[High-intensity interval training (HIIT) induces hepatic ketone body production possibly through altering expression of mTORC1, PPARα and FGF21 in mice].

The present study aims to investigate the production of ketone body in the liver of mice after 6 weeks of high-intensity interval training (HIIT) intervention and explore the possible mechanisms. Male C57BL/6J mice (7-week-old) were randomly divided into control and HIIT groups. The control group did not engage in exercise, while the HIIT group underwent a 6-week HIIT (10° slope treadmill exercise). Changes in weight and body composition were recorded, and blood ketone body levels were measured before, immediately after, and 1 h after each HIIT exercise. After 6-week HIIT, the levels of free fatty acids in the liver and serum were detected using reagent kits, and expression levels of regulatory factors and key enzymes of ketone body production in the mouse liver were detected by Western blot and qPCR. The results showed that, the blood ketone body levels in the HIIT group significantly increased immediately after a single HIIT and 1 h after HIIT, compared with that before HIIT. The body weight of the control group gradually increased within 6 weeks, while the HIIT group mice did not show significant weight gain. After 6-week HIIT, compared with the control group, the HIIT group showed decreased body fat ratio, increased lean body weight ratio, and increased free fatty acid levels in liver and serum. Liver carnitine palmitoyl transferase-I (CPT-I), peroxisome proliferator activated receptor α (PPARα), and fibroblast growth factor 21 (FGF21) protein expression levels were up-regulated, whereas mammalian target of rapamycin complex 1 (mTORC1) protein expression level was significantly down-regulated in the HIIT group, compared with those in the control group. These results suggest that HIIT induces hepatic ketone body production through altering mTORC1, PPARα and FGF21 expression in mice.

Deciphering the Influence of Estradiol and Estrogen Receptors on Cognitive Function: A Bibliometric Analysis and Emerging Research Trends.

BACKGROUND The cognitive impact of estradiol (E2), a sex steroid hormone, particularly its unique characteristics mediated through different estrogen receptors (ERs), is garnering research interest to optimize estrogen replacement therapy (ERT) and mitigate adverse effects. However, a systematic bibliometric investigation elucidating the connection between E2/ERs and cognition is lacking. This study examines 3502 Web of Science Core Collection publications using CiteSpace to unveil trends in this research field. MATERIAL AND METHODS The primary goal was to analyze highly co-cited articles characterized by extensive citation, centrality, Sigma index, and burst strength. We identified six research themes and directions from ten distinct, highly credible clusters (Q=0.8266; S=0.978), established by frequently employed keywords. Secondly, we sought to highlight the most contributing countries, institutions, and authors in this domain. RESULTS The study unveiled that the 'critical age window period' hypothesis of ERT, hippocampus-derived E2, the mediating role of GPER, and crosstalk among ERs are the current hotspots in this field. Future research is likely to explore the links between E2/ERs and the hippocampus, various memory types, sex specificity, and receptor specificity. The United States and the University of Wisconsin have the most publications, while Scotland and Stanford University have the highest centrality. The most influential authors are Woolley CS, Frick KM, Tuscher JJ, and Espeland MA. CONCLUSIONS These findings inform prospective research directions and hint at potential E2 targets for cognitive enhancement.

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.

The signaling mechanisms of hippocampal endoplasmic reticulum stress affecting neuronal plasticity-related protein levels in high fat diet-induced obese rats and the regulation of aerobic exercise.

