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Cordyceps militaris acidic polysaccharides improve learning and memory impairment in mice with exercise fatigue through the PI3K/NRF2/HO-1 signalling pathway
Abstract
Excessive exercise leads to body fatigue and destroys the balance of the oxidation/oxidation resistance system in the body, thus damaging the central nervous system and reducing learning and memory ability. Nrf2 is an important transcription factor that regulates the cell oxidative stress response. Therefore, the research and development of natural antioxidants with the effect of regulating Nrf2-related signalling pathways to improve central fatigue caused by body fatigue has application value. Methods and results: Cordyceps militaris polysaccharides were extracted, isolated and purified via DEAE-cellulose 52 and Sepharose CL-6B columns to obtain two saccharides, Cordyceps militaris acidic polysaccharides (CMPB) and CMPB-b. The results of behavioural tests showed that compared with the model group, the learning and memory abilities of the CMPB-H group (800 mg/kg) mice were remarkably improved in the dark avoidance and Morris water maze tasks (p < 0.01), and the levels of fatigue metabolites and oxidative stress in the body were obviously decreased (p < 0.01). The expression level of BDNF, PI3K, Nrf2 and HO-1 proteins in the hippocampus were significantly increased (p < 0.01). In vitro experiments, compared with the PC12 oxidative stress model group, CMPB-b high-dose group (100 μg/mL) had remarkably improved oxidative stress. CMPB-b also obviously promoted the phosphorylation of PI3K and AKT proteins (p < 0.01) and the nuclear translocation of Nrf2 (p < 0.01), and significantly increased the expression of HO-1 (p < 0.01). Conclusion: CMPB can alleviate the fatigue state of high-intensity swimming mice and improve the learning and memory impairment of exercise-fatigue mice by regulating the Nrf2-related signalling pathway. Its antioxidant active component CMPB-b exerts in vitro antioxidative neurological damage by the same mechanism. Our systematic studies provide strong supporting evidence for the future use of Cordyceps militaris acidic polysaccharides in health products to improve resistance to fatigue.
... Numerous studies have highlighted the protective role of the Nrf2/ HO-1 pathway against exercise fatigue [10,11]. Additionally, several studies have shown that Nrf2 can be modulated by the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway to play a protective role in exercise fatigue [15,16]. Therefore, activation of the PI3K/Akt/Nrf2 pathway may be an important mechanism to alleviate exercise fatigue. ...
... Excessive oxidative stress is a key factor in the development of exercise-induced fatigue, ultimately leading to decreased exercise performance [11,15,16]. MDA is commonly used as a biomarker for lipid peroxidation, while SOD and GSH-Px are key antioxidants [20]. ...
... The PI3K/AKT pathway plays a crucial role in cellular metabolism, proliferation, and survival, with its activation promoting glycogen synthesis and fatty acid oxidation, thereby improving energy metabolism [28,29]. Existing research indicates that the PI3K/AKT pathway plays an important role in alleviating exercise-induced fatigue by regulating energy metabolism and reducing oxidative stress [15,16]. The Nrf2 pathway is a classic antioxidant and anti-stress signaling pathway that helps reduce oxidative stress and inflammation, protecting cells from damage [9][10][11]. ...
Background
Fatigue is a prevalent issue that can lead individuals to a sub-health condition, impacting their work efficiency and quality of life. There are limited effective treatment options available for fatigue. Ren-Shen-Bu-Qi decoction (RSBQD) is a proprietary herbal remedy that is designed to address fatigue. However, the specific pharmacological mechanisms and basis of RSBQD are not yet fully understood.
Purpose
This study aimed to investigate the pharmacological effects and mechanisms of RSBQD in a mouse model of exercise fatigue.
Materials and methods
UPLC-Q-Orbitrap HRMS was used to analyze the chemical composition of RSBQD. The pharmacological basis and molecular mechanism of RSBQD on exercise fatigue were predicted using network pharmacology analysis. Subsequently, an exercise fatigue mouse model was established and used to analysis the effects of RSBQD. The potential mechanisms were verified by hematoxylin–eosin (HE) staining, real-time fluorescence quantitative PCR (RT-qPCR), Western blot (WB) and molecular docking.
Results
The results showed that 88 main components of RSBQD were identified, which have mainly belonged to flavonoids and carboxylic acid compounds. The network pharmacology analysis indicated that RSBQD ameliorate fatigue through PI3K/AKT signaling pathway. Notably, RSBQD prolonged the swimming time and diminished body weight loss of exercise fatigue mice ( P < 0.05). Meanwhile, RSBQD significantly alleviated the injury of liver and kidney induced by exhaustive exercise, and decreasing the serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea and BUN levels ( P < 0.05). In addition, RSBQD was found could relieve exercise fatigue by decreasing the content of creatine kinase (CK), lactate dehydrogenase (LDH), and lactic acid (LA), but increasing the blood glucose (GLU) and liver glycogen (HG) levels ( P < 0.05). RSBQD also significantly increased the hepatic superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) but decreased hepatic malondialdehyde (MDA) levels. Moreover, RSBQD was able to upregulate protein level of activated Nrf2 and PI3K/AKT signaling pathways.
Conclusions
RSBQD mitigates exercise fatigue by reversing metabolic changes and reducing oxidative damage through the PI3K/AKT/Nrf2 signaling pathway. This study offers pharmacological support for the utilization of RSBQD in exercise fatigue treatment.
Graphical Abstract
... Polysaccharides have been considered to be a new natural and effective anti-fatigue substance [9]. Some natural polysaccharides, such as Semen cassiae (Cassia obtusifolia L.) [14], Ganoderma lucidum [15], Lycium barbarum [68], Cordyceps militaris [69], and apple pomace [70], exert beneficial antifatigue effects via different pathways (Figure 1). The monosaccharide composition and the anti-fatigue mechanisms of natural polysaccharides are summarized in Table 1. ...
... Polysaccharides have been considered to be a new natural and effective anti-fatigue substance [9]. Some natural polysaccharides, such as Semen cassiae (Cassia obtusifolia L.) [14], Ganoderma lucidum [15], Lycium barbarum [68], Cordyceps militaris [69], and apple pomace [70], exert beneficial anti-fatigue effects via different pathways ( Figure 1). The monosaccharide composition and the anti-fatigue mechanisms of natural polysaccharides are summarized in Table 1. ...
... The anti-fatigue effect of APS-1 is related to its regulation of AMPK and PGC-1α in mouse muscle [78]. Furthermore, as a typical cellular antioxidant regulator at the transcriptional level, nuclear factor erythroidderived 2-like 2 (Nrf2) can control the basic and induced expression of a series of antioxidant response element-dependent genes [69,97]. Studies have proven that the activation of the Kelch-like ECH-associated protein 1 (Keap1)/Nrf2/heme oxygenase-1 (HO-1) pathway is the dominant mechanism of cellular defense systems against oxidative stress, and it also participates in enhancing the exercise-induced fatigue state [47,94]. ...
Due to today’s fast-paced lifestyle, most people are in a state of sub-health and face “unexplained fatigue”, which can seriously affect their health, work efficiency, and quality of life. Fatigue is also a common symptom of several serious diseases such as Parkinson’s, Alzheimer’s, cancer, etc. However, the contributing mechanisms are not clear, and there are currently no official recommendations for the treatment of fatigue. Some dietary polysaccharides are often used as health care supplements; these have been reported to have specific anti-fatigue effects, with minor side effects and rich pharmacological activities. Dietary polysaccharides can be activated during food processing or during gastrointestinal transit, exerting unique effects. This review aims to comprehensively summarize and evaluate the latest advances in the biological processes of exercise-induced fatigue, to understand dietary polysaccharides and their possible molecular mechanisms in alleviating exercise-induced fatigue, and to systematically elaborate the roles of gut microbiota and the gut-muscle axis in this process. From the perspective of the gut-muscle axis, investigating the relationship between polysaccharides and fatigue will enhance our understanding of fatigue and may lead to a significant breakthrough regarding the molecular mechanism of fatigue. This paper will provide new perspectives for further research into the use of polysaccharides in food science and food nutrition, which could help develop potential anti-fatigue agents and open up novel therapies for sub-health conditions.
... Furthermore, LBP can mitigate exercise-induced oxidative stress by modulating the Nrf2/HO-1 pathway and influencing energy metabolism through the AMPK/PGC-1α pathway [135]. Studies have also shown that Cordyceps militaris acidic polysaccharides (CMPB) can improve exercise fatigue and boost cognitive function in mice by increasing the expression of PI3K, AKT, Nrf2, and HO-1 proteins in the hippocampus [136]. Another polysaccharide-rich extract, PCS, can effectively combat fatigue, extend swimming time in mice, and regulate liver enzyme levels like ALT, AST, and ALP [137]. ...
... GRAF1, a Rho-specific GTPase activating protein, is suggested to play a role in increasing fatigue resistance by maintaining elevated levels of its expression in gastrocnemius muscles [68]. BDNF, a crucial regulator of energy balance, can be upregulated by CMPB, demonstrating its anti-fatigue effects [136]. Furthermore, APS-1 can enhance fatigue endurance by upregulating LKB1 expression associated with AMPK activation [127]. ...
