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Role of antioxidants in chronic fatigue syndrome

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Abstract

The present study was carried out using mice model of chronic fatigue syndrome (CFS) in which mice were forced to swim everyday for 7 days for a 6 min session. There was a significant increase in despair behavior (immobility period) in saline treated mice on successive days. Treatment with potent antioxidants carvedilol (5 mg/kg, i.p.) and melatonin (10 mg/kg, i.p.) produced a significant reduction in immobility period. Similar results were observed with herbal products St. John's Wort (Hypericum perforatum L) (10 mg/kg, p.o.) and GS-02 (20 mg/kg, p.o.). Fluoxetine, a selective serotonin reuptake inhibitor produced a significant effect only on first and second day of its treatment. Biochemical analysis revealed that chronic swim test significantly increased lipid peroxidation and catalase levels in whole brains of mice. There was a decrease in the levels of super oxide dismutase (SOD) and glutathione reductase (GSH) in the brain. Administration of carvedilol, melatonin, GS-02 and St. John's Wort restored the levels of lipid peroxidation and glutathione. The enzymes SOD and catalase were also restored. Fluoxetine affected the biochemical variables not to the same extent as other treatments. The findings of the present study suggest that oxidative stress might play a significant role in the pathophysiology of CFS. Thus antioxidants and herbal products like St. Johns wort and GS-02 could be useful in the treatment of CFS.

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... For catalase assay, the post nuclear fraction was obtained by centrifugation of the homogenate at 1000 g for 15 min at 4 °C. For malondialdehyde (MDA) assay homogenate was centrifuged at 12000 g for 60 min at 4 °C (17). Biochemical assessment of brain homogenate included the following: ...
... The method of 7 days exposure of mouse to forced swimming is a well validated animal model of CFS (17). In this model, mice are chronically exposed to aversive situation (swimming) from which there is no possibility to escape. ...
... It also inhibits the enzyme nitric oxide synthase. (17). Thus flavonoid content of EECF may be responsible for the beneficial effects of EECF in CFS. ...
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The fruit of Cassia fistula Linn. is a legume, has antioxidant and lots of other medicinal properties. As oxidants are involved in the pathogenesis of chronic fatigue syndrome, the present study was done to evaluate the effect of ethanolic extract of fruit pulp of C. fistula Linn. (EECF) on forced swimming induced chronic fatigue syndrome (CFS). Albino mice of 25-40 grams were grouped into five groups (n=5). Group A served as naive control and group B served as stress control. Group C received EECF 200 mg/kg and group D received EECF 400 mg/kg respectively. Group E received imipramine 20 mg/kg (standard). All animals were treated with their respective agent orally daily for 7 days. Except for group A, animals in other groups were subjected to force swimming 6 min daily for 7 days to induce a state of chronic fatigue. Duration of immobility was assessed on day 1st, 3rd, 5th and 7th. Anxiety level (by elevated plus maze and mirrored chamber) and loco-motor activity (by open field test) were assessed 24 h after last force swimming followed by biochemical estimations of oxidative biomarkers in brain homogenate at the end of study. Treatment with EECF resulted in significant reduction in the duration of immobility, reduced anxiety and increased locomotor activity. Malondialdehyde level was also reduced and catalase level was increased in the extract treated group and standard group compared to stress control group. The study indicates that EECF has protective effect against experimentally induced CFS.
... Chronic fatigue syndrome (CFS) is a heterogeneous disorder [1] characterized by persistent and unexplained fatigue, which results in severe impairment of daily functioning. [2] CFS patients complain of headache, gastrointestinal disturbance, paresthesia, cognitive dysfunction, neuropsychiatric problems (e.g., anxiety), [3] depression, and immunological disturbances. ...
... [2] CFS patients complain of headache, gastrointestinal disturbance, paresthesia, cognitive dysfunction, neuropsychiatric problems (e.g., anxiety), [3] depression, and immunological disturbances. [1] Oxidative stress [4,5] and nitric oxide (NO) are being proposed in pathophysiology of CFS. [3] Psychological and physical stress may elicit the onset of CFS. ...
... [7,8] Various anti-oxidants were found to be useful in treatment of CFS. [1,7] Imipramine and citalopram were found to have neuroprotective effect against CFS-induced biochemical and behavioral alterations. [3] Caesalpinia bonducella Flem, belongs to the family Fabaceae, is a shrub which is widely distributed all over the world, especially in India and Sri Lanka. ...
... In the mouse model of chronic fatigue in which mice were forced to swim every day for 7 days for a 6 min session, potent antioxidants as well as the antioxidant rich herbal product, St John's Wort (Hypericum perforatum L), produced a significant reduction in the immobility period (Singh et al., 2002). Similarly, Trichopus zeylanicus treatment is known to combat fatigue, resulting in an extended swim time in laboratory rodents in the forced swim test (Pushpangadan et al., 1988;Singh et al., 2001, Evans et al., 2002). ...
... Mitochondrial membrane glycophospholipids, fatty acids and other essential lipids are damaged by the oxidation process. A significant increase in lipid peroxidation in the whole brain tissue is reported in mice subjected to the chronic swim test (Singh et al., 2002). Lipid peroxidation is also known to play an important role in the pathophysiology of chronic fatigue syndrome (Manuel y Keenoy et al., 2001). ...
Article
Chronic fatigue is considered a complex symptom for which currently there is no curative treatment available. Oxidative stress plays an important role in the etiology of fatigue and antioxidant treatment might be a valuable therapeutic approach. The Kani, a tribal high altitude living population in southern India, traditionally use the seeds of Trichopus zeylanicus to combat fatigue. In this study, the antioxidant properties of Trichopus zeylanicus were established on free radicals (DPPH and ABTS), its ability to reduce iron, lipoxygenase activity and hydrogen peroxide-induced lipid peroxidation. The effects of Trichopus zeylanicus on reactive oxygen species induced plasmid DNA (pBR322) cleavage were also investigated. Trichopus zeylanicus significantly scavenged free radicals, reduced lipid peroxidation and inhibited lipoxygenase activity. Trichopus zeylanicus also exhibited iron-chelating activity and inhibited reactive oxygen species induced DNA damage. Trichopus zeylanicus contains NADH, polyphenols and sulfhydryl compounds, which have the ability to scavenge reactive oxygen species suggesting that the antioxidant activity may be an important mechanism of action of Trichopus zeylanicus to combat fatigue.
... There is emerging evidence supporting an early and major role of mechanisms able to cope with oxidative stress and to protect against oxidative damage in the response to stress (Jazwinski, 1996;Parsons, 1995). Such hypotheses derive from work on the invertebrate fruit-fly and nematode C. elegans, but several recent rodents studies report an increase in oxidative mediators and associated damage to the brain (Abidin et al., 2004;Bhattacharya et al., 2001;Bhattacharya et al., 2000;Fontella et al., 2005;Kaushik and Kaur, 2003;Lee et al., 2006;Liu et al., 1996;Madrigal et al., 2001Madrigal et al., , 2003Manoli et al., 2000;Munhoz et al., 2004;Pajovic et al., 2005;Radak et al., 2001;Reagan et al., 2000;Singal et al., 2005;Singh et al., 2002;Zaidi and Banu, 2004; see Table 1) and other organs (Davydov and Shvets, 2003;Zaidi et al., 2005) after acute and chronic stress exposure. The acute stress response is meant to be protective to the organism. ...
... Recently, this variable was found to predict age-related cognitive and neuroendocrine alterations which were prominent in a low self-esteem group but unaffected by age in a high self-esteem group (Pruessner et al., 2004). (Singh et al., 2002;Singal et al., 2005) Copper, zinc-superoxide dismutase (CuZnSOD), cyclooxygenase 2 (COX-2), glutathione peroxidase (GPx), glutathione reductase (GRe), glutathione (GSH), glutathione-S-transferase (GST), manganese-superoxide dismutase (MnSOD), inducible nitric oxide synthase (NOS-2), reactive oxygen species (ROS), total superoxide dismutase (SOD). ...
Article
Gerontology has made considerable progress in the understanding of the mechanisms underlying the ageing process and age-related neurodegenerative disorders. However, ways to improve quality of life in the elderly remain to be elucidated. It is now clear that stress and the ageing process share a number of underlying mechanisms bound in a very close, if not indissociable, relationship. The ageing process is regulated by the factors underlying the ability to adjust to stress, whilst stress has an influence on the life span and the quality of ageing. In addition, the ability to cope with stress in adulthood predicts life expectancy and quality of life at senescence. The ageing process and stress also share several common mechanisms, particularly in relation to the energy factor. Stress consumes energy and ageing may be considered as a cost of the energy expended to deal with the stressors to which the body is exposed throughout its lifetime. This suggests that the ageing process is associated with and/or a consequence of a long-lasting activation of the major stress responsive systems. However, despite common features, the interaction between stress and the ageing process gives rise to some paradoxes. Stress can either diminish or exacerbate the ageing process just as the ageing process can worsen or counter the effects of stress. There has been little attempt to understand how ageing and stress might interact to promote "successful" or pathological ageing. A key factor in this respect is the individual's ability to adapt to stress. Viewed from this angle, the quality of life of aged subjects may be improved through therapy designed to improve the tolerance to stress.