High fat diet (HFD)-induced obesity has been shown to reduce the levels of neuronal plasticity-related proteins, specifically brain-derived neurotrophic factor (BDNF) and synaptophysin (SYN), in the hippocampus. However, the underlying mechanisms are not fully clear. Endoplasmic reticulum stress (ERS) has been reported to play a key role in regulating gene expression and protein production by affecting stress signaling pathways and ER functions of protein folding and post-translational modification in peripheral tissues of obese rodent models. Additionally, HFD that is associated with hyperglycemia could induce hippocampal ERS, thus impairing insulin signaling and cognitive health in HFD mice. One goal of this study was to determine whether hyperglycemia and hyperlipidemia could cause hippocampal ERS in HFD-induced obese SD rats, and explore the potential mechanisms of ERS regulating hippocampal BDNF and SYN proteins production. Additionally, although regular aerobic exercise could reduce central inflammation and elevate hippocampal BDNF and SYN levels in obese rats, the regulated mechanisms are poorly understood. Nrf2-HO-1 pathways play roles in anti-ERS, anti-inflammation and anti-apoptosis in peripheral tissues. Therefore, the other goal of this study was to determine whether aerobic exercise could activate Nrf2-HO-1 in hippocampus to alleviate obesity-induced hippocampal ERS, which would lead to increased BDNF and SYN levels. Male SD rats were fed on HFD for 8weeks to establish the obese model. Then, 8weeks of aerobic exercise treadmill intervention was arranged for the obese rats. Results showed that HFD-induced obesity caused hyperglycemia and hyperlipidemia, and significantly promoted hippocampal glucose transporter 3 (GLUT3) and fatty acid transport protein 1 (FATP1) protein expression. These results were associated with the activation of hippocampal ERS and ERS-mediated apoptosis. At the same time, we found that excessive hippocampal ERS not only significantly decreased proBDNF-the precursor of mature BDNF, but also attenuated p38/ERK-CREB signaling pathways and activated NLRP3-IL-1ß pathways in obese rats. These results were associated with reduced BDNF and SYN protein production. However, these adverse changes were obviously reversed by aerobic exercise intervention through activating the Nrf2-HO-1 pathways. These results suggest that dietary obesity could induce hippocampal ERS in male SD rats, and excessive hippocampal ERS plays a critical role in decreasing the levels of BDNF and SYN. Moreover, aerobic exercise could activate hippocampal Nrf2 and HO-1 to relieve ERS and heighten BDNF and SYN production in obese rats.

WNK1 is involved in Nogo66 inhibition of OPC differentiation.

LINGO-1 is a transmembrane receptor expressed primarily in the central nervous system (CNS) and plays an important role in myelination. Recent studies have indicated that it is also involved in oligodendrocyte precursor cell (OPC) survival and differentiation; however, the downstream signaling pathway underlying OPC development is unknown. In our previous study, we found that LINGO-1 is associated with WNK1 in mediating Nogo-induced neurite extension inhibition by RhoA activation. In an effort to identify the role of LINGO-1-WNK1 in OPCs, we first confirmed that WNK1 is also expressed in OPCs and co-localized with LINGO-1, which suppresses WNK1 expression by RNA interference-attenuated Nogo66-induced inhibition of OPC differentiation. Furthermore, we mapped the WNK1 kinase domain using several fragmented peptides to identify the key region of interaction with LINGO-1. We found that a sequence corresponding to the D6 peptide is necessary for the interaction. Finally, we found that using the TAT-D6 peptide to introduce D6 peptide into primary cultured OPC inhibits the association between LINGO-1 and WNK1 and significantly attenuates Nogo66-induced inhibition of OPC differentiation. Taken together, our results show that WNK1, via a specific region on WNK1 kinase domain, interacts with LINGO-1, thus mediating Nogo66-inhibited OPC differentiation.

Resistance training boosts lactate transporters and synaptic proteins in insulin-resistance mice.

Background: This investigation delineates the influence of resistance training on the expression of synaptic plasticity-related proteins in the hippocampi of insulin-resistant mice and explores the underlying molecular mechanisms. Methods: Six-week-old male C57BL/6 J mice were stratified into a control group and a high-fat diet group to induce insulin resistance over a 12-week period. Subsequently, the mice were further divided into sedentary and resistance training cohorts, with the latter engaging in a 12-week ladder-climbing regimen. Post-intervention, blood, and hippocampal specimens were harvested for analytical evaluation. Results: In the insulin-resistant mice, elevated blood lactate levels were observed alongside diminished expression of synaptic plasticity-related proteins, monocarboxylate transporters (MCTs), and reduced phosphorylation of protein kinase B (Akt) and mechanistic target of rapamycin (mTOR). In contrast, the expression of eukaryotic translation initiation factor 4 E-binding protein 2 was significantly augmented. Resistance training mitigated insulin resistance, decreased blood lactate levels, and enhanced the expression and phosphorylation of mTOR, regulatory-associated protein of mTOR, MCTs, and synaptic plasticity-related proteins. Conclusions: Resistance training mitigates insulin resistance and improves hippocampal synaptic plasticity by normalizing blood lactate levels and enhancing mTOR, MCTs, and synaptic plasticity-related proteins. It may also activate mTORC1 via the PI3K/Akt pathway, promote lactate utilization, and enhance synaptic plasticity proteins, potentially alleviating peripheral insulin resistance. Further research is needed to confirm these mechanisms.

