Joint association of sedentary time and physical activity with abnormal heart rate recovery in young and middle-aged adults.

BACKGROUND: Abnormal heart rate recovery (HRR), representing cardiac autonomic dysfunction, is an important predictor of cardiovascular disease. Prolonged sedentary time (ST) is associated with a slower HRR. However, it is not clear how much moderate-to-vigorous physical activity (MVPA) is required to mitigate the adverse effects of sedentary behavior on HRR in young and middle-aged adults. This study aimed to examine the joint association of ST and MVPA with abnormal HRR in this population. METHODS: A cross-sectional analysis was conducted on 1253 participants (aged 20-50 years, 67.8% male) from an observational study assessing cardiopulmonary fitness in Fujian Province, China. HRR measured via cardiopulmonary exercise tests on a treadmill was calculated as the difference between heart rate at peak exercise and 2 min after exercise. When the HRR was ≤ 42 beats·minute-1 within this time, it was considered abnormal. ST and MVPA were assessed by the IPAQ-LF. Individuals were classified as having a low sedentary time (LST [< 6 h·day-1]) or high sedentary time (HST [≥ 6 h·day-1]) and according to their MVPA level (low MVPA [0-149 min·week-1], medium MVPA [150-299 min·week-1], high MVPA [≥ 300 min·week-1]). Finally, six ST-MVPA groups were derived. Associations between ST-MVPA groups with abnormal HRR incidence were examined using logistic regression models. RESULTS: 53.1% of the young and middle-aged adults had less than 300 min of MVPA per week. In model 2, adjusted for possible confounders (e.g. age, sex, current smoking status, current alcohol consumption, sleep status, body mass index), HST was associated with higher odds of an abnormal HRR compared to LST (odds ratio (OR) = 1.473, 95% confidence interval (CI) = 1.172-1.852). Compared with the reference group (HST and low MVPA), the HST and high MVPA groups have a lower chance of abnormal HRR (OR, 95% CI = 0.553, 0.385-0.795). Compared with individuals with HST and low MVPA, regardless of whether MVPA is low, medium, or high, the odds of abnormal HRR in individuals with LST is significantly reduced (OR, 95% CI = 0.515, 0.308-0.857 for LST and low MVPA; OR, 95% CI = 0.558, 0.345-0.902 for LST and medium MVPA; OR, 95% CI = 0.476, 0.326-0.668 for LST and high MVPA). CONCLUSION: Higher amounts of MVPA appears to mitigate the increased odds of an abnormal HRR associated with HST for healthy young and middle-aged adults.

The regulatory mechanisms and inhibitors of isocitrate dehydrogenase 1 in cancer.

Reprogramming of energy metabolism is one of the basic characteristics of cancer and has been proved to be an important cancer treatment strategy. Isocitrate dehydrogenases (IDHs) are a class of key proteins in energy metabolism, including IDH1, IDH2, and IDH3, which are involved in the oxidative decarboxylation of isocitrate to yield α-ketoglutarate (α-KG). Mutants of IDH1 or IDH2 can produce d-2-hydroxyglutarate (D-2HG) with α-KG as the substrate, and then mediate the occurrence and development of cancer. At present, no IDH3 mutation has been reported. The results of pan-cancer research showed that IDH1 has a higher mutation frequency and involves more cancer types than IDH2, implying IDH1 as a promising anti-cancer target. Therefore, in this review, we summarized the regulatory mechanisms of IDH1 on cancer from four aspects: metabolic reprogramming, epigenetics, immune microenvironment, and phenotypic changes, which will provide guidance for the understanding of IDH1 and exploring leading-edge targeted treatment strategies. In addition, we also reviewed available IDH1 inhibitors so far. The detailed clinical trial results and diverse structures of preclinical candidates illustrated here will provide a deep insight into the research for the treatment of IDH1-related cancers.

Increased low frequency fluctuation in the brain after acupuncture treatment in CSVDCI patients: A randomized control trial study.

