The mitochondrial quality control system: a new target for exercise therapeutic intervention in the treatment of brain insulin resistance-induced neurodegeneration in obesity.

Obesity is a major global health concern because of its strong association with metabolic and neurodegenerative diseases such as diabetes, dementia, and Alzheimer's disease. Unfortunately, brain insulin resistance in obesity is likely to lead to neuroplasticity deficits. Since the evidence shows that insulin resistance in brain regions abundant in insulin receptors significantly alters mitochondrial efficiency and function, strategies targeting the mitochondrial quality control system may be of therapeutic and practical value in obesity-induced cognitive decline. Exercise is considered as a powerful stimulant of mitochondria that improves insulin sensitivity and enhances neuroplasticity. It has great potential as a non-pharmacological intervention against the onset and progression of obesity associated neurodegeneration. Here, we integrate the current knowledge of the mechanisms of neurodegenration in obesity and focus on brain insulin resistance to explain the relationship between the impairment of neuronal plasticity and mitochondrial dysfunction. This knowledge was synthesised to explore the exercise paradigm as a feasible intervention for obese neurodegenration in terms of improving brain insulin signals and regulating the mitochondrial quality control system.

Clinical application of repetitive transcranial magnetic stimulation in improving functional impairments post-stroke: review of the current evidence and potential challenges.

In recent years, the stroke incidence has been increasing year by year, and the related sequelae after stroke, such as cognitive impairment, motor dysfunction, and post-stroke depression, seriously affect the patient's rehabilitation and daily activities. Repetitive transcranial magnetic stimulation (rTMS), as a safe, non-invasive, and effective new rehabilitation method, has been widely recognized in clinical practice. This article reviews the application and research progress of rTMS in treating different functional impairments (cognitive impairment, motor dysfunction, unilateral spatial neglect, depression) after stroke in recent years, and preliminary summarized the possible mechanisms. It has been found that the key parameters that determine the effectiveness of rTMS in improving post-stroke functional impairments include pulse number, stimulated brain areas, stimulation intensity and frequency, as well as duration. Generally, high-frequency stimulation is used to excite the ipsilateral cerebral cortex, while low-frequency stimulation is used to inhibit the contralateral cerebral cortex, thus achieving a balance of excitability between the two hemispheres. However, the specific mechanisms and the optimal stimulation mode for different functional impairments have not yet reached a consistent conclusion, and more research is needed to explore and clarify the best way to use rTMS. Furthermore, we will identify the issues and challenges in the current research, explore possible mechanisms to deepen understanding of rTMS, propose future research directions, and offer insightful insights for better clinical applications.

Effects of dual-task training on gait and motor ability in patients with Parkinson's disease: A systematic review and meta-analysis.

OBJECTIVE: Parkinson's disease is one of the most common neurodegenerative diseases in the world, which seriously damages motor and balance ability. Dual-task training is discussed as an appropriate intervention. The aim of this review was to synthesize the existing research findings on the efficacy of dual-task training for people with Parkinson's disease. DATA RESOURCES: A systematic search on PubMed, CENTRAL, Embase, Web of Science, and PEDro, randomized-controlled trials (RCTs) of dual-task training for individuals with Parkinson's disease. METHODS: Articles published until 1 November 2022 were included. Our search identified 7 RCTs with a total of 406 subjects. Review Manager 5.4 software was used for bias evaluation and to process the results of the outcome measures collected from the investigations. RESULTS: Dual-task training was associated with significant improvement in most motor and balance outcomes including gait velocity (standard mean difference (SMD) = 0.62; 95% CI, 0.37-0.87; I2 = 31%; P = 0.21), cadence (SMD = 0.29; 95% CI, 0.05-0.53; I2 = 0%; P = 0.71), timed-up-and-go test (mean difference (MD) = -2.38; 95% CI, -3.93 to -0.84; I2 = 32%; P = 0.22) and mini-balance evaluation systems test (MD = 2.04; 95% CI, 1.05-3.03; I2 = 0%; P = 0.92). CONCLUSION: Evidence from meta-analyses suggests that dual-task training may improve motor and balance abilities in Parkinson's disease patients. Future research should focus on finding the most appropriate dual-task treatment model for patients with different degrees, in order to further improve the rehabilitation treatment of Parkinson's disease.

