Muscle-enriched microRNA-486-mediated regulation of muscular atrophy and exercise.

The objectives of this review were to understand the impact of microRNA-486 on myogenesis and muscle atrophy, and the change of microRNA-486 following exercise, and provide valuable information for improving muscle atrophy based on exercise intervention targeting microRNA-486. Muscle-enriched microRNAs (miRNAs), also referred to as myomiRs, control various processes in skeletal muscles, from myogenesis and muscle homeostasis to different responses to environmental stimuli such as exercise. MicroRNA-486 is a miRNA in which a stem-loop sequence is embedded within the ANKYRIN1 (ANK1) locus and is strictly conserved across mammals. MicroRNA-486 is involved in the development of muscle atrophy caused by aging, immobility, prolonged exposure to microgravity, or muscular and neuromuscular disorders. PI3K/AKT signaling is a positive pathway, as it increases muscle mass by increasing protein synthesis and decreasing protein degradation. MicroRNA-486 can activate this pathway by inhibiting phosphatase and tensin homolog (PTEN), it may also indirectly inhibit the HIPPO signaling pathway to promote cell growth. Exercises regulate microRNA-486 expression both in blood and muscle. This review focused on the recent elucidation of sarcopenia regulation by microRNA-486 and its effects on pathological states, including primary muscular disease, secondary muscular disorders, and age-related sarcopenia. Additionally, the role of exercise in regulating skeletal muscle-enriched microRNA-486 was highlighted, along with its physiological significance. Growing evidence indicates that microRNA-486 significantly impacts the development of muscle atrophy. MicroRNA-486 has great potential to become a therapeutic target for improving muscle atrophy through exercise intervention.

The role of estrogen in Alzheimer's disease pathogenesis and therapeutic potential in women.

Estrogens are pivotal regulators of brain function throughout the lifespan, exerting profound effects from early embryonic development to aging. Extensive experimental evidence underscores the multifaceted protective roles of estrogens on neurons and neurotransmitter systems, particularly in the context of Alzheimer's disease (AD) pathogenesis. Studies have consistently revealed a greater risk of AD development in women compared to men, with postmenopausal women exhibiting heightened susceptibility. This connection between sex factors and long-term estrogen deprivation highlights the significance of estrogen signaling in AD progression. Estrogen's influence extends to key processes implicated in AD, including amyloid precursor protein (APP) processing and neuronal health maintenance mediated by brain-derived neurotrophic factor (BDNF). Reduced BDNF expression, often observed in AD, underscores estrogen's role in preserving neuronal integrity. Notably, hormone replacement therapy (HRT) has emerged as a sex-specific and time-dependent strategy for primary cardiovascular disease (CVD) prevention, offering an excellent risk profile against aging-related disorders like AD. Evidence suggests that HRT may mitigate AD onset and progression in postmenopausal women, further emphasizing the importance of estrogen signaling in AD pathophysiology. This review comprehensively examines the physiological and pathological changes associated with estrogen in AD, elucidating the therapeutic potential of estrogen-based interventions such as HRT. By synthesizing current knowledge, it aims to provide insights into the intricate interplay between estrogen signaling and AD pathogenesis, thereby informing future research directions and therapeutic strategies for this debilitating neurodegenerative disorder.

Role of astrocytes in Alzheimer's disease pathogenesis and the impact of exercise-induced remodeling.

Alzheimer's disease (AD) is a prevalent and debilitating brain disorder that worsens progressively with age, characterized by cognitive decline and memory impairment. The accumulation of amyloid-beta (Aß) leading to amyloid plaques and hyperphosphorylation of Tau, resulting in intracellular neurofibrillary tangles (NFTs), are primary pathological features of AD. Despite significant research investment and effort, therapies targeting Aß and NFTs have proven limited in efficacy for treating or slowing AD progression. Consequently, there is a growing interest in non-invasive therapeutic strategies for AD prevention. Exercise, a low-cost and non-invasive intervention, has demonstrated promising neuroprotective potential in AD prevention. Astrocytes, among the most abundant glial cells in the brain, play essential roles in various physiological processes and are implicated in AD initiation and progression. Exercise delays pathological progression and mitigates cognitive dysfunction in AD by modulating astrocyte morphological and phenotypic changes and fostering crosstalk with other glial cells. This review aims to consolidate the current understanding of how exercise influences astrocyte dynamics in AD, with a focus on elucidating the molecular and cellular mechanisms underlying astrocyte remodeling. The review begins with an overview of the neuropathological changes observed in AD, followed by an examination of astrocyte dysfunction as a feature of the disease. Lastly, the review explores the potential therapeutic implications of exercise-induced astrocyte remodeling in the context of AD.

