Physical activity has long been hypothesized to influence the risk and pathology of Alzheimer's disease. However, the amount of physical activity necessary for these benefits is unclear. We examined the effects of three months of low and high intensity exercise training on soluble Aβ40 and Aβ42 levels in extracellular enriched fractions from the cortex and hippocampus of young Tg2576 mice. Low (LOW) and high (HI) intensity exercise training animals ran at speeds of 15m/min on a level treadmill and 32 m/min at a 10% grade, respectively for 60 min per day, five days per week,from three to six months of age. Sedentary mice (SED) were placed on a level, non-moving, treadmill for the same duration. Soleus muscle citrate synthase activity increased by 39% in the LOW group relative to SED, and by 71% in the HI group relative to LOW, indicating an exercise training effect inthese mice. Soluble Aβ40 concentrations decreased significantly in an exercise training dose-dependent manner in the cortex. In the hippocampus, concentrations were decreased significantly in the HI group relative to LOW and SED. Soluble Aβ42 levels also decreased significantly in an exercise training dose-dependent manner in both the cortex and hippocampus. Five proteins involved in Aβ clearance (neprilysin, IDE, MMP9, LRP1 and HSP70) were elevated by exercise training with its intensity playing a role in each case. Our data demonstrate that exercise training reduces extracellular solubleAβ in the brains of Tg2576 mice in a dose-dependent manner through an up-regulation of Aβ clearance.

The mushroom Inonotus obliquus has been widely used as a folk medicine in Russia, Poland and most of the Baltic countries. In this study, water-soluble and alkali-soluble crude polysaccharides (IOW and IOA) were isolated from I. obliquus, and the carbohydrate-rich fractions IOW-1 and IOA-1 were obtained respectively after deproteination and depigmentation. Their contents, such as neutral carbohydrate, uronic acid and protein, were measured. Their antioxidant properties against chemicals-induced reactive species (ROS) including 1,1'-Diphenyl-2-picrylhydrazyl (DPPH) radical, hydroxyl radical and superoxide anion radical, as well as their protective effects on H(2)O(2)-induced PC12 cell death were investigated. Results showed that I. obliquus polysaccharides can scavenge all ROS tested above in a dose-dependent manner. IOA and its product IOA-1 could rescue PC12 cell viability from 38.6% to 79.8% and 83.0% at a concentration of 20μg/mL. Similarly, IOW and its product IOW-1 at the same dose, can also increase cell viability to 84.9% and 88.6% respectively. The antioxidative activities of water-soluble and alkali-soluble polysaccharide constituents from I. obliquus might contribute to diverse medicinal and nutritional valuesof this mushroom.

Supraphysiological concentrations of oxygen (hyperoxia) can compromise host defense and increase susceptibility to bacterial infections, causing ventilator-associated pneumonia. The phagocytic activity of macrophages is impaired by hyperoxia-induced increases in the levels of reactive oxygen species (ROS) and extracellular high-mobility group box protein B1 (HMGB1). Ascorbic acid (AA), an essential nutrient and antioxidant, has been shown to be beneficial in various animal models of ROS-mediated diseases. The aim of this study was to determine whether AA could attenuate hyperoxia-compromised host defense and improve macrophage functions against bacterial infections. C57BL/6 male mice were exposed to hyperoxia (≥98% O2, 48 h), followed by intratracheal inoculation with Pseudomonas aeruginosa, and simultaneous intraperitoneal administration of AA. AA (50 mg/kg) significantly improved bacterial clearance in the lungs and airways, and significantly reduced HMGB1 accumulation in the airways. The incubation of RAW 264.7 cells (a macrophage-like cell line) with AA (0-1,000 μM) before hyperoxic exposure (95% O2) stabilized the phagocytic activity of macrophages in a concentration-dependent manner. The AA-enhanced macrophage function was associated with significantly decreased production of intracellularROS and accumulation of extracellular HMGB1. These data suggest that AA supplementation can prevent or attenuate the development of ventilator-associated pneumonia in patients receiving oxygen support.