LncRNA LINC02574 Inhibits Influenza A Virus Replication by Positively Regulating the Innate Immune Response.

Studies have shown that long noncoding RNAs (lncRNAs) play crucial roles in regulating virus infection, host immune response, and other biological processes. Although some lncRNAs have been reported to be involved in antiviral immunity, many lncRNAs have unknown functions in interactions between the host and various viruses, especially influenza A virus (IAV). Herein, we demonstrate that the expression of lncRNA LINC02574 can be induced by IAV infection. Treatment with viral genomic RNA, poly (I:C), or interferons (IFNs) significantly stimulated LINC02574 expression, while RIG-I knockdown and IFNAR1 knockout significantly decreased LINC02574 expression after viral infection or IFN treatment. In addition, inhibition of LINC02574 expression in A549 cells enhanced IAV replication, while overexpression of LINC02574 inhibited viral production. Interestingly, knockdown of LINC02574 attenuated the expression of type I and type III IFNs and multiple ISGs, as well as the activation of STAT1 triggered by IAV infection. Moreover, LINC02574 deficiency impaired the expression of RIG-I, TLR3, and MDA5, and decreased the phosphorylation level of IRF3. In conclusion, the RIG-I-dependent interferon signaling pathway can induce LINC02574 expression. Moreover, the data reveal that LINC02574 inhibits IAV replication by positively regulating the innate immune response.

Effects of high-intensity interval training on improving arterial stiffness in Chinese female university students with normal weight obese: a pilot randomized controlled trial.

BACKGROUND: High intensity interval training (HIIT) has been reported to exert better effects on cardiovascular fitness in obesity, but little known about the arterial stiffness (AS) in female university students with normal weight obesity (NWO). Thus, this study aimed to investigate the effects of HIIT on the body composition, heart rate (HR), blood pressure (BP), blood lipids metabolism as well as the novel parameters of propensity for AS (arterial velocity pulse index [AVI], arterial pressure volume index [API]) for female university students with NWO. METHODS: Forty female university students with NWO were randomly assigned to control group (n = 20) and HIIT group (3 bouts of 9­min intervals at 90% of the maximal heart rate [HRmax], interspersed by 1 min rest, 5 days a week, n = 20). Tests were performed before and after 4 weeks of training. Repeated measures ANOVA and simple effect test analysis were used to analyze dependent variable changes. RESULTS: After 4 weeks HIIT statistically significantly improved the body composition by decreasing the body mass index, body fat percent, total body fat mass (BFM), BFM of left arm, measured circumference of left arm, and obesity degree, and increasing the total body skeletal muscle mass, protein content, total body water, fat free mass, body cell mas, and InBody score. HIIT also statistically significantly decreased the HR and BP. As for the lipid profile, HIIT obviously ameliorated the blood lipids metabolism by decreasing the levels of total cholesterol (TC), triglyceride, low-density lipoprotein, and TC/HDL, and increasing the levels of high-density lipoprotein (HDL). In addition, the AVI and API were markedly decreased via HIIT intervention. CONCLUSIONS: HIIT produced significant and meaningful benefits for body composition, HR, BP, and blood lipids metabolism, and could decrease AS in female university students with NWO. This suggests that HIIT may effectively reduce the risk of arteriosclerosis and protect the cardiovascular function for female university students with NWO. Trial registration ChiCTR2100050711. Registered 3 September 2021. Retrospectively registered.

Interactions between Endoplasmic Reticulum Stress and Autophagy: Implications for Apoptosis and Neuroplasticity-Related Proteins in Palmitic Acid-Treated Prefrontal Cells.

