Does the liver facilitate aging-related cognitive impairment: Conversation between liver and brain during exercise?

Liver, an important regulator of metabolic homeostasis, is critical for healthy brain function. In particular, age-related neurodegenerative diseases seriously reduce the quality of life for the elderly. As population aging progresses rapidly, unraveling the mechanisms that effectively delay aging has become critical. Appropriate exercise is reported to improve aging-related cognitive impairment. Whereas current studies focused on exploring the effect of exercise on the aging brain itself, ignoring the persistent effects of peripheral organs on the brain through the blood circulation. The aim of this paper is to summarize the communication and aging processes of the liver and brain and to emphasize the metabolic mechanisms of the liver-brain axis about exercise ameliorating aging-related neurodegenerative diseases. A comprehensive understanding of the potential mechanisms about exercise ameliorating aging is critical for improving adaptation to age-related brain changes and formulating effective interventions against age-related cognitive decline.

Effects of exercise-targeted hippocampal PDE-4 methylation on synaptic plasticity and spatial learning/memory impairments in D-galactose-induced aging rats.

Physical exercise reduces the effects of aging and cognitive decline by improving synaptic plasticity and spatial learning. However, the underlying neurobiological mechanisms are unclear. A total of 45 Male SPF Sprague-Dawley rats were acclimatized and then allocated into three groups, 15 in each group: the saline control (DC) group, D-gal-induced aging (DA) group, and D-gal-induced aging + exercise (DE) group. Six weeks of intraperitoneal injections of D-gal at a concentration of 100 mg/kg body weight/d was injected to establish model of aging in the DA and DE groups. Morris water maze test was implemented to evaluate the hippocampus related cognition. SOD activity and MDA was tested to assess the aging in all groups. H&E and Nissl staining was used to observe the histopathological changes of hippocampal neurons in aging rats. Quantitative real-time polymerase chain reaction, western blotting and immunofluorescence staining techniques were used to investigate the expression of synaptic genes and proteins in the hippocampus. Massarray methylation system was employed to measure the PDE-4 gene methylation level in rat hippocampal tissues. Our results demonstrated that exercise intervention improves cognitive function in D-gal-induced aging rats. The methylation of CpG sites in PDE-4 in the hippocampus was significantly increased. The physical exercise significantly increased PDE-4 gene methylation and effectively decreased PDE-4 gene and protein expression. These beneficial behavioral and morphological effects were attributed to PDE-4 methylation, which was activated cAMP/PKA/CREB pathway and improved synaptic plasticity. Exercise induced PDE-4 methylation is key mechanism underpinning the amelioration of learning/memory impairment, suggesting the potential efficacy of physical exercise training in delaying brain aging.

Effect of aerobic exercise on brain metabolite profiles in the mouse models of methamphetamine addiction: LC-MS-based metabolomics study.

Methamphetamine (MA) abuse is recognized as a brain disorder, and physical activity has clear benefits for MA use disorders. The specific mechanisms by which physical activity alleviates MA use disorders are currently not fully understood. Based on this, the present study used untargeted metabolomics using liquid chromatography-mass spectrometry (LC-MS) to analyze the metabolic changes induced by MA in the brains of mice by exercise intervention. It was found that after 2 weeks of treadmill training, aerobic exercise modulated MA-induced brain metabolic disorders, in which 129 metabolites existed that were significantly differentiated in response to MA induction, and 32 metabolites were significantly affected by exercise. These differential metabolites were mainly enriched in glycerophospholipid metabolism, steroid hormone biosynthesis and degradation, and renin-angiotensin system pathways. To our knowledge, this study is the first to use LC-MS to investigate the effects of aerobic exercise on MA-induced brain metabolic profiling. The findings of this study provide new insights into exercise therapy using MA.

[Study on morphological classification and chemical-type of Perilla frutescens cultivated germplasm].