... In another mouse model of CFS, chronic fatigue was correlated with elevated markers of oxidative stress [41][42][43]. A number of antioxidants were found to be useful in treatment [41][42][43], suggesting that oxidative stress has a substantial causal role. ...
... In another mouse model of CFS, chronic fatigue was correlated with elevated markers of oxidative stress [41][42][43]. A number of antioxidants were found to be useful in treatment [41][42][43], suggesting that oxidative stress has a substantial causal role. ...
Article
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Cases of chronic fatigue syndrome/mylagic encephalomyelitis (CFS) are reported to be initiated by nine different short-term stressors, each of which increase levels of nitric oxide in the body. Elevated nitric oxide, acting through its oxidant product, peroxynitrite, initiates a local biochemical vicious cycle, the NO/ONOO-cycle, which is proposed to be the cause CFS and related diseases. Evidence supporting this cycle mechanism in CFS comes from each of the following types of evidence: Case initiation by such stressors, the extensive evidence supporting the existence of individual cycle mechanisms, evidence showing that various cycle elements are elevated in CFS cases, evidence for a basically local mechanism in CFS and related disease, evidence from CFS animal models, genetic evidence from genetic polymorphism studies and evidence from clinical trials of agents predicted to down-regulate the NO/ONOO-cycle. Each of the five principles underlying the NO/ONOO-cycle mechanism is supported by one or more of the above described types of evidence. The cycle involves oxidative stress, excessive nitric oxide synthase (NOS) activity, mitochondrial dysfunction, inflammatory biochemistry, excitotoxicity including excessive NMDA activity and tetrahydrobiopterin depletion. There is evidence, ranging from extensive to modest, supporting roles for each of these in CFS. Clinical studies of treatment protocols containing 14 or more agents predicted to down-regulate the NO/ONOO-cycle appear to be effective in the treatment of CFS and related diseases. However, none of these have yet been shown to be able to cure substantial numbers of cases of CFS or related illnesses. The author discusses one such protocol and suggests an approach, previously tested only as a single agent treatment, that may strenthen these multi-agent protocols to obtain at least some of the needed cures.
... ME/CFS has been reported as a multisystemic disease in which neuronal function is inhibited by the activation of ROS/RNS and immuno-inflammatory pathways [51]. Increased ROS induced by oxidative stress in the pathological mechanism of ME/CFS induces depression-or pain-like behaviors through decreased levels of anti-oxidative enzymes, such as SOD, catalase, and glutathione, and increased lipid peroxidation [52]. Meanwhile, scavenging of oxygen free radicals by antioxidants induces the activation of antioxidant enzymes and inhibition of cytokine release by nitric oxide synthase (NOS), contributing to the prevention or treatment of ME/CFS [53]. ...
Article
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Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is associated with various symptoms, such as depression, pain, and fatigue. To date, the pathological mechanisms and therapeutics remain uncertain. The purpose of this study was to investigate the effect of myelophil (MYP), composed of Astragali Radix and Salviaemiltiorrhizae Radix, on depression, pain, and fatigue behaviors and its underlying mechanisms. Reserpine (2 mg/kg for 10 days, intraperitoneally) induced depression, pain, and fatigue behaviors in mice. MYP treatment (100 mg/kg for 10 days, intragastrically) significantly improved depression behaviors, mechanical and thermal hypersensitivity, and fatigue behavior. MYP treatment regulated the expression of c-Fos, 5-HT1A/B receptors, and transforming growth factor β (TGF-β) in the brain, especially in the motor cortex, hippocampus, and nucleus of the solitary tract. MYP treatment decreased ionized calcium binding adapter molecule 1 (Iba1) expression in the hippocampus and increased tyrosine hydroxylase (TH) expression and the levels of dopamine and serotonin in the striatum. MYP treatment altered inflammatory and anti-oxidative-related mRNA expression in the spleen and liver. In conclusion, MYP was effective in recovering major symptoms of ME/CFS and was associated with the regulation of dopaminergic and serotonergic pathways and TGF-β expression in the brain, as well as anti-inflammatory and anti-oxidant mechanisms in internal organs.
... These radicals are scavenged by SOD to form H 2 O 2 and this will be further neutralized by the catalytic activity of CAT and GPx and thereby diminishes the toxic effects of the radical. The free radicals from the crackers smoke are capable of reducing molecular oxygen to superoxide and other free radicals whose excessive generation inactivates these antioxidant enzymes (Anand et al., 2012;Singh et al., 2002). In addition non-enzymatic antioxidants also become weaker during chronic fatigue and stress. ...
... It has also been shown that plasma lipid peroxidation is elevated in CFS patients (Brkic et al., 2010), indicating a poor membrane integrity. It has also been shown that supplements of essential fatty acids can relieve the symptoms in CFS patients (Warren et al., 1999), while antioxidant supplements have been shown to be effective in the animal model (Singh et al., 2002). However, blood acidosis may also affect cellular membrane function, hence the underpinning mechanism of CFS cannot be fully resolved directly in this work, and extensive further work with detailed blood composition analysis is necessary to validate the pathophysiological model implicated here. ...
Article
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Cerebral blood flow (CBF) is maintained despite changing systemic blood pressure through cerebral vascular control, with such tight regulation believed to be under local tissue control. Chronic fatigue syndrome (CFS) associates with a wide range of symptoms, including orthostatic intolerance, skeletal muscle pH abnormalities and cognitive impairment. CFS patients are known to have reduced CBF and orthostatic intolerance associates with abnormal vascular regulation, while skeletal muscle pH abnormalities associate with autonomic dysfunction. These findings point to autonomic dysfunction as the central feature of CFS, and cerebral vascular control being influenced by factors outside of the brain, a macroscopic force affecting the stability of regional regulation. We therefore explored whether there was a physiological link between cerebral vascular control and skeletal muscle pH management in CFS. Seventeen consecutive CFS patients fulfilling the Fukuda criteria were recruited from our local CFS clinical service. To probe the static scenario, CBF and skeletal muscle pH were measured at rest using MRI and 31P magnetic resonance spectroscopy (31P-MRS). To examine dynamic control, brain functional MRI was performed concurrently with Valsalva manoeuvre (VM), a standard autonomic function challenge, while 31P-MRS was performed during plantar flexion exercise. Significant inverse correlation was seen between CBF and skeletal muscle pH at rest (r = − 0.67, p < 0.01). Prolonged cerebral vascular constriction during the sympathetic phase of VM was associated with higher pH in skeletal muscle after plantar flexion exercise (r = 0.69, p < 0.008). In conclusion, cerebral vascular control is closely related to skeletal muscle pH both at rest and after dynamic stimulation in CFS.
... This is important when we consider that other potential advantages of carvedilol include the suppression of seizures which may be more common in diabetic and stroke patients (Kirchner et al., 2006;Schwechter et al., 2003;El-kharashi and El-Samad, 2011;Goel and Goel, 2013). Carvedilol is more potent than amlodipine in preventing cytotoxicity in cortical neurons from stroke-prone states (Yamagata et al., 2004).Carvedilol's inhibition of acid sphingomyelinase (Reddy et al., 2014) leads to inhibition of ceramide production (Beckmann et al., 2014) and this may likely contribute to beneficial effects in insulin resistance (Smith et al., 2006;Hansen et al., 2014), status epilepticus (Mikati et al., 2003;Schauwecke, 2012), Alzheimer's disease, bipolar disorder and depression which may be co-morbid with DCM (Arrieta-Cruz et al., 2010;Schwarz et al., 2008;Singh et al., 2002). Score in the GDS became normal after 3 months in this patient. ...
Article
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The incidence of diabetic cardiomyopathy, the leading cause of heart failure amongst diabetic patients, is on the increase in the same proportion with the ageing of the population. Reactive oxygen species (ROS) and mitochondrial dysfunction are front runners in the mechanisms of the pathobiology of diabetic cardiomyopathy. Carvedilol reverses mitochondria to nucleus stress signalling and the retrograde response to offer survival advantages over other beta adrenoceptor antagonists due to its peculiar mechanisms of action, especially its anti-oxidant effect which is tenfold above that of vitamin E. The nitric oxide and hydrogen sulphide dependent vasodilator carvedilol is a biased agonist at β I-adrenoceptors involving β I-arrestin-mediated downstream transactivation of the epidermal growth factor receptor (EGFR) and extra-cellular signal-regulated kinase (ERK) which signals to increase Akt-mediated cardioprotection, anti-apoptosis, mitochondrial biogenesis and insulin sensitivity. Upregulation of Transforming growth factor beta (TGF-β) activity and increased central sympathetic outflow by central neurons may be a sequel of increased superoxide generation from free fatty acids (FFA) and shear stress mediated uncoupling of endothelial nitric oxide synthase (eNOS), hyperglycaemic stress, ET-I activation and AT I A-R upregulation. The anti-oxidant carvedilol reduces cardiac catecholamine toxicity by inhibition of ROS-mediated upregulation of central Rho A and ROCK II kinase to decrease central sympathetic activation and baroreceptor imbalance while attenuating eNOS mRNA destabilisation. It thus successfully redresses the sympatho-cholinergic imbalance, chronotropic incompetence and enhanced arrhythmogenesis in heart failure. Carvedilol also blocks transforming growth factor-beta (TGF-β)-mediated calcineurin phosphatase activity and thus decreases extracellular matrix (ECM) accumulation and cardiac hypertrophy. This case report is of an elderly Nigerian male patient with diabetes induced dilated cardiomyopathy who responded well to active management with adjunctive carvedilol after the apparent non-response to adjunctive metoprolol. After 3 months on carvedilol treatment, ejection fraction rose from 39±2% to 45± 4% and there was also improvement in well-being as reflected in the Geriatric Depression Scale which fell from 14.20 ± 5 to 8.50 ± 4. Carvedilol may thus be the ideal beta-blocker for patients with diabetes mellitus with cardiomyopathy and deserves regular deployment.