BACKGROUND:Combining different analgesic drugs for improvement of drug efficacy is a recommended strategy intended to achieve the optimal therapeutic effects.

OBJECTIVES:The purpose of the present study was to assess the nature of the interaction between ascorbic acid and two analgesic drugs, morphine and tramadol.

MATERIALS AND METHODS:The analgesic activity was assessed by the acetic acid writhing test in male Naval Medical Research Institute (NMRI) mice. The results were obtained using four to six animals in each group. All the drugs were injected intraperitoneally. The effective doses (ED) that produced 20%, 50%, and 65% antinociception (ED20, ED50 and ED65) were calculated from the dose-response curve of each drug alone as well as co-administration of ascorbic acid and tramadol or morphine. The interaction index was calculated as experimental ED/theoretical ED. For each drug combination, ED50, ED20 and ED65 were determined by linear regression analysis of the dose-response curve, and they were compared to theoretical ED50, ED20 and ED65 using t-test.

RESULTS:The antinociceptive effects of all drugs were dose-dependent (ED50was 206.1 mg/kg for ascorbic acid, 8.33 mg/kg for tramadol, and 0.79 mg/kg for morphine). The interaction index demonstrated additive effects at ED50 and ED65 for co-administration of ascorbic acid and tramadol or morphine. However, at ED20, combination of ascorbic acid and tramadol or morphine showed synergic effects. The interaction index values of the combinations demonstrated the potency ratio of ascorbic acid/morphine to be lower than ascorbic acid/tramadol.

CONCLUSIONS:This study demonstrated the results of interactions between ascorbic acid and tramadol or morphine. The results showed that the interaction effects on antinociception may be synergistic or additive, depending on the level of effect.

We attempted to systematically determine the association between dietary intake of vitamin C and risk of prostate cancer. PubMed and Embase were searched to obtain eligible studies published before February 2015. Cohort or case-control studies that reported the relative risk (RR)/odds ratio (OR) estimates with 95% confidence intervals (CIs) for the association between vitamin C intake and prostate cancer risk were included. Eighteen studies regarding dietary vitamin C intake were finally obtained, with a total of 103,658 subjects. The pooled RR of prostate cancer for the highest versus the lowest categories of dietary vitamin C intake was 0.89 (95%CI: 0.83-0.94; p = 0.000) with evidence of a moderate heterogeneity (I(2) = 39.4%, p = 0.045). Meta-regression analysis suggested that study design accounted for a major proportion of the heterogeneity. Stratifying the overall study according to study design yielded pooled RRs of 0.92 (95%CI: 0.86-0.99, p = 0.027) among cohort studies and 0.80 (95%CI: 0.71-0.89, p = 0.000) among case-control studies, with no heterogeneity in either subgroup. In the dose-response analysis, an inverse linear relationship between dietary vitamin C intake and prostate cancer risk was established, with a 150 mg/day dietary vitamin C intake conferred RRs of 0.91 (95%CI: 0.84-0.98, p = 0.018) in the overall studies, 0.95 (95%CI: 0.90-0.99, p = 0.039) in cohort studies, and 0.79 (95%CI: 0.69-0.91, p = 0.001) in case-control studies. In conclusion, intake of vitamin C from food was inversely associated with prostate cancer risk in this meta-analysis.

We evaluated the ability of cannabidiol (CBD) to impair the migration of tumor cells stimulated by conditioned medium. CBD caused concentration-dependent inhibition of the migration of U87 glioma cells, quantified in a Boyden chamber. Since these cells express both cannabinoid CB1 and CB2 receptors in the membrane, we also evaluated their engagement in the antimigratory effect of CBD. The inhibition of cell was not antagonized either by the selective cannabinoid receptor antagonists SR141716 (CB1) and SR144528 (CB2) or by pretreatment with pertussis toxin, indicating no involvement of classical cannabinoid receptors and/or receptors coupled to Gi/o proteins. These results reinforce the evidence of antitumoral properties of CBD, demonstrating its ability to limit tumor invasion, although the mechanism of its pharmacological effects remains to be clarified.