Repurposing Ketamine in the Therapy of Depression and Depression-Related Disorders: Recent Advances and Future Potential.

Depression represents a prevalent and enduring mental disorder of significant concern within the clinical domain. Extensive research indicates that depression is very complex, with many interconnected pathways involved. Most research related to depression focuses on monoamines, neurotrophic factors, the hypothalamic-pituitary-adrenal axis, tryptophan metabolism, energy metabolism, mitochondrial function, the gut-brain axis, glial cell-mediated inflammation, myelination, homeostasis, and brain neural networks. However, recently, Ketamine, an ionotropic N-methyl-D-aspartate (NMDA) receptor antagonist, has been discovered to have rapid antidepressant effects in patients, leading to novel and successful treatment approaches for mood disorders. This review aims to summarize the latest findings and insights into various signaling pathways and systems observed in depression patients and animal models, providing a more comprehensive view of the neurobiology of anxious-depressive-like behavior. Specifically, it highlights the key mechanisms of ketamine as a rapid-acting antidepressant, aiming to enhance the treatment of neuropsychiatric disorders. Moreover, we discuss the potential of ketamine as a prophylactic or therapeutic intervention for stress-related psychiatric disorders.

Can pre-exercise photobiomodulation improve muscle endurance and promote recovery from muscle strength and injuries in people with different activity levels? A meta-analysis of randomized controlled trials.

Photobiomodulation therapy (PBMT) was introduced as an ergogenic aid for sport performance in healthy individuals is still controversial. The main aim of this study is to assess the potential enhancements in muscle endurance and recovery from muscle strength and injuries mediated by PBMT among individuals exhibiting diverse activity levels. Randomized controlled trials (RCT) of PBMT interventions for healthy people (both trained and untrained individuals) exercising were searched (up to January 16, 2024) in four electronic databases: Web of Science, PubMed, Scopus and Embase. Primary outcome measures included muscle endurance, muscle strength and creatine kinase (CK) levels; secondary outcome measure included Lactate dehydrogenase (LDH) levels. Subgroup analyses based on physical activity levels were conducted for each outcome measure. Thirty-four RCTs were included based on the article inclusion and exclusion criteria. Statistical results showed that PBMT significantly improved muscle endurance (standardized mean difference [SMD] = 0.31, 95%CI 0.11, 0.51, p < 0.01), indicating a moderate effect size. It also facilitated the recovery of muscle strength (SMD = 0.24, 95%CI 0.10, 0.39, p < 0.01) and CK (mean difference [MD] = -77.56, 95%CI -112.67, -42.44, p < 0.01), indicating moderate and large effect sizes, respectively. Furthermore, pre-application of PBMT significantly improved muscle endurance, recovery of muscle strength and injuries in physically inactive individuals and athletes (p < 0.05), while there was no significant benefit for physically active individuals. Pre-application of PBMT improves muscle endurance and promotes recovery from muscle strength and injury (includes CK and LDH) in athletes and sedentary populations, indicating moderate to large effect sizes, but is ineffective in physically active populations. This may be due to the fact that physically active people engage in more resistance training, which leads to a decrease in the proportion of red muscle fibres, thus affecting photobiomodulation.

Methylene Blue Pretreatment Protects Against Repeated Neonatal Isoflurane Exposure-Induced Brain Injury and Memory Loss.