Fifty cultivated Perilla seeds were collected all over the country and planted in Beijing experiment field for morphology and chemical-type researches. Twenty morphological characteristics were selected and observed, and the essential oil from leaves was extracted by steam distillation and analyzed by GC-MS to confirm chemical-types. There were significant diversities in plant height, leaf color and morphology, and fruit color and weight. Clustering analysis was carried out based on these morphological characteristics. Six types were divided with their chemical-type designated. Type Ⅰ: Six germplasms, attributed to P. frutescens var. crispa, with dwarf plants, thin creased purple leaf, named Crispa, their chemical types were diversified, including EK, PAPK, PA and PK. Type Ⅱ: Six germplasms, attributed to P. frutescens var. crispa, plants were taller than type I and with thin and creased green leaf, named Big Crispa, all PK type. Type Ⅲ: Seventeen germplasms, attributed to P. frutescens var. frutescens with leaf color upside green and underside purple, tall plant and wide distribution all over the China, named Ordinary Frutescens, all PK. Type Ⅳ: Four germplasms, attributed to P. frutescens var. acuta with tall plant and small seed, named Acuta, all PK. Type Ⅴ: Seven germplasms, attributed to P. frutescens var. frutescens with green leaves, tall plants and long clusters, named Long-spike Frutescens, all PK. Type Ⅵ: Ten germplasms, attributed to P. frutescens var. frutescens with big, thick and creased leaf, named Thick-leaf Frutescens, including PK, PP, PL and PA. The morphological classification of this paper would lay the foundation for the taxonomic naming and following evaluation of the Perilla germplasm resources.This study also showed that there was no correspondence but a certain correlation between volatile oil chemical-types and subspecies classification and morphological characteristics of Perilla.

[Morphological characteristics of Chinese Perilla fruits].

The morphological traits of 55 Chinese Perilla fruit samples (size, 100 grains weight, color, hardness, surface ridge height) are described and the statistically analyzed. It can be divided into 6 categories by cluster analysis, namely: Ⅰ, big grain (diameter 1.5 mm above and 100 grains weight above 0.16 g), low ridge, hard; Ⅱ, big grain, low ridge, soft; Ⅲ, big grain, high ridge, soft, fruit; Ⅳ, big grain. high ridge, gray brown or dark brown; Ⅴ, small grain (diameter 1.5 mm below and 100 grain weight 0.16 g below), low ridge, hard, dark brown; Ⅵ, small grain, low ridge, hard, yellow brown. The 38 fruit samples were planted, among which 31 ones were P. frutescens var. frutescens, 4 ones P. frutescens var. crispa and 3 ones P. frutescens var. acuta. By chemotype classification, they were 29 PK type, 3 PA type, 2 PL type, 2 PP type, 1 EK type and 1 PAPK type. According the description of herb Perillae Fructus in China Pharmacopoeia, the plant originates from P. frutescens var. frutescens. In contrast, not all fruits of P. frutescens var. frutescens have accord features. The fruits with white pericarp are mainly from P. frutescens var. frutescens with purple leaves. The materials with small grain, low ridge, hard, yellow brown or dark brown, are likely to be PA type and mainly P. frutescens var. crispa.

[Research on effects of chemotype and components of Perilla frutescens leaf volatile oil I: different phenological periods].

This experiment researched on three kinds of Perilla frutescens including the widespread PK, PA and rare PL chemotype. The Perilla samples were the mature leaves collected in nutrition, flowering and frutescence three different phenological periods, and at 7 am, 12 pm and 6 pm three day time. The volatile oil was extracted by steam distillationand analyzed by GC-MS, as a result, the three chemotype samples'volatile oil yield was between 0.08% and 0.96%; volatile oil yield of different growth period was as follow: nutrition>flowering>fructescence, and the volatile oil yield of nutrition period: PA type>PK type>PL type. Each chemotype was not affected by the growth and development, indicating that the chemotype is determined by genetic factors. Characteristic and main components of PA and PK type are relatively stable, and the characteristic components of PL type are significantly decreased with the growth. There are still a large number of upstream metabolism components, and the chemical type may have their primitiveness and changeability. The relative content of perillaldehyde, characteristic components of PA type, is basically decreased from morning to night, in all the period. The relative content of perillaketone, characteristic components of PK type, in nutrition and flowering period, when samples were collected at 12 noon is relatively higher than that at 7 am and 6 pm, and contrary to samples collected in frutescence period. The relative content of perillene, characteristic components of PL type, in nutrition and frutescence period are highest at 12 noon, while in flowering period is highest at 6 pm. According to the volatile oil yield and relative content of maincomponents, the best harvest time of PA type is in the morning of the nutrition period; the best harvest time of PK type is in the morning of all the period; and the best harvest time of PL type is at dusk of the nutrition period.