Background: Cerebral small vessel disease (CSVD) is one of two cognition-impairing diseases. Acupuncture (Acu) is a flexible treatment with few adverse effects and is thus widely used to treat neurological problems. Methods: We recruited a total of 60 patients and assigned them to two groups (n = 30 each group). During the study, some participants were excluded by quality control, and a total of 44 subjects (25 Acu and 19 controls) were completed to investigate the therapeutic efficacy of acupuncture on CSVD cognitive impairment (CSVDCI). The following demographic and clinical variables were compared between the two groups: gender, age, education, smoking, alcohol, Montreal cognitive assessment (MoCA), symbol digit modalities test (SDMT), verbal fluency test (VFT), digit span task (DST), Boston naming test (BNT) scores, and amplitude of low-frequency fluctuation (ALFF) under the typical band (0.01-0.08 Hz). Mixed effect analysis was utilized to test for differences between the two groups before and after the treatment. Results: Following acupuncture treatment, the Acu group scored higher on MoCA, SDMT, VFT, DST, and BNT compared to controls (P < 0.05). The brain regions showing substantially greater ALFF values in the Acu group were the right inferior temporal gyrus, left middle occipital gyrus, left superior occipital gyrus, left insula, bilateral postcentral gyrus, right superior parietal gyrus, right cerebellum, right precuneus, and right precentral gyrus (P < 0.005, no correction). The ALFF values in the right inferior temporal gyrus (P = 0.027), left middle occipital gyrus (P = 0.005), left superior occipital gyrus (P = 0.011), and right superior parietal gyrus (P = 0.043) were positively associated with MoCA. Conclusion: We found that acupuncture modulates the functional activity of temporal, occipital, and parietal regions of the brain in CSVDCI patients.

Targeting lactate-related cell cycle activities for cancer therapy.

Lactate has long been considered as a metabolic by-product of aerobic glycolysis for cancer. However, more and more studies have shown that lactate can regulate cancer progression via multiple mechanisms such as cell cycle regulation, immune suppression, energy metabolism and so on. A recent discovery of lactylation attracted a lot of attention and is already a hot topic in the cancer field. In this review, we summarized the latest functions of lactate and its underlying mechanisms in cancer. We also included our analysis of protein lactylation in different rat organs and compared them with other published lactylation data. The unresolved challenges in this field were discussed, and the potential application of these new discoveries of lactate-related cell cycle activities for cancer target therapy was speculated.

Effect of Electroacupuncture on Short-Chain Fatty Acids in Peripheral Blood after Middle Cerebral Artery Occlusion/Reperfusion in Rats Based on Gas Chromatography-Mass Spectrometry.

Previous fundamental and clinical research has shown that electroacupuncture (EA) at the acupoints of Quchi (LI11) and Zusanli (ST36) can successfully alleviate motor dysfunction following stroke. Additionally, it has been discovered that gut microbiota and their metabolites play an essential role in stroke. However, the relationship between the metabolites of gut microbiota and the efficacy of EA is still unclear. Therefore, the aim of this study was to evaluate the mechanism of EA at LI11 and ST36 in the treatment of motor dysfunction after middle cerebral artery occlusion/reperfusion (MCAO/R) in model rats by comparing the differences and correlation between different short-chain fatty acids (SCFAs) and the recovery of motor function. The results indicated that EA at LI11 and ST36 acupoints enhanced the neurological function, motor function, and infarct volume of MCAO/R rats. The levels of acetic acid, propionic acid, and total SCFAs were considerably lower in the MCAO/R group than in the sham group (P < 0.05). Acetic acid, propionic acid, and total SCFA concentrations were substantially higher in the MCAO/R + EA group than in the MCAO/R group (P < 0.05). Finally, Pearson correlation analysis revealed that the propionic acid concentration was substantially favorably connected with the duration on the rotarod (r = 0.633 and P < 0.05) and highly negatively correlated with the modified neurological severity score (mNSS) (r = -0.698 and P < 0.05) and the percentage of cerebral infarct volume (r = -0.729 and P < 0.05). Taken together, these findings indicate that the increase in propionic acid may be one of the mechanisms and targets of EA at LI11 and ST36 acupoints to improve poststroke motor dysfunction in MCAO/R rats.

The impact of physical activity on blood inflammatory cytokines and neuroprotective factors in individuals with mild cognitive impairment: a systematic review and meta-analysis of randomized-controlled trials.