In the last three decades, our understanding of how exercise induces oxidative stress has significantly advanced. Plant polysaccharides, such as dietary fibers and resistant starches, have been shown to enhance exercise performance by improving energy metabolism, reducing fatigue, increasing strength and stamina, mitigating oxidative stress post-exercise, facilitating muscle recovery, and aiding in detoxification. Moreover, antioxidants found in plant-based foods play a crucial role in protecting the body against oxidative stress induced by intense physical activity. By scavenging free radicals and reducing oxidative damage, antioxidants can improve exercise endurance, enhance recovery, and support immune function. Furthermore, the interaction between plant polysaccharides and antioxidants in the gut microbiota can lead to synergistic effects on overall health and performance. This review provides a comprehensive overview of the current research on plant polysaccharides and antioxidants in relation to exercise performance and gut health.
... stress, leading to an imbalance in central excitatory and inhibitory neurotransmitters, significantly impacting the excitability of hippocampal neurones and the plasticity of synaptic transmission within the hippocampus, which reduces the ability to learn and remember [4][5][6] . Oxidative stress results from an imbalance between the antioxidant defense system and ROS production of reactive oxygen species, leading to neuronal death or neurodegeneration. ...
Excessive exercise can lead to physical fatigue and disruption of the antioxidant system, resulting in neurological damage and cognitive decline. Cordycepin, the main component of Cordyceps militaris, has anti-inflammatory, antioxidant and neuroprotective effects. In this study, the anti-fatigue effect and potential mechanism of action of cordycepin were investigated using a forced exercise mouse model. The results showed that oral administration of cordycepin enhanced exercise endurance, increased liver and muscle glycogen content, and simultaneously decreased serum levels of lactic acid, lactate dehydrogenase, creatine kinase, and blood urea nitrogen (p < 0.05). In addition, cordycepin had antioxidant effects, increasing superoxide dismutase activity and decreasing serum malondialdehyde (MDA) levels (p < 0.01). In vitro experiments further demonstrated the antioxidant and anti-fatigue effects of cordycepin. Behavioral tests showed that the learning and memory ability of mice in the excessive exercise model group decreased to 40% compared with the control group. Cordycepin alleviated the learning and memory deficits in the over-exercised mice, significantly reduced the levels of fatigue metabolites and oxidative stress in vivo (p < 0.05), and altered the levels of neurotransmitters levels (p < 0.05). Furthermore, cordycepin modulated Keap1/Nrf2/HO-1-mediated oxidative stress and enhanced BDNF levels (p < 0.05). These findings suggest that cordycepin can alleviate excessive exercise-induced fatigue by modulating the Keap1/Nrf2/HO-1 signaling pathway and BDNF expression, providing strong supporting evidence for the development of cordycepin-functional foods or anti-fatigue drugs.
... a precious edible medicinal fungus, rich in numerous bioactive substances like polysaccharides, cordycepin, and adenosine [1]. Research indicates that Cordyceps militaris exhibits a range of pharmacological properties, including anti-tumor, antioxidant [2], antibacterial [3], anti-inflammatory [4], antifatigue [5], and the protective effects of liver and kidney [6]. Currently, it has been reported that the polysaccharide in Cordyceps militaris (CSP) has good immune activity [7]. ...
Yong Chong Cao polysaccharides (CSPs) are extracted from Cordyceps militaris which has a wide range of pharmacological effects, especially in immune regulation. However, CSPs face certain drawbacks, including rapid metabolism and poor bioavailability, which hinder their use. The objective of this research was to enhance the preparation parameters of polyetherimide (PEI)-modified poly lactic-co-glycolic acid (PLGA), PLGA-PEI, which encapsulated CSP nanospheres using response surface methodology; investigate their properties; and evaluate their impact on RAW26.4 cells. The CSP-PLGA-PEI nanospheres were synthesized using the double emulsion solvent evaporation technique, and the best preparation conditions were determined to be a 0.5% concentration of poloxamer 188 (F68) (W/V), an organic phase (O) to water phase (W1) ratio (V/V) of 7:1, an external water (W2) to primary emulsion (PE) ratio (V/V) of 8:1, and a PLGA to PEI ratio (W/W) of 20:1, achieving a maximum encapsulation efficiency (EE) of 64.98%. The CSP-PLGA-PEI nanoparticles exhibited a nearly spherical form with a smooth exterior, were uniform in size, and demonstrated clear sustained release properties and consistent stability. Macrophages are important immune cells in innate immunity, and have remarkable polarization. CSP-PLGA-PEI nanospheres showed a good promoting effect on the activation of macrophages in our present study. In addition, CSP-PLGA-PEI nanospheres were much more effectively swallowed by RAW264.7 so that its promoting effect on immune regulation was higher than that of CSP. CSP-PLGA-PEI nanoparticles were able to effectively activate ROS signaling in zebrafish in vivo experiments and induce an immune response in their organism. Finally, CSP-PLGA-PEI nanospheres showed the potential to become a new type of immune enhancer or immune enhancement adjuvant.
Graphical abstract
... In addition, Nrf2 is one of the important transcription factors regulating oxidative stress reaction. Therefore, it is of application value to develop natural antioxidants that can regulate Nrf2-related signaling pathways to improve exercise-induced central fatigue [56].Proper exercise is paramount for enhancing rat brain antioxidant capacities. Moreover, antioxidant supplements exhibit pronounced pharmacological benefits in mitigating fatigue [57,58]. ...
... These effects collectively resulted in a reduction in the generation of muscle energy, ultimately culminating in the onset of muscle fatigue [128]. Similarly, it has been proved that many experimental drugs with antioxidant properties can improve and alleviate chronic fatigue-like behaviors by changing ROS signaling pathways [129,130]. However, excessive oxidative stress could impair the female reproductive system by destroying oocyte quality [131,132], damaging endometrial receptivity [133], promoting trophoblast apoptosis, medicating implantation failure, and early pregnancy loss [134]. ...
Fatigue, an increasingly acknowledged symptom in various chronic diseases, has garnered heightened attention, during the medical era of bio-psycho-social model. Its persistence not only significantly compromises an individual’s quality of life but also correlates with chronic organ damage. Surprisingly, the intricate relationship between fatigue and female reproductive health, specifically infertility, remains largely unexplored. Our exploration into the existing body of evidence establishes a compelling link between fatigue with uterine and ovarian diseases, as well as conditions associated with infertility, such as rheumatism. This observation suggests a potentially pivotal role of fatigue in influencing overall female fertility. Furthermore, we propose a hypothetical mechanism elucidating the impact of fatigue on infertility from multiple perspectives, postulating that neuroendocrine, neurotransmitter, inflammatory immune, and mitochondrial dysfunction resulting from fatigue and its co-factors may further contribute to endocrine disorders, menstrual irregularities, and sexual dysfunction, ultimately leading to infertility. In addition to providing this comprehensive theoretical framework, we summarize anti-fatigue strategies and accentuate current knowledge gaps. By doing so, our aim is to offer novel insights, stimulate further research, and advance our understanding of the crucial interplay between fatigue and female reproductive health.
... The PI3K/Akt/mTOR signaling pathway is regulated by a variety of conditions such as growth factors, energy deficiency, insulin, hypoxia, and exercise. In addition, Cordyceps acidic polysaccharide modulates the PI3K/Nrf2/HO-1 pathway to exert antioxidant effects on nerve injury, suggesting that PI3K and Nrf2 combine to exert antioxidant effects (Bai et al., 2023). ...
Exercise fatigue is a normal protective mechanism of the body. However, long-term fatigue hinders normal metabolism and exercise capacity. The generation and recovery from exercise fatigue involves alterations in multiple signaling pathways, mainly AMPK, PI3K/Akt, Nrf2/ARE, NF-κB, PINK1/Parkin, and BDNF/TrkB, as well as MAPK signaling pathways that mediate energy supply, reduction of metabolites, oxidative stress homeostasis, muscle fiber type switching, and central protective effects. In recent studies, a rich variety of natural active ingredients have been identified in traditional Chinese medicines and plant extracts with anti-fatigue effects, opening up the field of research in new anti-fatigue drugs. In this review we give an overview of the signaling pathways associated with the activity of natural food active ingredients against exercise fatigue. Such a comprehensive review is necessary to understand the potential of these materials as preventive measures and treatments of exercise fatigue. We expect the findings highlighted and discussed here will help guide the development of new health products and provide a theoretical and scientific basis for future research on exercise fatigue.
... Unfortunately, it remains unclear what molecules RPT6 works with (transcription factors, epigenetic marks) or if free RPT6 can work with proteasome functions to regulate clearance of transcription factors. However, some genes identified as being dysregulated by RPT6 knockdown have known roles in memory formation such as Hmox1, shown to be upregulated by a molecule that rescues fatigue-induced memory deficits (Bai et al., 2023). Timp1 expression has been found to regulate hippocampus-dependent learning (Chaillan et al., 2006). ...