This study investigates the anticancer properties of cannabisin B, purified from hempseed hull, in HepG2 human hepatoblastoma cells. The results indicate that cannabisin B significantly inhibited cell proliferation by inducing autophagic cell death rather than typical apoptosis. Cell viability transiently increased upon the addition of a low concentration of cannabisin B but decreased upon the addition of high concentrations. Cannabisin B-induced changes in cell viability were completely inhibited by pre-treatment with 3-methyladenine (3-MA), indicating that the induction of autophagy by cannabisin B caused cell death. Additionally, cannabisin B induced S phase cell cycle arrest in a dose-dependent manner. Moreover, cannabisin B was found to inhibit survival signaling by blocking the activation of AKT and down-stream targets of the mammalian target of rapamycin (mTOR). These findings suggest that cannabisin B possesses considerable antiproliferative activity and that it may be utilised as a promising chemopreventive agent against hepatoblastoma disease.

In this study, a high yield of crude polysaccharide (16.73± 0.756%) was extracted from the spent mushroom substrate of Lentinus edodes using a hot alkali extraction method. Two groups of polysaccharides (designated as LSMS-1 and LSMS-2) were obtained from the crude extract by size exclusion chromatography (SEC), and their molecular characteristics were examined by a multiangle laser-light scattering (MALLS) and refractive index detector system. The weight-average molar masses of LSMS-1 and LSMS-2 were determined to be 6.842 × 106 and 2.154 × 106 g/mol, respectively. The SEC/MALLS analysis revealed that the molecular shapes of LSMS-1 and LSMS-2 were sphere-like forms in aqueous solution. Carbohydrate composition analysis using chromatography--mass spectrometry revealed that they were both acid heteropolysaccharides. LSMS-1 comprised mainly glucose and galacturonic acid, whereas LSMS-2 mainly consisted of xylose and glucuronic acid. Fourier transform infrared spectral analysis of the purified fractions revealed typical characteristic polysaccharide groups. In addition, MTT assays with refined polysaccharide doses of 25, 50, 100, 200, and 400 µg/mL suggested that both of the polysaccharide fractions exhibited antiproliferative activity against 6 tested human tumor cell lines in a concentration-dependent manner, and LSMS-2 had better anticancer capacity in vitro than LSMS-1. The inhibition ratio of LSMS-2 against A549 human lung cancer cells, the SGC7901 gastric cancer cell line, MCF-7 breast cancer cells, the U937 histiocytic lymphoma cell line, and the MG-63 human osteosarcoma cell line reached 43.55%, 29.97%, 19.63%, 18.24%, and 17.93%, respectively, at a concentration of 400 µg/mL.

Most population studies on physical activity and health have involved largely inactive men and women, thus making it difficult to infer if health benefits occur at exercise levels above the current minimum guidelines. The aim was to examine associations between cycling volume and classical cardiovascular risk markers, including hypertension and hypercholesterolemia, in a population sample of habitual cyclists. A nationwide sample comprising 6949 men and women (aged 47.6 years on average) completed questions about their cycling levels, demographics and health. Nearly the entire sample (96.3%) achieved the current minimum physical activity recommendation through cycling alone. There was a dose-response association between cycling volume and risk of diagnosed hypertension (P-trend =0.001), with odds ratios of 0.98 (95% confidence interval (CI), 0.80-1.21), 0.86 (0.70, 1.06), 0.67 (95% CI, 0.53-0.83) across categories of 23-40, 40-61 and>61 metabolic equivalent hours/week (MET-h/week) compared with<23 MET-h/week. These associations persisted in models adjusted for age, sex, smoking, alcohol, body mass index (BMI) and other moderatevigorous physical activities. We also observed inverse associations between cycling volume and other risk factors including BMI and hypercholesterolemia. In summary, results from a population sample of cyclists suggest that additional cardiovascular health benefits can be achieved beyond the current minimum physical activity recommendation.

