Mitochondrial calcium uniporter knockdown in hippocampal neurons alleviates anxious and depressive behavior in the 3XTG Alzheimer's disease mouse model.

Alzheimer's disease (AD) is a progressive and degenerative disorder accompanied by emotional disturbance, especially anxiety and depression. More and more evidence shows that the imbalance of mitochondrial Ca2+ (mCa2+) homeostasis has a close connection with the pathogenesis of anxiety and depression. The Mitochondrial Calcium Uniporter (MCU), a key channel of mCa2+ uptake, induces the imbalance of mCa2+ homeostasis and may be a therapeutic target for anxiety and depression of AD. In the present study, we revealed for the first time that MCU knockdown in hippocampal neurons alleviated anxious and depressive behaviors of APP/PS1/tau mice through elevated plus-maze (EPM), elevated zero maze (EZM), sucrose preference test (SPT) and tail suspension test (TST). Western blot analysis results demonstrated that MCU knockdown in hippocampal neurons increased levels of glutamate decarboxylase 67 (GAD67), vesicular GABA transporter (vGAT) and GABAA receptor α1 (GABRA1) and activated the PKA-CREB-BDNF signaling pathway. This study indicates that MCU inhibition has the potential to be developed as a novel therapy for anxiety and depression in AD.

Physicochemical characterization of a composite flour: Blending purple sweet potato and rice flours.

In this study, the physicochemical characterization of different ratios of purple sweet potato flour (PSPF) and rice flour was investigated to improve the nutritional value and enrich the variety of rice-based staple food. The results showed that adding PSPF increased total dietary fiber and anthocyanin content whereas decreased amylose content of the composite flours. Additionally, the composite flours exhibited lower thermodynamic parameters and displayed darker, redder, and bluer colors. There were no noticeable changes in the functional group structure of the composite flours. The addition of PSPF decreased the crystallinity and water-holding capacity of the composite flours, whereas increased the average particle size and iodine blue value. PSPF increased the pasting temperature of the flours whereas decreased the breakdown and setback values. Overall, the addition of PSPF significantly affects the nutrition, color and physicochemical properties of the composite flours.

Therapeutic strategies targeting mechanisms of macrophages in diabetic heart disease.

Diabetic heart disease (DHD) is a serious complication in patients with diabetes. Despite numerous studies on the pathogenic mechanisms and therapeutic targets of DHD, effective means of prevention and treatment are still lacking. The pathogenic mechanisms of DHD include cardiac inflammation, insulin resistance, myocardial fibrosis, and oxidative stress. Macrophages, the primary cells of the human innate immune system, contribute significantly to these pathological processes, playing an important role in human disease and health. Therefore, drugs targeting macrophages hold great promise for the treatment of DHD. In this review, we examine how macrophages contribute to the development of DHD and which drugs could potentially be used to target macrophages in the treatment of DHD.

Selective Orexin 2 Receptor Blockade Alleviates Cognitive Impairments and the Pathological Progression of Alzheimer's Disease in 3xTg-AD Mice.

The orexin system is closely related to the pathogenesis of Alzheimer's disease (AD). Orexin-A aggravates cognitive dysfunction and increases amyloid ß (Aß) deposition in AD model mice, but studies of different dual orexin receptor (OXR) antagonists in AD have shown inconsistent results. Our previous study revealed that OX1R blockade aggravates cognitive deficits and pathological progression in 3xTg-AD mice, but the effects of OX2R and its potential mechanism in AD have not been reported. In the present study, OX2R was blocked by oral administration of the selective OX2R antagonist MK-1064, and the effects of OX2R blockade on cognitive dysfunction and neuropsychiatric symptoms in 3xTg-AD mice were evaluated via behavioral tests. Then, immunohistochemistry, western blotting, and ELISA were used to detect Aß deposition, tau phosphorylation, and neuroinflammation, and electrophysiological and wheel-running activity recording were recorded to observe hippocampal synaptic plasticity and circadian rhythm. The results showed that OX2R blockade ameliorated cognitive dysfunction, improved LTP depression, increased the expression of PSD-95, alleviated anxiety- and depression-like behaviors and circadian rhythm disturbances in 3xTg-AD mice, and reduced Aß pathology, tau phosphorylation, and neuroinflammation in the brains of 3xTg-AD mice. These results indicated that chronic OX2R blockade exerts neuroprotective effects in 3xTg-AD mice by reducing AD pathology at least partly through improving circadian rhythm disturbance and the sleep-wake cycle and that OX2R might be a potential target for the prevention and treatment of AD; however, the potential mechanism by which OX2R exerts neuroprotective effects on AD needs to be further investigated.