Memory formation requires coordinated control of gene expression, protein synthesis, and ubiquitin–proteasome system (UPS)-mediated protein degradation. The catalytic component of the UPS, the 26S proteasome, contains a 20S catalytic core surrounded by two 19S regulatory caps, and phosphorylation of the 19S cap regulatory subunit RPT6 at serine 120 (pRPT6-S120) has been widely implicated in controlling activity-dependent increases in proteasome activity. Recently, RPT6 was also shown to act outside the proteasome where it has a transcription factor-like role in the hippocampus during memory formation. However, little is known about the proteasome-independent function of “free” RPT6 in the brain or during memory formation and whether phosphorylation of S120 is required for this transcriptional control function. Here, we used RNA-sequencing along with novel genetic approaches and biochemical, molecular, and behavioral assays to test the hypothesis that pRPT6-S120 functions independently of the proteasome to bind DNA and regulate gene expression during memory formation. RNA-sequencing following siRNA-mediated knockdown of free RPT6 revealed 46 gene targets in the dorsal hippocampus of male rats following fear conditioning, where RPT6 was involved in transcriptional activation and repression. Through CRISPR-dCas9-mediated artificial placement of RPT6 at a target gene, we found that RPT6 DNA binding alone may be important for altering gene expression following learning. Further, CRISPR-dCas13-mediated conversion of S120 to glycine on RPT6 revealed that phosphorylation at S120 is necessary for RPT6 to bind DNA and properly regulate transcription during memory formation. Together, we reveal a novel function for phosphorylation of RPT6 in controlling gene transcription during memory formation.
... Nrf2 can regulate glucose uptake and metabolism of neurons (Esteras et al., 2023), autophagy (Li et al., 2021), ferroptosis (Song et al., 2023), inflammation (Wang J. et al., 2023), mitochondrial function (Jamwal et al., 2021), and promote energy metabolism (Esteras et al., 2023), which helps to maintain the health and survival of neurons. For example, CMPB can improve learning and memory impairment caused by fatigue by regulating PI3K/NRF2/HO-1 signal pathway, scavenging free radicals and fatigue metabolites, increasing the content of glycogen and regulating the content of central neurotransmitters in the body (Bai et al., 2023). Pharmacological or genetic activation of Nrf2 has shown promising therapeutic potential in preclinical models of neurological disorders (Li et al., 2021). ...
Background: Nrf2 plays a pivotal role in governing the antioxidant defense system, triggering the transcription of diverse genes involved in cellular protection. Its role in mitigating oxidative damage and modulating inflammatory processes has made Nrf2 an attractive target for therapeutic interventions. Despite the growing interest in Nrf2 research, a bibliometric analysis is relatively rare. This study aimed to clarify Nrf2’s role in multiple diseases, identify emerging trends and hotspots using bibliometric analysis, and provide valuable insights and potential directions for future therapeutic interventions.
Methods: The Science Citation Index of Web of Science Core library from 2000 to 2022 was searched on 22 October 2022. Use Microsoft Excel, CiteSpace, Bibliometrix, and VOS viewers for data collection and visualization of research focus and trends.
Results: A vast collection of 22,040 research studies on Nrf2 published between 2000 and 2022 were identified. Nrf2 research has seen significant growth globally from 2000 to 2022. China leaded in publication numbers (9,623, 43.66%), while the United States dominated in citation frequency with 261,776 citations. China Medical University was the most productive institutions (459, 2.08%). Masayuki Yamamoto topped in publications (307), while Itoh K. ranked first in citations with 3669. Free Radical Biology and Medicine was the journal with the most studies and citations on Nrf2 (613, 29,687 citations). The analysis of keyword clustering enhanced the categorization of topics and can be summarized as oxidative stress, cancer, disorders in glycolipid metabolism, inflammation, and neurological conditions.
Conclusion: China and the United States are the pioneers in Nrf2 research. Recently, there has been a comprehensive exploration of Nrf2 involving both experimental and clinical aspects, as well as mechanisms and therapeutic applications. Investigating novel molecular mechanisms, including NF-κB, Ho1, and Keap1, and developing enhanced, targeted Nrf2 activators or inhibitors to uncover the interplay among cancer, glycolipid metabolic disorder, inflammation, and neurological disorders will be upcoming trends and hotspots.
... What is novel is that the acidic polysaccharides purified from Codyceps militaris (CMPB) is beneficial for learning and memory impairment in mice. It can improve the fatigue state of high-intensity swimming mice and regulate the Nrf2-related signaling pathway to reverse the learning and memory impairment [130]. Zhang et al. [26] found that the polysaccharide (GLP-1) from Ganoderma lucidum could improve cognitive impairment in mice. ...
Traditional Chinese medicine (TCM) is a class of natural drugs with multiple components and significant therapeutic effects through multiple targets. It also originates from a wide range of sources containing plants, animals and minerals, and among them, plant-based Chinese medicine also includes fungi. Fungal traditional Chinese medicine is a medicinal resource with a long history and widespread application in China. Accumulating evidence confirms that polysaccharide is the main pharmacodynamic material on which fungal TCM is based. The purpose of the current systematic review is to summarize the extraction, isolation, structural identification, biological functions, quality control and medicinal and edible applications of polysaccharides from fungal TCM in the past three years. This paper will supplement and deepen the understanding and application of polysaccharides from fungal TCM, and propose some valuable insights for further research and development of drugs and functional foods.
... In an antifatigue study of Polygonatum cyrtonema Hua polysaccharide, we observed a signifcant increase in the exhaustive swimming time of mice compared to that in the normal control group [10]. Similarly, in the investigation of Cordyceps militaris acidic polysaccharides (CMPB), mice gavaged with CMPB had considerably longer stick rotation times in the rotarod test than those in the model group, which suggested enhanced exercise endurance [22]. Previous research has highlighted Ganoderma lucidum as an antifatigue food, with Ganoderma lucidum polysaccharide (GLPs) identifed as its main antifatigue component [23]. ...
This study aimed at examining the structure-role modeling and antifatigue mechanism of polysaccharides, including M. androsaceus exopolysaccharide 3 (MEPS3), isolated from Marasmius androsaceus fermentation broth. The molecular weight of MEPS3 was 10.47 kDa. Furthermore, monosaccharide analysis showed the presence of mannose, glucose, and galactose in MEPS3 in a molar ratio of 0.08 : 0.34 : 1.46. Mannose, α-galactose, and α-d-glucose anomeric hydrogen signals were detected using nuclear magnetic resonance spectroscopy. MEPS3 was found to contain glyoxylic acid, forming rod-like chains that support high-purity polymerization. The weight-loaded swimming test results showed that MEPS3 treatment reduced lactic acid (LA) levels by 25.72% and increased the lactate dehydrogenase (LDH) activity by 5.67% in the plasma. Furthermore, it lowered malondialdehyde (MDA) levels by 47.09% and increased reactive oxygen species (ROS) and glutathione peroxidase (GSH-Px) levels by 52.42 and 97.03%, respectively, in the plasma. In addition, MEPS3 treatment reduced MDA and ROS levels in the liver by 28.85 and 18.64% while increasing superoxide dismutase (SOD) and GSH-Px levels by 17.41 and 38.13%, respectively. MEPS3 treatment increased the expression of nuclear factor-erythroid 2-related factor 2, glutamate-cysteine ligase, quinone oxidoreductase 1, and heme oxygenase 1 by 22.5, 24.8, 20.3, and 43.1%, respectively, in the liver. These findings demonstrate that MEPS3 effectively alleviates fatigue by removing harmful metabolites and indicate that the antifatigue mechanism is related to the Nrf-2 signaling pathway.
Cordyceps and its allied species have many applications in traditional medicine and biological control in some Asian countries, such as China, Japan, Korea, India, Thailand, and Vietnam. Many studies on Cordyceps and its allied species have been published, focusing on both its fundamental and applied aspects, globally, including metabolite profiles, secondary metabolites, and its biological activities such as antibacterial, anticancer, antifungal, antioxidant, antitumor, antiviral, and immunomodulatory activities. At the same time, the number of studies on the mechanisms of secondary metabolites of Cordyceps and its allies is increasing, which helps to elucidate the profound benefits or risks of the products that have been used for a long time. Most of the studies provided evidence that supports the use of these Cordyceps and their allied species in traditional medicine. However, there are also some studies that provide evidence that warns us of the harmful sides of the products. This chapter provides an update on secondary metabolites of Cordyceps and related species published recently and basic, systematic information about Cordyceps and its allies, including biodiversity, antagonistic abilities, secondary metabolite production abilities, functions and acting mechanisms of some well-known metabolites, fermentation, molecular and genetic technology applications, the present commercial situation of Cordyceps and its allied products, and development trends. Based on the diverse information, future prospects for Cordyceps and its allies in research and application are provided.