BACKGROUND: Accumulated evidence has proved that both neuroinflammation and neuroprotection existing at the stage of mild cognitive impairment (MCI) may mediate its progression, which can conversely be modulated by physical activity (PA). However, further research is needed to clarify which factors are involved in that process. OBJECTIVES: To identify the impact of PA on inflammatory cytokines and neuroprotective factors in individuals with MCI. METHODS: Four databases [PubMed, Cochrane Library, Cochrane Library (Trials), Embase and Web of Science Core Collection] were searched from their inception to October 2021 for randomized-controlled trials (RCTs) assessing the biochemical effect of PA on biomarkers in participants with MCI. Pooled effect size was calculated by the standardized mean difference (SMD). RESULTS: A total of 13 RCTs involving 514 participants by reporting 8 inflammatory cytokines [tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, -6, -8, -10, -15, C-reactive protein (CRP) and interferon-γ (IFN-γ) and 5 neuroprotective factors (brain-derived neurotrophic factor (BDNF), insulin-like growth factor (IGF-1), vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), irisin] were included. The meta-analysis showed that PA had positive effects on decreasing TNF-α (SMD = - 0.32, 95% CI - 0.58 to 0.07, p = 0.01; I2 = 32%) and CRP (SMD = - 0.68, 95% CI - 1.05 to 0.32, p = 0.0002; I2 = 18%), while significantly improving BDNF (SMD = 0.32, 95% CI 0.09-0.56, p = 0.007; I2 = 42%) and IGF-1 (SMD = 0.42, 95% CI 0.03-0.81, p = 0.03; I2 = 0%). CONCLUSION: PA had a certain effect on inhibiting inflammatory cytokines but promoting neuroprotective factors in individuals with MCI which may provide a possible explanation for the potential molecular mechanism of PA on cognitive improvement.

The Global Burden of Disease attributable to low physical activity and its trends from 1990 to 2019: An analysis of the Global Burden of Disease study.

Introduction: Low physical activity (LPA) is associated with several major non-communicable diseases (NCDs) and premature mortality. In this study, we aimed to assess the global burden and trends in disease attributable to LPA (DALPA) from 1990 to 2019. Methods: Annual age-standardized disability-adjusted life years (DALYs) and death rates of DALPA [all-cause and five specific causes (ischaemic heart disease, diabetes mellitus, stroke, colon and rectal cancer, and breast cancer)] by sex, age, geographical region and social deprivation index (SDI) score from 1990 to 2019 were available from the Global Burden of Disease (GBD) study 2019. The estimated annual percentage changes (EAPCs) were calculated to quantify the changing trend. A generalized linear model (GLM) was used to explore the relationship between DALYs/death rates of DALPA and sociodemographic factors. Results: Globally, in 2019, the age-standardized DALYs and death rates of DALPA were 198.42/100,000 (95% UI: 108.16/100,000-360.32/100,000) and 11.10/100,000 (95% UI: 5.66/100,000-19.51/100,000), respectively. There were 15.74 million (8.51-28.61) DALYs and 0.83 million (0.43-1.47) deaths attributable to LPA. Overall, age-standardized DALYs and death rates presented significant downward trends with EAPCs [-0.68% (95% CI: -0.85- -0.50%) for DALYs and -1.00% (95% CI: -1.13- -0.86%) for deaths] from 1990 to 2019. However, age-standardized DALYs and death rates of diabetes mellitus attributable to LPA were substantially increased [EAPC: 0.76% (95% CI: 0.70-0.82%) for DALYs and 0.33% (95% CI: 0.21-0.51%) for deaths]. In the 15-49 age group, DALPA presented significant upward trends [EAPC: 0.74% (95% CI: 0.58-0.91%) for DALYs and 0.31% (95% CI: 0.1-0.51%) for deaths]. The GLM revealed that higher gross domestic product and current health expenditure (% of GDP) were negatively associated with DALYs and death rates of DALPA. Conclusion: Although global age-standardized DALYs and death rates of DALPA presented downward trends, they still cause a heavy burden worldwide. These rates showed upward trends in the diabetic and 15-49 age groups, which need more attention and health interventions.

Activation of Adenosine Monophosphate-Activated Protein Kinase Drives the Aerobic Glycolysis in Hippocampus for Delaying Cognitive Decline Following Electroacupuncture Treatment in APP/PS1 Mice.

