Association Between Genes in the Nuclear Factor E2-Related Factor 2 Antioxidative Response Elements Pathway and Cancer-Related Fatigue in Women With Early-Stage Breast Cancer.

OBJECTIVES: To explore genes in the nuclear factor E2-related factor 2 antioxidative response elements (Nrf2-ARE) signaling pathway using a multiomics approach for associations with variability of cancer-related fatigue (CRF) in postmenopausal women with early-stage hormone receptor-positive breast cancer. SAMPLE & SETTING: Postmenopausal women (N = 116) with early-stage hormone receptor-positive breast cancer were recruited from western Pennsylvania. METHODS & VARIABLES: Candidate genes from the Nrf2-ARE pathway were investigated for associations with CRF occurrence and severity. Associations were evaluated using logistic regression for occurrence and linear regression for severity. RESULTS: The rs2706110 TT genotype in NFE2L2 was associated with a 3.5-fold increase in odds of CRF occurrence. The cytosine-phosphate-guanine (CpG) site cg22820568 in PRDX1 was associated with CRF occurrence and severity. IMPLICATIONS FOR NURSING: Biomarkers based on Nrf2-ARE genes may help to identify women at increased risk for more severe CRF and to develop targeted interventions.

Vitamin D, chronic pain, and depression: linear and non-linear Mendelian randomization analyses.

Vitamin D deficiency has been linked to various chronic pain conditions. However, randomized trials of vitamin D supplementation have had mixed results. In contrast, systematic reviews of randomized trials indicate a protective effect of vitamin D supplementation on depression. We undertake a Mendelian randomization investigation in UK Biobank, a study of UK residents aged 40-65 at recruitment. We perform linear and non-linear Mendelian randomization analyses for four outcomes: fibromyalgia, clinical fatigue, chronic widespread pain, and probable lifetime major depression. We use genetic variants from four gene regions with known links to vitamin D biology as instruments. In linear analyses, genetically-predicted levels of 25-hydroxyvitamin D [25(OH)D], a clinical marker of vitamin D status, were not associated with fibromyalgia (odds ratio [OR] per 10 nmol/L higher 25(OH)D 1.02, 95% confidence interval [CI] 0.93, 1.12), clinical fatigue (OR 0.99, 95% CI 0.94, 1.05), chronic widespread pain (OR 0.95, 95% CI 0.89, 1.02), or probable lifetime major depression (OR 0.97, 95% CI 0.93, 1.01). In non-linear analyses, an association was observed between genetically-predicted 25(OH)D levels and depression in the quintile of the population with the lowest 25(OH)D levels (OR 0.75, 95% CI 0.59, 0.94); associations were null in other strata. Our findings suggest that population-wide vitamin D supplementation will not substantially reduce pain or depression; however, targeted supplementation of deficient individuals may reduce risk of depression.

Cross-kingdom regulation of ginseng miRNA156 on immunity and metabolism.

AIM OF THE STUDY: To study the cross-border regulation of immunity and energy metabolism by ginseng miRNA156, and to provide a new perspective for further exploring the possibility of ginseng miRNA156 as a pharmacodynamic substance. MATERIALS AND METHODS: Combined with the previous research results of our research group, miRNA156 with high expression in blood sequencing of intragastrically administered with ginseng decoction was selected. Bioinformatics analysis was performed on the selected differential miRNA156. The target genes of differential miRNA156 were mainly enriched in metabolic, immune and other signaling pathways. According to the analysis results, the experimental part will use qi deficiency fatigue model and RAW264.7 cells. The contents of lactic acid (LA), creatine kinase (CK), blood urea nitrogen (BUN), lactate dehydrogenase (LD), liver glycogen (LG), muscle glycogen (MG), interleukin 4 (IL-4), matrix metallo-proteinase 9 (MMP-9), superoxide dismutase (SOD), malondialdehyde, phosphor-enolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6pase), nitric oxide (NO) and tumor necrosis factor-α (TNF-α) were measured after administration of miRNA156. RESULTS: Ginseng miRNA156 can accelerate the removal of metabolic waste during exercise. Increase the glycogen reserve in, provide energy for the body, regulate the activity of key gluconeogenesis enzyme phosphorus, improve the energy metabolism system of, and enhance the endurance of fatigue mice. The contents of matrix metalloproteinase 9, superoxide dismutase and malondialdehyde were affected, and the content of TNF-α in the supernatant of RAW264.7 cells was significantly increased, which had certain antioxidant capacity and potential immunomodulatory effects. CONCLUSION: Ginseng miRNA156 has a certain regulatory effect on the energy metabolism and immune function of mice, which makes it possible to regulate the cross-species regulation of ginseng miRNA in theory, provides ideas for ginseng miRNA to become a new pharmacodynamic substance.

