Exercise is a potential treatment to improve sleep quality in middle-aged and elderly individuals. Understanding exercise-induced changes in functional plasticity of brain circuits that underlie improvements in sleep among middle-aged and older adults can inform treatment of sleep problems. The aim of the study is to identify the effects of a 12-week exercise program on sleep quality and brain functional connectivity in middle-aged and older adults with insomnia. The trial was registered with Chinese Clinical Trial Register (ChiCTR2000033652). We recruited 84 healthy sleepers and 85 individuals with insomnia. Participants with insomnia were assigned to receive either a 12-week exercise intervention or were placed in a 12-week waitlist control condition. Thirty-seven middle-aged and older adults in the exercise group and 30 in the waitlist group completed both baseline and week 12 assessments. We found that middle-aged and older adults with insomnia showed significantly worse sleep quality than healthy sleepers. At the brain circuit level, insomnia patients showed decreased connectivity in the widespread motor network. After exercise intervention, self-reported sleep was increased in the exercise group (P < 0.001) compared to that in the waitlist group. We also found increased functional connectivity of the motor network with the cerebellum in the exercise group (P < 0.001). Moreover, we observed significant correlations between improvement in subjective sleep indices and connectivity changes within the motor network. We highlight exercise-induced improvement in sleep quality and functional plasticity of the aging brain.

1Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, U.S. Department of Agriculture, Beltsville, MD, USA; 2Department of Radiation Oncology University of Maryland School of Medicine, Baltimore, MD, USA; 3Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, MD, USA Introduction: Endemic obesity is considered the driving force for the dramatic increase in incidence of type 2 diabetes (T2D). There is mounting evidence that chronic, low-grade inflammation driven by Th1/Th17 cells and M1 macrophages, is a critical link between obesity and insulin resistance. IL-25 promotes development of a Th2 immune response and M2 macrophages that counteract the inflammation associated with obesity and T2D. Methods: Mice were fed a high-fat diet (HFD) for 16 weeks and then treated with IL-25 or BSA as a control for 21 days. Body weight, blood glucose levels, intraperitoneal glucose tolerance, and gene expression were evaluated in mice treated with BSA or IL-25. Ob/ob mice fed a normal control diet were also treated with BSA or IL-25 and body weight and blood glucose levels were measured. Transepithelial electrical resistance and sodium-linked glucose absorption were determined in muscle-free small intestinal tissue and glucose absorption assessed in vitro in intestinal epithelial and skeletal muscle cell lines. Results: Administration of IL-25 to HFD fed mice reversed glucose intolerance, an effect mediated in part by reduction in SGLT-1 activity and Glut2 expression. Importantly, the improved glucose tolerance in HFD mice treated with IL-25 was maintained for several weeks post-treatment indicating long-term changes in glucose metabolism in obese mice. Glucose intolerance was also reversed by IL-25 treatment in genetically obese ob/ob mice without inducing weight loss. In vitro studies demonstrated that glucose absorption was inhibited by IL-25 treatment in the epithelial IPEC-1 cells but increased glucose absorption in the L6 skeletal muscle cells. This supports a direct cell-specific effect of IL-25 on glucose metabolism. Conclusion: These results suggest that the IL-25 pathway may be a useful target for the treatment of metabolic syndrome.

INTRODUCTION:Endemic obesity is considered the driving force for the dramatic increase in incidence of type 2 diabetes (T2D). There is mounting evidence that chronic, low-grade inflammation driven by Th1/Th17 cells and M1 macrophages, is a critical link between obesity and insulin resistance. IL-25 promotes development of a Th2 immune response and M2 macrophages that counteract the inflammation associated with obesity and T2D.METHODS:Mice were fed a high-fat diet (HFD) for 16 weeks and then treated with IL-25 or BSA as a control for 21 days. Body weight, blood glucose levels, intraperitoneal glucose tolerance, and gene expression were evaluated in mice treated with BSA or IL-25. Ob/ob mice fed a normal control diet were also treated with BSA or IL-25 and body weight and blood glucose levels were measured. Transepithelial electrical resistance and sodium-linked glucose absorption were determined in muscle-free small intestinal tissue and glucose absorption assessed in vitro in intestinal epithelial and skeletal muscle cell lines.RESULTS:Administration of IL-25 to HFD fed mice reversed glucose intolerance, an effect mediated in part by reduction in SGLT-1 activity and Glut2 expression. Importantly, the improved glucose tolerance in HFD mice treated with IL-25 was maintained for several weeks post-treatment indicating long-term changes in glucose metabolism in obese mice. Glucose intolerance was also reversed by IL-25 treatment in genetically obese ob/ob mice without inducing weight loss. In vitro studies demonstrated that glucose absorption was inhibited by IL-25 treatment in the epithelial IPEC-1 cells but increased glucose absorption in the L6 skeletal muscle cells. This supports a direct cell-specific effect of IL-25 on glucose metabolism.CONCLUSION:These results suggest that the IL-25 pathway may be a useful target for the treatment of metabolic syndrome.