Exploring the mechanism of ShenGui capsule in treating heart failure based on network pharmacology and molecular docking: A review.

ShenGui capsule (SGC), as a herbal compound, has significant effects on the treatment of heart failure (HF), but its mechanism of action is unclear. In this study, we aimed to explore the potential pharmacological targets and mechanisms of SGC in the treatment of HF using network pharmacology and molecular docking approaches. Potential active ingredients of SGC were obtained from the traditional Chinese medicine systems pharmacology database and analysis platform database and screened by pharmacokinetic parameters. Target genes of HF were identified by comparing the toxicogenomics database, GeneCards, and DisGeNET databases. Protein interaction networks and gene-disorder-target networks were constructed using Cytoscape for visual analysis. Gene ontology and Kyoto Encyclopedia of Genes and Genomes were also performed to identify protein functional annotations and potential target signaling pathways through the DAVID database. CB-DOCK was used for molecular docking to explore the role of IL-1ß with SGC compounds. Sixteen active ingredients in SGC were screened from the traditional Chinese medicine systems pharmacology database and analysis platform, of which 36 target genes intersected with HF target genes. Protein-protein interactions suggested that each target gene was closely related, and interleukin-1ß (IL-1ß) was identified as Hub gene. The network pharmacology analysis suggested that these active ingredients were well correlated with HF. Kyoto Encyclopedia of Genes and Genomes enrichment analysis suggested that target genes were highly enriched in pathways such as inflammation. Molecular docking results showed that IL-1ß binds tightly to SGC active components. This experiment provides an important research basis for the mechanism of action of SGC in the treatment of HF. In this study, the active compounds of SGC were found to bind IL-1ß for the treatment of heart failure.

Intermittent fasting and Alzheimer's disease-Targeting ketone bodies as a potential strategy for brain energy rescue.

Alzheimer's disease (AD) lacks effective clinical treatments. As the disease progresses, the cerebral glucose hypometabolism that appears in the preclinical phase of AD gradually worsens, leading to increasingly severe brain energy disorders. This review analyzes the brain energy deficit in AD and its etiology, brain energy rescue strategies based on ketone intervention, the effects and mechanisms of IF, the differences in efficacy between IF and ketogenic diet and the duality of IF. The evidence suggests that brain energy deficits lead to the development and progression of AD pathology. IF, which improves brain energy impairments by promoting ketone metabolism, thus has good therapeutic potential for AD.

Principle and design of clinical efficacy observation of extracorporeal cardiac shock wave therapy for patients with myocardial ischemia-reperfusion injury: A prospective randomized controlled trial protocol.