[Effects of hypoxia conditioned medium of cerebral cortex cells on the differentiation of neural stem cells and related signal pathways].

The aim of this study was to investigate the effects of hypoxia conditioned medium (HCM) of cerebral cortex cells on the differentiation of neural stem cells (NSCs) and to clarify the signal transduction mechanism. The cerebral cortex cells from newborn SD rats were primarily cultured for 5 d, and then the cells were cultured in environments of 4% O2, 1% O2 and normal oxygen concentration, respectively, for 6 h. The culture mediums were collected and centrifuged as the HCM and normoxia conditioned medium (NCM). The neurospheres of NSCs were obtained from the rat cerebral cortex by suspending culture. Immunohistochemical staining was used after adherence culture for 48 h to identify neurons and astrocytes in the progeny of NSCs. LY294002, a PI3-K inhibitor, and SP600125, a JNK inhibitor, were added into the HCM to culture NSCs for 48 h. The results showed that NSCs in the cerebral cortex could differentiate into ß-Tubulin III immunoreactive neurons and GFAP immunoreactive astrocytes in three conditioned mediums, and the neurons proportion in progeny of NSCs was higher than astrocytes in all three groups. The proportion of neurons in 4% HCM was higher than that in NCM (P < 0.01). But the proportion of neurons in 1% HCM was less than that in NCM (P < 0.01). Both LY294002 and SP600125 inhibited NSCs to differentiate into high proportion neurons induced by 4% HCM (P < 0.01), but the inhibitory effect of LY294002 was stronger than that of SP600125 (P < 0.01). In conclusion, 4% HCM can induce NSCs to differentiate into more neurons mainly through the PI3-K pathway.

From mitochondria to sarcopenia: role of 17ß-estradiol and testosterone.

Sarcopenia, characterized by a loss of muscle mass and strength with aging, is prevalent in older adults. Although the exact mechanisms underlying sarcopenia are not fully understood, evidence suggests that the loss of mitochondrial integrity in skeletal myocytes has emerged as a pivotal contributor to the complex etiology of sarcopenia. Mitochondria are the primary source of ATP production and are also involved in generating reactive oxygen species (ROS), regulating ion signals, and initiating apoptosis signals in muscle cells. The accumulation of damaged mitochondria due to age-related impairments in any of the mitochondrial quality control (MQC) processes, such as proteostasis, biogenesis, dynamics, and mitophagy, can contribute to the decline in muscle mass and strength associated with aging. Interestingly, a decrease in sex hormones (e.g., 17ß-estradiol and testosterone), which occurs with aging, has also been linked to sarcopenia. Indeed, 17ß-estradiol and testosterone targeted mitochondria and exhibited activities in regulating mitochondrial functions. Here, we overview the current literature on the key mechanisms by which mitochondrial dysfunction contribute to the development and progression of sarcopenia and the potential modulatory effects of 17ß-estradiol and testosterone on mitochondrial function in this context. The advance in its understanding will facilitate the development of potential therapeutic agents to mitigate and manage sarcopenia.

The function of previously unappreciated exerkines secreted by muscle in regulation of neurodegenerative diseases.

The initiation and progression of neurodegenerative diseases (NDs), distinguished by compromised nervous system integrity, profoundly disrupt the quality of life of patients, concurrently exerting a considerable strain on both the economy and the social healthcare infrastructure. Exercise has demonstrated its potential as both an effective preventive intervention and a rehabilitation approach among the emerging therapeutics targeting NDs. As the largest secretory organ, skeletal muscle possesses the capacity to secrete myokines, and these myokines can partially improve the prognosis of NDs by mediating the muscle-brain axis. Besides the well-studied exerkines, which are secreted by skeletal muscle during exercise that pivotally exert their beneficial function, the physiological function of novel exerkines, e.g., apelin, kynurenic acid (KYNA), and lactate have been underappreciated previously. Herein, this review discusses the roles of these novel exerkines and their mechanisms in regulating the progression and improvement of NDs, especially the significance of their functions in improving NDs' prognoses through exercise. Furthermore, several myokines with potential implications in ameliorating ND progression are proposed as the future direction for investigation. Elucidation of the function of exerkines secreted by skeletal muscle in the regulation of NDs advances the understanding of its pathogenesis and facilitates the development of therapeutics that intervene in these processes to cure NDs.