Type I interferons, inflammation, and fatigue in a longitudinal RNA study of women with breast cancer.

BACKGROUND: Fatigue is a common side effect of cancer and its treatment and is thought to be driven in part by activation of the proinflammatory cytokine network. However, the cellular and molecular underpinnings of cancer-related fatigue (CRF) have not been determined, nor have immune pathways beyond inflammation been carefully investigated. The goal of this study was to examine the association between CRF and activation of canonical proinflammatory gene regulation pathways and Type I interferon (IFN) signaling pathways in breast cancer patients during and after treatment. METHODS: Women diagnosed with early-stage breast cancer (n = 181) completed assessments before and after treatment with radiation and/or chemotherapy and at 6, 12, and 18-month post-treatment follow-ups. Assessments included self-reported fatigue (Multidimensional Fatigue Symptom Inventory - Short Form) and expression of pre-specified sets of Type I IFN and pro-inflammatory immune response genes determined from mRNA sequencing of PBMCs. Mixed effect linear models examined changes in fatigue and immune gene expression over time and tested the hypothesis that fatigue would be associated with increased expression of Type I IFN and inflammatory response genes. RESULTS: There were significant changes in fatigue and immune gene expression across the assessment period; all measures increased from pre- to post-treatment but showed diverging patterns over the follow-up, with declines in fatigue and persistent elevations in Type I IFN and proinflammatory gene expression. In mixed effect linear models, expression of Type I IFN response genes was elevated in association with fatigue across the assessment period, from pre-treatment to 18-month follow-up. In contrast, pro-inflammatory gene expression was associated with fatigue only at 6, 12, and 18-month follow-ups. Analyses controlling for changes in leukocyte subsets continued to show a significant association between fatigue and Type I IFN gene expression but reduced the time-dependent association with pro-inflammatory gene expression to non-significant. CONCLUSIONS: Results revealed unexpected complexity in the immune underpinnings of CRF and identify a novel role for IFN signaling as a robust contributor to this symptom before, during, and after treatment. Pro-inflammatory gene expression emerged as a predictor of fatigue later in the cancer trajectory, and that effect was primarily accounted for by a concurrent increase in monocyte prevalence.

Associations of Germline Genetic Variants With Depression and Fatigue Among Hematologic Cancer Patients Treated With Allogeneic Hematopoietic Cell Transplantation.

OBJECTIVE: Depression and fatigue are common among cancer patients and are associated with germline genetic variation. The goal of this pilot study was to examine genetic associations with depression and fatigue in the year after allogeneic hematopoietic cell transplant (HCT). METHODS: Blood was collected from patients and their donors before HCT. Patients completed self-report measures of depression and fatigue before HCT (T1), 90 days post-HCT (T2), and 1 year post-HCT (T3). Of the 384 genetic variants genotyped on a custom Illumina BeadChip microarray, 267 were retained for analysis based on quality control. Main effects of patient and donor variants as well as their interaction were examined using regression analyses. Significant variants were defined as those with a false discovery rate-adjusted p value of <.05. RESULTS: The sample consisted of 59 patient-donor pairs. Mean levels of depression and fatigue did not change significantly over time ( p values of > .41). Increases in depression from T1 to T2 were associated with patient-donor interactions at rs1928040 ( p = 3.0 × 10 -4 ) and rs6311 ( p = 2.0 × 10 -4 ) in HTR2A . Increases in fatigue from T1 to T2 were associated with patient rs689021 in SORL1 ( p = 6.0 × 10 -5 ) and a patient-donor interaction at rs1885884 in HTR2A ( p < 1.0 × 10 -4 ). CONCLUSIONS: Data suggest that variants in genes regulating the serotonergic system ( HTR2A ) and lipid metabolism ( SORL1 ) are associated with changes in depression and fatigue in allogeneic HCT patients, implicating patients' own genetic inheritance as well as that of donors. Additional studies are warranted to confirm these findings.

Circulating short chain fatty acids and fatigue in patients with head and neck cancer: A longitudinal prospective study.

