20 and 40 mM) and irradiated them with 50 mW/cm2 microwaves for 3 or 6 hours. Flow cytometry, atomic force microscopy and western blot assays revealed that irradiated cells pretreated with quinacrine showed markedly less apoptosis, necrosis, and membrane damage, and greater expression of heat shock protein 70, than cells exposed to microwave irradiation alone. These results suggest that quinacrine stabilizes the neuronal membrane structure by upregulating the expression of heat shock protein 70, thus reducing neuronal injury caused by microwave radiation.

Cortical Inflammation is Increased in a DSS-Induced Colitis Mouse Model.

While inflammatory bowel disease (IBD) might be a risk factor in the development of brain dysfunctions, the underlying mechanisms are largely unknown. Here, mice were treated with 5% dextran sodium sulfate (DSS) in drinking water and sacrificed on day 7. The serum level of IL-6 increased, accompanied by elevation of the IL-6 and TNF-α levels in cortical tissue. However, the endotoxin concentration in plasma and brain of mice with DSS-induced colitis showed a rising trend, but with no significant difference. We also found significant activation of microglial cells and reduction in occludin and claudin-5 expression in the brain tissue after DSS-induced colitis. These results suggested that DSS-induced colitis increases systemic inflammation which then results in cortical inflammation via up-regulation of serum cytokines. Here, we provide new information on the impact of colitis on the outcomes of cortical inflammation.