Soil microorganisms are critical to the occurrence of Cordyceps sinensis (Chinese Cordyceps), a medicinal fungi used in Traditional Chinese Medicine. The over-collection of Chinese Cordyceps has caused vegetation degradation and impacted the sustainable occurrence of Cordyceps. The effects of Chinese Cordyceps collection on soil microorganisms have not been reported. Metagenomic analysis was performed on the soil of collecting and non-collecting areas of production and non-production areas, respectively. C. sinensis collection showed no alteration in alpha-diversity but significantly affected beta-diversity and the community composition of soil microorganisms. In Cordyceps production, Thaumarchaeota and Crenarchaeota were identified as the dominant archaeal phyla. DNA repair, flagellar assembly, propionate metabolism, and sulfur metabolism were affected in archaea, reducing the tolerance of archaea in extreme habitats. Proteobacteria, Actinobacteria, Acidobacteria, Verrucomicrobia, and Nitrospirae were identified as the dominant bacterial phyla. The collection of Chinese Cordyceps enhanced the bacterial biosynthesis of secondary metabolites and suppressed ribosome and carbon metabolism pathways in bacteria. A more complex microbial community relationship network in the Chinese Cordyceps production area was found. The changes in the microbial community structure were closely related to C, N, P and enzyme activities. This study clarified soil microbial community composition and function in the Cordyceps production area and established that collection clearly affects the microbial community function by altering microbial community structure. Therefore, it would be important to balance the relationship between cordyceps production and microbiology.
The current study aimed to investigate the effects and mechanisms of Paris polyphylla polysaccharide component 1 (PPPm-1) to improve learning and memory in D-galactose-induced aging model mice. We determined the effects of PPPm-1 on the brain, organ index, and behavior in the aging model mice induced by D-galactose to study learning and memory improvement. UV-Vis spectrophotometry helped determine the PPPm-1 effect on antioxidant parameters associated with learning and memory in the brain and related organs of aging mice. Moreover, in the hippocampi of aging model mice, PPPm-1 effect on the mRNA and protein expressions of p19, p53, p21, P16, Rb, Wnt/1, β-catenin, CyclinD1, TCF-4, and GSK-3β were detected using the quantitative real-time PCR and enzyme-linked immunosorbent assay (ELISA), respectively. The results indicated that PPPm-1 could increase the brain and organ indexes, the avoidance latency, the total distance and average speed in the water maze, and the SOD and GSH-PX activities in the brain, liver tissues, and plasma. Moreover, the mRNA and protein expressions of Wnt/1, β-catenin, CyclinD1, and TCF-4 were also elevated in the hippocampi of aging model mice. However, the error times in step-through tests, the MDA content in the brain and liver tissues, the AChE activity in the brain tissue, the protein expressions of P16, Rb in the hippocampi, and the mRNA and protein expressions of p19, p53, p21, and GSK-3β in the hippocampi of aging model mice were significantly decreased. Thus, PPPm-1 significantly enhanced the learning and memory impairment induced by D-galactose in mice. The action mechanisms were associated with anti-oxidative stress, cholinergic nervous system function regulation, LTP enhancement in long-term memory, down-regulated expression of p19/p53/p21 signaling pathway factors, and Wnt/β-catenin signaling pathway activation.
Sonchus arvensis L. is a nutritious vegetable and herbal medicine that is consumed worldwide. The aim of this study was to evaluate the anti-fatigue effects and underlying effects of aqueous extract of Sonchus arvensis L. (SA). Male C57BL/6 mice from four groups designated vehicle, exercise, exercise with low dose (250 mg/kg) or high dose of SA (500 mg/kg), were trained by swimming exercise and orally administrated with SA every other day for 28 days. The anti-fatigue activity was determined by exhaustive swimming test, as well as the muscle structure, levels of blood hemoglobin, and metabolites including lactate and urea nitrogen. SA alleviated mice fatigue behaviors by eliminating metabolites, while improving muscle structure and hemoglobin levels. Moreover, SA enhanced glycogen synthesis of liver but not muscle via increasing GCK and PEPCK gene expressions. Importantly, SA improved antioxidant enzymes expression and activities in both liver and muscle, which was possibly related to its primary components polysaccharides and the antioxidant components including chlorogenic acid, luteolin, and chicoric acid. Taken together, the anti-fatigue effects of SA could be partly explained by its antioxidant activity and mediating effects on glycogen synthesis and metabolites elimination. Therefore, SA could be a potential nutraceutical for improving exercise performance and alleviating physical fatigue.
Exercise is a preferred strategy for improving cardiac function, especially for patients with cardiovascular diseases. Increasing evidence indicates that oxidative stress is involved in exercise-induced cardioprotection, while the underlying mechanism remains unclear. Furthermore, the effect of antioxidant supplementation during or post-exercise still exists despite divergences. To explore the effect of oxidative stress and antioxidant supplementation on cardiovascular homeostasis during or post-exercise, we take insights into the progress of exercise-induced oxidative stress, antioxidant supplementation, and cardiovascular homeostasis. In particular, antioxidants such as vitamin C or E, gamma-oryzanol, and other natural antioxidants are discussed concerning regulating exercise-associated oxidative stress. Additionally, our present study reviewed and discussed a meta-analysis of antioxidant supplementation during exercise. Overall, we take an insight into the essential biological adaptations in response to exercise and the effects of antioxidant supplementation on cardiac function, which aid us in giving recommendations on antioxidant supplementation for exercisers and exercised people. A better understanding of these issues will broaden our knowledge of exercise physiology.
Graphical abstract
The aim of this work is to develop a green route for platinum nanoparticles (PtNPs) biosynthesized using Cordyceps flower extract and to evaluate their antioxidant activity and antibacterial activity. Different characterization techniques were utilized to characterize the biosynthetic PtNPs. The results showed that PtNPs were spherical particles covered with Cordyceps flower extract. The average particle size of PtNPs in Dynamic Light Scattering was 84.67 ± 5.28 nm, while that of PtNPs in Transmission Electron Microscope was 13.34 ± 4.06 nm. Antioxidant activity of PtNPs was evaluated by DPPH free radical scavenging ability test. The results showed that the antioxidant activity was positively correlated with the concentration of PtNPs, the DPPH scavenging efficiency of PtNPs (0.50-125.00 μg/mL) was 27.77-44.00%. In addition, the morphological changes of four kinds of bacteria (Escherichia coli, Salmonella typhimurium, Bacillus subtilis, Staphylococcus aureus) exposed to PtNPs were observed by scanning electron microscope. The results showed that the antibacterial activity of PtNPs against Gram-negative bacteria was stronger than that of Gram-positive bacteria.
Cordyceps militaris is a parasitic edible fungus and has been used as tonics for centuries. Polysaccharides are a major water-soluble component of C. militaris. Recently, C. militaris-derived polysaccharides have been given much attention due to their various actions including antioxidant, anti-inflammatory, anti-tumor, anti-hyperlipidemic, anti-diabetic, anti-atherosclerotic, and immunomodulatory effects. These bioactivities are determined by the various structural characteristics of polysaccharides including monosaccharide composition, molecular weight, and glycosidic linkage. The widespread use of advanced analytical analysis tools has greatly improved the elucidation of the structural characteristics of C. militaris-derived polysaccharides. However, the methods for polysaccharide structural characterization and the latest findings related to C. militaris-derived polysaccharides, especially the potential structure-activity relationship, have not been well-summarized in recent reviews of the literature. This review will discuss the methods used in the elucidation of the structure of polysaccharides and structural characteristics as well as the signaling pathways modulated by C. militaris-derived polysaccharides. This article provides information useful for the development of C. militaris-derived polysaccharides as well as for investigating other medicinal polysaccharides.
Citrus essential oils (CEOs) possess physiological functions due to diverse aroma components. However, evidence for the effects of CEOs on exercise performance and exercise-induced fatigue is limited. The CEOs with discrepancies in components may exert different effects on the amelioration of exercise-induced fatigue. In this study, sweet orange (Citrus sinensis L.) essential oil (SEO), lemon (Citrus limon Osbeck) essential oil (LEO), and bergamot (Citrus bergamia Risso and Poit) essential oil (BEO) were chosen to explore the effect on amelioration of exercise-induced fatigue. Our results demonstrated that SEO and LEO increased the swimming time by 276% and 46.5%, while BEO did not. Moreover, the three CEOs exerted varying effects on mitigating exercise-induced fatigue via inhibiting oxidative stress, protecting muscle injury, and promoting glucose-dependent energy supply. Accordingly, BEO showed the best efficiency. Moreover, the GC-MS and Pearson correlation analysis of BEO showed that the contents of the major components, such as (±)-limonene (32.9%), linalyl butyrate (17.8%), and linalool (7.7%), were significantly positively correlated with relieving exercise-induced fatigue.
Diabetic kidney disease (DKD) is the major reason of chronic kidney disease (CKD)-caused end-stage renal failure (ESRF), and leads to high mortality worldwide. At present, the treatment of DKD is mainly focused on controlling the hyperglycemia, proteinuria, and hypertension, but is insufficient on the effective delay of DKD progression. Cordyceps sinensis is a kind of wild-used precious Chinese herb. Its extracts have effects of nephroprotection, hepatoprotection, neuroprotection, and protection against ischemia/reperfusion-induced injury, as well as anti-inflammatory and anti-oxidant activities. According to the theory of traditional Chinese medicine, Cordyceps sinensis can tonify the lung and the kidney. Several Chinese patent medicines produced from Cordyceps sinensis are often used to treat DKD and achieved considerable efficacy. This review summarized the clinical usage of Cordyceps sinensis, as well as its mainly biological activities including anti-hyperglycemic, anti-inflammatory, immunomodulatory, anti-oxidant, anti-fibrotic activities and regulation of apoptosis.
