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 neurodegenerative disorder Huntington's disease (HD) is typically characterized by extensive loss of striatal neurons and the midlife onset of debilitating and progressive chorea, dementia, and psychological disturbance. HD is caused by a CAG repeat expansion in the Huntingtin (HTT) gene, translating to an elongated glutamine tract in the huntingtin protein. The pathogenic mechanism resulting in cell dysfunction and death beyond the causative mutation is not well defined. To further delineate the early molecular events in HD, we performed RNA-sequencing (RNA-seq) on striatal tissue from a cohort of 5-y-old OVT73-line sheep expressing a human CAG-expansion HTT cDNA transgene. Our HD OVT73 sheep are a prodromal model and exhibit minimal pathology and no detectable neuronal loss. We identified significantly increased levels of the urea transporter SLC14A1 in the OVT73 striatum, along with other important osmotic regulators. Further investigation revealed elevated levels of the metabolite urea in the OVT73 striatum and cerebellum, consistent with our recently published observation of increased urea in postmortem human brain from HD cases. Extending that finding, we demonstrate that postmortem human brain urea levels are elevated in a larger cohort of HD cases, including those with low-level neuropathology (Vonsattel grade 0/1). This elevation indicates increased protein catabolism, possibly as an alternate energy source given the generalized metabolic defect in HD. Increased urea and ammonia levels due to dysregulation of the urea cycle are known to cause neurologic impairment. Taken together, our findings indicate that aberrant urea metabolism could be the primary biochemical disruption initiating neuropathogenesis in HD.

What's known on the subject? and What does the study add? It is known that both lactate inhibition and carbohydrate restriction inhibit tumour growth. What is unknown is whether the two work synergistically together. This study adds that though the combination of lactate inhibition and carbohydrate restriction did not synergistically slow tumour growth in our model, we confirmed that carbohydrate restriction started after tumour inoculation slowed tumour growth. Moreover, lactate inhibition resulted in changes in the tumour microenvironment that may have implications for future metabolic targeting of prostate cancer growth. OBJECTIVE:•  To determine if a no-carbohydrate ketogenic diet (NCKD) and lactate transporter inhibition can exert a synergistic effect on delaying prostate tumour growth in a xenograft mouse model of human prostate cancer. MATERIALS AND METHODS: •  120 nude athymic male mice (aged 6-8 weeks) were injected s.c. in the flank with 1.0 × 10(5) LAPC-4 prostate cancer cells. •  Mice were randomized to one of four treatment groups: Western diet (WD, 35% fat, 16% protein, 49% carbohydrate) and vehicle (Veh) treatment; WD and mono-carboxylate transporter-1 (MCT1) inhibition via α-cyano-4-hydroxycinnamate (CHC) delivered through a mini osmotic pump; NCKD (84% fat, 16% protein, 0% carbohydrate) plus Veh; or NCKD and MCT1 inhibition. •  Mice were fed and weighed three times per week and feed was adjusted to maintain similar body weights. •  Tumour size was measured twice weekly and the combined effect of treatment was tested via Kruskal-Wallis analysis of all four groups. Independent effects of treatment (NCKD vs WD and CHC vs Veh) on tumour volume were tested using linear regression analysis. •  All mice were killed on Day 53 (conclusion of pump ejection), and serum and tumoursections were analysed for various markers. Again, combined and independent effects of treatment were tested using Kruskal-Wallis and linear regression analysis, respectively. RESULTS: •  There were no significant differences in tumour volumes among the four groups (P= 0.09). •  When testing the independent effects of treatment, NCKD was significantly associated with lower tumour volumes at the end of the experiment (P= 0.026), while CHC administration was not (P= 0.981). However, CHC was associated with increased necrotic fraction (P<0.001). CONCLUSIONS:•  Differences in tumour volumes were observed only in comparisons between mice fed a NCKD and mice fed a WD. •  MCT1 inhibition did not have a significant effect on tumour volume, although it was associated with increased necrotic fraction.

Coenzyme Q10 (CoQ10) is an essential cofactor of the electron transport gene as well as an important antioxidant, which is particularly effective within mitochondria. A number of prior studies have shown that it can exert efficacy in treating patients with known mitochondrial disorders. We investigated the potential usefulness of coenzyme Q10 in animal models of Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). It has been demonstrated that CoQ10 can protect against striatal lesions produced by the mitochondrial toxins malonate and 3-nitropropionic acid. These toxins have been utilized to model the striatal pathology, which occurs in HD. It also protects against 1-methyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity in mice. CoQ10 significantly extended survival in a transgenic mouse model of ALS. CoQ10 can significantly extend survival, delay motor deficits and delay weight loss and attenuate the development of striatal atrophy in a transgenic mouse model of HD. In this mouse model, it showed additive efficacy when combined with the N-methyl-D-aspartate (NMDA) receptor antagonist, remacemide. CoQ10 is presently being studied as a potential treatment for early PD as well as in combination with remacemide as a potential treatment for HD.