... Various studies have now focused on the involvement of reactive oxygen species in the pathophysiology of fatigue (Singh et al., 2002;McKenna et al., 2006;Ferreira and Reid, 2008). There is an increase in lipid peroxidation and decreased levels of antioxidant enzymes in brain in the mouse model of chronic fatigue syndrome. ...
Article
Chronic fatigue syndrome, infection and oxidative stress are interrelated in epidemiological case studies. However, data demonstrating scientific validation of epidemiological claims regarding effectiveness of nutritional supplements for chronic fatigue syndrome are lacking. This study is designed to evaluate the effect of natural polyphenol, curcumin, in a mouse model of immunologically induced fatigue, where purified lipopolysaccharide (LPS) and Brucella abortus (BA) antigens were used as immunogens. The assessment of chronic fatigue syndrome was based on chronic water-immersion stress test for 10 min daily for 19 days and the immobility time was taken as the marker of fatigue. Mice challenged with LPS or BA for 19 days showed significant increase in the immobility time and hyperalgesia on day 19, as well as marked increase in serum tumor necrosis factor-alpha (TNF-alpha) levels. Concurrent treatment with curcumin resulted in significantly decreased immobility time as well as hyperalgesia. There was significant attenuation of oxidative stress as well as TNF-alpha levels. These findings strongly suggest that during immunological activation, there is significant increase in oxidative stress and curcumin can be a valuable option in the treatment of chronic fatigue syndrome.
... Other species of Hypericum have been shown in many experimental systems to scavenge reactive oxygen species, inhibit oxidative DNA damage and lipid peroxidation and to be effective in hypercholesterolemia (Singh et al., 2002;Valentao et al., 2002;El Sherbiny et al., 2003;Hakimoglu et al., 2006). The antioxidant potentials of ethanol extract of Hypericum perforatum and methanol extracts of Hypericum triquetrifolium aerial parts were also studied using different antioxidant tests, and compounds isolated from these extracts or fractions possess a significant antioxidant activity (Conforti et al., 2002;Benedi et al., 2004;Silva et al., 2005). ...
Article
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The antioxidative potential of ethanol extracts of Hypericum triquetrifolium Turra (Hypericaceae) and Hypericum scabroides Robson Poulter (Hypericaceae) were investigated for the first time using 1,1-diphenyl-2-picrylhydrazyl (DPPH), metal chelating, reducing power, hydroxyl radical, total antioxidant activity, and lipid peroxidation inhibition assays. Both extracts tested were found to be highly active in the DPPH radical scavenging assay. The IC(50) values of H. triquetrifolium (HT) and H. scabroides (HS) in the DPPH radical scavenging assay were 39.0 and 33.8 mu g/mL, respectively. The amounts of total phenolic compounds were also determined, and total phenolic content of 1 mg H. triquetrifolium and H. scabroides ethanol extracts were equivalent to 267 and 333 mu g gallic acid. Metal chelating ability was found to be low compared with EDTA. Both ethanol extracts of Hypericum species exhibited a high reducing power, suggesting that extracts had strong electron-donating capacity. The degradation of deoxyribose by hydroxyl radicals was shown to be inhibited by Hypericum extracts, acting mainly by scavenging hydroxyl radicals rather than as chelators of iron ions. Total antioxidant activity of ethanol extracts of HT and HS were tested by using ferric thiocyanate (FTC) and thiobarbituric acid (TBA) methods. Antioxidative activities of both extracts were found to be comparable with vitamin E. Moreover, both extracts showed notable capacity to suppress Fe(2+)-induced lipid peroxidation in rat brain homogenate. The results obtained in the current study indicate that ethanol extracts of HS and HT are a potential source of natural antioxidants.
... The mitochondrial membrane glycophospholipids, fatty acids, and other essential lipids are damaged by the lipid peroxidation process. A significant increase in lipid peroxidation in the brain tissue was reported in mice subjected to a chronic swim test [28]. Lipid peroxidation plays an important role in the pathophysiology of chronic fatigue syndrome [11,19]. ...
Article
Full-text available
L-carnitine (LC) plays a central role in fatty acid metabolism and in skeletal muscle bioenergetics. LC supplementation is known to improve physical performance and has become widespread in recent years without any unequivocal support to this practice. A scientific-based knowledge is needed, to understand the implications of LC supplementation on physical fatigue. In current study, we have explored synergistic effects of dietary LC and fat content against physical fatigue in rats. Ninety male Wistar rats were supplemented with different concentrations of LC (0.15, 0.3, and 0.5 %) and fat content (5, 10, and 15 %) through diet in different combinations. Our results elucidated that LC (0.5 %) along with 10 and 15 % fat diet supplemented rats showed significant ergogenic effect. The swimming time until exhaustion was increased by ~2- and ~1.5-fold in rats fed with 10 and 15 % fat diet containing LC (0.5 %). LC supplementation improved the energy charge by increasing the levels of ATP, tissue glycogen, reduced GSH, plasma triglyceride, plasma glucose levels, and enzymatic antioxidant status, i.e., superoxide dismutase, catalase, and glutathione peroxidase. LC supplementation also significantly reduced lipid peroxidation, lactic acid, plasma urea nitrogen, creatinine, creatinekinase, and lactate dehydrogenase levels in various tissues compared to its respective control group. Thus the present study indicates that LC ameliorates the various impairments associated with physical endurance in rats.
... GSH acts as an essential cofactor for glutathione peroxidase, resulting in the reduction or elimination of ROS and minimizing the formation of methemoglobin ME/CFS. Several authors have reported findings of low glutathione in studies using mouse models of ME/CFS where fatigue has been induced mechanically or by immunological means and relieved by the use of certain dietary supplements or acupuncture [280][281][282][283][284][285]. ...
Article
Full-text available
Glutathione (GSH) has a crucial role in cellular signaling and antioxidant defenses either by reacting directly with reactive oxygen or nitrogen species or by acting as an essential cofactor for GSH S-transferases and glutathione peroxidases. GSH acting in concert with its dependent enzymes, known as the glutathione system, is responsible for the detoxification of reactive oxygen and nitrogen species (ROS/RNS) and electrophiles produced by xenobiotics. Adequate levels of GSH are essential for the optimal functioning of the immune system in general and T cell activation and differentiation in particular. GSH is a ubiquitous regulator of the cell cycle per se. GSH also has crucial functions in the brain as an antioxidant, neuromodulator, neurotransmitter, and enabler of neuron survival. Depletion of GSH leads to exacerbation of damage by oxidative and nitrosative stress; hypernitrosylation; increased levels of proinflammatory mediators and inflammatory potential; dysfunctions of intracellular signaling networks, e.g., p53, nuclear factor-κB, and Janus kinases; decreased cell proliferation and DNA synthesis; inactivation of complex I of the electron transport chain; activation of cytochrome c and the apoptotic machinery; blockade of the methionine cycle; and compromised epigenetic regulation of gene expression. As such, GSH depletion has marked consequences for the homeostatic control of the immune system, oxidative and nitrosative stress (O&NS) pathways, regulation of energy production, and mitochondrial survival as well. GSH depletion and concomitant increase in O&NS and mitochondrial dysfunctions play a role in the pathophysiology of diverse neuroimmune disorders, including depression, myalgic encephalomyelitis/chronic fatigue syndrome and Parkinson's disease, suggesting that depleted GSH is an integral part of these diseases. Therapeutical interventions that aim to increase GSH concentrations in vivo include N-acetyl cysteine; Nrf-2 activation via hyperbaric oxygen therapy; dimethyl fumarate; phytochemicals, including curcumin, resveratrol, and cinnamon; and folate supplementation.
... Mitochondrial membrane glycophospholipids, fatty acids and other essential lipids are damaged by the oxidation process. A significant increase in lipid peroxidation in the brain tissue was reported in mice subjected to a chronic swim test (Singh et al., 2002). Lipid peroxidation is also known to play an important role in the pathophysiology of chronic fatigue syndrome (Manuel et al., 2001). ...