[Perilla resources of China and essential oil chemotypes of Perilla leaves].

This study, based on the findings for Perilla resources, aimed to describe the species, distribution, importance, features, utilization and status of quantitative Perilla resources in China. This not only helps people to know well about the existing resources and researching development, but also indicates the overall distribution, selection and rational use of Perilla resource in the future. According to the output types, Perilla resources are divided into two categories: wild resources and cultivated resources; and based on its common uses, the cultivated resources are further divided into medicine resources, seed-used resources and export resources. The distribution areas of wild resources include Henan, Sichuan, Anhui, Jiangxi, Guangxi, Hunan, Jiangsu and Zhejiang. The distribution areas of medicine resources are concentrated in Hebei, Anhui, Chongqing, Guangxi and Guangdong. Seed-used resources are mainly distributed in Gansu, Heilongjiang, Jilin, Chongqing and Yunnan. Export resource areas are mainly concentrated in coastal cities, such as Zhejiang, Jiangsu, Shandong and Zhejiang. For the further study, the essential oil of leaf samples from different areas were extracted by the steam distillation method and analyzed by GC-MS. The differences in essential oil chemotypes among different Perilla leaves were compared by analyzing their chemical constituents. The main 31 constituents of all samples included: perillaketone (0.93%-96.55%), perillaldehyde (0.10%-61.24%), perillene (52.15%), caryophyllene (3.22%-26.67%), and α-farnesene (2.10%-21.54%). These samples can be classified into following five chemotypes based on the synthesis pathways: PK-type, PA-type, PL-type, PP-type and EK-type. The chemotypes of wild resources included PK-type and PA-type, with PK-type as the majority. All of the five chemotypes are included in cultivated resources, with PA-type as the majority. Seed-used resources are all PK-type, and export resources are all PA-type. The P. frutescens var. frutescens include five chemotypes, with PK-type as the majority. The PK-type leaves of P. frutescens var. acuta are green, while the PA-type leaves are reddish purple. The P. fruteseens var. crispa was mainly PA type with reddish purple leaves. The differences of the main chemotypes provide a scientific basis for distinguishing between Zisu and Baisu in previous literatures. Based on the lung toxicity of PK and the traditional use of Perilla, the testing standard of essential oil and Perilla herb shall be built, and PA type is recommended to be used in traditional Chinese medicine.

[Advances in research of volatile oil and its different chemotypes in leaves of Perilla frutescens].

The volatile oil is the main component in the leaves of Perilla frutescens. According to the main types of monoterpenoids or aromatic compounds, it can be divided into different chemotypes and the main chemotypes of Chinese producing Perilla are PA type (mainly containing Perilla aldehyde and limonene), PK type (mainly containing perillaketone) and PP type (subdivided as PP-a type, with apiole as its main component; PP-m type, with myristicin as its main component; PP-e type, with elemicin as main component; PP-as type, with asarone as main component). Based on the biosynthetic pathways analysis, we also found that the formation of the particular chemotype is usually controlled by a single gene or a few genes, and different types have different pharmacological effects. In this paper, the classification under the species P. frutescens, main chemotypes of the volatile oil, and their biogenesis and regulation, pharmacological effect and influence factors are summarized and reviewed.

Time-resolved map of serum metabolome profiling in D-galactose-induced aging rats with exercise intervention.

Exercise, an intervention with wide-ranging effects on the whole body, has been shown to delay aging. Due to aging and exercise as modulator of metabolism, a picture of how exercise delayed D-galactose (D-gal)-induced aging in a time-resolved manner was presented in this paper. The mapping of molecular changes in response to exercise has become increasingly accessible with the development of omics techniques. To explore the dynamic changes during exercise, the serum of rats and D-gal-induced aging rats before, during, and after exercise was analyzed by untargeted metabolomics. The variation of metabolites was monitored to reveal the specific response to D-gal-induced senescence and exercise in multiple pathways, especially the basal amino acid metabolism, including glycine serine and threonine metabolism, cysteine and methionine metabolism, and tryptophan metabolism. The homeostasis was disturbed by D-gal and maintained by exercise. The paper was expected to provide a theoretical basis for the study of anti-aging exercise.