Aim
The purpose of this study is to study the antioxidant effect of Lactobacillus fermentum CQPC08 (CQPC08) on exercise-induced fatigue, and the beneficial intervention of GOS on CQPC08.
Methods
We use the treadmill to establish a fatigue model caused by exercise, and perform drug treatment after exercise. We tested the exhaustive exercise time of mice; investigated the changes of mice body weight, liver index, histopathology, serum biochemical indicators and mRNA expression levels of oxidative and inflammation-related genes; and assessed the potential fatigue inhibitory effect of CQPC08, and the anti-oxidation effect of the combination of GOS and CQPC08.
Results
The results suggest that CQPC08 and combination with GOS reduces fatigue-induced oxidative damage of the liver, and it decreases blood urea nitrogen (BUN), lactic acid (LA), glutamic-oxaloacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT), malonaldehyde (MDA), inducible nitric oxide synthase (iNOS), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in serum. Higher levels of serum catalase (CAT), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) were found. Treatment with the CQPC08 and combination with GOS correlates with lower relative mRNA expression levels of neuronal NOS (nNOS), iNOS, and TNF-α, and with higher mRNA expression levels of catalase and copper/zinc (Cu/Zn) and manganese (Mn) SOD enzymes in the liver and muscles.
Conclusion
These results suggest that CQPC08 can resolve exercise-induced fatigue by improving antioxidant ability in mice, and the combination of GOS and CQPC08 enhances this ability of CQPC08.
Performance in self-paced endurance exercises results from continuous fatigue symptom management. While it is suggested that perceived responses and neuromuscular fatigue development may determine variations in exercise intensity, it is uncertain how these fatigue components interact throughout the task. To address the fatigue development in self-paced endurance exercises, the following topics were addressed in the present review: (1) fatigue development during constant-load vs. self-paced endurance exercises; (2) central and peripheral fatigue and perceived exertion interconnections throughout the self-paced endurance exercises; and (3) future directions and recommendations. Based on the available literature, it is suggested (1) the work rate variations during a self-paced endurance exercise result in transitions between exercise intensity domains, directly impacting the end-exercise central and peripheral fatigue level when compared to constant-load exercise mode; (2) central and peripheral fatigue, as well as perceived exertion response contribute to exercise intensity regulation at the different stages of the trial. It seems that while neuromuscular fatigue development might be relevant at beginning of the trial, the perceived exertion might interfere in the remaining parts to achieve maximal values only at the finish line; (3) future studies should focus on the mechanisms underpinning fatigue components interactions throughout the task and its influence on exercise intensity variations.
Two new water‐soluble polysaccharide fractions (SCP II‐1 and SCP II‐2) were obtained from silkworm cordycepsusing DEAE Sepharose FF and Superose 6 columns chromatography. The characterization of their basic structure was studied by high performance liquid chromatography, high performance ion chromatography, infrared spectroscopy and atomic force microscope (AFM). The results showed that the molecular weight of SCP II‐1 and SCP II‐2 were 35.2 kDa and 23.4 kDa, and they were mainly composed of ribose, mannose, glucose, and galactose in molar ratio of 1.0:27.38:8.52:17.99 and 1.0:21.21:1.95:14.28, respectively. The AFM topography confirmed the highly branched chain conformation of SCP II‐1, while SCP II‐2 had more polymerized chain morphology. These two fractions possessed excellent antioxidant and antitumor activities, especially SCP II‐1 showed better inhibition than SCP II‐2. Those data suggested that purified polysaccharides from silkworm cordyceps have potential application in functional food and pharmaceutical industry.
Practical applications
Silkworm cordyceps is cultivated on the 5th instar larvae inoculated with Cordyceps sp. and the functions of cordyceps have been reported recently. The separation and purification of silkworm cordyceps polysaccharide is helpful to better exert important biological functions. The study on the structure‐function relations of polysaccharides will be useful to the application of polysaccharides in functional food and pharmaceutical industry.
The first report demonstrating that prolonged endurance exercise promotes oxidative stress in humans was published more than four decades ago. Since this discovery, many ensuing investigations have corroborated the fact that muscular exercise increases the production of reactive oxygen species (ROS) and results in oxidative stress in numerous tissues including blood and skeletal muscles. Although several tissues may contribute to exercise-induced ROS production, it is predicted that muscular contractions stimulate ROS production in active muscle fibers and that skeletal muscle is a primary source of ROS production during exercise. This contraction-induced ROS generation is associated with 1) oxidant damage in several tissues (e.g., increased protein oxidation and lipid peroxidation), 2) accelerated muscle fatigue, and 3) activation of biochemical signaling pathways that contribute to exercise-induced adaptation in the contracting muscle fibers. While our understanding of exercise and oxidative stress has advanced rapidly during the last decades, questions remain about whether exercise-induced increases in ROS production are beneficial or harmful to health. This review will address this issue by discussing the site(s) of oxidant production during exercise and detailing the health consequences of exercise-induced ROS production.
The present study aimed to evaluate the anti-fatigue effects of Aralia continentalis kitagawa (AC) extract during exhaustive exercise of rats by forced swimming. Rats were subjected to forced swimming until exhausted after pre-treatment with AC extract for 21 days. Exhaustion time significantly increased in rats treated with AC extract. AC treatment also preserved blood homeostasis during fatigue due to exhaustive exercise. For fatigue-related serum biomarkers, AC extract significantly fail to decrease glucose and triglyceride (TG), but ameliorated increased lactate levels compared with levels in control rats. Metabolic acidosis, a major cause of fatigue, was effectively attenuated by AC extract, according to metabolic acidosis-related blood parameters. AC extract suppressed muscle injury and attenuated gastrocnemius muscle apoptotic responses due to exhaustive exercise. To investigate the mechanisms behind the AC extract anti-fatigue effect, we evaluated its effect on oxidative stress-related fatigue. We showed that pro-oxidants were inhibited, while antioxidants were preserved by AC extract treatment. Therefore, the anti-fatigue effect of AC extract was mediated by suppression of oxidative stress. Overall, the study demonstrated that AC extract effectively attenuates fatigue from exhaustive exercise through oxidative stress inhibition. AC extract, as an antioxidant, could be utilized as a therapeutic or preventive strategy against exhaustive exercise fatigue.
Alzheimer’s disease (AD) is an age-related neurodegenerative disorder with cognitive deficits, which is becoming markedly more common in the world. Currently, the exact cause of AD is still unclear, and no curative therapy is available for preventing or mitigating the disease progression. Caffeic acid phenethyl ester (CAPE), a natural phenolic compound derived from honeybee hive propolis, has been reported as a potential therapeutic agent against AD, while its application is limited due to the low water solubility and poor bioavailability. Here, caffeic acid phenethyl ester 4- O -glucoside (FA-97) is synthesized. We validate that FA-97 attenuates H 2 O 2 -induced apoptosis in SH-SY5Y and PC12 cells and suppresses H 2 O 2 -induced oxidative stress by inhibiting the ROS level, malondialdehyde (MDA) level, and protein carbonylation level, as well as induces cellular glutathione (GSH) and superoxide dismutase (SOD). Mechanistically, FA-97 promotes the nuclear translocation and transcriptional activity of Nrf2 associated with the upregulated expression of HO-1 and NQO-1. The prime importance of Nrf2 activation in the neuroprotective and antioxidant effects of FA-97 is verified by Nrf2 siRNA transfection. In addition, FA-97 prevents scopolamine- (SCOP-) induced learning and memory impairments in vivo via reducing neuronal apoptosis and protecting against cholinergic system dysfunction in the hippocampus and cortex. Moreover, the increased MDA level and low total antioxidant capacity in SCOP-treated mouse brains are reversed by FA-97, with the increased expression of HO-1, NQO-1, and nuclear Nrf2. In conclusion, FA-97 protects against oxidative stress-mediated neuronal cell apoptosis and SCOP-induced cognitive impairment by activating Nrf2/HO-1 signaling, which might be developed as a therapeutic drug for AD.
Background/aims:
Pterostilbene (Pts), a natural dimethylated analog of resveratrol from blueberries, exerts antioxidative and anti-apoptotic effects in various diseases. This study aims to investigate the protective effects and mechanism of Pts against acetaminophen (APAP)-induced hepatotoxicity in vivo.
Methods:
C57BL/6 mice were treated with APAP or APAP+Pts. HepG2 cells were used to further explore the underlying mechanisms in vitro. The effects of Pts on hepatotoxicity were measured by commercial kits, Hematoxylin and Eosin (H&E) straining, TUNEL assay, Western blot analysis, and Flow cytometry assay.