Article
The antifatigue effect of bacoside extract (BME) from Bacopa monniera (L.) Wettst. was investigated. Rats were subjected to weight-loaded forced swim test (WFST) every alternate day for 3 weeks. The BME at a dosage of 10 mg/kg body weight was administered orally to rats for 2 weeks in order to evaluate the following biomarkers of physical fatigue: swimming time, change in body weight, lipid peroxidation, lactic acid (LA), glycogen, antioxidant enzyme activities such as superoxide dismutase (SOD) and catalase (CAT) and blood parameters, namely blood urea nitrogen (BUN) and creatine kinase (CK). The exhaustive swimming time was increased by 3-fold in the BME supplemented group compared with that of the control group on day 13. The BME treatment lowered malondialdehyde (MDA) levels in brain, liver and muscle tissues by 11.2%, 16.2% and 37.7%, respectively, compared with the control exercised group (p < 0.05). The BME also reduced the LA, serum BUN and CK activities significantly compared with that of the control. Administration of BME significantly protected the depletion of SOD and CAT activities. The HSP-70 expression studies by western blot also confirmed the antifatigue property of BME. The present study thus indicates that BME ameliorates the various impairments associated with physical fatigue.
... B) Products of lipid peroxidation were also found increased in the renal homogenates from FST rats (p = 0.005). suggesting that increased renal oxidative metabolism could be a localized phenomenon, however, since it has been reported increased oxidative metabolism in the brain of mouse subjected to FST [39], we cannot rule out the induction of oxidative stress in other tissues. One potential source for reactive oxygen species (ROS) in the kidney is the infiltrating leukocytes. ...
Article
Depression has been associated to inflammatory and oxidative events. Previous report has shown renal oxidative stress in patients with depression. In order to analyze if depressive status is related to renal oxidative and inflammatory events, Sprague Dawley rats were submitted to forced swimming test (FST) and the renal oxidative metabolism, monocyte-macrophage infiltration and Angiotensin II (Ang II) expression were determined. Rats were submitted to FST daily (30 min) for 15 days. Motor activity was analyzed before FST. Kidney sections were homogenized to measure nitric oxide (NO), malondialdehyde (MDA), reduced glutathione (GSH) and catalase activity by enzymatic and biochemical methods. Renal frozen sections were studied for superoxide anion (O2-), monocyte/macrophage infiltration and Ang II expression by histochemical and immunofluorescence methods. In addition, three groups of FST rats were treated with losartan, sertraline or water for 18 days with further renal O2-analysis. In the FST group, struggle time, motor activity, food intake and body weight gain were found decreased. Increased number of glomerular, interstitial and tubular O2-positive cells was observed in FST rats. High renal content of nitrite/nitrate (NO), MDA and decreased amount of GSH were found in FST rats. Values of renal ED-1 or Ang II positive cells in FST rats remained similar to controls; however, AT1 receptor blocking (losartan) and sertraline reduced both depressive-like behavior and renal O2-expression. These data suggests that depression-like behavior in rats is involved in kidney oxidative stress probably mediated by AT1 receptors.
... The results of the present study are also in agreement with animal models of ME/CFS, e.g. the forced swimming test and administration of LPS to mice. Thus, forced swimming (one 6-minute session a day during 7-15 days) induces ROS and RNS and decreases antioxidant defenses [35][36][37]. Administration of LPS to mice induces a behavior complex, characterized by an increased immobility period, post swim fatigue and thermal hyperalgesia, which is associated with increased O&NS and reduced antioxidant levels [38]. ...
Article
There is evidence that myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by activation of immune, inflammatory, oxidative and nitrosative stress (IO&NS) pathways. The present study was carried out in order to examine whether ME/CFS is accompanied by increased levels of plasma peroxides and serum oxidized LDL (oxLDL) antibodies, two biomarkers of oxidative stress. Blood was collected from 56 patients with ME/CFS and 37 normal volunteers. Severity of ME/CFS was measured using the Fibromyalgia and Chronic Fatigue Syndrome (FF) Rating Scale. Plasma peroxide concentrations were significantly higher in patients with ME/CFS than in normal controls. There was a trend towards significantly higher serum oxLDL antibodies in ME/CFS than in controls. Both biomarkers contributed significantly in discriminating between patients with ME/CFS and normal controls. Plasma peroxide and serum oxLDL antibody levels were both significantly related to one of the FF symptoms. The results show that ME/CFS is characterized by increased oxidative stress.
... As the objective parameter of supplement efficiency, the activity of the most important antioxidant enzyme -superoxide dismutase (SOD) -was used. SOD has previously been used as a marker of oxidative stress in numerous studies, including CFS animal models [38][39][40][41]. Higher SOD activity is considered a measure of good antioxidant status and lower SOD activity is considered a sign of increased oxidative stress [42][43][44]. ...
Article
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Background Chronic fatigue syndrome (CFS) is characterized by medically unexplained persistent or reoccurring fatigue lasting at least 6 months. CFS has a multifactorial pathogenesis in which oxidative stress (OS) plays a prominent role. Treatment is with a vitamin and mineral supplement, but this therapeutic option so far has not been properly researched. Material/Methods This prospective study included 38 women of reproductive age consecutively diagnosed by CDC definition of CFS and treated with a multivitamin mineral supplement. Before and after the 2-month supplementation, SOD activity was determined and patients self-assessed their improvement in 2 questionnaires: the Fibro Fatigue Scale (FFS) and the Quality of Life Scale (SF36). Results There was a significant improvement in SOD activity levels; and significant decreases in fatigue (p=0.0009), sleep disorders (p=0.008), autonomic nervous system symptoms (p=0.018), frequency and intensity of headaches (p=0.0001), and subjective feeling of infection (p=0.0002). No positive effect on quality of life was found. Conclusions Treatment with a vitamin and mineral supplement could be a safe and easy way to improve symptoms and quality of life in patients with CFS.
... The findings comprise: increased isoprostane levels; increased oxidized low density lipoproteins (LDL), increased protein carbonyl levels; and increased LDL thiobarbituric acid reactive substances (TBARS) (Kennedy et al 2005;Smirnova & Pall 2003;Vecchiet et al 2003). Translational research shows that in animal models of stress-induced chronic fatigue O&NS plays a key role (Singh et al 2002a;2002b). Also, the antioxidative defences are decreased in CFS, as indicated by a) lower serum levels of zinc, a strong antioxidant; and b) lowered plasma levels of dehydroepiendrosteronesulfate, a hormone with strong antioxidant properties Maes et al 2006a;). ...
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There is now evidence that the pathophysiology of chronic fatigue syndrome (CFS) is related to inflammation and oxidative & nitrosative stress (IO&NS) with a) signs of immune activation and a suppression of ex vivo cellular immune responses; and b) damage to membrane lipids, functional proteins and DNA by O&NS. The above disorders are mediated by intracellular inflammation as indicated by an increased production of nuclear factor kappa Βeta (NFκΒ), cyclo-oxygenase-2 (COX-2) and inducible NO synthase (iNOS). The above inflammatory reactions may by activated by a number of etiological factors, e.g. psychological stress, strenuous exercise, viral and bacterial infections. The purpose of this paper is to review the evidence that an increased translocation of gram negative bacteria is another inflammatory pathway that is involved in CFS. The serum concentrations of IgM and IgA to lipopolysaccharide (LPS) of gram-negative enterobacteria, i.e. Hafnia Alvei; Pseudomonas Aeruginosa, Morganella Morganii, Pseudomonas Putida, Citrobacter Koseri, and Klebsielle Pneumoniae are significantly increased in patients with CFS. This suggests that in CFS there is an increased LPS translocation through a weakened tight junction barrier with subsequent gut-derived inflammation. This condition indicates an increased gut permeability or leaky gut. Treatment for 10-14 months with specific anti-inflammatory and-oxidative substances (NAIOSs), such as glutamine, N-acetyl cysteine and zinc, with or without immunoglobins intravenously (IVIg), significantly attenuates the initially increased IgA and IgM responses to LPS, showing that the gut-derived inflammation is attenuated and thus that the weakened tight junction barrier is partly restored. The attenuation of gut-derived inflammation predicts the clinical improvement 10-14 months after intake of NAIOSs. The above findings show that an increased translocation of gram negative bacteria with subsequent inflammation is a new pathway that contributes to the systemic IO&NS responses in CFS.
... In rodent models of chronic fatigue, e.g. administration of LPS or the forced swimming test, increases in O&NS, lowered antioxidant defences and O&NS damage, especially lipid peroxidation, are observed in the periphery and brain (Singal et al. 2005;Singh et al. 2002a;2002b;Sachdeva et al. 2009). ME/CFS is accompanied by other specific disorders in IO&NS pathways, i.e. increased IgM-mediated autoimmune responses directed against oxidative specific epitopes (OSEs) (Maes et al. 2006;2007a;2012a). ...