Perioperative neurocognitive impairment (PND) is a common medical complication in the postoperative period. General anesthesia through volatile anesthetics poses a high risk of POCD. Moreover, the developing brain is especially vulnerable to anesthesia-induced neurotoxicity. Therefore, finding a practical approach to prevent or alleviate neonatal isoflurane (ISO) exposure-induced brain injury and cognitive decline is essential for reducing medical complications following major surgery during the early postnatal period. Using a repeated neonatal ISO exposure-induced PND rat model, we investigated the effects of methylene blue (MB) pretreatment on repeated neonatal isoflurane exposure-induced brain injury and memory loss. Intraperitoneal injection of low-dose MB (1 mg/kg) was conducted three times 24 h before each ISO exposure. The Barnes maze and novel objection test were conducted to assess learning and memory. Immunofluorescence staining, F-Jade C staining, TUNEL staining, and Western blot analysis were performed to determine mitochondrial fragmentation, neuronal injury, degeneration, and apoptosis. Evans blue extravasation assay, total antioxidant capacity assay, MDA assay kit, and related inflammatory assay kits were used to test blood-brain barrier (BBB) disruption, antioxidant capacity, and neuroinflammation. Behavioral tests revealed that MB pretreatment significantly ameliorated ISO exposure-induced cognitive deficits. In addition, MB pretreatment alleviates neuronal injury, apoptosis, and degeneration. Furthermore, the BBB integrity was preserved by MB pretreatment. Additional studies revealed that ISO-induced excessive mitochondrial fragmentation, oxidative stress, and neuroinflammation were significantly attenuated by MB pretreatment in the PND rat model. Our findings suggest that MB pretreatment alleviates ISO exposure-induced brain injury and memory loss for the first time, supporting MB pretreatment as a promising approach to protect the brain against neonatal ISO exposure-induced postoperative cognitive dysfunction.

Photobiomodulation therapy alleviates repeated closed head injury-induced anxiety-like behaviors.

Repeated closed head injury (rCHI) is one of the most common brain injuries. Although extensive studies have focused on how to treat rCHI-induced brain injury and reduce the possibility of developing memory deficits, the prevention of rCHI-induced anxiety has received little research attention. The current study was designed to assess the effects of photobiomodulation (PBM) therapy in preventing anxiety following rCHI. The rCHI disease model was constructed by administering three repeated closed-head injuries within an interval 5 days. 2-min daily PBM therapy using an 808 nm continuous wave laser at 350 mW/cm2 on the scalp was implemented for 20 days. We found that PBM significantly ameliorated rCHII-induced anxiety-like behaviors, neuronal apoptosis, neuronal injury, promotes astrocyte/microglial polarization to anti-inflammatory phenotype, preserves mitochondrial fusion-related protein MFN2, attenuates the elevated mitochondrial fission-related protein DRP1, and mitigates neuronal senescence. We concluded that PBM therapy possesses great potential in preventing anxiety following rCHI.

Oligodendrocyte progenitor cells in Alzheimer's disease: from physiology to pathology.

Oligodendrocyte progenitor cells (OPCs) play pivotal roles in myelin formation and phagocytosis, communicating with neighboring cells and contributing to the integrity of the blood-brain barrier (BBB). However, under the pathological circumstances of Alzheimer's disease (AD), the brain's microenvironment undergoes detrimental changes that significantly impact OPCs and their functions. Starting with OPC functions, we delve into the transformation of OPCs to myelin-producing oligodendrocytes, the intricate signaling interactions with other cells in the central nervous system (CNS), and the fascinating process of phagocytosis, which influences the function of OPCs and affects CNS homeostasis. Moreover, we discuss the essential role of OPCs in BBB formation and highlight the critical contribution of OPCs in forming CNS-protective barriers. In the context of AD, the deterioration of the local microenvironment in the brain is discussed, mainly focusing on neuroinflammation, oxidative stress, and the accumulation of toxic proteins. The detrimental changes disturb the delicate balance in the brain, impacting the regenerative capacity of OPCs and compromising myelin integrity. Under pathological conditions, OPCs experience significant alterations in migration and proliferation, leading to impaired differentiation and a reduced ability to produce mature oligodendrocytes. Moreover, myelin degeneration and formation become increasingly active in AD, contributing to progressive neurodegeneration. Finally, we summarize the current therapeutic approaches targeting OPCs in AD. Strategies to revitalize OPC senescence, modulate signaling pathways to enhance OPC differentiation, and explore other potential therapeutic avenues are promising in alleviating the impact of AD on OPCs and CNS function. In conclusion, this review highlights the indispensable role of OPCs in CNS function and their involvement in the pathogenesis of AD. The intricate interplay between OPCs and the AD brain microenvironment underscores the complexity of neurodegenerative diseases. Insights from studying OPCs under pathological conditions provide a foundation for innovative therapeutic strategies targeting OPCs and fostering neurodegeneration. Future research will advance our understanding and management of neurodegenerative diseases, ultimately offering hope for effective treatments and improved quality of life for those affected by AD and related disorders.