Results:
In vivo, Pts treatment effectively protected against APAP-induced severe liver injury by decreasing the lethality rate, the serum alanine transaminase (ALT) and aspartate aminotransferase (AST) levels, liver histological injury, liver malondialdehyde (MDA) formation and myeloperoxidase (MPO) levels and by increasing liver glutathione (GSH) and superoxide dismutase (SOD) levels. Moreover, in Pts-treated mice, the nuclear factor-erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway was activated; however, APAP-induced c-Jun NH2-terminal kinase (JNK) activation, mitochondrial Bcl-2 Associated X Protein (Bax) translocation, apoptosis-inducing factor (AIF) levels and cytochrome c release were attenuated. In vitro, Pts was found to reverse hydrogen peroxide (H2O2) -induced cytotoxicity, reactive oxygen species (ROS) production and apoptosis that depended on Nrf2 activation. Moreover, Pts induced a dose-dependent increase in the phosphorylation of AMP-activated protein kinase (AMPK), serine/threonine kinase (Akt), and glycogen synthase kinase 3β (GSK3β) in HepG2 cells. Moreover, Pts protect against APAP or H2O2-induced toxicity were effectively attenuated or abolished in HepG2 Nrf2-/- cells and Nrf2-/- mice.
Conclusion:
Our data suggest that Pts protects against APAP-induced toxicity by activating Nrf2 via the AMPK/Akt/GSK3β pathway.
Abstract The linkage between oxidative stress and idiopathic chronic fatigue (ICF) has not been explored in detail. This study thoroughly compared the serum levels of biomarkers for oxidative stress and antioxidants from 103 subjects with ICF (20 men and 83 women) to those of 82 healthy volunteers (27 men and 55 women). Oxidative parameters, which included reactive oxygen species (ROS), malondialdehyde (MDA) and F2-isoprotan, and tumor necrosis factor-alpha (TNF-α) were significantly elevated, while antioxidant parameters, which included total antioxidant activity (TAC), catalase, superoxide dismutase, SOD and GSH activity, were decreased compared to those of healthy subjects (by approximately 1.2- to 2.3-fold, p
Background:
Grape seed proanthocyanidin extract (GSPE) has been extensively reported to possess a wide range of beneficial properties in multiple tissue damage. Previous studies have shown that exhaustive exercise-induced fatigue associates with oxidative stress injury, inflammatory response, and mitochondrial dysfunction.
Objective:
The aim of this study is to investigate the anti-fatigue effects of GSPE in mice and explore its possible underlying mechanism.
Design:
The mouse model of exhaustive exercise-induced fatigue was established by using the forced swimming test, and GSPE was orally treated for successive 28 days at 0, 1, 50 and 100 mg/kg/day of body weight, designated the control, GSPE-L, GSPE-M and GSPE-H groups, respectively.
Results:
The presented results showed that treatment of GSPE at a dose of 50 and 100 mg/kg/day of body weight significantly relieved exhaustive exercise-induced fatigue, indicated by increasing the forced swimming time. In addition, treatment of GSPE significantly improved the creatine phosphokinase and lactic dehydrogenase, as well as lactic acid level in exhaustive swimming. For underlying mechanisms, treatment of GSPE had anti-fatigue effects by promoting antioxidant ability and resisting oxidative effect, as represented by increased total antioxidative capability levels, enhanced superoxide dismutase and catalase activities, and ameliorated malondialdehyde levels. Furthermore, treatment of GSPE significantly inhibited the activity of tumor necrosis factor-α and interleukin-1β, which suggested that its protective effects on exhaustive exercise-induced fatigue may be attributed to inhibition of inflammatory response. Last but not the least, treatment of GSPE significantly improved succinate dehydrogenase and Na+-K+-ATPase levels to enhance mitochondrial function during exhaustive swimming-induced fatigue.
Conclusions:
These results proved that treatment of GSPE possessed the beneficial properties of anti-inflammatory, antioxidant, and mitochondrial protection to improve exhaustive exercise, which suggested that GSPE could be used as an effective functional food to delay fatigue.
Context: Oxidative stress has a critical role in the development of physical fatigue and activation of matrix metalloproteinases-9 (MMP-9). Naringin (Nar) is a bioflavonoid that has antioxidant activity and suppresses MMP-9 expression.
Objective: The present study evaluates the anti-fatigue activity of Nar on physical fatigue and serum MMP-9 concentration in rats.
Materials and methods: Fifty female Wistar rats were randomly divided into five groups (n = 10); a control group, vehicle group and three Nar treatment groups. The Nar treated groups received different doses of Nar (40, 80 and 160 mg/kg/day) for 30 days. On the 30th day, rats were sacrificed immediately after exhaustive swimming test. Serum MMP-9 concentration and several biochemical parameters related to fatigue were measured.
Results: Exhaustive swimming time in the Nar-80 group significantly increased 1.78-, 1.53-, 1.5- and 1.3-fold compared with the control, vehicle, Nar-40 and Nar-160 groups, respectively. In addition, exhaustive swimming time in the Nar-160 group significantly increased 1.36-fold compared with the control group. Nar-80 significantly decreased LDH activity by 60.45% and 57.47% compared with the vehicle and control groups, respectively. Furthermore, Nar-80 and Nar-160 increased blood glucose levels by 19.56% and 18.38% compared with the control group, respectively. Nar-80 and Nar-160 significantly decreased serum MMP-9 concentration by 61.57% and 83.39% compared with the control group, respectively.
Conclusion: Based on our data, Nar has anti-fatigue effects which may be attributed to its property in modulating energy metabolism and reducing serum MMP-9 concentration. Thus, Nar may be a promising agent for the treatment of physical fatigue.
Free radicals are reactive compounds that are naturally produced in the human body. They can exert positive effects (e.g. on the immune system) or negative effects (e.g. lipids, proteins or DNA oxidation). To limit these harmful effects, an organism requires complex protection - the antioxidant system. This system consists of antioxidant enzymes (catalase, glutathione peroxidase, superoxide dismutase) and non-enzymatic antioxidants (e.g. vitamin E [tocopherol], vitamin A [retinol], vitamin C [ascorbic acid], glutathione and uric acid). An imbalance between free radical production and antioxidant defence leads to an oxidative stress state, which may be involved in aging processes and even in some pathology (e.g. cancer and Parkinson's disease). Physical exercise also increases oxidative stress and causes disruptions of the homeostasis. Training can have positive or negative effects on oxidative stress depending on training load, training specificity and the basal level of training. Moreover, oxidative stress seems to be involved in muscular fatigue and may lead to overtraining.
Both acute bouts of prior exercise (preconditioning) and antioxidant nutrients have been used in an attempt to attenuate muscle injury or oxidative stress in response to resistance exercise. However, most studies have focused on untrained participants rather than on athletes. The purpose of this work was to determine the independent and combined effects of antioxidant supplementation (vitamin C + mixed tocopherols/tocotrienols) and prior eccentric exercise in attenuating markers of skeletal muscle injury and oxidative stress in resistance trained men.
Thirty-six men were randomly assigned to: no prior exercise + placebo; no prior exercise + antioxidant; prior exercise + placebo; prior exercise + antioxidant. Markers of muscle/cell injury (muscle performance, muscle soreness, C-reactive protein, and creatine kinase activity), as well as oxidative stress (blood protein carbonyls and peroxides), were measured before and through 48 hours of exercise recovery.
No group by time interactions were noted for any variable (P > 0.05). Time main effects were noted for creatine kinase activity, muscle soreness, maximal isometric force and peak velocity (P < 0.0001). Protein carbonyls and peroxides were relatively unaffected by exercise.
There appears to be no independent or combined effect of a prior bout of eccentric exercise or antioxidant supplementation as used here on markers of muscle injury in resistance trained men. Moreover, eccentric exercise as used in the present study results in minimal blood oxidative stress in resistance trained men. Hence, antioxidant supplementation for the purpose of minimizing blood oxidative stress in relation to eccentric exercise appears unnecessary in this population.
Fatigue syndrome is a major health problem that affects the voluntary activities of an individual. Particularly, exercise-induced fatigue has become a serious concern in people's health. Since polysaccharides from various medicinal plants have been reported for anti-fatigue effect, the current study deals with the anti-fatigue potential of water-soluble polysaccharides of the Chinese medicinal plant Semen cassiae (Cassia obtusifolia L.) in BALB/c mice. Water-soluble polysaccharides from Semen cassiae were extracted using aqueous solvent (water). An orthogonal test design was employed for the optimization of polysaccharide extraction. The conditions optimized through this design unveiled the raw materials to solvent ratio as 1:30. The optimal temperature and time duration were found to be 80°C and 3.5 h, respectively. The yield of soluble polysaccharides at these specified conditions was 5.42%. Strikingly, the water-soluble polysaccharide from S. cassiae exhibited strong anti-fatigue activity at 100 mg/kg in BALB/c mice. S. cassiae polysaccharide extended the weight-loaded swimming duration in BALB/c mice. In addition, it ameliorated the level of antioxidant enzymes (SOD, GPX) while decreased the blood urea nitrogen, creatine phosphokinase, triglyceride, lactic acid, lactate dehydrogenase, and malondialdehyde levels in blood serum. Moreover, the assessment of the immunomodulatory effect of S. cassia polysaccharides unveiled the enhancement of B-cell and T-cell lymphocytes, denoting the positive effect on physical immunity.
Objective
To examine acute (single-bout) and training effects of high-intensity interval training (HIIT) vs standard exercise therapy (moderate continuous training [MCT]) on plasma neurofilament light chain (pNfL) and kynurenine (KYN) pathway of tryptophan degradation metabolites in persons with multiple sclerosis (pwMS).
