Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Administration of the cytokines interferon-alpha and interleukin-2 is used for the treatment of various disorders, such as hepatitis C and various forms of cancer. The most serious side-effects are symptoms associated with depression, including fatigue, increased sleepiness, irritability, loss of appetite as well as cognitive changes. However, great differences exist in the prevalence of the development of depressive symptoms across studies. Differences in doses and duration of therapy may be sources of variation as well as individual differences of patients, such as a history of psychiatric illness. In addition, sensitization effects may contribute to differential responses of patients to the administration of cytokines. In animals administration of pro-inflammatory cytokines induces a pattern of behavioural alterations called 'sickness behaviour' which resembles the vegetative symptoms of depression in humans. Changes in serotonin (5-HT) receptors and in levels of 5-HT and its precursor tryptophan in depressed people support a role for 5-HT in the development of depression. In addition, evidence exists for a dysregulation of the noradrenergic system and a hyperactive hypothalamic-pituitary-adrenal (HPA) axis in depression. Some mechanisms exist which make it possible for cytokines to cross the blood-brain barrier. Pro-inflammatory cytokines such as IL-1beta, IFN-alpha, IFN-gamma and TNF-alpha affect the 5-HT metabolism directly and/or indirectly by stimulating the enzyme indoleamine 2,3-dioxygenase which leads to a peripheral depletion of tryptophan. IL-1, IL-2 and TNF-alpha influence noradrenergic activity and IL-1, IL-6 and TNF-alpha are found to be potent stimulators of the HPA axis. Altogether, administration of cytokines may induce alterations in the brain resembling those found in depressed patients, which leads to the hypothesis that cytokines induce depression by their influence on the 5-HT, noradrenergic and HPA system.
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PMID:The psychoneuroimmuno-pathophysiology of cytokine-induced depression in humans. 1246 36

In general, the elderly show a significant age-related decline in their immune response, thus leading to an increased vulnerability to infections or to an increase in the occurrence of malignant tumors. In this study, we examined the effect of Hochu-ekki-to (HOT or TJ-41) on the immunological capacity of the elderly. A group of elderly patients complaining of general fatigue or weakness were orally administered 7.5 g of HOT everyday for at least 120 days (4 months), whereas another group of aged patients mainly complaining of a loss of appetite were daily given 7.5 g of Anchu-san (TJ-5) during the same period and served as a control group. From the immunological point of view, the total number of circulating leukocytes remained unchanged, during the observation period both in the HOT and Anchu-san groups, as well as the ratios between CD3(+) T and CD20(+) B cells and between CD4(+) T and CD8(+) T cells. In addition, no differences were observed in the expression of CD25 antigen, which represents an activated state of T cells. However, as verified on day 30 as well as on day 120 after the administration of HOT, the natural killer (NK) activity against K562 target cells was significantly enhanced, in comparison to the results on day 0 in the HOT group, as well as to that activity on days 0, 30 and 120 in the Anchu-san group. In addition, on days 30 and 120 in the HOT group, there was a significant increase in the serum IFN-gamma level, which is thought to be associated with the NK activity, whereas no significant changes in that level were observed in the Anchu-san group, during the study period. From these results, it may be concluded that the administration of HOT to elderly people may help them improve, at least to some degree, their immunological capacity.
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PMID:Effect of a traditional Japanese herbal medicine, hochu-ekki-to (Bu-Zhong-Yi-Qi Tang), on immunity in elderly persons. 1499 23