Lipotoxicity of palmitic acid (PA) or high-fat diets has been reported to increase endoplasmic reticulum (ER) stress and autophagy in peripheral tissue as well as apoptotic cell death. It also can lead to an AD-like pathological pattern. However, it has been unknown that PA-induced ER stress and autophagy are involved in the regulation of neuroplastic abnormalities. Here, we investigated the roles of ER stress and autophagy in apoptosis and neuroplasticity-related protein expression in PA-treated prefrontal cells. Prefrontal cells dissected from newborn Sprague-Dawley rats were treated with PA compound with ER stress inhibitor 4-phenylbutyric acid (4-PBA) and autophagy inhibitor 3-methyladenine (3-MA) or PA alone. PA promoted ER stress and autophagy and also cause apoptosis as well as a decline in the expression of neuroplasticity-related proteins. Inhibition of ER stress decreased the expressions of neuroplasticity-related proteins and reduced autophagy activation and apoptosis in PA-treated prefrontal cells. Inhibition of autophagy exacerbated apoptosis and enhanced ER stress in PA-treated prefrontal cells. The present study illustrated that both ER stress and autophagy could be involved in apoptosis and decreased neuroplasticity-related proteins, and the interaction between ER stress and autophagy may play a critical role in apoptosis in PA-treated prefrontal cells. Our results provide new insights into the molecular mechanisms in vitro of lipotoxicity in obesity-related cognitive dysfunction.

[Research advances on high-intensity interval training and cognitive function].

High-intensity interval training (HIIT) has proven to be a time-saving and efficient exercise strategy. Compared with traditional aerobic exercise, it can provide similar or even better health benefits. In recent years, a number of studies have suggested that HIIT could be used as a potential exercise rehabilitation therapy to improve cognitive impairment caused by obesity, diabetes, stroke, dementia and other diseases. HIIT may be superior to regular aerobic exercise. This article reviews the recent research progress on HIIT with a focus on its beneficial effect on brain cognitive function and the underlying mechanisms. HIIT may become an effective exercise for the prevention and/or improvement of brain cognitive disorder.

The roles of GRP81 as a metabolic sensor and inflammatory mediator.

GPR81 (also named as HCA1) is a member of a subfamily of orphan G-protein coupled receptors (GPCRs), coupled to Gi -type G proteins. GPR81 was discovered in 2001 and identified as the only known endogenous receptor of lactate under physiological conditions in 2008, which opened a new field of research on how lactate may act as a signal molecule along with the GPR81 expression in the roles of metabolic process and inflammatory response. Recent studies showed that the physiological functions of GPR81 include lipid metabolism in adipose tissues, metabolic excitability in the brain, cellular development, and inflammatory response modulation. These findings may reveal a novel therapeutic strategy to treat clinical, metabolic, and inflammatory diseases. This article will summarize past research on GPR81, including its characteristics of distribution and expression, functional residues, pharmacological, and physiological agonists, involvement in signal transduction, and pharmacological applications.

The metabolic changes in the hippocampus of an atherosclerotic rat model and the regulation of aerobic training.

Atherosclerosis has been associated with the progression of cognitive impairment and the effect of metabolic changes in the brain on cognitive function may be pronounced. The aim is to reveal the metabolic changes during atherosclerosis and clarify the possible role of exercise in regulating hippocampal metabolism. Hence, A rat model of atherosclerosis was established by high-fat diet feeding in combination with vitamin D3 intraperitoneal injection, then 4 weeks of aerobic exercise was conducted. Metabolomics based on GC-MS was applied to detect small molecules metabolites and western blot was used to detect the concentration of enzymes involved in metabolic changes in rat hippocampus. Compared to the control group, metabolites including xylulose 5-phosphate, threonine, succinate, and nonanoic acid were markedly elevated, whereas methyl arachidonic acid and methyl stearate decreased in the AS group, accompanied by a raised concentration of aldose reductase and glucose 6-phosphate dehydrogenase as well as a declined concentration of acetyl-CoA carboxylase and fatty acid synthase. After 4 weeks' aerobic exercise, the levels of succinic acid, branched chain amino acids, nonanoic acid, desmosterol, and aldose reductase decreased, whereas methyl arachidonic acid, methyl stearate, and glyceraldehyde-3-phosphate elevated in the hippocampus of the TAS group in comparison with the AS group. These results suggest that atherosclerosis could cause a severe metabolic disturbance, and aerobic exercise plays an important role in regulating atherosclerosis-induced disorder of glucose metabolism in the hippocampus.