Fatigue among patients with head and neck cancer (HNC) has been associated with higher inflammation. Short-chain fatty acids (SCFAs) have been shown to have anti-inflammatory and immunoregulatory effects. Therefore, this study aimed to examine the association between SCFAs and fatigue among patients with HNC undergoing treatment with radiotherapy with or without concurrent chemotherapy. Plasma SCFAs and the Multidimensional Fatigue Inventory-20 were collected prior to and one month after the completion of treatment in 59 HNC patients. The genome-wide gene expression profile was obtained from blood leukocytes prior to treatment. Lower butyrate concentrations were significantly associated with higher fatigue (p = 0.013) independent of time of assessment, controlling for covariates. A similar relationship was observed for iso/valerate (p = 0.025). Comparison of gene expression in individuals with the top and bottom 33% of butyrate or iso/valerate concentrations prior to radiotherapy revealed 1,088 and 881 significantly differentially expressed genes, respectively (raw p < 0.05). The top 10 Gene Ontology terms from the enrichment analyses revealed the involvement of pathways related to cytokines and lipid and fatty acid biosynthesis. These findings suggest that SCFAs may regulate inflammatory and immunometabolic responses and, thereby, reduce inflammatory-related symptoms, such as fatigue.

Exploring causal effects of smoking and alcohol related lifestyle factors on self-report tiredness: A Mendelian randomization study.

Self-reported tiredness or low energy, often referred to as fatigue, has been linked to lifestyle factors, although data from randomized-controlled trials are lacking. We investigate whether modifiable lifestyle factors including smoking and alcohol intake related exposures (SAIEs) are causal factors for fatigue using Mendelian randomization (MR). A two-sample MR study was performed by using genome-wide association summary results from UK Biobank (UKBB), and each of the sample size is more than 100,000. We used the inverse variance weighted method, and sensitivity analyses (MR Egger, weighted median, penalized median estimators, and multivariable MR) to account for pleiotropy. The two-sample MR analyses showed inverse causal effect of never-smoking status and positive effect of current smoking status on the risk of fatigue. Similarly, genetically predicted alcoholic intake was positively associated with fatigue. The results were consistent across the different MR methods. Our Mendelian randomization analyses do support that the cessation of smoking and alcohol can decrease the risk of fatigue, and limit alcohol intake frequency can also reduce the risk.

Exploratory Analysis of Associations Between Whole Blood Mitochondrial Gene Expression and Cancer-Related Fatigue Among Breast Cancer Survivors.

BACKGROUND: Cancer-related fatigue is a prevalent, debilitating, and persistent condition. Mitochondrial dysfunction is a putative contributor to cancer-related fatigue, but relationships between mitochondrial function and cancer-related fatigue are not well understood. OBJECTIVES: We investigated the relationships between mitochondrial DNA (mtDNA) gene expression and cancer-related fatigue, as well as the effects of fish and soybean oil supplementation on these relationships. METHODS: A secondary analysis was performed on data from a randomized controlled trial of breast cancer survivors 4-36 months posttreatment with moderate-severe cancer-related fatigue. Participants were randomized to take 6 g fish oil, 6 g soybean oil, or 3 g each daily for 6 weeks. At pre- and postintervention, participants completed the Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire and provided whole blood for assessment of mtDNA gene expression. The expression of 12 protein-encoding genes was reduced to a single dimension using principal component analysis for use in regression analysis. Relationships between mtDNA expression and cancer-related fatigue were assessed using linear regression. RESULTS: Among 68 participants, cancer-related fatigue improved and expression of all mtDNA genes decreased over 6 weeks with no effect of treatment group on either outcome. Participants with lower baseline mtDNA gene expression had greater improvements in cancer-related fatigue. No significant associations were observed between mtDNA gene expression and cancer-related fatigue at baseline or changes in mtDNA gene expression and changes in cancer-related fatigue. DISCUSSION: Data from this exploratory study add to the growing literature that mitochondrial dysfunction may contribute to the etiology and pathophysiology of cancer-related fatigue.

Fatigue in breast cancer patients on chemotherapy: a cross-sectional study exploring clinical, biological, and genetic factors.