Aerobic glycolysis (AG), an important pathway of glucose metabolism, is dramatically declined in Alzheimer's disease (AD). AMP-activated protein kinase (AMPK) is a key regulator to maintain the stability of energy metabolism by promoting the process of AG and regulating glucose metabolism. Interestingly, it has been previously reported that electroacupuncture (EA) treatment can improve cognitive function in AD through the enhancement of glucose metabolism. In this study, we generated AMPK-knockdown mice to confirm the EA effect on AMPK activation and further clarify the mechanism of EA in regulating energy metabolism and improving cognitive function in APP/PS1 mice. The behavioral results showed that EA treatment can improve the learning and memory abilities in APP/PS1 mice. At the same time, the glucose metabolism in the hippocampus was increased detected by MRI-chemical exchange saturation transfer (MRI-CEST). The expression of proteins associated with AG in the hippocampus was increased simultaneously, including hexokinase II (HK2), 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), and pyruvate kinase M2 (PKM2). Moreover, the knockdown of AMPK attenuated AG activated by EA treatment. In conclusion, this study proves that EA can activate AMPK to enhance the process of AG in the early stage of AD.

Longitudinal tracing of white matter integrity on diffusion tensor imaging in the chronic cerebral ischemia and acute cerebral ischemia.

Brain ischemia leads to insufficient oxygen supply or hypoxia and thus to ischemic stroke or chronic hypoperfusion, which results in neuronal death and white matter damage is irreversible or partially recoverable under the interruption of blood flow more than a few minutes. The present study investigated the abnormal characteristics of white matter integrity after the chronic cerebral ischemia in a mouse model of bilateral carotid artery stenosis and the acute cerebral ischemia in a mouse model of middle cerebral artery occlusion via longitudinal diffusion tensor imaging, which revealed that the mean diffusivity of corpus callosum (cc) was decreased as early as the 1 st day after chronic cerebral ischemia, and then the damage gradually aggravated and lasted to the 28th day. Moreover, the brain regions, including cingulum (cg), dorsal hippocampal commissure (dhc), forceps major of the corpus callosum (fmj), alveus of the hippocampus (alv) and medial lemniscus (ml), were damaged in duration of 7∼28 days after chronic cerebral ischemia. Oppositely, white matter signals in the contralateral hemisphere appeared compensatory increase in the internal capsule (ic) at the 1 st day after acute cerebral ischemia, simultaneously the ipsilateral hemisphere signals were decreased in alv, cerebral peduncle (cp), external capsule (ec), ml, fimbria of the hippocampus (fi), ic, forceps minor of the corpus callosum (fmi) and dhc. While these regional white matter signals were decreased in the bilateral hemisphere at the 7th day after acute cerebral ischemia. In addition, the motor function was impaired after acute cerebral ischemia, and cognitive function were impaired after chronic and acute cerebral ischemia. Furthermore, voxel-wise analysis revealed the obvious differences of white matter integrity in these two models of ischemia. The chronic cerebral ischemia showed better white matter integrity in the ipsilateral hemisphere of acute cerebral ischemic model at the 1 st day after surgery, but worse in the contralateral hemisphere. Subsequently, these differences were reduced significantly and just only the ipsilateral cp and bilateral ml signals were higher in chronic cerebral ischemia. Taken together, the present study demonstrates that the chronic and acute cerebral ischemia cause progressive damages of white matter that are irreversible in a relatively long time, of which the contralateral white matter present transient compensation in acute cerebral ischemia but not in chronic cerebral ischemia. These might be helpful to better diagnosis of clinical different cerebral ischemia.

Electroacupuncture ameliorates learning and memory deficits via hippocampal 5-HT1A receptors and the PKA signaling pathway in rats with ischemic stroke.

Hippocampal 5-HT1A receptors and the PKA signaling pathway have been implicated in learning and memory. This study aimed to investigate whether PKA signaling mediated by 5-HT1A receptors was involved in the electroacupuncture (EA)-mediated learning and memory in a rat model of middle cerebral artery occlusion-induced cognitive deficit (MICD). Compared to no treatment or non-acupoint EA treatment, EA at DU20 and DU24 acupoints improved the neurological deficit of scores, shortened escape latency and increased the frequency of crossing the platform in the Morris water maze test. T2-weighted imaging demonstrated that the MICD rat brain lesions were mainly located in the cortex and hippocampus, and injured volumes were reduced after EA. Furthermore, we found that these behavioral changes were concomitant with the deficit of the 5HT1A and PKA signaling pathways in the hippocampus, as the activation of the 5-HT1A receptor, the reduction of PKA kinase activity, and AMPA and NMDA receptor phosphorylation occurred in the injured hippocampus at Day 14 after MICD. Additionally, EA dramatically elevated the activation of PKA. Moreover, EA significantly increased intracellular calcium concentrations regulated by the activation of NMDA receptors. Therefore, PKA kinase and NMDA receptors mediated by 5-HT1A receptors in the hippocampus might contribute to improving learning and memory during the recovery process following ischemic stroke with an EA intervention.