[Aerobic exercise reduces the expression of pyroptosis-related proteins and inflammatory factors in hippocampus of mice with insulin resistance].

The aim of the present study was to observe the expression of pyroptosis- and inflammation-related proteins in the hippocampus of mice with insulin resistance (IR) after aerobic exercise, and to explore the possible mechanism of exercise to improve IR. C57BL/6J male mice of 6 weeks old were randomly fed with normal diet (n = 12) and high-fat diet (HFD) (n = 26) for 12 weeks respectively. Glucose tolerance test (GTT) and insulin tolerance test (ITT) were performed to determine whether IR occurred in HFD mice. Then the mice were randomly divided into control group (n = 12), IR group (n = 10) and IR + aerobic exercise group (AE, n = 10). Mice in AE group performed a 12-week progressive speed treadmill training after being adapted to the treadmill for one week. After the intervention, the expression of pyroptosis- and inflammation-related proteins in hippocampus was detected by Western blot. The results showed that compared with control group, NFκB, Nod-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing CARD (ASC), pyroptosis-related proteins like pro-Caspase-1, gasdermin D (GSDMD), GSDMD-N, and inflammatory factors IL-1ß, IL-18 were significantly increased. The inflammasome-related protein NIMA-related kinase 7 (NEK7) and pyroptosis-related protein Caspase-1 showed an increasing trend, but there was no significant difference. Compared with the IR group, progressive speed treadmill training significantly reduced the expression of NFκB, NLRP3, NEK7, ASC, pro-Caspase-1, GSDMD, GSDMD-N, IL-1ß, and IL-18 in the hippocampus of mice with IR. These results suggested 12-week progressive speed treadmill training can significantly reduce the expression of pyroptosis-related proteins and inflammatory factors in the hippocampus of mice with IR, and inhibit pyroptosis.

Mechanisms of Aerobic Exercise Upregulating the Expression of Hippocampal Synaptic Plasticity-Associated Proteins in Diabetic Rats.

We investigated the effects of aerobic exercise on the expression of hippocampal synaptic plasticity-associated proteins in rats with type 2 diabetes and their possible mechanisms. A type 2 diabetes rat model was established with 8 weeks of high-fat diet combined with a single intraperitoneal injection of streptozotocin (STZ). Then, a 4-week aerobic exercise intervention was conducted. Memory performance was measured with Y maze tests. The expression and activity of synaptic plasticity-associated proteins and of proteins involved in the PI3K/Akt/mTOR, AMPK/Sirt1, and NFκB/NLRP3/IL-1ß signaling pathways were evaluated by western blot. Our results show that aerobic exercise promotes the expression of synaptic plasticity-associated proteins in the hippocampus of diabetic rats. Aerobic exercise also activates the PI3K/Akt/mTOR and AMPK/Sirt1 signaling pathways and inhibits the NFκB/NLRP3/IL-1ß signaling pathway in the hippocampus of diabetic rats. Therefore, modulating the PI3K/Akt/mTOR, AMPK/Sirt1, and NFκB/NLRP3/IL-1ß signaling pathways is probably the mechanism of aerobic exercise upregulating the expression of hippocampal synaptic plasticity-associated proteins in diabetic rats.

[Research advances on anti-inflammatory, antioxidant and anti-apoptotic biological effects of methane].

Methane (CH4) is the simplest hydrocarbons and endogenous CH4 has been thought only to be generated by methanogens in the oral cavity and gastrointestinal tract of the mammals. However, recent animal studies have shown that endogenous CH4 can also be generated from choline and its metabolites in the mammals to protect the plasma membrane from reactive oxygen species attack and repair the membrane. In addition, exogenous CH4 can ameliorate the oxidative stress injury of multiple tissues and organs through its anti-inflammatory, antioxidant and anti-apoptosis effects. This paper reviews the recent researches about CH4 synthetic metabolism and biological functions, and highlights its potential of wide application in the prevention and treatment of oxidative stress related diseases and the significance for the development of gas medicine.