Effect of Aerobic Exercise on Intestinal Microbiota with Amino Acids and Short-Chain Fatty Acids in Methamphetamine-Induced Mice.

This study aimed to investigate the changes in intestinal homeostasis and metabolism in mice after methamphetamine (MA) administration and exercise intervention. In this study, male C57BL/B6J mice were selected to establish a model of methamphetamine-induced addiction, and the gut microbiota composition, short-chain fatty acids (SCFAs), and amino acid levels were assessed by 16S rRNA, liquid chromatography-tandem mass spectrometry, and gas chromatography-tandem mass spectrometry, respectively. The results showed that 23 dominant microbiota, 12 amino acids, and 1 SCFA were remarkably higher and 9 amino acids and 6 SCFAs were remarkably lower in the exercise model group than in the control group. Among the top 10 markers with opposite trends between the exercise intervention group and model group, the differential microbiomes included Oscillibacter, Alloprevotella, Colidextribacter, Faecalibaculum, Uncultured, Muribaculaceae, and Negativibacillus; amino acids included proline; and SCFAs included isovaleric acid and pentanoic acid. Proline was negatively correlated with Negativibacillus and positively correlated with pentanoic acid. The results suggested that moderate-intensity aerobic exercise may modulate changes in the composition of the gut microbiota and the levels of amino acids and SCFAs induced by MA administration.

Mass Spectrometry Chromatography-Based Metabolomics: The Effect of Long-Term Aerobic Exercise on Learning Ability and the Metabolism of Intestinal Contents in Mice with Alzheimer's Disease.

This study aimed to investigate the effect of long-term aerobic exercise on the metabolism of intestinal contents in APP/PS1 mice was studied using a non-targeted metabolomics technique based on high-performance liquid chromatography-mass spectrometry (HPLC-MS) coupling, providing a theoretical basis for exercise to regulate the metabolism of Alzheimer's disease (AD) organisms. Three-month-old male C57BL/6JNju mice, six wild-type (NC, n = 6); 12 APP/PS1 double transgenic species in total, were randomly divided into AD model (AM, n = 6) and AD model exercise (AE, n = 6) groups. The mice in the NC group were fed naturally, the mice in the AM group were statically placed on a running platform, and the mice in the AE group received a 20-week long-term moderate intensity running platform exercise intervention. Following the exercise intervention, the cecum contents of the mice in each group were collected and analyzed using the HPLC-MS technique, with those meeting both variable important in projection (VIP)> 1.5 and p < 0.05 being screened as differential metabolites. A total of 32 different metabolites were detected between the AM and NC groups, with 19 up-regulated in the AM group such as phosphatidic acid (PA) (18:4(6Z,9Z,12Z,15Z)/21:0) and 13 down-regulated in the AM group, such as 4,8-dimethylnonanoyl, compared to the NC group; 98 different metabolites were found between the AM and AE groups, 41 of which were upregulated such as Lyso phosphatidylcholine (LysoPC) and 57 of which were downregulated compared to the AM group such as Phosphatidylinositol (PI). The regulation of linoleic acid metabolism, glycerophospholipid metabolism, bile secretion, phenylalanine metabolism, and other pathways was predominantly regulated by nine metabolites, which were subsequently identified as indicators of exercise intervention to enhance metabolism in AD mice. The metabolomic technique can identify the metabolic problems of intestinal contents in AD mice and initially screen the biomarkers of exercise to improve the metabolic disorders in AD. These findings can help us better understand the impact of aerobic exercise on AD metabolism.

Bioinformatics Analysis and Experimental Verification of Exercise for Aging Mice in Different Brain Regions Based on Transcriptome Sequencing.