Considerable evidence implicates cellular senescence in the biology of aging and chronic disease. Diet and exercise are determinants of healthy aging; however, the extent to which they affect the behavior and accretion of senescent cells within distinct tissues is not clear. Here we tested the hypothesis that exercise prevents premature senescent cell accumulation and systemic metabolic dysfunction induced by a fast food diet (FFD). Using transgenic mice that express enhanced green fluorescent protein (EGFP) in response to activation of the senescence-associated p16(INK4a) promoter, we demonstrate that FFD consumption causes deleterious changes in body weight and composition, as well as measures of physical, cardiac, and metabolic health. The harmful effects of the FFD were associated with dramatic increases in several markers of senescence, including p16, EGFP, senescence-associatedβ-galactosidase, and the senescence-associated secretory phenotype (SASP), specifically in visceral adipose tissue. We show that exercise prevents both the accumulation of senescent cells and the expression of the SASP, while nullifying the damaging effects of the FFD on parameters of health. We also demonstrate that exercise initiated following long-term FFD-feeding reduces senescent phenotype makers in visceral adipose while attenuating physical impairments, suggesting that exercise may provide restorative benefit by mitigating accrued senescent burden. These findings highlight a novel mechanism by which exercise mediates its beneficial effects and reinforce the impact of modifiable lifestyle choices on healthspan.

Both n-3 fatty acids (n-3 FA) and calorie-restriction (CR) exert anti-inflammatory effects in animal models of autoimmunity and inflammation. In the present study we investigated the synergistic anti-inflammatory effects of n-3 FA and CR on LPS-mediated inflammatory responses using fat-1 transgenic mice that generate n-3 FA endogenously. Wild-type (WT) and fat-1 mice were maintained on ad libitum (AL) or CR (40% less than AL) diet for 5 mo; splenocytes were cultured in vitro with/without LPS. Our results show: (i) no difference in body weights between WT and fat-1 mice on AL or CR diets, (ii) lower n-6/n-3 FA ratio in splenocytes from fat-1 mice on both AL and CR diets, (iii) significant reduction in NF-kappaB (p65/p50) and AP-1 (c-Fos/c-Jun) DNA-binding activities in splenocytes from fat-1/CR mice following LPS treatment, and (iv) significant reduction in kappaB- and AP-1-responsive IL-6 and TNF-alpha secretion following LPS treatment in splenocytes from fat-1/CR mice. The inhibition of LPS-mediated effects was more pronounced in fat-1/CR mice when compared to fat-1/AL or WT/CR mice. These data show that transgenic expression of fat-1 results in decreased pro-inflammatory n-6 FA, and demonstrate for the first time that splenocytes from fat-1 mice on CR diet exhibit reduced pro-inflammatory response when challenged with LPS. These results suggest that n-3 lipids with moderate CR may confer protection in autoimmune and inflammatory diseases.

The known association between hepatitis B and vasculitis has been reported in rare cases in adults after hepatitis B vaccination. We here describe a 35-day-old infant who developed Kawasaki disease 1 day after receiving his second dose of hepatitis B vaccine. Although extremely rare, this possible side effect should be noted and further investigated.

Huntington's disease (HD) is an inherited neurodegenerative disease that is caused by the abnormal expansion of CAG repeats in the gene encoding huntingtin (Htt). Reduced AKT phosphorylation and inhibited AKT activity have been shown to be involved in mutant Htt (mHtt)-induced cell death. Lycium barbarum polysaccharide (LBP), the main bioactive component of Lycium barbarum, reportedly has neuroprotective roles in neural injuries, including neurodegenerative diseases. Here, we report that treatment with LBP can increased the viability of HEK293 cells that stably expressed mHtt containing 160 glutamine repeats and significantly improved motor behavior and life span in HD-transgenic mice. Furthermore, we found that in LBP-treated HEK293 cells expressing mHtt, mHtt levels were reduced and the phosphorylation of AKT at Ser473 (p-AKT-Ser473) was significantly increased. We also found that treatment with LBP increased p-AKT-Ser473 and decreased mHtt in the cortex, hippocampus and striatum in HD-transgenic mice. The level of phosphorylation of p-GSK3β-Ser9 remained unchanged in both cultured cells and HD-transgenic mice. Our findings suggest that LBP alleviates the cytotoxicity of mHtt by activating AKT and reducing mHtt levels, indicating that LBP may be potentially useful for treating HD.