Microglia and Astrocytes in Alzheimer's Disease: Significance and Summary of Recent Advances.

Alzheimer's disease, one of the most common forms of dementia, is characterized by a slow progression of cognitive impairment and neuronal loss. Currently, approved treatments for AD are hindered by various side effects and limited efficacy. Despite considerable research, practical treatments for AD have not been developed. Increasing evidence shows that glial cells, especially microglia and astrocytes, are essential in the initiation and progression of AD. During AD progression, activated resident microglia increases the ability of resting astrocytes to transform into reactive astrocytes, promoting neurodegeneration. Extensive clinical and molecular studies show the involvement of microglia and astrocyte-mediated neuroinflammation in AD pathology, indicating that microglia and astrocytes may be potential therapeutic targets for AD. This review will summarize the significant and recent advances of microglia and astrocytes in the pathogenesis of AD in three parts. First, we will review the typical pathological changes of AD and discuss microglia and astrocytes in terms of function and phenotypic changes. Second, we will describe microglia and astrocytes' physiological and pathological role in AD. These roles include the inflammatory response, "eat me" and "don't eat me" signals, Aß seeding, propagation, clearance, synapse loss, synaptic pruning, remyelination, and demyelination. Last, we will review the pharmacological and non-pharmacological therapies targeting microglia and astrocytes in AD. We conclude that microglia and astrocytes are essential in the initiation and development of AD. Therefore, understanding the new role of microglia and astrocytes in AD progression is critical for future AD studies and clinical trials. Moreover, pharmacological, and non-pharmacological therapies targeting microglia and astrocytes, with specific studies investigating microglia and astrocyte-mediated neuronal damage and repair, may be a promising research direction for future studies regarding AD treatment and prevention.

Effects of physical activity in child and adolescent depression and anxiety: role of inflammatory cytokines and stress-related peptide hormones.

Depression and anxiety are the most common mental illnesses affecting children and adolescents, significantly harming their well-being. Research has shown that regular physical activity can promote cognitive, emotional, fundamental movement skills, and motor coordination, as a preventative measure for depression while reducing the suicide rate. However, little is known about the potential role of physical activity in adolescent depression and anxiety. The studies reviewed in this paper suggest that exercise can be an effective adjunctive treatment to improve depressive and anxiety symptoms in adolescents, although research on its neurobiological effects remains limited.

Exercise-derived skeletal myogenic exosomes as mediators of intercellular crosstalk: a major player in health, disease, and exercise

Exosomes are extracellular membrane vesicles that contain biological macromolecules such as RNAs and proteins. It plays an essential role in physiological and pathological processes as carrier of biologically active substances and new mediator of intercellular communication. It has been reported that myokines secreted by the skeletal muscle are wrapped in small vesicles (e.g., exosomes), secreted into the circulation, and then regulate the receptor cells. This review discussed the regulation of microRNAs (miRNAs), proteins, lipids, and other cargoes carried by skeletal muscle-derived exosomes (SkMCs-Exs) on the body and their effects on pathological states, including injury atrophy, aging, and vascular porosis. We also discussed the role of exercise in regulating skeletal muscle-derived exosomes and its physiological significance. (AU)

Exercise-derived skeletal myogenic exosomes as mediators of intercellular crosstalk: a major player in health, disease, and exercise.