Article
There is evidence that inflammatory, oxidative and nitrosative stress (IO&NS) pathways participate in the pathophysiology of a subgroup of patients with Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS). Increased IgM-related autoimmune responses to oxidative specific epitopes (OSEs), including malondialdehyde (MDA), oleic acid and phosphatidyl inositol (Pi), and nitroso-(NO)-adducts, including NO-tryptophan (NOW), NO-arginine and NO-cysteinyl, are frequently observed in ME/CFS. Autoimmune responses in ME/CFS may be driven by increased bacterial translocation as measured by IgM and IgA responses to LPS of gram negative bacteria. The aim of this study is to examine whether IgM responses to OSEs and NO-adducts are related to a better outcome as measured by the Fibromyalgia and Fatigue Rating Scale (FF). 76 ME/CFS patients with initially abnormal autoimmune responses were treated with care-as-usual, including nutraceuticals with anti-IO&NS effects (NAIOS), such as L-carnitine, coenzyme Q10, taurine + lipoic acid, with or without curcumine + quercitine or N-acetyl-cysteine, zinc + glutamine. We found that use of these NAIOS was associated with highly significant reductions in initially increased IgM-mediated autoimmune responses to OSEs and NO-adducts. A greater reduction in autoimmune responses to OSEs during intake of these NAIOS was associated with a lower FF score. Reductions in IgM responses to oleic acid, MDA and Pi, but not in any of the NO-adducts, were associated with reductions in severity of illness. These associations remained significant after adjusting for possible effects of increased bacterial translocation (leaky gut). Our results show that autoimmune responses to OSEs are involved in the pathophysiology of ME/CFS and that these pathways are a new drug target in a subgroup of ME/CFS patients. Although hypernitrosylation and nitrosative stress play a role in ME/CFS, reductions in these pathways are not associated with lowered severity of illness. Randomized controlled trials with NAIOS should be carried out in the subgroup of ME/CFS patients with initially increased autoimmune responses to OSEs.
... CFS in childhood and adolescents is characterized by five major symptoms: sleep disorders, easy fatigability, disturbed learning and memorization, immunological problems, and circadian rhythm disturbances. In mouse models of CFS, melatonin and other antioxidants were found to be useful in the treatment of this disease [78]. ...
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During the last 20 years, numerous clinical trials have examined the therapeutic usefulness of melatonin in different fields of medicine. The objective of this article is to review, in depth, the science regarding clinical trials performed to date. The efficacy of melatonin has been assessed as a treatment of ocular diseases, blood diseases, gastrointestinal tract diseases, cardiovascular diseases, diabetes, rheumatoid arthritis, fibromyalgia, chronic fatigue syndrome, infectious diseases, neurological diseases, sleep disturbances, aging and depression. Melatonin has been also used as a complementary treatment in anaesthesia, hemodialysis, in vitro fertilization and neonatal care. The conclusion of the current review is that the use of melatonin as an adjuvant therapy seems to be well funded for macular degeneration, glaucoma, protection of the gastric mucosa, irritable bowel syndrome, arterial hypertension, diabetes, side effects of chemotherapy and radiation in cancer patients or hemodialysis in patients with renal insufficiency and, especially, for sleep disorders of circadian etiology (jet lag, delayed sleep phase syndrome, sleep deterioration associated with aging, etc.) as well as in those related with neurological degenerative diseases (Alzheimer, etc.,) or Smith-Magenis syndrome. The utility of melatonin in anesthetic procedures has been also confirmed. More clinical studies are required to clarify whether, as the preliminary data suggest, melatonin is useful for treatment of fibromyalgia, chronic fatigue syndrome, infectious diseases, neoplasias or neonatal care. Preliminary data regarding the utility of melatonin in the treatment of ulcerative colitis, Crohn's disease, rheumatoid arthritis are either ambiguous or negative. Although in a few cases melatonin seems to aggravate some conditions, the vast majority of studies document the very low toxicity of melatonin over a wide range of doses.
... Besides, the relationship between antioxidant activity and fatigue relief is also a hotspot that scholars study. Porsolt et al. (1977) used swimming experiment verified that food with antioxidant substances can relieve fatigue and Singh et al. (2002) found that fatigue can be relieved from reducing lipid oxidation. The physiological changes of human body produced in sports are mainly energy substances consumption, loss of moisture, loss of electrolyte, accumulation of lactic acid, free radical damage, internal environment disturbance, etc. ...
... Chronic stress is known to increase lipid peroxidation in the plasma, hippocampus and intestinal mucosa of rats (31–33) and in the brain of mice (34). Previous workers have reported an increased ROS production in the CNS during chronic restraint stress (35–40). ...
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The space within the great pyramid and its smaller replicas is believed to have an antistress effect. Research has shown that the energy field within the pyramid can protect the hippocampal neurons of mice from stress-induced atrophy and also reduce neuroendocrine stress, oxidative stress and increase antioxidant defence in rats. In this study, we have, for the first time, attempted to study the antistress effects of pyramid exposure on the status of cortisol level, oxidative damage and antioxidant status in rats during chronic restraint stress. Adult female Wistar rats were divided into four groups as follows: normal controls (NC) housed in home cage and left in the laboratory; restrained rats (with three subgroups) subject to chronic restraint stress by placing in a wire mesh restrainer for 6 h per day for 14 days, the restrained controls (RC) having their restrainers kept in the laboratory; restrained pyramid rats (RP) being kept in the pyramid; and restrained square box rats (RS) in the square box during the period of restraint stress everyday. Erythrocyte malondialdehyde (MDA) and plasma cortisol levels were significantly increased and erythrocyte-reduced glutathione (GSH) levels, erythrocyte glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities were significantly decreased in RC and RS rats as compared to NC. However, these parameters were maintained to near normal levels in RP rats which showed significantly decreased erythrocyte MDA and plasma cortisol and significantly increased erythrocyte GSH levels, erythrocyte GSH-Px and SOD activities when compared with RS rats. The results showed that housing in pyramid counteracts neuroendocrine and oxidative stress caused by chronic restraint in rats.
... As reported in certain previous studies, the increased generation of radicals during exercise and the decreased exercise capacity are most closely associated with the performance of radicals and lipid peroxidation in the biofilm of various organs. GSH, SOD and catalase (CAT) levels of the mice fed with antioxidants, such as carvedilol and melatonin, were increased while the lipid peroxidation was attenuated (31). ...
Article
Physical fatigue is extremely common and occurs daily, and is considered to be associated with oxidative stress. The diverse functions of deep sea water (DSW) have recently gained increasing attention. Previous studies have emphasized the anti-fatigue effect of DSW, but the intrinsic mechanism behind the effect remains to be elucidated. In the imprinting control region (ICR) mice model, DSW delayed the exhaustive swimming time. In addition, DSW decreased the area under the blood lactate (BLA) curve, which was associated with the area under the BLA curve of pre-swimming, post-swimming and post-rest. Furthermore, DSW reduced the basal levels of malondialdehyde and the post-swimming concentration of blood urea nitrogen, lactate dehydrogenase and creatine kinase after swimming, along with an increase in the normal level of antioxidant enzyme activity such as superoxide dismutase and glutathione peroxidase. However, no significant effect on body weight, hepatic glycogen and muscle glycogen was observed between any group. In conclusion, DSW can improve the athletic ability and alleviate physical fatigue of ICR mice. This effect is achieved by enhancing the antioxidant capacity.
... Chronic fatigue syndrome also is known as myalgic encephalomyelitis was first defined in 1988 by US Centre for Disease Control and Prevention as "fatigue lasting more than 6 mo, usually acute in onset, associated with secondary symptoms and inducing 50% decreased the ability to participate in ordinary activities" [1]. CFS patients complain of a headache, gastrointestinal disturbance, paresthesia, cognitive dysfunction and neuropsychiatric problems including anxiety-like behaviour [2]. ...
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p> Objective: To study the protective effect of ethanolic extract of leaves of Punica granatum Linn. (EEPG) on forced swimming induced chronic fatigue syndrome (CFS) in mice. Methods : Male albino mice of 25-40 grams were grouped into five groups taking 5 mice in each. Group A served as naïve control, Group B as stress control, Group C and D received EEPG at a dose of 100 mg/kg and 200 mg/kg respectively. Group E was given a standard drug (Imipramine 20 mg/kg). All animals received their respective agent orally daily for 7 d. Except for group A animals, animals in all other groups were subjected to force swimming 6 min daily for 7 d to induce a state of chronic fatigue. Animals were assessed for the duration of immobility on day 1<sup>st</sup>, 3<sup>rd</sup>, 5<sup>th</sup> and 7<sup>th</sup>. Level of anxiety (elevated plus maze and mirrored chamber test) and locomotor activity (open field test) were assessed 24 h after last force swimming which was followed by estimation of oxidative biomarkers in brain homogenate. Results : Treatment with EEPG (100 mg/kg and 200 mg/kg) and imipramine resulted in a statistically significant (p≤0.05) reduction in anxiety and duration of immobility and there was a significant increase in locomotor activity when compared to stress control group. Significant reduction in MDA level and increase in catalase level were seen in EEPG and imipramine-treated group compared to stress control group. Conclusion : The study confirmed that EEPG has protective action effect against experimentally induced CFS.</p
... various agents with antioxidant properties can reduce fatiguelike behavior (Singh et al., 2002a,b Davis et al., 2009Fu et al., 2010;Zhuang et al., 2014). For these studies, it should be noted that the models of fatigue pose a significant limitation. ...