BACKGROUND: Acute ST-segment elevation myocardial infarction (STEMI) remains a serious life threatening event with a poor prognosis due to myocardial ischemia/reperfusion injury despite coronary revascularization. Extracorporeal cardiac shock wave (ECSW) is a safe, effective and non-invasive new method for the treatment of cardiovascular diseases. The current results show that extracorporeal cardiac shock wave provides a new treatment option for patients with severe and advanced coronary heart disease. However, there are relatively few clinical studies on the application of in vitro cardiac shock waves in patients with myocardial ischemia-reperfusion injury. We hypothesized that extracorporeal cardiac shock therapy would also be effective in reducing clinical endpoints in patients with STEMI reperfusion. OBJECTIVE: This study is order to provide a new therapeutic method for patients with myocardial ischemia-reperfusion injury and reveal the possible mechanism of ECSW for ischemia-reperfusion injury. METHODS AND MATERIALS: CEECSWIIRI is a single-center, prospective randomized controlled trial that plans to enroll 102 eligible patients with acute ST-segment elevation myocardial infarction reperfusion. Eligible patients with STEMI reperfusion will be randomly divided into external cardiac shock therapy (ECSW) trial group and blank control group. The blank control group will receive optimal drug therapy, and the experimental group will receive optimal drug therapy combined with ECSW. The shock wave treatment plan will be 3-month therapy, specifically 1 week of treatment per month, 3 weeks of rest, 3 times of ECSW in each treatment week, respectively on the first day, the third day and the fifth day of the treatment week, lasting for 3 months and follow-up for 2 years. The primary endpoint will be to assess the 2-year improvement in all-cause death, re-hospitalization due to cardiovascular disease, major unintentional cerebrovascular events, including cardiogenic death, myocardial infarction, heart failure, arrhythmia, emergency coronary revascularization, and stroke in patients with STEMI reperfusion. Secondary endpoints will include improvements in angina pectoris, quality of life, cardiac structure and function, coronary microcirculation, and endothelial progenitor cell-derived miR-140-3p in relation to survival outcomes. TRIAL REGISTRATION NUMBER: ClinicalTrial.gov.org PRS:NCT05624203; Date of registration: November 12, 2022.

Interpretable prediction of 3-year all-cause mortality in patients with chronic heart failure based on machine learning.

BACKGROUND: The goal of this study was to assess the effectiveness of machine learning models and create an interpretable machine learning model that adequately explained 3-year all-cause mortality in patients with chronic heart failure. METHODS: The data in this paper were selected from patients with chronic heart failure who were hospitalized at the First Affiliated Hospital of Kunming Medical University, from 2017 to 2019 with cardiac function class III-IV. The dataset was explored using six different machine learning models, including logistic regression, naive Bayes, random forest classifier, extreme gradient boost, K-nearest neighbor, and decision tree. Finally, interpretable methods based on machine learning, such as SHAP value, permutation importance, and partial dependence plots, were used to estimate the 3-year all-cause mortality risk and produce individual interpretations of the model's conclusions. RESULT: In this paper, random forest was identified as the optimal aools lgorithm for this dataset. We also incorporated relevant machine learning interpretable tand techniques to improve disease prognosis, including permutation importance, PDP plots and SHAP values for analysis. From this study, we can see that the number of hospitalizations, age, glomerular filtration rate, BNP, NYHA cardiac function classification, lymphocyte absolute value, serum albumin, hemoglobin, total cholesterol, pulmonary artery systolic pressure and so on were important for providing an optimal risk assessment and were important predictive factors of chronic heart failure. CONCLUSION: The machine learning-based cardiovascular risk models could be used to accurately assess and stratify the 3-year risk of all-cause mortality among CHF patients. Machine learning in combination with permutation importance, PDP plots, and the SHAP value could offer a clear explanation of individual risk prediction and give doctors an intuitive knowledge of the functions of important model components.

Exposure duration of ambient fine particulate matter determines the polarization of macrophages.