BACKGROUND: Cancer-related fatigue (CRF) is one of the most common and distressing complaints reported by cancer patients during chemotherapy considerably impacting all aspects of a patient's life (physical, psychosocial, professional, and socioeconomic). The aim of this study was to assess the severity of cancer-related fatigue in a group of breast cancer patients undergoing chemotherapy and explore the association between fatigue scores and sociodemographic, clinical, biological, psychiatric, and genetic factors. METHODS: A cross-sectional pilot study carried out at the oncology outpatient unit of Hôtel-Dieu de France University Hospital recruited 67 breast cancer patients undergoing chemotherapy between November 2017 and June 2019 to evaluate fatigue using the EORTC QLQ-C30 scale (European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire). Genotyping for seven gene polymorphisms (COMT, DRD2, OPRM1, CLOCK, PER2, CRY2, ABCB1) was performed using the Lightcycler® (Roche). RESULTS: The prevalence of fatigue was 46.3%. Multivariable analysis taking the fatigue score as the dependent variable showed that a higher number of cycles and a lower hemoglobin level were significantly associated with higher odds of exhibiting fatigue. Moreover, having at least one C allele for DRD2 SNP (vs. TT) was significantly associated with a 4.09 higher odds of expressing fatigue compared to TT patients. Finally, patients with at least one C allele for CLOCK SNP tended to display higher fatigue levels than TT patients. CONCLUSIONS: Our study showed that anemic breast cancer patients with a high number of chemotherapy cycles and those carrying at least one C allele for DRD2 and CLOCK SNPs are at greater risk of exhibiting fatigue. Since no previous research has reported such genetic results, future studies are necessary to confirm our findings.

Propofol ameliorates acute postoperative fatigue and promotes glucagon-regulated hepatic gluconeogenesis by activating CREB/PGC-1α and accelerating fatty acids beta-oxidation.

Postoperative fatigue (POF) is the most common and long-lasting complication after surgery, which brings heavy burden to individuals and society. Recently, hastening postoperative recovery receives increasing attention, but unfortunately, the mechanisms underlying POF remain unclear. Propofol is a wildly used general anesthetic in clinic, and inspired by the rapid antidepressant effects induced by ketamine at non-anesthetic dose, the present study was undertaken to investigate the anti-fatigue effects and underlying mechanisms of propofol at a non-anesthetic dose in 70% hepatectomy induced POF model in rats. We first showed here that single administration of propofol at 0.1 mg/kg ameliorated acute POF in hepatectomy induced POF rats. Based on metabonomics analysis, we hypothesized that propofol exerted anti-fatigue activity in POF rats by facilitating free fatty acid (FFA) oxidation and gluconeogenesis. We further confirmed that propofol restored the deficit in FFA oxidation and gluconeogenesis in POF rats, as evidenced by the elevated FFA utilization, acetyl coenzyme A content, pyruvic acid content, phosphoenolpyruvic acid content, hepatic glucose output and glycogen storage. Moreover, propofol stimulated glucagon secretion and up-regulated expression of cAMP-response element binding protein (CREB), phosphorylated CREB, peroxlsome prolifeator-activated receptor-γ coactivator-1α (PGC-1α), phosphoenolpyruvate carboxykinade1 and carnitine palmitoltransferase 1A. In summary, our study suggests for the first time that propofol ameliorates acute POF by promoting glucagon-regulated gluconeogenesis via CREB/PGC-1α signaling and accelerating FFA beta-oxidation.

Dietary Supplementation of Octacosanol Improves Exercise-Induced Fatigue and Its Molecular Mechanism.

Several publications report that octacosanol (OCT) has different biological functions. This study was designed to evaluate the antifatigue effect and molecular mechanism of octacosanol (200 mg/(kg day)) in forced exercise-induced fatigue models of trained male C57BL/6 mice. Results showed that octacosanol ameliorated the mice's autonomic activities, forelimb grip strength, and swimming endurance, and the levels of liver glycogen (LG), muscle glycogen (MG), blood lactic acid (BLA), lactate dehydrogenase (LDH), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) were also regulated. Gene analysis results showed that treatment with OCT upregulated 29 genes, while 38 genes were downregulated in gastrocnemius tissue. Gene ontology (GO) analyses indicated that these genes enriched functions in relation to myofibril, contractile fiber, and calcium-dependent adenosinetriphosphatase (ATPase) activity. Octacosanol supplementation significantly adjusted the messenger RNA (mRNA) and protein expression levels related to fatigue performance. Octacosanol has an observably mitigating effect in exercise-induced fatigue models, and its molecular mechanism may be related to the regulation of tripartite motif-containing 63 (Trim63), periaxin (Prx), calcium voltage-gated channel subunit α1 H (Cacna1h), and myosin-binding protein C (Mybpc3) expression.