The relationship between exercise and amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder characterized by motor neuron loss, rapidly progressive weakness and early death has been controversial. We studied the effect of a high (HEX) and moderate-level exercise (MEX) on body weight, motor performance and motor neuron counts in the ventral horn of spinal cords in a transgenic mouse model of ALS (G93A-SOD1) that overexpresses a mutated form of the human SOD1 gene that is a cause of familial ALS. These transgenic mice show several similarities to the human disease, including rapid progressive motor weakness from 100 days of age and premature death at around 135 days of age. Mice were exposed to high or mid-level exercise of left sedentary (SED). At 70, 95 and 120 days of age, spinal cords were processed following euthanasia. Motor neurons larger than 15 mum in diameter were counted with a design-based stereological protocol using an optical fractionator probe in the ventral horn of different regions of the cord and compared to wild-type littermates. Moderate exercise delayed the onset of motor deficit by over a week. High exercise slightly but significantly hastened the onset of motor performance deficits. Motor neuron density in the lumbar cord was significantly higher in MEX group compared to SED at 95 days of age. These results show the beneficial effects of moderate exercise on the preservation of motor performance that correlates with higher motor neuron density in the ventral horn of the lumbar spinal cord in G93A mice.

The evidence for a protective role of physical activity on the risk and progression of Alzheimer's disease (AD) has been growing in the last years. Here we studied the influence of a prolonged physical and cognitive stimulation on neurodegeneration, with special emphasis on hippocampal neuron loss and associated behavioral impairment in the Tg4-42 mouse model of AD. Tg4-42 mice overexpress Aβ4-42 without any mutations, and develop an age-dependent hippocampal neuron loss associated with a severe memory decline. We demonstrate that long-term voluntary exercise diminishes CA1 neuron loss and completely rescues spatial memory deficits in different experimental settings. This was accompanied by changes in the gene expression profile of Tg4-42 mice. Deep sequencing analysis revealed an upregulation of chaperones involved in endoplasmatic reticulum protein processing, which might be intimately linked to the beneficial effects seen upon long-term exercise. We believe that we provide evidence for the first time that enhanced physical activity counteracts neuron loss and behavioral deficits in a transgenic AD mouse model. The present findings underscore the relevance of increased physical activity as a potential strategy in the prevention of dementia.

Calorie restriction or a low-carbohydrate diet (LCD) can increase life span in normal cells while inhibiting carcinogenesis. Various phytochemicals also have calorie restriction-mimetic anticancer properties. We investigated whether an isocaloric carbohydrate-restriction diet and AMP-activated protein kinase (AMPK)-activating phytochemicals induce synergic tumor suppression. We used a mixture of AMPK-activating phytochemical extracts including curcumin, quercetin, catechins, and resveratrol. Survival analysis was carried out in a B16F10 melanoma model fed a control diet (62.14% kcal carbohydrate, 24.65% kcal protein and 13.2% kcal fat), a control diet with multiple phytochemicals (MP), LCD (16.5, 55.2, and 28.3% kcal, respectively), LCD with multiple phytochemicals (LCDmp), a moderate-carbohydrate diet (MCD, 31.9, 62.4, and 5.7% kcal, respectively), or MCD withphytochemicals (MCDmp). Compared with the control group, MP, LCD, or MCD intervention did not produce survival benefit, but LCDmp (22.80±1.58 vs. 28.00±1.64 days, P=0.040) and MCDmp (23.80±1.08 vs. 30.13±2.29 days, P=0.008) increased the median survival time significantly. Suppression of the IGF-1R/PI3K/Akt/mTOR signaling, activation of the AMPK/SIRT1/LKB1pathway, and NF-κB suppression were the critical tumor-suppression mechanisms. In addition, SIRT1 suppressed proliferation of the B16F10 and A375SM cells under a low-glucose condition. Alterations in histone methylation within Pten and FoxO3a were observed after the MCDmp intervention. In the transgenic liver cancer model developed by hydrodynamic transfection of the HrasG12V and shp53, MCDmp and LCDmp interventions induced significant cancer-prevention effects. Microarray analysis showed that PPARα increased with decreased IL-6 and NF-κB within the hepatocytes after an MCDmp intervention. In conclusion, an isocaloric carbohydrate-restriction diet and natural AMPK-activating agents induce synergistic anticancer effects. SIRT1 acts as a tumor suppressor under a low-glucose condition.This is an open-access article distributedunder the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/3.0.

Huntington disease (HD) represents a family of neurodegenerative diseases that are caused by misfolded proteins. The misfolded proteins accumulate in the affected brain regions in an age-dependent manner to cause late-onset neurodegeneration. Transgenic mouse models expressing the HD protein, huntingtin, have been widely used to identify therapeutics that may retard disease progression. Here we report that Berberine (BBR), an organic small molecule isolated from plants, has protective effects on transgenic HD (N171-82Q) mice. We found that BBR can reduce the accumulation of mutant huntingtin in cultured cells. More importantly, when given orally, BBR could effectively alleviate motor dysfunction and prolong the survival of transgenic N171-82Q HD mice. We found that BBR could promote the degradation of mutant huntingtin by enhancing autophagic function. Since BBR is an orally-taken drug that has been safely used to treat a number of diseases, our findings suggest that BBR can be tested on different HD animal models and HD patients to further evaluate its therapeutic effects.