Ambient fine particulate matter (FPM) promotes airway inflammation and aggravates respiratory and cardiovascular diseases. Macrophage polarization plays an essential role in FPM-induced inflammation and tissue repair. The balance of pro-inflammatory M1-type and anti-inflammatory M2-type macrophages determines the fate of tissues and is involved in the pathogenesis of various FPM-induced diseases. The mechanism of macrophage polarization induced by FPM is still not fully understood. Here, we explored the effect of ambient FPM exposure duration on the polarization of peritoneal macrophages. Mice were exposed to concentrated ambient FPM for different duration. Markers of M1-type macrophage and M2-type macrophage in peritoneal macrophages were detected. We found that macrophage polarization was affected by FPM both in vitro and in vivo. Acute FPM stimulation in vitro and short-term concentrated ambient FPM exposure in vivo promoted the expression of NLRP3 and NOS2 and inhibited the expression of ARG1 and CD206. With the extension of concentrated ambient FPM exposure time, ARG1 was gradually up-regulated, and NLRP3 was gradually down-regulated. These results indicate that FPM exposure duration interferes with macrophage polarization. This may provide new insight into the treatment of patients exposed to FPM.

Semaglutide ameliorates cognition and glucose metabolism dysfunction in the 3xTg mouse model of Alzheimer's disease via the GLP-1R/SIRT1/GLUT4 pathway.

Disorders of brain glucose metabolism is known to affect brain activity in neurodegenerative diseases including Alzheimer's disease (AD). Furthermore, recent evidence has shown an association between AD and type 2 diabetes. Numerous reports have found that glucagon-like peptide-1 (GLP-1) receptor agonists improve the cognitive behavior and pathological features in AD patients and animals, which may be related to the improvement of glucose metabolism in the brain. However, the mechanism by which GLP-1 agonists improve the brain glucose metabolism in AD patients remains unclear. In this study, we found that SIRT1 is closely related to expression of GLP-1R in hippocampus of 3xTg mice. Therefore, we used semaglutide, a novel GLP-1R agonist currently undergoing two phase 3 clinical trials in AD patients, to observe the effect of SIRT1 after semaglutide treatment in 3XTg mice and HT22 cells, and to explore the mechanism of SIRT1 in the glucose metabolism disorders of AD. The mice were injected with semaglutide on alternate days for 30 days, followed by behavioral experiments including open field test, new object recognition test, and Y-maze. The content of glucose in the brain was also measured by using 18FDG-PET-CT scans. We measured the expression of Aß and tau in the hippocampus, observed the expression of GLUT4 which is downstream of SIRT1, and tested the Glucose oxidase assay (GOD-POD) and Hexokinase (HK) in HT22 cells. Here, we found in the 3xTg mouse model of AD and in cultured HT22 mouse neurons that SIRT1 signaling is involved in the impairment of glucose metabolism in AD. Semaglutide can increased the expression levels of SIRT1 and GLUT4 in the hippocampus of 3xTg mice, accompanied by an improvement in learning and memory, decreased in Aß plaques and neurofibrillary tangles. In addition, we further demonstrated that semaglutide improved glucose metabolism in the brain of 3xTg mice in vitro, semaglutide promoted glycolysis and improved glycolytic disorders, and increased the membrane translocation of GLUT4 in cultured HT22 cells. These effects were blocked by the SIRT1 inhibitor (EX527). These findings indicate that semaglutide can regulate the expression of GLUT4 to mediate glucose transport through SIRT1, thereby improving glucose metabolism dysfunction in AD mice and cells. The present study suggests that SIRT1/GLUT4 signaling pathway may be an important mechanism for GLP-1R to promote glucose metabolism in the brain, providing a reliable strategy for effective therapy of AD.

Response of active layer thickening to wildfire in the pan-Arctic region: Permafrost type and vegetation type influences.

Northern high-latitude permafrost holds the largest soil carbon pool in the world. Understanding the responses of permafrost to wildfire is crucial for improving our ability to predict permafrost degradation and further carbon emissions. Recently, studies have demonstrated that wildfires in the pan-Arctic region induced the thickening of the active layer based on site or fire event observations. However, how this induced thickening is influenced by vegetation and permafrost types remains not fully understood due to the lack of wall-to-wall analysis. Therefore, this study employed remotely sensed fire data and modelled active layer thickness (ALT) to identify the fire-induced ALT change (ΔALT) for the pan-Arctic region, and the contributions of vegetation and permafrost were quantified using the random forest (RF) model. Our results showed that the average ΔALT and the sensitivity of ΔALT to burn severity both increased with decreasing ground ice content in permafrost. The largest values were detected in thick permafrost with low ground ice content. Regarding vegetation, the average and sensitivity of ΔALT in tundra were highest, followed by those in forest and shrub. When the individual environmental factors were all taken into account, the results showed that the contribution of vegetation types was much higher than that of permafrost types (20.2 % vs. 3.5 %). Our findings highlighted the importance of environmental factors in regulating the responses of permafrost to fire.