L-carnitine supplementation for muscle weakness and fatigue in children with neurofibromatosis type 1: A Phase 2a clinical trial.

Reduced muscle tone, muscle weakness, and physical fatigue can impact considerably on quality of life for children with neurofibromatosis type 1 (NF1). Human muscle biopsies and mouse models of NF1 deficiency in muscle show intramyocellular lipid accumulation, and preclinical data have indicated that L-carnitine supplementation can ameliorate this phenotype. The aim of this study is to examine whether daily L-carnitine supplementation is safe and feasible, and will improve muscle strength and reduce fatigue in children with NF1. A 12-week Phase 2a trial was conducted using 1000 mg daily oral levocarnitine tartrate supplementation. Recruited children were between 8 and 12 years old with a clinical diagnosis of NF1, history of muscle weakness and fatigue, and naïve to L-carnitine. Primary outcomes were safety (self-reporting, biochemical testing) and compliance. Secondary outcomes included plasma acylcarnitine profiles, functional measures (muscle strength, long jump, handwriting speed, 6-minute-walk test [6MWT]), and parent-reported questionnaires (PedsQL™, CBCL/6-18). Six children completed the trial with no self-reported adverse events. Biochemical tests for kidney and liver function were normal, and the average compliance was 95%. Plasma acylcarnitine levels were low, but within a range not clinically linked to carnitine deficiency. For strength measures, there was a mean 53% increase in dorsiflexion strength (95% confidence interval [CI] 8.89-60.75; p = 0.02) and mean 66% increase in plantarflexion strength (95% CI 12.99-134.1; p = 0.03). In terms of muscle performance, there was a mean 10% increase in long jump distance (95% CI 2.97-16.03; p = 0.01) and 6MWT distance (95% CI 5.88-75.45; p = 0.03). Comparison with the 1000 Norms Project data showed a significant improvement in Z-score for all of these measures. Parent reports showed no negative impact on quality of life, and the perceived benefits led to the majority of individuals remaining on L-carnitine after the study. Twelve weeks of L-carnitine supplementation is safe and feasible in children with NF1, and a Phase 3 trial should confirm the efficacy of treatment.

Epigenetic age acceleration, fatigue, and inflammation in patients undergoing radiation therapy for head and neck cancer: A longitudinal study.

BACKGROUND: The authors measured epigenetic age acceleration (EAA) during and after cancer treatment and its association with inflammation and fatigue, which is a debilitating symptom in patients with cancer. METHODS: Patients who had head and neck cancer without distant metastases were assessed before, immediately after, and at 6 months and 12 months postradiotherapy. Blood DNA methylation was assessed using a proprietary bead chip (the Illumina MethylationEPIC BeadChip). EAA was calculated using the Levine epigenetic clock (DNAmPhenoAge), adjusted for chronological age. Fatigue was assessed using the Multidimensional Fatigue Inventory-20. Inflammatory markers were measured using standard techniques. RESULTS: Most patients (N = 133) were men, White, had advanced disease, and received concurrent chemoradiation. EAA changes over time were significant, with the largest increase (4.9 years) observed immediately after radiotherapy (P < .001). Increased EAA was associated with elevated fatigue (P = .003) over time, and patients who had severe fatigue experienced 3.1 years higher EAA than those who had low fatigue (P < .001), which was more prominent (5.6 years; P = .018) for patients who had human papillomavirus-unrelated disease at 12 months posttreatment. EAA was also positively associated with inflammatory markers, including C-reactive protein (CRP) and interleukin-6 (IL-6), over time (P < .001), and patients who had high CRP and IL-6 levels exhibited increases of 4.6 and 5.9 years, respectively, in EAA compared with those who had low CRP and IL-6 levels (P < .001). CRP and IL-6 mediated the association between EAA and fatigue (CRP: 95% CI, 0.060-0.279; IL-6: 95% CI, 0.024-0.220). CONCLUSIONS: Patients with head and neck cancer experienced increased EAA, especially immediately after treatment completion. EAA was associated with greater fatigue and inflammation, including 1 year after treatment. Inflammation may be a target to reduce the impact of age acceleration on poor functional outcomes.

Fear of pain moderates the relationship between self-reported fatigue and methionine allele of catechol-O-methyltransferase gene in patients with fibromyalgia.