Effect of Aerobic Exercise on Inflammatory Markers in Healthy Middle-Aged and Older Adults: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background: Chronic inflammation plays a significant role in accelerating the aging process and is closely associated with the initiation and progression of a broad range of age-related diseases. Physical exercise is considered beneficial in alleviating these conditions, but the effects of aerobic exercise on inflammatory markers in a healthy population should be furtherly clarified. Objective: The purpose of this systematic review and meta-analysis was to evaluate the effect of aerobic exercise on inflammatory markers in middle-aged and older adults. Methods: The literature search was conducted utilizing PubMed, Web of Science, Embase, and the Cochrane Library from their inception through April 2018, and the reference lists were screened to identify appropriate studies. Only randomized controlled trials that investigated the effect of aerobic exercise on inflammatory markers in middle-aged and older adults were eligible for this review. Results: Eleven studies involving 1,250 participants were retrieved from the databases for analysis. The pooled results showed that aerobic exercise significantly reduced inflammatory markers (C-reactive protein (CRP): SMD = 0.53, 95% CI 0.26-0.11, p = 0.0002; tumor necrosis factor-alpha (TNF-α): SMD = 0.75, 95% CI 0.31-1.19, p = 0.0007; interleukin 6 (IL-6): SMD = 0.75, 95% CI 0.31-1.19, p = 0.0007). No significant improvement was found in relation to interleukin 4 (IL-4). Conclusions: Aerobic exercise may have a positive effect on reduction of CRP, TNF-α, and IL-6 in middle-aged and older adults. Further randomized controlled trials (RCTs) need to be conducted to determine the effect of aerobic exercise on additional inflammatory markers in the population of middle-aged and older adults.

Electroacupuncture Regulates Hippocampal Synaptic Plasticity via Inhibiting Janus-Activated Kinase 2/Signal Transducer and Activator of Transcription 3 Signaling in Cerebral Ischemic Rats.

OBJECTIVE: To determine the mechanism(s) involved in electroacupuncture (EA)-mediated improvements in synaptic plasticity in a rat model of middle cerebral artery occlusion and reperfusion (MCAO/R)-induced cognitive deficits. METHODS: Focal cerebral ischemic stroke was induced by (MCAO/R) surgery. Rats were randomly split into 4 groups: control group (sham operation control), MCAO group, Baihui (GV 20) and Shenting (GV 24) acupoint EA group (verum acupuncture, MCAO + VA), and nonacupoint EA group (control acupuncture, MCAO + CA). EA treatment was administered for 14 consecutive days in MCAO + VA and MCAO + CA groups. Neurological assessment, behavioral performance testing, and molecular biology assays were used to evaluate the MCAO/R model, EA therapeutic effect and potential therapeutic mechanism(s) of EA. RESULTS: Significant amelioration of neurological deficits was found in MCAO + VA rats compared with MCAO rats (P < .01). Moreover, learning and memory significantly improved in EA-treated rats compared with MCAO or MCAO + CA rats (P < .05) together with an increase in the number of PSD-95+ and SYN+ cells and synapses in the hippocampal CA1 region (P < .05). MCAO + VA rats also showed amelioration of pathological synaptic ultrastructural changes compared with MCAO or MCAO + CA groups (P < .001). In contrast, EA decreased the levels and phosphorylation of JAK2 (Janus-activated kinase 2) and STAT3 (signal transducer and activator of transcription 3) in the hippocampal CA1 region compared with MCAO or MCAO + CA group (P < .01). CONCLUSION: EA at GV 20 and GV 24 acupoints improved cognitive deficits in cerebral ischemic rats via the JAK2/STAT3 signaling pathway and mediated synaptic plasticity in the peri-infarct hippocampal CA1 region of rats following ischemic stroke.