Prognostic Significance of Serum Chloride Level Reduction in Patients with Chronic Heart Failure with Different Ejection Fractions.

Little is known regarding the prognostic value of serum chloride in patients with chronic heart failure (CHF) with different ejection fractions. We sought to determine the postdischarge outcomes associated with lower serum chloride between different CHF types.We reviewed the medical records of 1221 consecutive patients with CHF admitted to the First Affiliated Hospital of Kunming Medical University from January 2017 to October 2021. After excluding patients with in-hospital death, missing follow-up data, missing serum chloride level data, or chronic dialysis therapy, 791 patients were included. Of these patients, 343 had heart failure with reduced ejection fraction (HFrEF; i.e., left ventricular ejection fraction (LVEF) < 40%), and 448 had heart failure with preserved ejection fraction (HFpEF) or heart failure with median ejection fraction (HFmrEF; HFpEF plus HFmrEF; i.e., LVEF ≥40%). Over a median follow-up of 750 days, 344 patients (43.5%) had all-cause mortality. In the univariate analysis, serum sodium and chloride were strongly associated with mortality in both HF subgroups (P < 0.0001). A multivariable model including both serum sodium and chloride showed the highly significant association between serum chloride and survival (P < 0.0001), whereas the association between serum sodium and mortality was not reported (HFpEF plus HFmrEF, hazard ratio (HR) 0.975, 95% confidence interval [CI] 0.942-1.010, P = 0.158; HFrEF, HR 1.007, 95% CI 0.966-1.051, P = 0.734). Kaplan-Meier survival curve analysis revealed a significant difference in mortality risk with decreasing chloride levels in all patients with CHF. The optimal cutoff value of chloride in predicting all-cause mortality was 102.95 mmol/L with area under the curve value of 0.76 [HR 0.760, 95% CI 0.727-0.793, P < 0.0001], sensitivity of 60.2%, and specificity of 78.3%.Lower serum chloride is an independent predictor of death in CHF, regardless of heart failure subtype.

Causal Association Between mTOR-Dependent Protein Levels and Alzheimer's Disease: A Mendelian Randomization Study.

BACKGROUND: Most previous studies supported that the mammalian target of rapamycin (mTOR) is over-activated in Alzheimer's disease (AD) and exacerbates the development of AD. It is unclear whether the causal associations between the mTOR signaling-related protein and the risk for AD exist. OBJECTIVE: This study aims to investigate the causal effects of the mTOR signaling targets on AD. METHODS: We explored whether the risk of AD varied with genetically predicted AKT, RP-S6K, EIF4E-BP, eIF4E, eIF4A, and eIF4G circulating levels using a two-sample Mendelian randomization analysis. The summary data for targets of the mTOR signaling were acquired from published genome-wide association studies for the INTERVAL study. Genetic associations with AD were retrieved from the International Genomics of Alzheimer's Project. We utilized the inverse variance weighted as the primary approach to calculate the effect estimates. RESULTS: The elevated levels of AKT (OR = 0.910, 95% CI=0.840-0.986, p = 0.02) and RP-S6K (OR = 0.910, 95% CI=0.840-0.986, p = 0.02) may decrease the AD risk. In contrast, the elevated eIF4E levels (OR = 1.805, 95% CI=1.002-1.174, p = 0.045) may genetically increase the AD risk. No statistical significance was identified for levels of EIF4-BP, eIF4A, and eIF4G with AD risk (p > 0.05). CONCLUSION: There was a causal relationship between the mTOR signaling and the risk for AD. Activating AKT and RP-S6K, or inhibiting eIF4E may be potentially beneficial to the prevention and treatment of AD.