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Chronic or persistent fatigue is a common, debilitating symptom of several diseases. Persistent fatigue has been associated with low-grade inflammation in several models of fatigue, including cancer-related fatigue and chronic fatigue syndrome. However, it is unclear how low-grade inflammation leads to the experience of fatigue. We here propose a model of an imbalance in energy availability and energy expenditure as a consequence of low-grade inflammation. In this narrative review, we discuss how chronic low-grade inflammation can lead to reduced cellular-energy availability. Low-grade inflammation induces a metabolic switch from energy-efficient oxidative phosphorylation to fast-acting, but less efficient, aerobic glycolytic energy production; increases reactive oxygen species; and reduces insulin sensitivity. These effects result in reduced glucose availability and, thereby, reduced cellular energy. In addition, emerging evidence suggests that chronic low-grade inflammation is associated with increased willingness to exert effort under specific circumstances. Circadian-rhythm changes and sleep disturbances might mediate the effects of inflammation on cellular-energy availability and non-adaptive energy expenditure. In the second part of the review, we present evidence for these metabolic pathways in models of persistent fatigue, focusing on chronic fatigue syndrome and cancer-related fatigue. Most evidence for reduced cellular-energy availability in relation to fatigue comes from studies on chronic fatigue syndrome. While the mechanistic evidence from the cancer-related fatigue literature is still limited, the sparse results point to reduced cellular-energy availability as well. There is also mounting evidence that behavioral-energy expenditure exceeds the reduced cellular-energy availability in patients with persistent fatigue. This suggests that an inability to adjust energy expenditure to available resources might be one mechanism underlying persistent fatigue.
... In our previous study using a complex fatigue animal model where rats are exposed to relatively long-lasting stress and partial sleep deprivation, which humans often experience in their daily lives, plasma levels of total nitric oxide metabolite species were increased, indicating enhancement of systemic oxidative stress [49]. An increase in lipid peroxidation and a decrease in levels of antioxidant enzymes in the brain in the mouse model of chronic fatigue syndrome were also reported [50]. In human studies, the impact of oxidative stress at different levels of fatigue in healthy individuals and patients with chronic fatigue syndrome has been reported [51], suggesting that antioxidants including ubiquinol are effective against fatigue [4,5]. ...
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Our double-blind, placebo-controlled study evaluated effects of ubiquinol, the reduced form of coenzyme Q10, on mild fatigue in healthy individuals experiencing fatigue in daily life that had continued for more than 1 and less than 6 months. The participants received 100-mg/day (Ubq100; age 44.0 ± 9.8 years; 14 females and 6 males) or 150-mg/day ubiquinol (Ubq150; age 40.4 ± 11.8 years; 14 females and 8 males) or placebo (Plc; age 41.3 ± 13.4 years; 13 females and 7 males) daily for 12 weeks. Measurements of subjective and objective fatigue were conducted by using questionnaires-based fatigue scales/visual analogue scales and autonomic nerve function/biological oxidation index, respectively, prior to the first dosing and every 4 weeks thereafter. Serum ubiquinol level increased three- to four-fold after 4 weeks and remained significantly higher than that after Plc administration throughout the intake period. Although a higher blood level of ubiquinol was observed with Ubq150 than with Ubq100, the difference was not statistically significant. In both Ubq100 and Ubq150 groups, subjective levels of fatigue sensation and sleepiness after cognitive tasks, which consisted of the modified Advanced Trail Making Test, the modified Stroop Color-Word Test, and the Digit Symbol Substitution Test, improved significantly compared with those in the placebo group, suggesting an anti-fatigue effect. The Ubq150 group demonstrated significant improvement compared with the Plc group regarding subjective level of relaxation after task, sleepiness before and after task, motivation for task, and serum level of oxidative stress. Correlation analysis between blood level of ubiquinol and each evaluated effect suggested a positive relationship with relaxation after task, motivation for cognitive task, and parasympathetic activity. The results of the study suggest that ubiquinol intake relieves mild fatigue in healthy individuals.
... Numerous studies have shown that ginseng as well as individual ginsenosides are potent anti-oxidative agents (Deng and Zhang, 1991; Feng et al., 1987; He et al., 2008; Huong et al., 1998; Lee et al., 1998; Li et al., 1999; Lin et al., 2008; Samukawa et al., 2008). In particular, ginseng extracts have shown strong effects on reducing MDA and increasing SOD levels in various animal models, including ischemia in the brain (Kim et al., 2009; Shah et al., 2005) and heart (Zheng and Min, 2008), mouse chronic fatigue syndrome in the brain (Singh et al., 2002), CCl 4 -induced injury in the liver (Chang et al., 2007), and glutamate toxicity in the lung (Shen et al., 2007). While it is not clear how the antioxidant system in the brain involves in depression, there have been reports on reduced antioxidant activity in peripheral blood of depression patients, including higher levels of MDA and reduced levels of SOD (Bilici et al., 2001; McDaniel et al., 1995; Ozcan et al., 2004; Peet et al., 1998). ...
Article
Ginseng has been used for mood adjustment in traditional Chinese medicine for thousands of years. Our previous study has shown that, total ginsenosides, the major pharmacologically functional ingredients of ginseng, possess antidepressant activity. In the present study, we hypothesized that an intestinal metabolite of ginseng, 20(S)-protopanaxadiol (code name S111), as a post metabolism compound (PMC) of ingested ginsenosides, may be responsible for the antidepressant activity of ginseng. To test this hypothesis, antidepressant-like activity of orally given S111 was measured in animal tests including tail suspension test, forced swimming test and rat olfactory bulbectomy depression model. In all those tests, S111 demonstrated antidepressant-like activity as potent as fluoxetine. S111 treated bulbectomy animals had higher levels of monoamine neurotransmitters in the brain and in vitro reuptake assay showed that S111 had a mild inhibitory effect. Furthermore, S111 but not fluoxetine significantly reduced brain oxidative stress and down-regulated serum corticosterone concentration in bulbectomy animals. No disturbance to central nervous system (CNS) normal functions were found in S111 treated animals. These results suggest that the ginseng active metabolite S111 is a potential antidepressant. Since the monoamine reuptake activity of this compound is rather weak, it remains to be investigated whether its antidepressant-like effect is by mechanisms that are different from current antidepressants. Furthermore, this study has demonstrated that post metabolism compounds (PMCs) of herb medicines such as S111 may be a novel source for drug discovery from medicinal herbs.
Article
The tonic effect of Cordyceps militaris (CM), Paecilomyces japonia (PJ), Phellinus linteus (PL), Ganoderma lucidum (GL), Grifola frondosa (GF), and Panax ginseng (PG) was examined based on the forced swimming capacity and the change of biochemical parameters in ICR mice. The treatment groups were orally administered medicinal plant extracts (500 mg/kg per day), while the control group received distilled water for 4 weeks. The swimming times to exhaustion were longer in the CM, PJ, and GF groups than in the control group (P < 0.05). Plasma TG levels were lower in the treatment groups than in the control group. Plasma glucose levels were not significantly different between the control group and each treatment group except the PG group. Plasma lactate and ammonia levels of the PJ and GF groups were lower than those of the control group (P < 0.05). There were no significant differences in the content of liver and gastrocnemius muscle glycogen between the control group and each treatment group. In conclusion, PJ and GF extracts enhanced the forced swimming capacity of mice by increasing fat utilization and by delaying the accumulation of plasma lactate and ammonia.
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The objective of this study is to test in vitro the antimicrobial efficacy of 39 water and 39 methanol extracts derived from different parts of 27 indigenous wild plant species that have been commonly used in Lebanese folk medicine. The antimicrobial efficacy was determined using the single disk diffusion method, with 10 and 20 microl load extract volume per disc. Nine test microorganisms were used namely, Escherichia coli, Proteus sp., Pseudomonas aeruginosa, Shigella dysenteria, Salmonella enteritidis, Salmonella typhi, Staphylococcus aureus, Streptococcus faecalis, and Candida albicans. Only one water extract out of 39 derived from whole plant of Alchemilla diademata showed an antimicrobial activity against Staphylococcus aureus. The percentage of test organisms that were susceptible to 10 most efficacious methanol plant extracts (20 microl/disc) were as follows: Achillea damascena whole plant (88.8%), Anthemis scariosa flower (88.8%), Cirsium sp. whole plant (88.8%), Centaurea ainetensis flowers (88.8%), Hieracium sp. whole plant (88.8%), Origanum libanoticum whole plant (99.9%), Ranunculus myosuroudes whole plant (88.8%), Nepata curviflora leaf (88.8%), Nepata curviflora stem, and Verbascum leptostychum flower (99.9%). The minimum inhibitory concentration (MIC) was determined on plant extracts that showed high efficacy against the test organisms. The chance to find antimicrobial activities was more apparent in methanol rather than water extracts of the same indigenous plants of Lebanon, with higher antimicrobial activities in 20 microl methanol extract-discs in comparison to that present in the 10 microl discs (P < 0.05).