Previous research has shown a consistent association among genetic factors, psychological symptoms and pain associated with fibromyalgia. However, how these symptoms interact to moderate genetic factors in fibromyalgia has rarely been studied to date. The present research investigates whether psychological symptoms can moderate the effects of catechol-O-methyltransferase on pain and fatigue. A total of 108 women diagnosed with fibromyalgia and 77 healthy control participants took part in the study. Pain, fatigue, and psychological symptoms (anxiety, depression, pain catastrophizing, fear of pain and fear of movement) were measured by self-report questionnaires. Two types of statistical analyses were performed; the first was undertaken to explore the influences of COMT genotypes on clinical symptoms by comparing patients with fibromyalgia and healthy controls. In the second analysis, moderation analyses to explore the role of psychological symptoms as potential factors that moderate the relationship between pain/fatigue and COMT genotypes were performed. The main results indicated that patients carrying the Met/Met genotype reported significantly higher levels of fatigue than heterozygote carriers (i.e., Met/Val genotype) and higher levels of fatigue, but not significantly different, than Val homozygote carriers. Among patients with fibromyalgia carrying methionine alleles (i.e., Met/Met + Met/Val carriers), only those who scored high on medical fear of pain, experienced an intensified feeling of fatigue. Thus, the present research suggests that fear of pain, as a psychological symptom frequently described in fibromyalgia may act as a moderating factor in the relationship between the Met allele of the COMT gene and the increase or decrease in self-reported fatigue. Although further research with wider patient samples is needed to confirm the present findings, these results point out that the use of psychological interventions focused on affective symptomatology might be a useful tool to reduce the severity of fibromyalgia.

Symptom Management in Pancreatic Cancer.

OPINION STATEMENT: Despite extensive research that has identified new risk factors, genetic mutations, and therapeutic options, pancreatic ductal adenocarcinoma continues to be a leading cause of cancer related death. Patients with pancreatic cancer, along with their clinicians, must balance realistic hope alongside a life-threatening diagnosis. As the search for treatments to reduce the morbidity and mortality continues, symptom management and quality of life remain the focus of our efforts. In addition to side effects of cancer-directed therapy, patients are at risk for malnutrition, pain, and fatigue. These factors are often overlooked in practice, so a multidisciplinary team is critical in optimizing the care of patients.

Supplementation with embryo chicken egg extract improves exercise performance and exerts anti-fatigue effects via AMPK/mTOR signalling pathway in mice.

BACKGROUND: Embryo chicken egg is a nutritional supplement that has been used to enhance physical fitness and promote wound healing according to traditional Chinese medicine for many years. In this study, we evaluated the effects of embryo chicken egg extract (ECE) on the exercise performance and fatigue in mice and the underlying mechanisms. RESULTS: The results indicated that ECE can prolong the exhaustive swimming time, decrease lactic acid, blood urea nitrogen, creatine kinase, and malondialdehyde levels, and increase superoxide dismutase, glutathione peroxidase, and glycogen levels. Additionally, ECE can also regulate the balance of oxidative stress via the adenosine monophosphate activated protein kinase/mammalian target of rapamycin signalling pathway. CONCLUSION: Taken together, these results showed that ECE can improve exercise performance and reduce physical fatigue in mice, which indicates that ECE can be used as a potential supplement to reduce physical fatigue. © 2020 Society of Chemical Industry.

Water and alcohol extracts from Diaphragma juglandis on anti-fatigue and antioxidative effects in vitro and vivo.

BACKGROUND: To estimate the anti-fatigue and antioxidative effects of water and alcohol extracts from Diaphragma juglandis (DJ), H2 O2 -treated HepG2 cells were used as an in vitro model to determine the total antioxidant capacities of these two extracts, and behavioral tests on mice and biochemical assay were performed via in vivo experiments. RESULTS: The results indicate that both extracts possess remarkable HepG2 protective capacities and were capable of scavenging 2,2-diphenyl-1-picrylhydrazyl and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) similar to vitamin C. Furthermore, they could significantly prolong the bar climbing time and force swimming time, as well as decrease the serum urea nitrogen and increase the lactate dehydrogenase level and glycogen content. These extracts could also improve the activities of total antioxidant capacity, malondialdehyde, superoxide dismutase, catalase and glutathione peroxidase. CONCLUSION: In conclusion, both water and alcohol extracts from DJ showed good performance with respect to anti-fatigue and could be a potential antioxidant additive in the field of functional foods. © 2020 Society of Chemical Industry.