Integrated analysis of the lncRNA-associated ceRNA network in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that worsens with age. Long non-coding RNAs (lncRNAs) dysregulation and its associated competing endogenous RNA (ceRNA) network have a potential connection with the occurrence and development of AD. A total of 358 differentially expressed genes (DEGs) were screened via RNA sequencing, including 302 differentially expressed mRNAs (DEmRNAs) and 56 differential expressed lncRNAs (DElncRNAs). Anti-sense lncRNA is the main type of DElncRNA, which plays a major role in the cis and trans regulation. The constructed ceRNA network consisted of 4 lncRNAs (NEAT1, LINC00365, FBXL19-AS1, RAI1-AS1719) and 4 microRNAs (miRNAs) (HSA-Mir-27a-3p, HSA-Mir-20b-5p, HSA-Mir-17-5p, HSA-Mir-125b-5p), and 2 mRNAs (MKNK2, F3). Functional enrichment analysis revealed that DEmRNAs are involved in related biological functions of AD. The co-expressed DEmRNAs (DNAH11, HGFAC, TJP3, TAC1, SPTSSB, SOWAHB, RGS4, ADCYAP1) of humans and mice were screened and verified by real-time quantitative polymerase chain reaction (qRT-PCR). In this study, we analyzed the expression profile of human AD-related lncRNA genes, constructed a ceRNA network, and performed functional enrichment analysis of DEmRNAs between human and mice. The obtained gene regulatory networks and target genes can be used to further analyze AD-related pathological mechanisms to optimize AD diagnosis and treatment.

[Sulfur dioxide in the caudal ventrolateral medulla reduces blood pressure and heart rate in rats via the glutamate receptor and NOS/cGMP signal pathways].

This study was designed to investigate the cardiovascular effects of sulfur dioxide (SO2) in the caudal ventrolateral medulla (CVLM) of anesthetized rats and its mechanism. Different doses of SO2 (2, 20, 200 pmol) or artificial cerebrospinal fluid (aCSF) were injected into the CVLM unilaterally or bilaterally, and the effects of SO2 on blood pressure and heart rate of rats were observed. In order to explore the possible mechanisms of SO2 in the CVLM, different signal pathway blockers were injected into the CVLM before the treatment with SO2 (20 pmol). The results showed that unilateral or bilateral microinjection of SO2 reduced blood pressure and heart rate in a dose-dependent manner (P < 0.01). Moreover, compared with unilateral injection of SO2 (2 pmol), bilateral injection of 2 pmol SO2 produced a greater reduction in blood pressure. Local pre-injection of the glutamate receptor blocker kynurenic acid (Kyn, 5 nmol) or soluble guanylate cyclase (sGC) inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 1 pmol) into the CVLM attenuated the inhibitory effects of SO2 on both blood pressure and heart rate. However, local pre-injection of nitric oxide synthase (NOS) inhibitor NG-Nitro-L-arginine methyl ester (L-NAME, 10 nmol) only attenuated the inhibitory effect of SO2 on heart rate but not blood pressure. In conclusion, SO2 in rat CVLM has cardiovascular inhibitory effects, and its mechanism is related to the glutamate receptor and NOS/cGMP signal pathways.

Orexin-A aggravates cognitive deficits in 3xTg-AD mice by exacerbating synaptic plasticity impairment and affecting amyloid ß metabolism.