Empowering mitochondrial metabolism: Exploring L-lactate supplementation as a promising therapeutic approach for metabolic syndrome.

Mitochondrial dysfunction plays a critical role in the pathogenesis of metabolic syndrome (MetS), affecting various cell types and organs. In MetS animal models, mitochondria exhibit decreased quality control, characterized by abnormal morphological structure, impaired metabolic activity, reduced energy production, disrupted signaling cascades, and oxidative stress. The aberrant changes in mitochondrial function exacerbate the progression of metabolic syndrome, setting in motion a pernicious cycle. From this perspective, reversing mitochondrial dysfunction is likely to become a novel and powerful approach for treating MetS. Unfortunately, there are currently no effective drugs available in clinical practice to improve mitochondrial function. Recently, L-lactate has garnered significant attention as a valuable metabolite due to its ability to regulate mitochondrial metabolic processes and function. It is highly likely that treating MetS and its related complications can be achieved by correcting mitochondrial homeostasis disorders. In this review, we comprehensively discuss the complex relationship between mitochondrial function and MetS and the involvement of L-lactate in regulating mitochondrial metabolism and associated signaling pathways. Furthermore, it highlights recent findings on the involvement of L-lactate in common pathologies of MetS and explores its potential clinical application and further prospects, thus providing new insights into treatment possibilities for MetS.

A new immune signature for survival prediction and immune checkpoint molecules in non-small cell lung cancer.

Background: Immune checkpoint blockade (ICB) therapy has brought remarkable clinical benefits to patients with advanced non-small cell lung carcinoma (NSCLC). However, the prognosis remains largely variable. Methods: The profiles of immune-related genes for patients with NSCLC were extracted from TCGA database, ImmPort dataset, and IMGT/GENE-DB database. Coexpression modules were constructed using WGCNA and 4 modules were identified. The hub genes of the module with the highest correlations with tumor samples were identified. Then integrative bioinformatics analyses were performed to unveil the hub genes participating in tumor progression and cancer-associated immunology of NSCLC. Cox regression and Lasso regression analyses were conducted to screen prognostic signature and to develop a risk model. Results: Functional analysis showed that immune-related hub genes were involved in the migration, activation, response, and cytokine-cytokine receptor interaction of immune cells. Most of the hub genes had a high frequency of gene amplifications. MASP1 and SEMA5A presented the highest mutation rate. The ratio of M2 macrophages and naïve B cells revealed a strong negative association while the ratio of CD8 T cells and activated CD4 memory T cells showed a strong positive association. Resting mast cells predicted superior overall survival. Interactions including protein-protein, lncRNA and transcription factor interactions were analyzed and 9 genes were selected by LASSO regression analysis to construct and verify a prognostic signature. Unsupervised hub genes clustering resulted in 2 distinct NSCLC subgroups. The TIDE score and the drug sensitivity of gemcitabine, cisplatin, docetaxel, erlotinib and paclitaxel were significantly different between the 2 immune-related hub gene subgroups. Conclusions: These findings suggested that our immune-related genes can provide clinical guidance for the diagnosis and prognosis of different immunophenotypes and facilitate the management of immunotherapy in NSCLC.

The combined analysis of urine and blood metabolomics profiles provides an accurate prediction of the training and competitive status of Chinese professional swimmers.