Lactate Mediates High-Intensity Interval Training-Induced Promotion of Hippocampal Mitochondrial Function through the GPR81-ERK1/2 Pathway.

Mitochondrial biogenesis and fusion are essential for maintaining healthy mitochondria and ATP production. High-intensity interval training (HIIT) can enhance mitochondrial function in mouse hippocampi, but its underlying mechanism is not completely understood. Lactate generated during HIIT may mediate the beneficial effects of HIIT on neuroplasticity by activating the lactate receptor GPR81. Furthermore, growing evidence shows that lactate contributes to mitochondrial function. Given that mitochondrial function is crucial for cerebral physiological processes, the current study aimed to determine the mechanism of HIIT in hippocampal mitochondrial function. In vivo, GPR81 was knocked down in the hippocampi of mice via the injection of adeno-associated virus (AAV) vectors. The GPR81-knockdown mice were subjected to HIIT. The results demonstrated that HIIT increased mitochondria numbers, ATP production, and oxidative phosphorylation (OXPHOS) in the hippocampi of mice. In addition, HIIT induced mitochondrial biogenesis, fusion, synaptic plasticity, and ERK1/2 phosphorylation but not in GPR81-knockdown mice. In vitro, Neuro-2A cells were treated with L-lactate, a GPR81 agonist, and an ERK1/2 inhibitor. The results showed that both L-lactate and the GPR81 agonist increased mitochondrial biogenesis, fusion, ATP levels, OXPHOS, mitochondrial membrane potential, and synaptic plasticity. However, the inhibition of ERK1/2 phosphorylation blunted L-lactate or the GPR81 agonist-induced promotion of mitochondrial function and synaptic plasticity. In conclusion, our findings suggest that lactate mediates HIIT-induced promotion of mitochondrial function through the GPR81-ERK1/2 pathway.

17beta-estradiol alleviates contusion-induced skeletal muscle injury by decreasing oxidative stress via SIRT1/PGC-1α/Nrf2 pathway.

PURPOSE: This study aimed to investigate the role of 17ß-estradiol (E2) in the repair of contusion-induced myoinjury in mice and to identify the underlying molecular mechanisms. METHODS: In vivo, contusion protocol was performed for preparing mice myoinjury model, and Injection (i.p.) of 17ß-estradiol (E2) or estrogen receptor antagonist ICI 182,780, or ovariectomy (OVX), was used to alter estrogen level of animal models. In vitro, C2C12 myoblasts were treated with H2O2 (oxidative stress inducer), SIRT1 inhibitor EX527, or aromatase inhibitor anastrozole. Serum E2 level was assessed by enzyme-linked immunosorbent assay (ELISA). Muscle damage repair was evaluated by H&E staining and the activities of serum creatine kinase (CK) and lactate dehydrogenase (LDH). The oxidative stress was estimated by the levels of catalase (CAT), superoxide dismutase (SOD), and malondialdehyde (MDA). Western blot was performed to measure the protein expressions of SIRT1, PGC-1α, Nrf2, and HO-1. RESULTS: We observed the elevated serum E2 levels and the upregulated oxidative stress in damaged muscle in female mice after contusion-induction. The E2 administration in vivo alleviated contusion-induced myoinjury in OVX mice by reducing CK and LDH activities, suppressing oxidative stress, and enhancing the expression levels of SIRT1, PGC-1α, Nrf2, and HO-1. These effects were inhibited by treatment with an ERα/ß antagonist. Moreover, EX527 or anastrozole treatment exacerbated H2O2-induced growth inhibition and oxidative stress, and expression downregulation of SIRT1, PGC-1α, Nrf2, and HO-1 in C2C12 cells in vitro. CONCLUSION: Our results suggest that E2 is a positive intervention factor for muscle repair followed contusion-induced myoinjury, through its effects on suppressing oxidative stress via activating the SIRT1/PGC-1α/Nrf2 pathway.

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.