Exercise has been shown to protect against cognitive decline and Alzheimer's disease (AD) progression, however the dose of exercise required to protect against AD is unknown. Recent studies show that the pathological processes leading to AD cause characteristic alterations in blood and brain inflammatory proteins that are associated with the progression of AD, suggesting that these markers could be used to diagnosis and monitor disease progression. The purpose of this study was to determine the impact of exercise frequency on AD blood chemokine profiles, and correlate these findings with chemokine brain expression changes in the triple transgenic AD (3xTg-AD) mouse model. Three month old 3xTg-AD mice were subjected to 12 weeks of moderate intensity wheel running at a frequency of either 1×/week or 3×/week. Blood and cortical tissue were analyzed for expression of monocyte chemotactic protein-1 (MCP-1) and regulated and normal T cell expressed and secreted (RANTES). Alterations in blood RANTES and MCP-1 expression were evident at 3 and 6 month old animals compared to WT animals. Three times per week exercise but not 1×/week exercise was effective at reversing serum and brain RANTES and MCP-1 expression to the levels of WT controls, revealing a dose dependent response to exercise. Analysis of these chemokines showed a strong negative correlation between blood and brain expression of RANTES. The results indicate that alterations in serum and brain inflammatory chemokines are evident as early signs of Alzheimer's disease pathology and that higher frequency exercise was necessary to restore blood and brain inflammatory expression levels in this AD mouse model.

OBJECTIVE:Some evidence suggests that Hatha yoga might be an effective practice to reduce anxiety. To examine the effect of Hatha yoga on anxiety, we conducted a meta-analysis of relevant studies extracted from PubMed, PsycINFO, the Cochrane Library, and manual searches.

METHODS:The search identified 17 studies (11 waitlist controlled trials) totaling 501 participants who received Hatha yoga and who reported their levels of anxiety before and after the practice. We estimated the controlled and within-group random effects of the practice on anxiety.

RESULTS:The pre-post within-group and controlled effect sizes were, Hedges' g = 0.44 and Hedges' g = 0.61, respectively. Treatment efficacy was positively associated with the total number of hours practiced. People with elevated levels of anxiety benefitted the most. Effect sizes were not moderated by study year, gender, presence of a medical disorder, or age. Although the quality of the studies was relatively low, the risk of study bias did not moderate the effect.

CONCLUSIONS:Hatha yoga is a promising method for treating anxiety. However, more well-controlled studies are needed to compare the efficacy of Hatha yoga with other more established treatments and to understand its mechanism. This article is protected by copyright. All rights reserved.

We developed a non-invasive method to measure and quantify human circadian PER2 gene expression in oral mucosa samples and show that this gene oscillates in a circadian (= about a day) fashion. We also have the first evidence that induction of human PER2 expression is stimulated by exposing subjects to 2 h of light in the evening. This increase in PER2 expression was statistically significant in comparison to a non-light control condition only after light at 460 nm (blue) but not after light exposure at 550 nm (green). Our results indicate that the non-image-forming visual system is involved in human circadian gene expression. The demonstration of a functional circadian machinery in human buccal samples and its response to light opens the door for investigation of human circadian rhythms at the gene level and their associated disorders.

Vitamin C in combination with vitamin K3 (vit CK3) has been shown to inhibit tumor growth and lung metastasis in vivo, but the mechanism of action is poorly understood. Herein, C57BL/6 mice were implanted (s.c.) with Lewis lung carcinoma (LLC) for 9 days before injection (i.p.) with low-dose (100 mg vit C/kg + 1 mg vit K3/kg), high-dose (1,000 mg vit C/kg + 10 mg vit K3/kg) vit CK3 twice a week for an additional 28 days. As expected, vit CK3 or cisplatin (6 mg/kg, as a positive control) significantly and dose-dependently inhibited tumor growth and lung metastasis in LLC-bearing mice. Vit CK3 restored thebody weight of tumor-bearing mice to the level of tumor-free mice. Vit CK3 significantly decreased activities of plasma metalloproteinase (MMP)-2, -9, and urokinase plasminogen activator (uPA). In lung tissues, vit CK3 1) increased protein expression of tissue inhibitor of metalloproteinase-1 (TIMP-1), TIMP-2, nonmetastatic protein 23 homolog 1 and plasminogen activator inhibitor-1; 2) reduced protein expression of MMP-2 and MMP-9; and 3) inhibited the proliferating cell nuclear antigen (PCNA). These results demonstrate that vit CK3 inhibits primary tumor growth and exhibits antimetastastic potential in vivo through attenuated tumor invasion and proliferation.