Exosomes are extracellular membrane vesicles that contain biological macromolecules such as RNAs and proteins. It plays an essential role in physiological and pathological processes as carrier of biologically active substances and new mediator of intercellular communication. It has been reported that myokines secreted by the skeletal muscle are wrapped in small vesicles (e.g., exosomes), secreted into the circulation, and then regulate the receptor cells. This review discussed the regulation of microRNAs (miRNAs), proteins, lipids, and other cargoes carried by skeletal muscle-derived exosomes (SkMCs-Exs) on the body and their effects on pathological states, including injury atrophy, aging, and vascular porosis. We also discussed the role of exercise in regulating skeletal muscle-derived exosomes and its physiological significance.

High-intensity interval training ameliorates Alzheimer's disease-like pathology by regulating astrocyte phenotype-associated AQP4 polarization.

Background: Alzheimer's disease (AD), one of the most common forms of dementia, is a widely studied neurodegenerative disease characterized by Aß accumulation and tau hyperphosphorylation. Currently, there is no effective cure available for AD. The astrocyte AQP4 polarized distribution-mediated glymphatic system is essential for Aß and abnormal tau clearance and is a potential therapeutic target for AD. However, the role of exercise on the AQP4 polarized distribution and the association between the AQP4 polarized distribution and astrocyte phenotype polarization are poorly understood. Methods: Using a streptozotocin (STZ)-induced sporadic AD rat model, we investigated the effects of high-intensity interval training on AD pathologies. The Branes maze task was conducted to measure spatial learning and memory. Immunofluorescence staining of NeuN with TUNEL, Fluoro-Jade C, and relative neuronal damage markers was applied to measure neuronal apoptosis, neurodegeneration, and damage. Sholl analysis was carried out to analyze the morphology of microglia. Line-scan analysis, 3D rendering, and the orthogonal view were applied to analyze the colocalization. Western blot analysis and enzyme-linked immunosorbent assay (ELISA) analysis were conducted to examine AQP4 and Aß, respectively. An APP/PS1 transgenic AD mice model was used to confirm the key findings. Results: High-intensity interval training (HIIT) alleviates cognitive dysfunction in STZ-induced AD-like rat models and provides neuroprotection against neurodegeneration, neuronal damage, and neuronal loss. Additionally, HIIT improved the drainage of abnormal tau and Aß from the cortex and hippocampus via the glymphatic system to the kidney. Further mechanistic studies support that the beneficial effects of HIIT on AD might be due, in part, to the polarization of glial cells from a neurotoxic phenotype towards a neuroprotective phenotype. Furthermore, an intriguing finding of our study is that the polarized distribution of AQP4 was strongly correlated with astrocyte phenotype. We found A2 phenotype exhibited more evident AQP4 polarization than the A1 phenotype. Conclusion: Our findings indicate that HIIT ameliorates Alzheimer's disease-like pathology by regulating astrocyte phenotype and astrocyte phenotype-associated AQP4 polarization. These changes promote Aß and p-tau clearance from the brain tissue through the glymphatic system and the kidney.

Exogenous lactate administration: A potential novel therapeutic approach for neonatal hypoxia-ischemia.

Neonatal hypoxic-ischemic encephalopathy (HIE) is the primary reason for neonatal mortality and prolonged disablement. Currently, hypothermia is the only approved clinical treatment available for HIE. However, hypothermia's limited therapeutic efficacy and adverse effects suggest an urgent need to advance our knowledge of its molecular pathogenesis and develop novel therapies. The leading cause of HIE is impaired cerebral blood flow and oxygen deprivation-initiated primary and secondary energy failure. Lactate was traditionally regarded as a marker of energy failure or a waste product of anaerobic glycolysis. Recently, the beneficial aspects of lactate as supplementary energy for neurons have been demonstrated. Under the conditions of HI, lactate supports various functions of neuronal cells, including learning and memory formation, motor coordination, and somatosensory. Furthermore, lactate contributes to the regeneration of blood vessels and has shown its beneficial effects on the immune system. This review first introduces the hypoxic or ischemic events-induced fundamental pathophysiological changes in HIE and then discusses the potential neuroprotective properties of lactate for the treatment and prevention of HIE. Finally, we discuss the possible protective mechanisms of lactate in the context of the pathological features of perinatal HIE. We conclude that exogenous and endogenous lactate exert neuroprotective effects in HIE. Lactate administration may be a potential approach to treating HIE injury.