Electroacupuncture ameliorate learning and memory by improving N -acetylaspartate and glutamate metabolism in APP/PS1 mice

OBJECTIVE: To explore the precise mechanism of electroacupuncture (EA) to delay cognitive impairment in Alzheimer disease. Methods N -Acetylaspartate (NAA), glutamate (Glu) and myoinositol (mI) metabolism were measured by magnetic resonance spectroscopy, learning and memory of APP/PS1 mouse was evaluated by the Morris water maze test and the step-down avoidance test, neuron survival number and neuronal structure in the hippocampus were observed by Nissl staining, and BDNF and phosphorylated TrkB detected by Western blot. RESULTS: EA at DU20 acupuncture significantly improve learning and memory in behavioral tests, up-regulate NAA, Glu and mI metabolism, increase the surviving neurons in hippocampus, and promote the expression of BDNF and TrkB in the APP/PS1 transgenic mice. CONCLUSION: These findings suggested that EA is a potential therapeutic for ameliorate cognitive dysfunction, and it might be due to EA could improve NAA and Glu metabolism by upregulation of BDNF in APP/PS1 mice.

Electroacupuncture ameliorating post-stroke cognitive impairments via inhibition of peri-infarct astroglial and microglial/macrophage P2 purinoceptors-mediated neuroinflammation and hyperplasia.

BACKGROUND: During ischemic stroke (IS), adenosine 5'-triphosphate (ATP) is released from damaged nerve cells of the infract core region to the extracellular space, invoking peri-infarct glial cellular P2 purinoceptors singling, and causing pro-inflammatory cytokine secretion, which is likely to initiate or aggravate motor and cognitive impairment. It has been proved that electroacupuncture (EA) is an effective and safe strategy used in anti-inflammation. However, EA for the role of purine receptors in the central nervous system has not yet been reported. METHODS: Ischemia-reperfusion injured rat model was induced by middle cerebral artery occlusion and reperfusion (MCAO/R). EA treatment at the DU 20 and DU 24 acupoints treatment were conducted to rats from the 12 h after MCAO/R injury for consecutive 7 days. The neurological outcomes, infarction volumes and the level of astroglial and microglial/macrophage hyperplasia, inflammatory cytokine and P2X7R and P2Y1R expression in the peri-infarct hippocampal CA1and sensorimotor cortex were investigated after IS to evaluate the MCAO/R model and therapeutic mechanism of EA treatment. RESULTS: EA effectively reduced the level of pro-inflammatory cytokine interleukin-1ß (IL-1ß) as evidenced by reduction in astroglial and microglial/macrophage hyperplasia and the levels of P2X7R and ED1, P2X7R and GFAP, P2Y1R and ED1, P2Y1R and GFAP co-expression in peri-infarct hippocampal CA1 and sensorimotor cortex compared with that of MCAO/R model and Non-EA treatment, accompanied by the improved neurological deficit and the motor and memory impairment outcomes. Therefore, our data support the hypothesis that EA could exert its anti-inflammatory effect via inhibiting the astroglial and microglial/macrophage P2 purinoceptors (P2X7R and P2Y1R)-mediated neuroinflammation after MCAO/R injury. CONCLUSION: Astroglial and microglial/macrophage P2 purinoceptors-mediated neuroinflammation and hyperplasia in peri-infarct hippocampal CA1 and sensorimotor cortex were attenuated by EA treatment after ischemic stroke accompanied by the improved motor and memory behavior performance.

Electroacupuncture attenuates learning and memory impairment via activation of α7nAChR-mediated anti-inflammatory activity in focal cerebral ischemia/reperfusion injured rats.

Studies have reported that electroacupuncture (EA) may reduce learning and memory impairment following cerebral ischemic injury. However, the precise mechanism of action remains unclear. In the present study, the attenuation of focal cerebral ischemia/reperfusion injury by EA in rats was investigated. EA at the Baihui (DU 20) and Shenting (DU 24) acupoints was demonstrated to significantly improve performance in the Morris water maze task, with shortened latency time and increased frequency of passing the platform. Molecular analysis revealed that EA activated the expression of α7 nicotinic acetylcholine receptors (α7nAChR) in the hippocampus. In addition, EA led to a decreased expression of the microglia/macrophage marker Iba1 and the astrocyte marker glial fibrillary acidic protein in the hippocampus. EA treatment also led to decreased production of the inflammatory cytokines tumor necrosis factor-α and interleukin-1ß. Treatment with methyllycaconitine, an α7nAChR antagonist, attenuated the improvement of learning and memory following EA treatment and the inhibitory effects of EA on glial cell activation and inflammatory cytokine production. In conclusion, the findings of the present study demonstrate that EA is able to improve learning and memory function following cerebral ischemic injury via activation of α7nAChR, which significantly decreases the neuroinflammatory response.