WooKiEum (WKE) has been used for the purpose of the development of increased immune-system strength in Korea. In the present study, we examined the anti-immobility effect of WKE on the forced swimming test (FST), and then measured blood biochemical parameters related to fatigue: glucose (Glc), blood urea nitrogen (BUN), lactic dehydrogenase (LDH), creatinine, and total protein (TP). WKE (0.1, 1 g/kg) was administered orally to mice for 7 d. After 2 d, the immobility time was decreased in the WKE-administered group. After 7 d, the immobility time was significantly decreased in the WKE-administered group (64.6+/-9.0 s for 0.1 g/kg) in comparison with the control group (101.3+/-32.7 s). In addition, amount of Glc in the blood serum was increased, whereas the contents of BUN, LDH and TP decreased in the WKE-administered group. Next, we investigated the effect of WKE on the production of cytokines in a human T-cell line, MOLT-4 cells and mouse peritoneal macrophages. WKE (1 mg/ml) significantly increased interferon (IFN)-gamma and TNF-alpha production compared with the media control (about 2.2-fold for IFN-gamma, about 1.7-fold for TNF-alpha, p<0.05) after 24 h. WKE increased the protein expression of IFN-gamma in MOLT-4 cells. These results suggest that WKE may be useful in immune function improvement.
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PMID:Immune-enhancing effect of the Korean natural medicine WooKiEum. 1546 88

Gamisipjundaebo-tang (GSDBT) has been used for the purpose of development of physical strength. In the present study, we investigated the immune enhancing effect induced by GSDBT. We investigated the anti-immobility effect of GSDBT via a forced-swimming test and blood biochemical parameters related to fatigue, glucose, blood urea nitrogen, lactic dehydrogenase, creatine kinase, and total protein. GSDBT (0.1 and 1 g/kg) was orally administered to mice for 14 days. After 7 and 14 days, as assessed through a forced-swimming test, immobility time was decreased in the GSDBT-administrated group (0.1 and 1 g/kg) in comparison with the control group. In addition, after 8 days, the contents of glucose and lactate dehydrogenase in the blood serum were increased, and contents of blood urea nitrogen were decreased in the GSDBT-administrated group. After 15 days, the contents of glucose were increased, and the contents of lactate dehydrogenase and blood urea nitrogen were decreased in the GSDBT-administrated group. However, it had no effect on the elevation of creatine kinase and total protein level. We also investigated the effect of GSDBT on the production of cytokines in human T-cell line, MOLT-4 cells, and splenocytes. GSDBT significantly increased interferon (IFN)-gamma and interleukin (IL)-2 levels compared with the media control but did not affect IL-4. GSDBT increased the protein expression of IFN-gamma in MOLT-4 cells. These results suggest that GSDBT may be useful in immune function improvement and may also have antifatigue properties.
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PMID:Decrease of immobility behavior in forced-swimming test and immune system enhancing effect of traditional medicine Gamisipjundaebo-tang. 1550

IFN-gamma (interferon-gamma) has several applications in the treatment of IFN-gamma-related skin disorders. While systemic delivery - the major route used to administer IFN-gamma - results in significant side effects and toxicity, including fever, fatigue, nausea, vomiting and neurotoxicity, transdermal delivery has a very low transduction efficiency. In order to improve the efficiency of transdermal IFN-gamma delivery, we introduced a Pen (penetratin) peptide, a 16-amino-acid-long polypeptide corresponding to the third helix of the DNA-binding domain (homoeodomain) of Antennapedia (a Drosophila transcription factor). The human IFN-gamma gene was then fused with a gene fragment that encodes the Pen of Antennapedia in a bacterial expression vector, producing a genetic in-frame Pen-IFN-gamma. The expressed and purified Pen-IFN-gamma was then found to have a much more efficient transduction profile than native IFN-gamma. In addition, compared with native IFN-gamma, Pen-IFN-gamma exhibited similar activities when added exogenously to a culture medium: (i) induction of IRF-1 gene expression, and (ii) NF-kappaB (nuclear factor kappaB) luciferase reporter activation. These results indicate that the transdermal delivery system using Pen may be an excellent way to replenish IFN-gamma in the various disorders related to this cytokine.
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PMID:Transdermal delivery of interferon-gamma (IFN-gamma) mediated by penetratin, a cell-permeable peptide. 1580 34