Methods
Sixty-nine pwMS (Expanded Disability Status Scale score 3.0–6.0) were randomly assigned to a HIIT or an MCT group. Changes in pNfL and KYN pathway metabolites measured in blood plasma were assessed before, after, and 3 hours after the first training session as well as after the 3-week training intervention.
Results
Acute exercise reduced pNfL and increased the KYN pathway flux toward the neuroprotective kynurenic acid (KA). Changes in pNfL correlated positively with changes in KA and negatively with the quinolinic acid-to-KA ratio. HIIT consistently led to greater effects than MCT. Following the 3-week training intervention, the KYN pathway was activated in HIIT compared with MCT.
Conclusion
Future studies and clinical assessments of pNfL should consider acute exercise as confounding factor for measurement reliability. Moreover, exercise-induced KYN pathway rerouting might mediate neuroprotection, potentially underlying the benefits in rehabilitation for pwMS.
Classification of Evidence
This study provides Class II evidence that acute HIIT diminishes pNfL and increases KA levels, and 3 weeks of HIIT activate the KYN pathway in pwMS.
Trial Registration Information
Clinical trial registration number: NCT03652519 .
A novel neutral exopolysaccharide (EPS-III) was isolated from culture broth of Cordyceps militaris (C. militaris). The EPS-III was a homogeneous polysaccharide with Mw of 1.56 × 10³ kDa. The yield of EPS-III from culture broth was 123.2 ± 3.1 mg/L and the sugar content was 93.32 ± 0.87%. The backbone of EPS-III was mainly consisted of →4)-α-D-Galp-(1→, while →3, 6)-α-D-Manp-(1→, →4)-α-D-Manp-(1→, →3)-β-D-Galp-(1→ and →3)-α-D-Glcp-(1→ were distributed in the backbone or in the branch chains. The EPS-III had helix structure when dissolved in weak alkaline solution. It also had branched and intertwined form on the surface. The inhibition of α-glucosidase significantly increased as the increase of purity of exopolysaccharides. The EPS-III had effective inhibition on the α-glucosidase with dose-effect relationship. Besides, the results of hypoglycemic activity analysis in vivo indicated that EPS-III can alleviate weight loss, reduce plasma glucose concentration, improve glucose tolerance, protect immune organs and repair dyslipidemia to relieve diabetes in STZ-induced diabetic mice. The manuscript first studied the hypoglycemic activity of exopolysaccharide of by C. militaris, proving and promoting the application value of culture broth. The structure characterization of EPS-III laid experimental foundations on the exploration of structure-activity relationship.
Cordyceps is a parasitic edible fungus with a variety of metabolically active ingredients. The main active ingredient, extracellular polysaccharide (EPS), shows favourable application prospects in prevention and treatment of certain diseases. EPS extracted from different parts of various Cordyceps species can be used in health foods or medicinal preparations because of the structural diversity and multiple bioactivities. In terms of the complexity of composition and structure, researchers have speculated on the anabolic pathways of EPSs and the genes involved in the synthesis process. Studies to increase the yield of polysaccharides are limited because the synthesis pathways and anabolic regulation mechanisms of Cordyceps exopolysaccharide remain unknown. This review summarises the current researches in the yield of Cordyceps polysaccharides. A mechanism for the biosynthesis of Cordyceps polysaccharides was proposed by referring to the polysaccharide synthesis in other species. Furthermore, we also discuss the future perspective and ongoing challenges of EPS in uses of health foods and pharmaceutics.
In this study, three sulfated polysaccharides (S-RSP1-2, S-RSP1-4 and S-RSP1-8) from Rhodiola sachalinensis were produced by chlorosulfonic acid-pyridine method. d-gal was used to develop an oxidative stress model in the mouse embryonic fibroblast cell line NIH 3T3. Effects of the three sulfated polysaccharides on d-gal-induced oxidative stress were investigated. The results showed that S-RSP1-4 improved the viability of the d-gal-induced oxidative stress in NIH 3T3 cells. The sulfated polysaccharides were found to have a better protective effect against d-gal-induced oxidative stress as compared to the native polysaccharide. Scanning electronmicroscopy also showed a significant change in the surface morphology of sulfated polysaccharides. In addition, the sulfated polysaccharides had noticeable DPPH radical-scavenging activity. In summary, our results demonstrated that d-gal was able to induce oxidative stress in NIH 3T3 cells, and sulfated group might play an important role in resistance to d-gal-induced oxidative damage.
The study of metabolomics in natural products using the diverse analytical instruments including GC-MS, LC-MS, and NMR is useful for the exploration of physiological and biological effects and the investigation of drug discovery and health functional foods. Cordyceps militaris has been very attractive to natural medicine as one of traditional Chinese medicines, due to its various bioactive properties including anti-cancer and anti-oxidant effects. In this study, we analyzed the metabolites profile in 50% ethanol extracts of C. militaris fruit bodies from three development periods (growth period, matured period, and aging period) using 1H-NMR, and identified 44 metabolites, which are classified as 16 amino acids, 10 organic acids, 5 carbohydrates, 3 nucleotide derivatives, and 10 other compounds. Among three development periods of C. militaris fruit body, the aging period showed significantly higher levels of metabolites including cordycepin, mannitol (cordycepic acid), and β-glucan. Interestingly, these bioactive metabolites are positively correlated with anti-tumor growth effect; the extract of aging period showed significant inhibition of HepG2 hepatic cancer cell proliferation. These results showed that the aging period of the developmet of C. militaris fruit bodies was enriched in the contents of bioactive metabolites which were associated with the biological effect of cancer cell growth inhibition.
In the present study, we obtained polysaccharides from Sagittaria sagittifolia L. (SSP) with subcritical water extraction (SWE). Two water-soluble polysaccharides (SSP-W1 and SSP-S1) from the acquired SSP were isolated with DEAE-52 and Sephadex G-100. Besides, the structural characteristics and immunostimulatory activity were also investigated. The results showed that both SSP-W1 and SSP-S1 were homogeneous polysaccharides and the molecular weight was 62.03 KDa and 15.2 KDa, respectively. In addition, both SSP-W1 and SSP-S1 are heteropolysaccharides. Moreover, FT-IR analysis showed that SSP-W1 was α-pyranose polysaccharide, while SSP-S1 was a typical β-pyranose polysaccharide. Congo red staining showed that there was no triple helix structure in both SSP-W1 and SSP-S1. Furthermore, both SSP-W1 and SSP-S1 could promote the proliferation, production of NO, and secretion of TNF-α and IL-10 of macrophages RAW 264.7, significantly. Therefore, the polysaccharides extracted from Sagittaria sagittifolia L. with SWE have the potential to be used as immunoreactive agent in medicine and functional foods.
Rheum rhabarbarum has been widely used as a herbal medicine and food in China. The objective of this study was to investigate the cytoprotective action and underlying mechanisms of rhein, one active ingredient isolated from R. rhabarbarum, on H2O2-challenged rat small intestine epithelial cells (IEC-6 cells). H2O2-challenged IEC-6 cells were incubated in the pretreatment with or without rhein or LY294002, a PI3K/Akt inhibitor. The cell viability, apoptosis, intracellular reactive oxygen species (ROS), and antioxidants were measured. The expressions of heme oxygenase 1 (HO-1), nuclear factor erythroid 2-related factor (Nrf2), Akt, and p-Akt were evaluated by western blotting. Meanwhile, LY294002 was also used to investigate the role of PI3K/Akt in the rhein-induced cytoprotective role. The results showed that pretreatment of rhein could reverse the inhibition of cell viability and suppress the apoptosis, caspase-3 activity, and intracellular ROS induced by H2O2. Rhein also supported SOD activity catalase activity, glutathione S-transferase activity, and glutathione content. Furthermore, rhein induced the protein expression of HO-1 together with its upstream mediator Nrf2 and activated the phosphorylation of Akt in IEC-6 cells. LY294002 inhibited increased cell viability, upregulated the lowered apoptotic rate, and enhanced the weakened ROS levels. Although the inhibition of PI3K/Akt did not inhibit the Nrf2 nuclear level under 4 μM rhein, LY294002 inhibited the Nrf2 nuclear level under 2 μM rhein and blocked HO-1 expression. These data demonstrated that rhein protected IEC-6 cells against oxidative damage partly via PI3K/Akt and Nrf2/HO-1 pathways.
Mitochondria play essential roles in cellular bioenergetics, biosynthesis, and apoptosis. During the process of respiration and oxidative phosphorylation, mitochondria utilize oxygen to generate ATP, and at the same time, there is an inevitable generation of reactive oxygen species (ROS). As excess ROS create oxidative stress and damage cells, the proper function of the antioxidant defense system is critical for eukaryotic cell survival under aerobic conditions. Nuclear factor, erythroid 2-like 2 (Nfe2l2/Nrf2) is a master transcription factor for regulating basal as well as inducible expression of multiple antioxidant proteins. Nrf2 has been involved in maintaining mitochondrial redox homeostasis by providing reduced forms of glutathione (GSH); the reducing cofactor NADPH; and mitochondrial antioxidant enzymes such as GSH peroxidase 1, superoxide dismutase 2, and peroxiredoxin 3/5. In addition, recent research advances suggest that Nrf2 contributes to mitochondrial regulation through more divergent intermolecular linkages. Nrf2 has been positively associated with mitochondrial biogenesis through the direct upregulation of mitochondrial transcription factors and is involved in the mitochondrial quality control system through mitophagy activation. Moreover, several mitochondrial proteins participate in regulating Nrf2 to form a reciprocal regulatory loop between mitochondria and Nrf2. Additionally, Nrf2 modulation in cancer cells leads to changes in the mitochondrial respiration system and cancer bioenergetics that overall affect cancer metabolism. In this review, we describe recent experimental observations on the relationship between Nrf2 and mitochondria, and further discuss the effects of Nrf2 on cancer mitochondria and metabolism.