Activation of brain glucose metabolism ameliorating cognitive impairment in APP/PS1 transgenic mice by electroacupuncture.

An essential feature of Alzheimer's disease (AD) is implicated in brain energy metabolic impairment that is considered underlying pathogenesis of cognitive impairment. Therefore, therapeutic interventions to allay cognitive deficits that target energy metabolism may be an efficacy strategy in AD. In this study, we found that electroacupuncture (EA) at the DU20 acupoint obviously increased glucose metabolism in specific brain regions such as cortex, hippocampus, cingulate gyrus, basal forebrain septum, brain stem, and cerebellum in APP/PS1 transgenic mice by animal 18F-Fluoro-2-deoxy-D-Glucose (18F-FDG)/positron emission tomography (PET) imaging, accompanied by cognitive improvements in the spatial reference learning and memory and memory flexibility and novel object recognition performances. Further evidence shown energy metabolism occurred in neurons or non-neuronal cells of the cortex and hippocampus in terms of the co-location of GLUT3/NeuN and GLUT1/GFAP. Simultaneously, metabolic homeostatic factors were critical for glucose metabolism, including phosphorylated adenosine monophosphate-activated protein kinase (AMPK) and AKT serine/threonine kinase. Furthermore, EA-induced phosphorylated AMPK and AKT inhibited the phosphorylation level of the mammalian target of rapamycin (mTOR) to decrease the accumulation of amyloid-beta (Aß) in the cortex and hippocampus. These findings are concluded that EA is a potential therapeutic target for delaying memory decline and Aß deposition of AD. The AMPK and AKT are implicated in the EA-induced cortical and hippocampal energy metabolism, which served as a contributor to improving cognitive function and Aß deposition in a transgenic mouse model of AD.

Salidroside Inhibits Inflammation Through PI3K/Akt/HIF Signaling After Focal Cerebral Ischemia in Rats.

Salidroside is being investigated for its therapeutic potential in stroke because it is neuroprotective over an extended therapeutic window of time. In the present study, we investigated the mechanisms underlying the anti-inflammatory effects of salidroside (50 mg/kg intraperitoneally) in rats, given 1 h after reperfusion of a middle cerebral artery that had been occluded for 2 h. After 24 h, we found that salidroside increased the neuronal nuclear protein NeuN and reduced the marker of microglia and macrophages CD11b in the peri-infarct area of the brain. Salidroside also decreased IL-6, IL-1ß, TNF-α, CD14, CD44, and iNOs mRNAs. At the same time, salidroside increased the ratio of phosphorylated protein kinase B (p-Akt) to total Akt. The phosphoinositide 3-kinase (PI3K) inhibitor LY294002 prevented this increase in p-Akt and reversed the inhibitory effects of salidroside on CD11b and inflammatory mediators. Salidroside also elevated the protein levels of hypoxia-inducible factor (HIF) subunits HIF1α, HIF2α, HIF3α, and of erythropoietin (EPO). The stimulatory effects of salidroside on HIFα subunits were blocked by LY294002. Moreover, YC-1, a HIF inhibitor, abolished salidroside-mediated increase of HIF1α and prevented the inhibitory effects of salidroside on CD11b and inflammatory mediators. Taken together, our results provide evidence for the first time that all three HIFα subunits and EPO can be regulated by PI3K/Akt in cerebral tissue, and that salidroside entrains this signaling pathway to induce production of HIFα subunits and EPO, one or more of which mediate the anti-inflammatory effects of salidroside after cerebral IRI.

Memantine attenuates cell apoptosis by suppressing the calpain-caspase-3 pathway in an experimental model of ischemic stroke.