Pancreaticβ-cell death or dysfunction mediated by oxidative stress underlies the development and progression of diabetes mellitus (DM). In this study, we evaluated the effect of lentinan (LNT), an active ingredient purified from the bodies of Lentinus edodes, on pancreatic β-cell apoptosis and dysfunction caused by streptozotocin (STZ) and the possible mechanisms implicated. The rat insulinoma cell line INS-1 were pre-treated with the indicated concentration of LNT for 30 min. and then incubated for 24 hrs with or without 0.5 mM STZ. We found that STZ treatment causes apoptosis of INS-1 cells by enhancement of intracellular reactive oxygen species (ROS) accumulation, inducible nitric oxide synthase (iNOS) expression and nitric oxide release and activation of the c-jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) signalling pathways. However, LNT significantly increasedcell viability and effectively attenuated STZ-induced ROS production, iNOS expression and nitric oxide release and the activation of JNK and p38 MAPK in a dose-dependent manner in vitro. Moreover, LNT dose-dependently prevented STZ-induced inhibition of insulin synthesis by blocking the activationof nuclear factor kappa beta and increasing the level of Pdx-1 in INS-1 cells. Together these findings suggest that LNT could protect against pancreatic β-cell apoptosis and dysfunction caused by STZ and therefore may be a potential pharmacological agent for preventing pancreatic β-cell damage caused by oxidative stress associated with diabetes.

High-intensity resistance exercise (RE) increases oxidative stress leading to deleterious effects on muscle performance and recovery. The aim of this study was to assess the effect of applying low-level laser therapy (LLLT) prior to a RE session on muscle oxidative stress and to determine the possible influence of the dosimetric parameters. Female Wistar rats were assigned to non-LLLT (Ctr: non-exercised control; RNI: RE) or LLLT groups subjected to RE (radiant energy: 4 J, 8 J, and 12 J, respectively). RE consisted of four maximum load climbs. An 830-nm DMC Lase Photon III was used to irradiate three points in gastrocnemius muscles (two limbs) before exercise. Animals were euthanized after 60 min after the end of the exercise, and muscle tissue was removed foranalysis of oxidative stress markers. All doses resulted in the prevention of increased lipoperoxidation; however, LLLT prevented protein oxidation only in rats that were pretreated with 8 J and 12 J of energy by LLLT. RE and LLLT did not change catalase activity. However, RE resulted in lower superoxide dismutase activity, and the opposite was observed in the LLLT group. These data indicate that LLLT prior to RE can prevent muscle oxidative stress. This study is the first to evaluate the impact of dosimetric LLLT parameters on the oxidative stress induced by RE, wherein both 8 J and 12 Jof energy afforded significant protection.

BACKGROUND:Studies of physical exercise in patients with Alzheimer's disease (AD) are few and results have been inconsistent.

OBJECTIVE:To assess the effects of a moderate-to-high intensity aerobic exercise program in patients with mild AD.

METHODS:In a randomized controlled trial, we recruited 200 patients with mild AD to a supervised exercise group (60-min sessions three times a week for 16 weeks) or to a control group. Primary outcome was changed from baseline in cognitive performance estimated by Symbol Digit Modalities Test (SDMT) in the intention-to-treat (ITT) group. Secondary outcomes included changes in quality of life, ability to perform activities of daily living, and in neuropsychiatric and depressive symptoms.