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Free radical scavenging and antioxidant activities of a standardized extract of Hypericum perforatum (SHP) were examined for inhibition of lipid peroxidation, for hydroxyl radical scavenging activity and interaction with 1,1-diphenyl-2-picrylhydrazyl stable free radical (DPPH). Concentrations between 1 and 50 microg/ml of SHP effectively inhibited lipid peroxidation of rat brain cortex mitochondria induced by Fe2+/ascorbate or NADPH system. The results showed that SHP scavenged DPPH radical in a dose-dependent manner and also presented inhibitory effects on the activity of xanthine oxidase. In contrast, hydroxyl radical scavenging occurs at high doses. The protective effect of the standardized extract against H2O2-induced oxidative damage on the pheochromocytoma cell line PC 12 was investigated by measuring cell viability via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), lactate dehydrogenase (LDH) assays, caspase-3-enzyme activity and accumulation of reactive oxygen species [2',7'-dichlorofluorescin (DCF) assay]. Following 8-h cell exposure to H2O2 (300 microM), a marked reduction in cell survival was observed, which was significantly prevented by SHP (pre-incubated for 24 h) at 1-100 microg/ml. In a separate experiment, different concentrations of the standardized extract (0.1-100 microg/ml) also attenuated the increase in caspase-3 activity and suppressed the H2O2 -induced reactive oxygen species generation. Taken together, these results suggest that SHP shows relevant antioxidant activity both in vitro and in a cell system, by means of inhibiting free radical generation and lipid peroxidation.
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Because the muscle response to incremental exercise is not well documented in patients suffering from chronic fatigue syndrome (CFS), we combined electrophysiological (compound-evoked muscle action potential, M wave), and biochemical (lactic acid production, oxidative stress) measurements to assess any muscle dysfunction in response to a routine cycling exercise. This case-control study compared 15 CFS patients to a gender-, age- and weight-matched control group (n=11) of healthy subjects. All subjects performed an incremental cycling exercise continued until exhaustion. We measured the oxygen uptake (VO2), heart rate (HR), systemic blood pressure, percutaneous O2 saturation (SpO2), M-wave recording from vastus lateralis, and venous blood sampling allowing measurements of pH (pHv), PO2 (PvO2), lactic acid (LA), and three markers of the oxidative stress (thiobarbituric acid-reactive substances, TBARS, reduced glutathione, GSH, and ascorbic acid, RAA). Compared with control, in CFS patients (i) the slope of VO2 versus work load relationship did not differ from control subjects and there was a tendency for an accentuated PvO2 fall at the same exercise intensity, indicating an increased oxygen uptake by the exercising muscles; (ii) the HR and blood pressure responses to exercise did not vary; (iii) the anaerobic pathways were not accentuated; (iv) the exercise-induced oxidative stress was enhanced with early changes in TBARS and RAA and enhanced maximal RAA consumption; and (v) the M-wave duration markedly increased during the recovery period. The response of CFS patients to incremental exercise associates a lengthened and accentuated oxidative stress together with marked alterations of the muscle membrane excitability. These two objective signs of muscle dysfunction are sufficient to explain muscle pain and postexertional malaise reported by our patients.
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An experimental model of chronic fatigue syndrome (CFS) is utilized for evaluation of antidepressant, anti-stress effects, wherein the rat is forced to swim in water for 15 min/day on 21 consecutive days. Rats were divided into stressed control, stressed plus standard drug (Panax ginseng) and stressed plus 200 and 500 mg/kg of test drug, i.e., Nardostachys jatamansi extract (NJE) given orally. The immobility during each 5 min periods of 0-5, 5-10 and 10-15 min of stress were noted. Similarly the climbing (struggling) behaviour was noted in the above four groups of rats in intervals of 5 min. The locomotor activity and also the anxiety state in animals were evaluated in an elevated plus maze after CFS in all the four groups. There was a significant increase in despair behaviour and anxiety in stressed control animals on successive days of CFS. Locomotor activity gradually decreased in stressed control group. Treatment with NJE (200 and 500 mg/kg) significantly reversed both paradigms. Biochemical analysis showed that CFS significantly increased lipid peroxidation, nitrite and superoxide dismutase levels and decreased catalase level in rat brain. Administration of NJE (200 and 500 mg/kg) tended to normalize both augmented lipid peroxidation, nitrite, superoxide dismutase activities and catalase level significantly. NJE per se has an antioxidant effect. The results indicate that CFS may lead to oxidative stress, which is mitigated by NJE and so its antioxidant property may be responsible for anti-stress effect of NJE.
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Major depression and chronic fatigue syndrome (CFS) are accompanied by signs of oxidative and nitrosative stress (O&NS) and an inflammatory response. Phosphatidyl inositol (Pi) is thought to play a role in depression. The aim of the present study is to examine whether depression and CFS are characterized by an IgM-mediated immune response directed against Pi. Toward this end, this study examines the serum IgM antibodies directed against Pi in 14 patients with major depression, 14 patients with CFS, 14 subjects with partial CFS, and in 11 normal controls. We found that the prevalence and mean value for the serum IgM levels directed against Pi were significantly greater in patients with major depression and CFS than in normal controls and patients with partial CFS. There were significant and positive correlations between serum IgM levels directed against Pi and two symptoms of the FibroFatigue Scale, i.e. fatigue and depression. The results show that an IgM-related immune response directed against Pi may occur in both depression and CFS and may play a role in the pathophysiology of the key symptom of CFS and major depression. It is suggested that the above disorders in Pi result from increased O&NS in both depression and CFS. Autoanti-Pi antibodies may have biological effects, for example, by changing inositol 1,4,5-triphosphate (IP3), phosphatidylinositol-4,5-bisphosphate (PIP2), diacylglycerol and phosphatidylinositol-3,4,5-triphosphate (PIP3) production, thus interfering with intracellular signalling processes. Future research in major depression and CFS should focus on the functional consequences of the immune responses directed against Pi.
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To improve the functional properties of peanut meal protein for wide utilization, hydrolysis was conducted by alcalase. Compared with saline and peanut meal protein, intragastric administration of low molecular weight (<1 kD) peanut meal peptide (PPH I) could significantly prolong swimming time, increase levels of blood sugar, non-esterified fatty acids (NEFA) and liver glycogen and decrease blood lactate content in mice. Levels of Pro, Leu, Val and His in low molecular weight peanut meal peptides were higher significantly than those in other peanut meal protein hydrolysates. Hydrophobic amino acids, such as Pro, Tyr and His, could perhaps capture free radical and increase antioxidant capacity of peanut peptide and retard fatigue induced by free radical. After separation by HPLC, a primary peptide P1, Pro-Glu-Ile-Glu-Val, was sequenced. Its N-terminal was Val, and it was rich in antioxidant amino acid, Pro and Ile. Levels of plasma glucose, NEFA and liver glycogen in PPH I group were higher than those in mice intragastric administration with peptide P1, and the swimming time is longer in PPH I group than in P1 group. So, the high content of P1 was one of the reason why PPH I had high endurance-enhancing capacity.
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There is a significant 'comorbidity' between depression and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Depressive symptoms frequently occur during the course of ME/CFS. Fatigue and somatic symptoms (F&S), like pain, muscle tension, and a flu-like malaise, are key components of depression. At the same time, depression and ME/CFS show major clinical differences, which allow to discriminate them with a 100% accuracy. This paper aims to review the shared pathways that underpin both disorders and the pathways that discriminate them. Numerous studies have shown that depression and ME/CFS are characterized by shared aberrations in inflammatory, oxidative and nitrosative (IO&NS) pathways, like systemic inflammation and its long-term sequels, including O&NS-induced damage to fatty acids, proteins and DNA; dysfunctional mitochondria; lowered antioxidant levels, like zinc and coenzyme Q10; autoimmune responses to neoepitopes formed by O&NS; lowered omega-3 polyunsaturated fatty acid levels; and increased translocation of gram-negative bacteria. Some IO&NS-related pathways, like the induction of indoleamine 2-3-dioxygenase, neurodegeneration and decreased neurogenesis, are more specific to depression, whereas other pathways, like the 2'-5' oligoadenylate synthetase/RNase L pathway, are specific to ME/CFS. Most current animal models of depression, e.g. those induced by cytokines, are not reminiscent of human depression but reflect a mixture of depressive and F&S symptoms. The latter symptoms, sometimes called sickness behavior, differ from depression and ME/CFS because the former is a (sub)acute response to infection-induced pro-inflammatory cytokines that aims to enhance recovery, whereas the latter are characterized by long-term sequels in multiple IO&NS pathways. Depression and ME/CFS are not 'comorbid' disorders, but should be regarded as 'co-associated disorders' that are clinical manifestations of shared pathways.