The objective of this study was to evaluate the safety and activity of the intratumoral administration of the immune costimulatory molecule, B7.1, encoded by a vector derived from the canarypox virus, ALVAC (ALVAC-B7.1), alone and with the intratumoral injection of ALVAC encoding the immune-stimulatory cytokine, interleukin 12 (ALVAC-IL-12). Fourteen patients with metastatic melanoma who had s.c. nodules received intratumoral injections on days 1, 4, 8, and 11. Nine patients were given escalating doses of up to 25 x 10(8) plaque-forming units of ALVAC-B7.1. Five patients were given 25 x 10(8) plaque-forming units of ALVAC-B7.1 combined with ALVAC-IL-12 50% tissue culture infective dose of 2 x 10(6). Toxicity was mild to moderate and consisted of inflammatory reactions at the injection site and fever, chills, myalgia, and fatigue. Higher levels of B7.1 mRNA were observed in ALVAC-B7.1-injected tumors compared with saline-injected control tumors. Higher levels of intratumoral vascular endothelial growth factor and IL-10, cytokines with immune suppressive activities, were also observed in ALVAC-B7.1- and ALVAC-IL-12-injected tumors compared with saline-injected controls. Serum levels of vascular endothelial growth factor increased at day 18 and returned to baseline at day 43. All patients developed antibody to ALVAC. Intratumoral IL-12 and IFN-gamma mRNA decreased. Changes in serum IL-12 and IFN-gamma levels were not observed. Tumor regressions were not observed. The intratumoral injections of ALVAC-B7.1 and ALVAC-IL-12 were well tolerated at these dose levels and at this schedule and resulted in measurable biological response. This response included the production of factors that may suppress the antitumor immunologic activity of these vectors.
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PMID:Phase I study of the intratumoral administration of recombinant canarypox viruses expressing B7.1 and interleukin 12 in patients with metastatic melanoma. 1593 Mar 53

Prolonged, exhaustive exercise has been associated with impaired immune responsiveness and increased susceptibility to infection. We have shown that one bout of exercise to fatigue followed by viral challenge increases mortality. Stress hormones such as corticosteroids and catecholamines have been suggested as potential mediators of exhaustive exercise-induced immunosuppression. The purpose of this study was to determine whether the administration of pharmacological agents to block the effect of catecholamines or corticosteroids would minimize the immunosuppression associated with this type of exercise. Mice either exercised to fatigue or were exposed to control conditions, and mice received an i.p. injection of either nadolol (beta-adrenergic receptor antagonist), RU486 (glucocorticoid type II receptor antagonist), or vehicle. Fifteen minutes post-exercise, mice were exposed to viral infection (Herpes simplex virus; HSV) via an intranasal route, and cells were collected 3 days post-infection. The results showed that exercise suppressed HSV-specific cell proliferation, HSV-specific IL-2, and IFN-gamma, but did not alter these same immune parameters when the mitogen ConA was used to stimulate cells. In addition, exercise reduced NK cell cytotoxicity, alveolar cell TNFalpha, and peritoneal IL-1beta, but did not affect IL-10. The pharmacological blockade did not attenuate the exercise-associated immunosuppression. In fact, RU486 treatment exacerbated the exercise-induced decline in HSV-induced IL-2 production and cell proliferation. RU486 and nadolol treatment also tended to decrease IL-10, IFN-gamma, TNFalpha (nadolol only), and IL-1beta (RU486 only) in both exercise and control mice, suggesting that stress hormones may be necessary during infection for optimal responsiveness. These findings suggest that suppression of immune defenses during viral infection persists for at least 3 days post-exercise, and stress hormones may be essential for optimal immune defense to viral challenge, rather than detrimental.
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PMID:Glucocorticoids produced during exercise may be necessary for optimal virus-induced IL-2 and cell proliferation whereas both catecholamines and glucocorticoids may be required for adequate immune defense to viral infection. 1593 13