Objective: The purpose of this study was to employ metabolomics for the analysis of urine metabolites in swimmers, with the aim of establishing models for assessing their athletic status and competitive potential. Furthermore, the study sought to compare the identification efficacy of multi-component (urine and blood) model versus single-component (urine or blood) models, in order to determine the optimal approach for evaluating training and competitive status. Methods: A total of 187 Chinese professional swimmers, comprising 103 elite and 84 sub-elite level athletes, were selected as subjects for this study. Urine samples were obtained from each participant and subjected to nuclear magnetic resonance (NMR) metabolomics analysis. Significant urine metabolites were screened through multivariable logistic regression analysis, and an identification model was established. Based on the previously established model of blood metabolites, this study compared the discriminative and predictive performance of three models: either urine or blood metabolites model and urine + blood metabolites model. Results: Among 39 urine metabolites, 10 were found to be significantly associated with the athletic status of swimmers (p < 0.05). Of these, levels of 2-KC, cis-aconitate, formate, and LAC were higher in elite swimmers compared to sub-elite athletes, while levels of 3-HIV, creatinine, 3-HIB, hippurate, pseudouridine, and trigonelline were lower in elite swimmers. Notably, 2-KC and 3-HIB exhibited the most substantial differences. An identification model was developed to estimate physical performance and athletic level of swimmers while adjusting for different covariates and including 2-KC and 3-HIB. The urine metabolites model showed an area under the curve (AUC) of 0.852 (95% CI: 0.793-0.912) for discrimination. Among the three identification models tested, the combination of urine and blood metabolites showed the highest performance than either urine or blood metabolites, with an AUC of 0.925 (95% CI: 0.888-0.963). Conclusion: The two urine metabolites, 2-KC and 3-HIV, can serve as significant urine metabolic markers to establish a discrimination model for identifying the athletic status and competitive potential of Chinese elite swimmers. Combining two screened urine metabolites with four metabolites reported exhibiting significant differences in blood resulted in improved predictive performance compared to using urine metabolites alone. These findings indicate that combining blood and urine metabolites has a greater potential for identifying and predicting the athletic status and competitive potential of Chinese professional swimmers.

Mask-Free Patterned Perovskite Microcavity Arrays via Inkjet Printing Targeting Laser Emission.

Perovskite materials are promising candidates for the implementation of electrically pumped lasers considering the enhanced performance of perovskite-based light-emitting diodes. Nonetheless, current methods of fabricating perovskite optical microcavities require complex patterning technologies to build suitable resonant cavities for perovskite laser emission, burdening the device structure design. To address this issue, we applied inkjet printing, a maskless patterning technique, to directly create spontaneous formations of polycrystalline perovskite microcavity arrays to explore their laser-emitting action. The substrate surface tension was tuned to modulate the perovskite crystallization process in combination with optimization of printing ink recipes. As a result, polycrystalline perovskite microcavity arrays were achieved, contributing to the laser emission at 528 nm with a lasing threshold of 1.37 mJ/cm2, while simultaneously achieving high-definition patterning of flexible display. These results clearly illustrate the efficiency of inkjet printing technology in the preparation of polycrystalline perovskite optical microcavities and promote the development of flexible laser arrayed displays, providing a facile process toward the realization of perovskite-cavity laser devices.

Development and validation of a newly developed nomogram for predicting the risk of deep vein thrombosis after surgery for lower limb fractures in elderly patients.

Background: Prevention of deep vein thrombosis (DVT) is indispensable in the treatment of lower limb fractures during the perioperative period. This study aimed to develop and validate a novel model for predicting the risk of DVT in elderly patients after orthopedic surgeries for lower limb fractures. Methods: This observational study included 576 elderly patients with lower limb fractures who were surgically treated from January 2016 to December 2018. Eleven items affecting DVT were optimized by least absolute shrinkage and selection operator regression analysis. Multivariable logistic regression analysis was performed to construct a predictive model incorporating the selected features. C-index was applied to evaluate the discrimination. Decision curve analysis was employed to determine the clinical effectiveness of this model and calibration plot was applied to evaluate the calibration of this nomogram. The internal validation of this model was assessed by bootstrapping validation. Results: Predictive factors that affected the rate of DVT in this model included smoking, time from injury to surgery, operation time, blood transfusion, hip replacement arthroplasty, and D-dimer level after operation. The nomogram showed significant discrimination with a C-index of 0.919 (95% confidence interval: 0.893-0.946) and good calibration. Acceptable C-index value could still be reached in the interval validation. Decision curve analysis indicated that the DVT risk nomogram was useful within all possibility threshold. Conclusion: This newly developed nomogram could be used to predict the risk of DVT in elderly patients with lower limb fractures during the perioperative period.