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o Se ha informado de casos del síndrome de fatiga crónica/ encefalomielitis miálgica (SFC) que inician con 9 diferentes factores estresantes a corto plazo que aumentan todos el nivel del óxido nítrico del cuerpo. El óxido nítrico elevado, actuando a través de su producto oxidante el peroxinitrito, inicia un ciclo vicioso bioquímico local, el ciclo NO/ONOO, del que se propone es la causa del SFC y de enfermedades relacionadas. La evidencia que apoya este mecanismo del ciclo en el SFC viene de cada uno de los siguientes tipos de evidencias: iniciación del caso por semejantes factores estresantes, extensa evidencia que apoya la existencia de mecanismos del ciclo individual, evidencia que demuestra que varios elementos del ciclo están elevados en casos de SFC, evidencia de un mecanismo básicamente local en el SFC y en enfermedades relacionadas, evidencia de SFC en modelos animales, evidencia genética de estudios de polimorfismos genéticos y evidencia de estudios clínicos de agentes sabidos que regulan a la baja el ciclo NO/ONOO.
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Malignant gliomas are the most common and fatal brain tumors in adults. In particular, the strong invasiveness of glioma cells into the normal brain tissue makes eradication of glioma very difficult. Matrix metalloproteinases (MMPs) play a pivotal role in glioma invasion, and thus controlling MMP expression has been suggested as an important therapeutic target for brain tumors. In the present study, we investigated the effect of protopanxatriol ginsenoside Rh1 on MMP expressions in human astroglioma U87MG and U373MG cells. RT-PCR analysis showed that Rh1 inhibits the mRNA expressions of MMP-1, -3, and -9 in PMA-stimulated U87MG and U373MG cells. Rh1 also suppressed the promoter activities of MMP-1, -3 and -9. The ELISA, Western blot, and zymographic analyses revealed that Rh1 inhibits the protein expression and/or enzymatic activity of MMP-1, -3 and -9. In accordance with the strong inhibitory effects of Rh1 on MMPs, Rh1 efficiently inhibited the invasion and migration of U87MG and U373MG glioma cells as demonstrated by Matrigel invasion assay and wound healing assay. Further mechanistic studies revealed that Rh1 inhibits MAPK and PI3K/Akt signaling pathways and downstream transcription factors such as NF-κB and AP-1, which play an important role in MMP gene expressions. The data collectively suggest that ginsenoside Rh1 may have a therapeutic potential for malignant gliomas.
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The protein content of rice residue is more than 60%, but so far rice residue is only used for low value-added feed industry. In order to improve the functional properties of the rice residue for wider utilization, hydrolysis was conducted by Alcalase. Purification with macroporous resin on the enzymatic hydrolysis product of rice residue was done to obtain rice residue peptide with high protein content. Rice residue peptide of different relative molecular weight range was separated by ultrafiltration separation. Compared with saline, rice residue peptide and high molecular weight rice residue peptide, low molecular weight (<1000) rice residue peptide oral administered in mice could significantly prolong swimming fatigue time and blood sugar levels and significantly lower blood lactate content in mice, indicating that small peptide has significant anti-fatigue effect. After separation by HPLC, an anti-fatigue peptide was got, and its sequence was Gln-Ser-Pro-Glu-Ile.
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The present work aims to investigate the effect of nicotine on learning and memory as well as on oxidative stress using both in- vivo and in-vitro methods. For the in-vivo methods, rats were appropriately grouped and tested for nootropic activity using various authenticated models and different doses in different routes. On the final day of study all the animals were sacrificed and the brain homogenates were estimated for antioxidant enzymes and lipid peroxidation levels. For the in-vitro studies, different concentrations of nicotine were used to measure hydroxyl radical scavenging and production as well as on Fe 2+/Ascorbate and vitamin-E induced lipid peroxidation and protein denaturation. From the above study it was concluded that nicotine possessed nootropic activity as well as antioxidant activity to some extent.
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The present study was carried out using mice model of chronic fatigue syndrome (CFS) in which mice were forced to swim everyday for 15 days for a 6 min session. There was a significant increase in despair behaviour (immobility period) in saline treated mice on successive days. Treatment with herbal products Glychyrrhiza glabra (100 & 200 mg/kg, po), Asparagus racemosus (100 & 200 mg/kg, po), & Convulvulus pluricaulis (100 & 200 mg/kg, po). Fluoxetine, a selective serotonin reuptake inhibitor produced a significant effect only on first and third day of its treatment. Biochemical analysis revealed that chronic swim test significantly increased lipid peroxidation and decreased in the levels of super oxide dismutase (SOD) in the brains of mice. Fluoxetine affected the biochemical variables not to the same extent as other treatments. The findings of the present study suggests that oxidative stress might play a significant role in the pathophysiology of CFS. Thus antioxidants as Glychyrrhiza glabra, Asparagus racemosus & Convulvulus pluricaulis could be useful in the treatment of CFS.
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Background Swarna Jibanti scientifically known as Coelogyne cristata Lindley (Orchidaceae), an orchid mentioned in Ayurvedic medicine is used to promote healthy life span. Objective(s) The present work was planned to study the efficacy of hydro-alcoholic extract of pseudobulbs of C. cristata (CCE) to assess its role on chronic fatigue syndrome (CFS) induced behavioural and biochemical changes in aged Wistar rats compared to Panax ginseng (PG), a prototype anti-stress agent. Materials and methods CFS was induced by forced swimming for consecutive 21 days for fixed duration (15 min sessions). The criteria of CFS due to fatigue were counted using locomotor activity, depression and anxiety through automated photactometer, immobility time and plus maze activity respectively. Acute toxicity study of CCE (upto 2 g/kg, Limit test) was also performed. For CFS, animals were divided into five groups, naive control, control, CCE treated (25 mg/kg b.w., 250 mg/kg b.w.) and standard PG treated (100 mg/kg b.w.) groups. All drugs were given orally for consecutive 21 days along with CFS. After assessing behavioural parameters, all animals were sacrificed at day 21 and in vivo antioxidant potential of CCE was determined by lipid peroxides, nitrite, catalase (CAT) and superoxide dismutase (SOD) in brain tissue. Results CCE was found to be non-toxic. CCE treated aged rats significantly improved (p < 0.001) the spontaneous locomotor movement with respect to control rats, while, decreased the mobility period or depression score. In CFS, CCE also enhanced the time spent (p < 0.001) in open arms while reducing the time spent in closed arm as compared to CFS control, indicating lowering anxiety score. Moreover, marked diminution in lipid peroxidation, nitrite and SOD level was exhibited after CCE treatment and significantly enhanced catalase level significantly (p < 0.01) with respect to CFS control. PG also showed similar actions. Conclusion The results confirmed the potential therapeutic actions of CCE against experimentally induced CFS in aged rats that might be due to its CNS mediatory antioxidant properties.
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Background Chronic fatigue syndrome (CFS) holds a mystery for researchers due to its multifactorial nature; hence, its diagnosis is still based on symptoms and aetiology remains obscured. Number of scientific evidences regarding the role of oxidative stress, immune dysfunction in CFS and alleviation of symptoms with the help of nutritional supplements guided us to study effect of ethanolic extract of Spilanthes oleracea (SPE) in CFS. Objectives Present study was designed to evaluate antioxidant, immunomodulatory properties of S. oleracea flower to ameliorate CFS infirmity in mice. Materials and method In order to induce fatigue, experimental animals were stressed by chronic water – immersion stress model. Meanwhile, parameters like immobility period and tail withdrawal latency were assessed. On the 21st day, mice blood was collected and they were immediately sacrificed for biochemical estimations. Results Biochemical analysis results revealed that CFS elevates lipid peroxidation, nitrite level and diminishes the endogenous antioxidant enzyme like catalase level in stressed animal’s brain homogenate. Stressful condition developed muscle fatigue leading in alteration of lactate dehydrogenase level (LDH), Blood urea nitrogen (BUN) and Triglycerides (TG) levels. Concurrent and chronic treatment of SPE for 21 days restored all these behavioural despairs and associated biochemical adaptation in mice in dose-dependent manner. Conclusion The outcome of this study indicates ability of SPE in amelioration of CFS by mitigating the oxidative stress and thus provide a powerful combat against CFS which may be due to its antioxidant and immunomodulatory properties.
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The present study was carried out using mice model of chronic fatigue syndrome (CFS) in which mice were forced to swim everyday for 7 days for 6 minute session. The despair behaviour (immobility period) was recorded. There was significant increase in despair behaviour in control mice on successive days. Treatment with antidepressant drugs altered the despair behaviour. Fluoxetine, a selective serotonin reuptake inhibitor and idazoxan, an alpha2- adrenoceptor antagonist produced significant effect on day 1 but were not effective on chronic treatment. On the other hand, mianserin, an atypical antidepressant produced significant reduction in chronic exposure-induced increase in immobility. The herbal psychotropic formulations like BR-16A® (100 mg/kg), Siotone® granules (100, 200 mg/kg), Withania somnifera root extract (100 mg/kg) and evening primrose oil (0.2 ml/20g) showed significant antidepressant effect on all the days of treatment in this mice model of CFS. The anxiety level in animals was also noted before and after subjecting them to chronic forced swimming on day 1 and 7.