Ischemic stroke, the second leading cause of death worldwide, leads to excessive glutamate release, over-activation of N-methyl-D-aspartate receptor (NMDAR), and massive influx of calcium (Ca2+), which may activate calpain and caspase-3, resulting in cellular damage and death. Memantine is an uncompetitive NMDAR antagonist with low-affinity/fast off-rate. We investigated the potential mechanisms through which memantine protects against ischemic stroke in vitro and in vivo. Middle cerebral artery occlusion-reperfusion (MCAO) was performed to establish an experimental model of ischemic stroke. The neuroprotective effects of memantine on ischemic rats were evaluated by neurological deficit scores and infarct volumes. The activities of calpain and caspase-3, and expression levels of microtubule-associated protein-2 (MAP2) and postsynaptic density-95 (PSD95) were determined by Western blotting. Additionally, Nissl staining and immunostaining were performed to examine brain damage, cell apoptosis, and neuronal loss induced by ischemia. Our results show that memantine could significantly prevent ischemic stroke-induced neurological deficits and brain infarct, and reduce ATP depletion-induced neuronal death. Moreover, memantine markedly suppressed the activation of the calpain-caspase-3 pathway and cell apoptosis, and consequently, attenuated brain damage and neuronal loss in MCAO rats. These results provide a molecular basis for the role of memantine in reducing neuronal apoptosis and preventing neuronal damage, suggesting that memantine may be a promising therapy for stroke patients.

Electroacupuncture improves cognitive ability following cerebral ischemia reperfusion injury via CaM-CaMKIV-CREB signaling in the rat hippocampus.

The aim of the present study was to investigate the effect of electroacupuncture (EA) on cognitive deficits, and the underlying mechanism following cerebral ischemia-reperfusion (I/R) via the calmodulin (CaM)-calmodulin-dependent protein kinase type IV (CaMKIV)-cyclic adenosine monophosphate response elements binding protein (CREB) intracellular signaling pathway in the hippocampus. In total, 45 adult female Sprague-Dawley rats were randomly divided into three groups, namely the sham group, the middle cerebral artery occlusion (MCAO) group and the MCAO + EA group. Rats in the MCAO and MCAO + EA groups were modeled for post-stroke cognitive impairment. EA was performed at the Baihui and Shenting acupuncture points for 30 min/day for one week in the MCAO + EA group. Behavioral testing was analyzed using a step-down apparatus, while 2,3,5-triphenyl tetrazolium chloride was used to detect the infarct volume and lesion size. In addition, CaM activity was assessed by cyclic nucleotide-dependent phosphodiesterase analysis, and the protein expression levels of CaM, CaMKIV, phosphorylated (p)-CaMKIV, CREB and p-CREB were analyzed by western blot analysis. The cerebral I/R injured rat model in the MCAO group was established successfully with regard to the infarct volume and neuronal lesion size, as compared with the sham group. EA was demonstrated to effectively improve the cognitive ability, as measured by the step-down apparatus test, and decrease the infarct volume when compared with the MCAO group (P<0.05). The step-down apparatus test for the EA-treated rats revealed improved learning and reduced memory impairment when compared with the MCAO group. Furthermore, CaM activity and CaM protein expression levels in the MCAO + EA group were lower compared with those in the MCAO group (P<0.05). By contrast, the protein expression levels of CaMKIV, p-CaMKIV, CREB and p-CREB were significantly reduced in the MCAO group when compared with the sham group (P<0.05), although the expression levels increased following EA treatment when compared with the MCAO group (P<0.05). Therefore, cognitive repair benefited from EA, and the main intracellular signaling pathway in the hippocampus was mediated by CaM-CaMKIV-CREB. EA effectively inhibited the expression and activity of CaM, while further enhancing the expression of CaMKIV and CREB, and their associated phosphorylated functions.

Electroacupuncture ameliorates post-stroke learning and memory through minimizing ultrastructural brain damage and inhibiting the expression of MMP-2 and MMP-9 in cerebral ischemia-reperfusion injured rats.

The aim of the present study was to investigate the potential neuroprotective effects of electroacupuncture (EA) in the treatment of cerebral ischemia/reperfusion (I/R) injury, and to elucidate the association between this neuroprotective effect and brain ultrastructure and expression of matrix metalloproteinase (MMP)­2 and 9. Rats underwent focal cerebral I/R injury by arterial ligation and received in vivo therapeutic EA at the Baihui (DU20) and Shenting (DU24) acupoints. The therapeutic efficacy was then evaluated following the surgery. The results of the current study demonstrated that EA treatment significantly ameliorated neurological deficits and reduced cerebral infarct volume compared with I/R injured rats. Furthermore, EA improved the learning and memory ability of rats following I/R injury, inhibited blood brain barrier breakdown and reduced neuronal damage in the ischemic penumbra. Furthermore, EA attenuated ultrastructural changes in the brain tissue following ischemia and inhibited MMP­2/MMP­9 expression in cerebral I/R injured rats. The results suggest that EA ameliorates anatomical deterioration, and learning and memory deficits in rats with cerebral I/R injury.