PURPOSE: Physical exercise mitigates the effects of aging and cognitive decline. However, the precise neurobiological mechanisms underlying this phenomenon remain unclear. The primary aim of this study was to investigate the protective effect of exercise on age-related memory deficits in the prefrontal cortex (PFC) and hippocampus using bioinformatic analysis and biochemical verification. METHODS: Young and aging mice were subjected to natural feeding or treadmill exercise (12 m/min, 8 weeks). Cognitive function was accessed using the Barnes maze and novel object recognition. Bioinformatic analysis was performed to identify co-expressed genes in different groups and brain regions. The selected genes and pathways were validated using RT-qPCR. RESULTS: Regular exercise significantly ameliorated age-related cognitive deficits. Four up-regulated targets (Ifi27l2a, Irf7, Oas1b, Ifit1) and one down-regulation (Septin2) were reversed by exercise, demonstrating the underlying mechanisms of cognitive functions induced by aging with exercise in the hippocampus and PFC. The Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses indicated that the NOD-like receptor signaling pathway was inhibited in the neuroinflammation effects of exercise in aging mice in both brain regions. CONCLUSION: Exercise enhances age-related learning and memory deficits. This beneficial effect may be attributed to the changes in five up/down-regulated genes and the NOD-like receptor signaling pathway in both the hippocampus and PFC. These findings establish the modulation of neuroinflammation as a pivotal molecular mechanism supporting exercise intervention in the brain aging process.

Long-term exercise training inhibits inflammation by suppressing hippocampal NLRP3 in APP/PS1 mice.

Behavioral experiments have demonstrated that long-term physical exercise can be beneficial for learning and memory dysfunction caused by neuroinflammation in Alzheimer's disease (AD). However, the molecular mechanism remains poorly understood due to a lack of sufficient pertinent biochemical evidence. We investigated the potential effect of long-term physical exercise on cognition and hippocampal gene and protein expression changes in a transgenic AD mouse model. Following twenty weeks of treadmill exercise, transgenic AD mice showed improvement in cognitive functions and downregulation of Nod-like receptor protein 3 (NLRP3) (p â€‹< â€‹0.01), interleukin-1beta (IL-1ß) (p â€‹< â€‹0.05), and amyloid-ß1-42 (Aß1-42) (p â€‹< â€‹0.05) expression levels. In addition, we observed significant reductions of microglial activation and hippocampal neuronal damage in the exercised AD mice (p â€‹< â€‹0.01), which might be a result of the downregulation of NLRP3-mediated signaling and neuro-inflammatory responses. As neuronal damage due to inflammation might be a likely cause of AD-associated cognitive dysfunction. Our results suggested that the anti-inflammatory effects of exercise training involved downregulating the expression of key inflammatory factors and might play an important role in protecting hippocampal neurons against damage during the course of AD.

Study on the mechanism of low shear stress restoring the viability of damaged breast tumor cells.

Blood vessel is one of the 'pathways' for cancer to metastasize, in which cells are exposed to the fluid shear stress. Although most cells are damaged by fluid shear stress, a small number of tumor cells survive and metastasize when they are exposed to low shear stress (LSS) of tiny capillary. It is important to study the survival state of damaged cells during LSS. In this study, high shear stress (HSS) was applied to simulate the blood circulation and damage cells. The viability and mitochondrial function of cells were detected after HSS and LSS loading, respectively. Further, the expression of mitochondrial related proteins and genes were detected by western blot and real-time quantitative polymerase chain reaction, respectively. The role of cytochrome c (Cyt C) was also verified in this process. The experimental results showed that the viability of HSS damaged cells was increased significantly when they were exposed to LSS subsequently. The function of mitochondria was improved via reducing the release of Cyt C by LSS during this process. This study is expected to provide potential target for suppressing hematogenous metastasis.

Preparation and Application of Magnetic Responsive Materials in Bone Tissue Engineering.

At present, many kinds of materials are used for bone tissue engineering, such as polymer materials, metals, etc., which in general have good biocompatibility and mechanical properties. However, these materials cannot be controlled artificially after implantation, which may result in poor repair performance. The appearance of the magnetic response material enables the scaffolds to have the corresponding ability to the external magnetic field. Within the magnetic field, the magnetic response material can achieve the targeted release of the drug, improve the performance of the scaffold, and further have a positive impact on bone formation. This paper first reviewed the preparation methods of magnetic responsive materials such as magnetic nanoparticles, magnetic polymers, magnetic bioceramic materials and magnetic alloys in recent years, and then introduced its main applications in the field of bone tissue engineering, including promoting osteogenic differentiation, targets release, bioimaging, cell patterning, etc. Finally, the mechanism of magnetic response materials to promote bone regeneration was introduced. The combination of magnetic field treatment methods will bring significant progress to regenerative medicine and help to improve the treatment of bone defects and promote bone tissue repair.