Neuroprotective Effects of Phenolic Antioxidant Tert-butylhydroquinone (tBHQ) in Brain Diseases.

Human life and health are gravely threatened by brain diseases. The onset and progression of the illnesses are influenced by a variety of factors, including pathogenic causes, environmental factors, mental issues, etc. According to scientific studies, neuroinflammation and oxidative stress play a significant role in the development and incidence of brain diseases by producing pro-inflammatory cytokines and oxidative tissue damage to induce inflammation and apoptosis. Neuroinflammation, oxidative stress, and oxidative stress-related changes are inseparable factors in the etiology of several brain diseases. Numerous neurodegenerative diseases have undergone substantial research into the therapeutic alternatives that target oxidative stress, the function of oxidative stress, and the possible therapeutic use of antioxidants. Formerly, tBHQ is a synthetic phenolic antioxidant, which has been widely used as a food additive. According to recent researches, tBHQ can suppress the processes that lead to neuroinflammation and oxidative stress, which offers a fresh approach to treating brain diseases. In order to achieve the goal of decreasing inflammation and apoptosis, tBHQ is a specialized nuclear factor erythroid 2-related factor (Nrf2) activator that decreases oxidative stress and enhances antioxidant status by upregulating the Nrf2 gene and reducing nuclear factor kappa-B (NF-κB) activity. This article reviews the effects of tBHQ on neuroinflammation and oxidative stress in recent years and looks into how tBHQ inhibits neuroinflammation and oxidative stress through human, animal, and cell experiments to play a neuroprotective role in Alzheimer's disease (AD), stroke, depression, and Parkinson's disease (PD). It is anticipated that this article will be useful as a reference for upcoming research and the creation of drugs to treat brain diseases.

Neuroprotective Effect of Sub-lethal Hyperthermia Preconditioning in a Rat Model of Repeated Closed Head Injury.

Repeated mild traumatic brain injury (rTBI), one of the most common forms of traumatic brain injury, is a worldwide severe public health concern. rTBI induces cumulative neuronal injury, neurological dysfunction, and cognitive deficits. Although there are clinical treatment methods, there is still an urgent need to develop preventive approaches for susceptible populations. Using a repeated closed head injury (rCHI) rat model, we interrogate the effect of sub-lethal hyperthermia preconditioning (SHP) on rCHI-induced neuronal injury and behavioral changes. Our study applied the repeated weight-drop model to induce the rCHI. According to the changes of heat shock protein 70 (HSP 70) in the cortex and hippocampus following a single SHP treatment in normal rats, the SHP was delivered to the rats 18 h before rCHI. We found that HSP significantly alleviated rCHI-induced anxiety-like behaviors and impairments in motor abilities and spatial memory. SHP exerts significant neuroprotection against rCHI-induced neuronal damage, apoptosis, and neuroinflammation. Our findings support the potential use of SHP as a preventative approach for alleviating rCHI-induced brain damage.

A novel promising neuroprotective agent: Ganoderma lucidum polysaccharide.

Nervous system diseases (NSDs) are characterized by a wide range of symptoms, a complex pathophysiology, an unclear etiology, a great deal of variation in treatment response, and lengthy therapy cycles, all of which pose considerable hurdles to clinical treatment. A traditional valuable medicine known as Ganoderma lucidum (GL) has a significant role to play in preserving health and treating diseases. Ganoderma lucidum polysaccharides (GLP) is one of the cardinal effective active ingredients of GL, which has a number of pharmacological actions, including liver protection, immune regulation, antioxidant activity, anticancer activity, antibacterial activity, and antiviral activity. Recently, studies on the structural characterization and biological functions of GLP were presented in this article to review the progress of researches about GLP on NSDs and summarize the potential mechanisms of action. These studies were anticipated to provide new research ideas for GLP as a novel promising neuroprotective agent and provide a reference for better development and utilization of GLP.