Dementia is the main clinical feature of Alzheimer's disease (AD). Orexin has recently been linked to AD pathogenesis, and exogenous orexin-A (OXA) aggravates spatial memory impairment in APP/PS1 mice. However, the effects of OXA on other types of cognitive deficits, especially in 3xTg-AD mice exhibiting both plaque and tangle pathologies, have not been reported. Furthermore, the potential electrophysiological mechanism by which OXA affects cognitive deficits and the molecular mechanism by which OXA increases amyloid ß (Aß) levels are unknown. In the present study, the effects of OXA on cognitive functions, synaptic plasticity, Aß levels, tau hyperphosphorylation, BACE1 and NEP expression, and circadian locomotor rhythm were evaluated. The results showed that OXA aggravated memory impairments and circadian rhythm disturbance, exacerbated hippocampal LTP depression, and increased Aß and tau pathologies in 3xTg-AD mice by affecting BACE1 and NEP expression. These results indicated that OXA aggravates cognitive deficits and hippocampal synaptic plasticity impairment in 3xTg-AD mice by increasing Aß production and decreasing Aß clearance through disruption of the circadian rhythm and sleep-wake cycle.

Incorporating Exercise Efficiency to Evaluate the Accessibility and Capacity of Medical Resources in Tibet, China.

Accessibility and capacity of medical resources are key for the health care and emergency response, while the efficiency of the medical resources is very much limited by hypoxia in Tibet, China. Through introducing exercise efficiency, this study explores the accessibility of township residence to county-ship medical resources in Tibet using weighted mean travel time (WMT), and evaluates the medical capacity accordingly. The results show that: 1) the average travel time of township residence to county-level hospital is around 2 h by motor vehicle in Tibet. More than half of the population can not reach the county-ship hospital within 1 h, 33.24% of the population can not reach within 2 h, and 3.75% of the population can not reach within 6 h. 2) When considering the catchment of the medical resources and the population size, the WMT of the county-ship medical resources ranges from 0.25 h to 10.92 h. 3) After adjusted by travel time and exercise efficiency, the county-ship medical capacity became more unequal, with 38 out of 74 counties could not meet the national guideline of 1.8 medical beds per 1000. 4) In total, there are 17 counties with good WMT and sufficient medical resources, while 13 counties having very high WMT and low capacity of medical resources in Tibet. In the end, suggestions on medical resources relocation and to improve the capacity are provided. This study provides a method to incorporate exercise efficiency to access the accessibility and evaluate medical capacity that can be applied in high altitude ranges. Electronic Supplementary Material: Supplementary material is available in the online version of this article at 10.1007/s11769-022-1321-1.

Selective orexin 1 receptor antagonist SB-334867 aggravated cognitive dysfunction in 3xTg-AD mice.

Cognitive dysfunction is the main clinical manifestation of Alzheimer's disease (AD). Previous research found that elevated orexin level in the cerebrospinal fluid was closely related to the course of AD, and orexin-A treatment could increase amyloid ß protein (Aß) deposition and aggravate spatial memory impairment in APP/PS1 mice. Furthermore, recent research found that dual orexin receptor (OXR) antagonist might affect Aß level and cognitive dysfunction in AD, but the effects of OX1R or OX2R alone is unreported until now. Considering that OX1R is highly expressed in the hippocampus and plays important roles in learning and memory, the effects of OX1R in AD cognitive dysfunction and its possible mechanism should be investigated. In the present study, selective OX1R antagonist SB-334867 was used to block OX1R. Then, different behavioral tests were performed to observe the effects of OX1R blockade on cognitive function of 3xTg-AD mice exhibited both Aß and tau pathology, in vivo electrophysiological recording and western blot were used to investigate the potential mechanism. The results showed that chronic OX1R blockade aggravated the impairments of short-term working memory, long-term spatial memory and synaptic plasticity in 9-month-old female 3xTg-AD mice, increased levels of soluble Aß oligomers and p-tau, and decreased PSD-95 expression in the hippocampus of 3xTg-AD mice. These results indicate that the detrimental effects of SB-334867 on cognitive behaviors in 3xTg-AD mice are closely related to the decrease of PSD-95 and depression of in vivo long-term potentiation (LTP) caused by increased Aß oligomers and p-tau.