The neurotrophin Brain-Derived Neurotrophic Factor (BDNF) induces complex neuronal
signaling cascades that are critical for the cellular changes underlying synaptic plasticity.
These pathways include activation of Ca2+ entry via N-methyl-D-aspartate receptors and
sequential activation of nitric oxide synthase and NADPH oxidase, which via generation of
reactive nitrogen/oxygen species stimulate Ca2+-induced Ca2+ release mediated by
Ryanodine Receptor (RyR) channels. These sequential events underlie BDNF-induced
spine remodeling and type-2 RyR up-regulation. In addition, BDNF induces the nuclear
translocation of the transcription factor Nrf2, a master regulator of antioxidant protein
expression that protects cells against the oxidative damage caused by injury and
inflammation. To investigate the possible BDNF-induced signaling cascades that mediate
Nrf2 nuclear translocation in primary hippocampal cultures, we tested here whether
reactive oxygen species, RyR-mediated Ca2+ release, ERK or PI3K contribute to this
response. We found that pre-incubation of cultures with inhibitory ryanodine to suppress
RyR-mediated Ca2+ release, with the reducing agent N-acetylcysteine or with inhibitors of
ERK or PI3K activity, prevented the nuclear translocation of Nrf2 induced by incubation
for 6 h with BFNF. Based on these combined results, we propose that the key role played
by BDNF as an inducer of neuronal antioxidant responses, characterized by BDNF-induced
Nfr2 nuclear translocation, entails crosstalk between reactive oxygen species and RyRmediated Ca2+ release, and the participation of ERK and PI3K activities.
Alzheimer's disease (AD) is a neurodegenerative disorder associated with loss of memory and cognitive abilities. Previous evidence suggested that exercise ameliorates learning and memory deficits by increasing brain derived neurotrophic factor (BDNF) and activating downstream pathways in AD animal models. However, upstream pathways related to increase BDNF induced by exercise in AD animal models are not well known. We investigated the effects of moderate treadmill exercise on Aβ-induced learning and memory impairment as well as the upstream pathway responsible for increasing hippocampal BDNF in an animal model of AD. Animals were divided into five groups: Intact, Sham, Aβ1-42, Sham-exercise (Sham-exe) and Aβ1-42-exercise (Aβ-exe). Aβ was microinjected into the CA1 area of the hippocampus and then animals in the exercise groups were subjected to moderate treadmill exercise (for 4 weeks with 5 sessions per week) 7 days after microinjection. In the present study the Morris water maze (MWM) test was used to assess spatial learning and memory. Hippocampal mRNA levels of BDNF, peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α), fibronectin type III domain-containing 5 (FNDC5) as well as protein levels of AMPK-activated protein kinase (AMPK), PGC-1α, BDNF, phosphorylation of AMPK were measured. Our results showed that intra-hippocampal injection of Aβ1-42 impaired spatial learning and memory which was accompanied by reduced AMPK activity (p-AMPK/total-AMPK ratio) and suppression of the PGC-1α/FNDC5/BDNF pathway in the hippocampus of rats. In contrast, moderate treadmill exercise ameliorated the Aβ1-42-induced spatial learning and memory deficit, which was accompanied by restored AMPK activity and PGC-1α/FNDC5/BDNF levels. Our results suggest that the increased AMPK activity and up-regulation of the PGC-1α/FNDC5/BDNF pathway by exercise are likely involved in mediating the beneficial effects of exercise on Aβ-induced learning and memory impairment.
A water soluble polysaccharide (SSPW1), with an average molecular weight of 191.18KD, was isolated and purified from the water extract of Schisandra sphenanthera by DEAE-52 and Sephadex G-100 column chromatography. SSPW1 contained 48.92% neutral sugar, 5.56% proteins and 42.83% uronic acid, and were composed of rhamnose, arabinose, mannose, galactose, glucose at a molar ratio of 13.52, 5.69, 3.92, 41.28 and 35.59. In vitro experiment showed that SSPW1 have a satisfactory scavenging effect on superoxide anion free radical, hydroxyl radical and DPPH free radical. In vivo experiment showed that SSPW1 could increase the body weight, improve the glucose tolerance, reduce FBG, and elevate the levels of FINS and the value of ISI in the diabetic rats. In addition, SSPW1 could reduce the MDA content, and increase GSH-PX, CAT and SOD activities. These results suggest that SSPW1 has both in vitro and in vivo antioxidant effect, which may be closely related to its antidiabetic effect.
Emerging findings suggest that brain-derived neurotrophic factor (BDNF) serves widespread roles in regulating energy homeostasis by controlling patterns of feeding and physical activity, and by modulating glucose metabolism in peripheral tissues. BDNF mediates the beneficial effects of energetic challenges such as vigorous exercise and fasting on cognition, mood, cardiovascular function, and on peripheral metabolism. By stimulating glucose transport and mitochondrial biogenesis BDNF bolsters cellular bioenergetics and protects neurons against injury and disease. By acting in the brain and periphery, BDNF increases insulin sensitivity and parasympathetic tone. Genetic factors, a 'couch potato' lifestyle, and chronic stress impair BDNF signaling, and this may contribute to the pathogenesis of metabolic syndrome. Novel BDNF-focused interventions are being developed for obesity, diabetes, and neurological disorders.
To evaluate the immune activation and reactive oxygen species scavenging activity of Cordyceps militaris polysaccharides (CMP) in vivo, 90 male BALB/c mice were randomly divided into six groups. The mice in the three experimental groups were given cyclophosphamide at 80 mg/kg/d via intraperitoneal injection and 17.5, 35, or 70 mg/kg body weight CMP via gavage. The lymphocyte proliferation, phagocytic index, and biochemical parameters were measured. The results show that the administration of CMP was able to overcome the CY-induced immunosuppression, significantly increased the spleen and thymus indices, and enhanced the spleen lymphocyte activity and macrophage function. CMP can also improve the antioxidation activity in immunosuppressed mice, significantly increase the superoxidase dismutase, catalase, and glutathione peroxidase levels and the total antioxidant capacity, and decrease the malondialdehyde levels in vivo.
The acid polysaccharide fraction (APSF) extracted from the mycelia of cultivated Cordyceps sinensis is water-soluble polysaccharide. In this study we evaluated the modulating effects of APSF on murine macrophage cell line RAW264.7. Phagocytotic assay by neutral red and FITC-dextran internalization showed that APSF stimulated the phagocytosis of macrophages. The nitrite levels in the culture supernatant determined using Griess reagent revealed the elevation of NO production after treatment with APSF. RT-PCR and immunocytochemistry assay indicated that APSF promoted both the mRNA and protein expressions of inducible nitric oxide synthase (iNOS). Furthermore, Western blotting demonstrated that NF-kappaB levels in nucleuses increased after APSF treatment, suggesting that APSF probably stimulated macrophage activities by activating the IkappaB-NF-kappaB pathway.
An acidic polysaccharide (APS) was isolated from the extract of Cordyceps militaris grown on germinated soybeans. Analyses of sugar composition indicated that APS consisted of d-galactose, L-arabinose, D-xylose, L-rhamnose, and D-galacturonic acid. On the basis of the result of methylation analysis, APS was considered to be mainly composed of Araf-(1-->, -->5)-Araf-(1-->, -->4)-Galp-(1--> and -->4)-GalAp-(1--> residues. When the polysaccharide was intranasally administered, it decreased virus titers in the bronchoalveolar lavage fluid and the lung of mice infected with influenza A virus and increased survival rate. Furthermore, APS increased TNF-alpha and IFN-gamma levels in mice when compared with those of untreated mice. APS enhanced nitric oxide (NO) production and induced iNOS mRNA and protein expressions in RAW 264.7 murine macrophage cells. The induction of mRNA expression of cytokines including IL-1beta, IL-6, IL-10, and TNF-alpha was also observed. These results demonstrated that APS might have beneficial therapeutic effects on influenza A virus infection at least in part by modulation of the immune function of macrophages.
Research progress on extraction and purification and biological activity of edible fungi polysaccharides
- Zhao
Glu/GABA learning and memory regulatory system in the brain
- Zhang
Comparative study of polysaccharide content and antioxidant activity of Chrysalis and Cordyceps rice
- Bai
Study on the effect of ginsenoside Rg1 in alleviating exercise fatigue in immunosuppressed mice[J]
- Kong
Astrocyte truncated tropomyosin receptor kinase B mediates brain-derived neurotrophic factor anti-apoptotic effect leading to neuroprotection
- Saba