Anti-fatigue property of the oyster polypeptide fraction and its effect on gut microbiota in mice.

We aimed to evaluate the anti-fatigue effects of the oyster polypeptide (OP) fraction and its regulatory effect on the gut microbiota in mice. Our exhaustive swimming experiment showed that the swimming time of the low-, middle- and high-dose groups of the OP fraction was increased by 1.82, 2.18 and 2.44 times compared with the control group, respectively. Besides, the liver glycogen levels of the three groups were increased by 19.3%, 42.02% and 65.07%, while the lactate levels were decreased by 18.85%, 21.18% and 28.74%, respectively. Moreover, administration of the OP fraction upregulated the expressions of PEPCK and AMPK, but downregulated the TNF-α expression. Correlation analysis between the gut microbiota and fatigue-related biochemical indicators showed that Faecalibacterium, Desulfovibri and Intestinibacter were negatively correlated with the swimming time, blood lactate, blood urea nitrogen, liver glycogen and muscle glycogen, while Yaniella and Romboutsia were positively correlated. Therefore, the OP fraction had anti-fatigue effects, and could regulate the abundance of gut microbiota and maintain its balance.

Toll-like receptor 4 mediates the development of fatigue in the murine Lewis Lung Carcinoma model independently of activation of macrophages and microglia.

Cancer-related fatigue at the time of tumor diagnosis is commonly attributed to inflammation associated with the disease process. However, we have previously demonstrated that running wheel deficits occur well before increased expression of proinflammatory cytokines in the liver and brain in a murine model of human papilloma virus-related head and neck cancer (mEER). Further, we have demonstrated that genetic deletion of type I interleukin-1 receptor and MyD88 has no effect. In the current investigation we sought to test the generality of this finding by assessing whether there is a role for toll-like receptor (TLR) 4-dependent inflammation in the fatigue-like behavior observed in mice with Lewis Lung Carcinoma (LLC) or mEER tumors. Genetic deletion of TLR4 attenuated tumor-induced elevations in liver pro-inflammatory cytokine expression in both models. However, it only abrogated wheel running deficits in LLC tumor bearing mice. To determine whether TLR4 signaling in the LLC model involves innate immune cells, mice were treated with the colony stimulating factor (CSF)-1 receptor antagonist PLX-5622 before and throughout tumor development to deplete microglia and peripheral macrophages. Administration of PLX-5622 had no protective effect on wheel running deficits in either mEER or LLC tumor models despite effective depletion of microglia and a down regulation of peripheral proinflammatory cytokine expression. These results indicate that the TLR4 signaling that mediates fatigue-like behavior in LLC mice is not dependent upon microglial or peripheral macrophage activation. Based on the literature and our data demonstrating attenuation of ubiquitin proteasome pathway activation in the gastrocnemius muscle of Tlr4-/- mice implanted with LLC cells, we interpret our current findings as indication that skeletal muscle TLR4 signaling may be involved. These results are important in that they add to the evidence that tumor-induced fatigue develops independently from classical neuroinflammation.

Brain-derived neurotrophic factor polymorphism Val66Met protects against cancer-related fatigue.

Cancer-related fatigue is an extremely common and debilitating psychiatric symptom that affects up to 80% of cancer patients. Despite its negative impact on the patient's quality of life, there is no well-established biomarker or mechanisms associated with this debilitating condition. The functional brain-derived neurotrophic factor (BDNF) Val66Met single nucleotide polymorphism (SNP) has been associated with a variety of psychiatric illnesses. We hypothesized that Val66Met may influence the risk for developing cancer-related fatigue. BDNF Val66Met was analyzed by polymerase chain reaction in 180 patients with confirmed cancer diagnoses. Fatigue was measured using the Functional Assessment of Cancer Therapy-Fatigue (FACIT-Fatigue) questionnaire. Depression was measured using the Hamilton Depression Scale (HAM-D). Data were transformed when necessary and regression models were constructed to access the association between genotype and symptom severity. Participants carrying the Met allele reported significantly less fatigue compared to the Val/Val genotype group. The presence of the Met allele did not influence depression levels. The results suggest that the BDNF Val66Met polymorphism confers protective advantage against cancer-related fatigue; whereas having the Val/Val genotype may be a genetic risk factor. Findings from this study not only provide clues to the neural basis of cancer-related fatigue, but also allow for symptom severity prediction and patient education with the goal to improve symptom management.