Low-Temperature Discrimination of Defect States by Exciton Dynamics in Thin-Film MAPbBr3 Perovskite.

Exciton dynamics significantly influences the performance of the optoelectronic devices, which is intensively studied in the light-emitting perovskite of CH3NH3PbBr3 (MAPbBr3). However, most of the existing investigations have focused on the free excitons. In this study, we investigate the emissive recombination from defect states in MAPbBr3 using temperature- and excitation-dependent photoluminescence measurements. It is revealed that two emission peaks centered at about 550 and 590 nm are presented at temperatures as low as 10 K, instead of one peak at 535 nm for the observation at room temperature. These two peaks are attributed to the emission of bound excitons after self-absorption and bulk defects, respectively. It is found that the distribution of the bound and trapped excitons is strongly influenced by the morphology of the MAPbBr3 films. These results provide deep insights into the exciton dynamics in MAPbBr3, facilitating new physics for the design of related optoelectronic materials and devices.

Effects of neural-derived estradiol on actin polymerization and synaptic plasticity-related proteins in prefrontal and hippocampal cells of mice.

Neural-derived 17ß-estradiol (E2) plays an important role in the synaptic plasticity of the hippocampus and prefrontal cortex, but the mechanism is not well defined. This study was designed to explore the effect and mechanism of neural-derived E2 on synaptic plasticity of the hippocampus and prefrontal cortex. Primary cultured hippocampal and prefrontal cells in mice were randomly divided into the DMSO (D), aromatase (Rate-limiting enzymes for E2 synthesizes) inhibitor letrozole (L), and ERs antagonist (MPG) treated groups. After intervention for 48 h, the cell was collected, and then, the expressions of AMPA-receptor subunit GluR1 (GluR1), synaptophysin (SYN), p-21-Activated kinase (PAK) phosphorylation, Rho kinase (ROCK), p-Cofilin, F-actin, and G-actin proteins were detected. Letrozole or ER antagonists inhibited the expression of GluR1, F-actin/G-actin, p-PAK and p-Cofilin proteins in prefrontal cells significantly. And the expressions of GluR1 and F-actin/G-actin proteins were declined in hippocampal cells markedly after adding letrozole or ERs antagonists. In conclusion, neural-derived E2 and ERs regulated the synaptic plasticity, possibly due to promoting actin polymerization in prefrontal and hippocampal cells. The regional specificity in the effect of neural-derived E2 and ERs on the actin polymerization-related pathway may provide a theoretical basis for the functional differences between the hippocampus and prefrontal cortex.

The potential mechanisms of lactate in mediating exercise-enhanced cognitive function: a dual role as an energy supply substrate and a signaling molecule.

Lactate has previously been considered a metabolic waste and is mainly involved in exercise-induced fatigue. However, recent studies have found that lactate may be a mediator of the beneficial effects of exercise on brain health. Lactate plays a dual role as an energy supply substrate and a signaling molecule in this process. On the one hand, astrocytes can uptake circulating glucose or degrade glycogen for glycolysis to produce lactate, which is released into the extracellular space. Neurons can uptake extracellular lactate as an important supplement to their energy metabolism substrates, to meet the demand for large amounts of energy when synaptic activity is enhanced. Thus, synaptic activity and energy transfer show tight metabolic coupling. On the other hand, lactate acts as a signaling molecule to activate downstream signaling transduction pathways by specific receptors, inducing the expression of immediate early genes and cerebral angiogenesis. Moderate to high-intensity exercise not only increases lactate production and accumulation in muscle and blood but also promotes the uptake of skeletal muscle-derived lactate by the brain and enhances aerobic glycolysis to increase brain-derived lactate production. Furthermore, exercise regulates the expression or activity of transporters and enzymes involved in the astrocyte-neuron lactate shuttle to maintain the efficiency of this process; exercise also activates lactate receptor HCAR1, thus affecting brain plasticity. Rethinking the role of lactate in cognitive function and the regulatory effect of exercise is the main focus and highlights of the review. This may enrich the theoretical basis of lactate-related to promote brain health during exercise, and provide new perspectives for promoting a healthy aging strategy.