Immunotherapy for the treatment of metastatic melanoma remains a major clinical challenge. The melanoma microenvironment may lead to local T cell tolerance in part through downregulation of costimulatory molecules, such as B7.1 (CD80). We report the results from the first clinical trial, to our knowledge, using a recombinant vaccinia virus expressing B7.1 (rV-B7.1) for monthly intralesional vaccination of accessible melanoma lesions. A standard 2-dose-escalation phase I clinical trial was conducted with 12 patients. The approach was well tolerated with only low-grade fever, myalgias, and fatigue reported and 2 patients experiencing vitiligo. An objective partial response was observed in 1 patient and disease stabilization in 2 patients, 1 of whom is alive without disease 59 months following vaccination. All patients demonstrated an increase in postvaccination antibody and T cell responses against vaccinia virus. Systemic immunity was tested in HLA-A*0201 patients who demonstrated an increased frequency of gp100 and T cells specific to melanoma antigen recognized by T cells 1 (MART-1), also known as Melan-A, by ELISPOT assay following local rV-B7.1 vaccination. Local immunity was evaluated by quantitative real-time RT-PCR, which suggested that tumor regression was associated with increased expression of CD8 and IFN-gamma. The local delivery of vaccinia virus expressing B7.1 was well tolerated and represents an innovative strategy for altering the local tumor microenvironment in patients with melanoma.
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PMID:Targeting the local tumor microenvironment with vaccinia virus expressing B7.1 for the treatment of melanoma. 1593 44

Exercise for individuals with multiple sclerosis (MS) has been shown to improve cardiovascular function, increase strength and endurance, and reduce fatigue. The impact of exercise on immune function in the disease, however, remains mostly unexplored. Ten female MS patients participated in an 8 week programme of twice-weekly progressive resistance training, with pre- and post-training assessment of serum concentrations of cytokines IL-2, IL-4, IL-6, IL-10, CRP, TNF-alpha and IFN-gamma. After training, IL-4, IL-10, CRP and IFN-gamma showed statistically reduced resting concentrations in blood, while TNF-alpha showed non-significant reductions and IL-2 and IL-6 remained unchanged. These results suggest that progressive resistance training may have an impact on cytokine concentrations in individuals with MS and should be confirmed in studies with stronger statistical power. The impact of these changes on overall immune function in MS and on disease status and prognosis remains to be determined.
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PMID:Cytokine responses to resistance training in people with multiple sclerosis. 1681 86

Lyme borreliosis (LB) can, despite adequate antibiotic treatment, develop into a chronic condition with persisting symptoms such as musculoskeletal pain, subjective alteration of cognition and fatigue. The mechanism behind this is unclear, but it has been postulated that an aberrant immunological response might be the cause. In this study we investigated the expression of the T helper 1 (Th1) marker interleukin (IL)-12Rbeta2, the marker for T regulatory cells, forkhead box P3 (FoxP3) and the cytokine profile in patients with a history of chronic LB, subacute LB, previously Borrelia-exposed asymptomatic individuals and healthy controls. Fifty-four individuals (12 chronic LB, 14 subacute LB, 14 asymptomatic individuals and 14 healthy controls) were included in the study and provided a blood sample. Mononuclear cells were separated from the blood and stimulated with antigens. The IL-12Rbeta2 and FoxP3 mRNA expression was analysed with real-time reverse transcription-polymerase chain reaction (RT-PCR). The protein expression of IL-12Rbeta2 on CD3(+), CD4(+), CD8(+) and CD56(+) cells was assessed by flow cytometry. Furthermore, the secretion of interferon (IFN)-gamma, IL-4, IL-5, IL-10, IL-12p70 and IL-13 was analysed by enzyme-linked immunospot (ELISPOT) and/or enzyme-linked immunosorbent assay (ELISA). Chronic LB patients displayed a lower expression of Borrelia-specific IL-12Rbeta2 on CD8(+) cells and also a lower number of Borrelia-specific IFN-gamma-secreting cells compared to asymptomatic individuals. Furthermore, chronic LB patients had higher amounts of Borrelia-specific FoxP3 mRNA than healthy controls. We speculate that this may indicate that a strong Th1 response is of importance for a positive outcome of a Borrelia infection. In addition, regulatory T cells might also play a role, by immunosuppression, in the development of chronic LB.
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PMID:Decreased up-regulation of the interleukin-12Rbeta2-chain and interferon-gamma secretion and increased number of forkhead box P3-expressing cells in patients with a history of chronic Lyme borreliosis compared with asymptomatic Borrelia-exposed individuals. 1717 59


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