RESULTS:The ITT analysis showed no significant differences between intervention and control groups in change from baseline of SDMT, other cognitive tests, quality of life, or activities of daily living. The change from baseline in Neuropsychiatric Inventory differed significantly in favor of the intervention group (mean: -3.5, 95% confidence interval (CI) -5.8 to -1.3, p = 0.002). In subjects who adhered to the protocol, we found a significant effect on change from baseline in SDMT as compared with the control group (mean: 4.2, 95% CI 0.5 to 7.9, p = 0.028), suggesting a dose-response relationship between exercise and cognition.

CONCLUSIONS:This is the first randomized controlled trial with supervised moderate-to-high intensity exercise in patients with mild AD. Exercise reduced neuropsychiatric symptoms in patients with mild AD, with possible additional benefits of preserved cognition in a subgroup of patients exercising with high attendance and intensity.

During a search for neuraminidase inhibitors derived from medicinal fungi, we found that the fermentation broth of Phellinus linteus exhibited potent neuraminidase inhibitory activity. Through bioassay-guided fractionation, two active compounds were purified from the ethyl acetate-soluble portion of the fermentation broth of P. linteus. These structures were identified as inotilone (1) and 4-(3,4-dihydroxyphenyl)-3-buten-2-one (2) by spectroscopic methods. Compounds 1 and 2 inhibited H1N1 neuraminidase activity with IC50 values of 29.1 and 125.6µM, respectively, in a dose-dependent manner. They also exhibited an antiviral effect in a viral cytopathic effect reduction assay using MDCK cells. These results suggest that compounds 1 and 2 from the culture broth of P. linteus would be good candidates for the prevention and therapeutic strategies towards viral infections.

Studies have emphasized an antineoplastic effect of the non-psychoactive, phyto-cannabinoid, Cannabidiol (CBD). However, the molecular mechanism underlying its antitumor activity is not fully elucidated. Herein, we have examined the effect of CBD on two different human breast cancer cell lines: the ER-positive, well differentiated, T-47D and the triple negative, poor differentiated, MDA-MB-231 cells. In both cell lines, CBD inhibited cell survival and induced apoptosis in a dose dependent manner as observed by MTT assay, morphological changes, DNA fragmentation and ELISA apoptosis assay. CBD-induced apoptosis was accompanied by down-regulation of mTOR, cyclin D1 and up-regulation and localization of PPARγ protein expression in the nuclei and cytoplasmic of the tested cells. The results suggest that CBD treatment induces an interplay among PPARγ, mTOR and cyclin D1 in favor of apoptosis induction in both ER-positive and triple negative breast cancer cells, proposing CBD as a useful treatment for different breast cancer subtypes.

Mushrooms are valuable sources of biologically active compounds possessing anticancer, antiplatelet, and anti-inflammatory properties. Phellinus baumii is a mushroom used in folk medicine for a variety of human diseases. However, its potential anti-inflammatory effect has remained unclear. Therefore, we studied the effect of P. baumii ethyl acetate extract (PBEAE) on inflammatory mediator and proinflammatory cytokine protein and/or mRNA expression levels using the nitric oxide (NO) assay, enzyme immunoassay (EIA), western blot, and reverse transcription polymerase chain reaction (RT-PCR) in lipopolysaccharide (LPS)-stimulated macrophage like RAW264.7 cells. PBEAE markedly inhibited NO generation and prostaglandin E(2) (PGE(2)) synthesis in a concentration-dependent pattern without any cytotoxic effect at the concentration range used. PBEAE also suppressed inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expression. In addition, LPS-induced iNOS and COX-2 mRNA expression levels were dose-dependently inhibited by PBEAE pretreatment. Furthermore, PBEAE attenuated the mRNA expression levels of proinflammatory cytokines, specifically interleukin (IL)-1β, IL-6, and granulocyte macrophage colony-stimulating factor (GM-CSF), in a concentration-dependent fashion. Our study suggests that P. baumii might exhibit anti-inflammatory properties by downregulating proinflammatory mediators. Thus, further study on compounds isolated from PBEAE is warranted to investigate the associated molecular mechanisms and identify the potential therapeutic targets.