Objective: slightly elevated have been independently reported to favorably impact blood glucose. To our knowledge, no study has combined these two ingredients through oral supplementation in an attempt to modify the glycemic response to a glucose load. We determined the impact of acute ingestion of a novel glycine-cinnamon extract mixture on blood glucose, insulin, and related variables following an oral glucose challenge.Methods: Ten men and women (25.4 ± 8.3 yrs) with elevated fasting blood glucose (101.2 ± 6.6 mg•dL-1) ingested a 25 gram glucose beverage with and without SugarClear™, a proprietary blend of glycine+cinnamon extract (as Cinnulin PF®), separated by approximately one week. Blood was collected before and at 20, 60, and 120 minutes post ingestion and analyzed for glucose, insulin, glucagon-like peptide-1 (GLP-1), glucagon, ATP, and brainderived neurotrophic factor (BDNF).Results: Significant reductions in the area under the curve (AUC) were noted for both glucose (15% for total AUC and 52% for net incremental AUC) and insulin (7% for total AUC and 57% for net incremental AUC). The total AUC for GLP-1 was increased by 36%, while the AUC for ATP was increased by 20%. Glucagon was lower by 10% and BDNF higher by 5% with treatment but not in a statistically significant manner (p>0.05).Conclusion: Acute ingestion of SugarClear™, a proprietary blend of glycine and cinnamon extract, promotes a positive impact on blood glucose and insulin following an oral glucose load. The mixture also leads to an increase in both the plasma GLP-1 and ATP. These alterations may have favourable metabolic implications in those with elevated blood glucose. Future work is needed to determine the effect of chronic ingestion of SugarClear™ on glucose regulation and related variables.

In occidental societies, high fat and high sugar diets often coincide with episodes of stress. The association is likely to modify brain energy control. Brain insulin signalling is rarely studied in stressed individuals consuming high fat diets. Furthermore the effects of cinnamon supplement are not known in these conditions. Therefore, we exposed rats, over a 12-week period, to a control (C) or a high fat/high fructose (HF/HFr) diet that induces peripheral insulin resistance. A cinnamon supplement (C+CN and HF/HFr +CN) was added or not. After diet exposure, one group of rats was exposed to a 30-min restraint followed by a 10-min open-field test, their combination featuring a moderate stressor, the other rats staying unstressed in their home cages. The insulin signalling in hippocampus and frontal cortex was studied through the mRNA expression of the following genes: insulin receptor (Ir), insulin receptor substrate (Irs1), glucose transporters (Glut1 and Glut3), glycogen synthase (Gys1) and their modulators, Akt1 and Pten. In C rats, stress enhanced the expression of Ir, Irs1, Glut1, Gys1 and Akt1 mRNA. In C+CN rats, stress induced an increase in Pten but a decrease in Gys1 mRNA expression. In HF/HFr rats, stress was associated with an increase in Pten mRNA expression. In HF/HFr+CN rats, stress increased Pten mRNA expression but also decreased Gys1 mRNA expression. This suggests that a single moderate stress favours energy refilling mechanisms, an effect blunted by a previous HF/HFr diet and cinnamon supplement.

Nutritional immunology, immunometabolism and identification of novel immunotherapeutic targets are areas of active investigation in parasitology. There is a well-documented crosstalk among immune cells and cells in metabolically active tissues that is important for homeostasis. The numbers and function of these cells are altered by obesity leading to inflammation. A variety of helminths spend some part of their life cycle in the gastrointestinal tract and even entirely enteral nematode infections exert beneficial effects on glucose and lipid metabolism. The foundation of this review is the ability of enteric nematode infections to improve obesity-induced type 2 diabetes and the metabolic syndrome, which are significant health issues in developed areas. It considers the impact of nutrition and specific nutritional deficiencies, which are occur in both undeveloped and developed areas, on the host's ability mount a protective immune response against parasitic nematodes. There are a number of proposed mechanisms by which parasitic nematodes can impact metabolism including effects gastrointestinal hormones, altering epithelial function and changing the number and/or phenotype of immune cells in metabolic tissues. Nematodes can also exert their beneficial effects through Th2 cytokines that activate the transcription factor STAT6, which upregulates genes that regulate glucose and lipid metabolism.

Increasing evidence suggests that the core clock proteins of the circadian system play important roles in prevention, development, and/or progression of various pathologies, such as obesity, diabetes and sleep disorders. In this study, we investigated if the natural compound, CLOCK ® (mixture of rosemary and hemerocallis fulva extract) regulates the key protein expression related circadian rhythms in rat C6 glioma cells, using immunefluorescence and Western blotting analysis. The CLOCK complex incubation significantly enhanced Clock (circadian locomotor output cycles kaput), Bmal1 (brain and muscle Arnt‐like protein 1), Sirt (Sirtuin 1), F‐box and leucine‐rich repeat protein 21 (Fbxl21) and Fbxl3 expression in a dose‐dependent manner, compared to the control cells. CLOCK also stimulates the protein levels of brain‐derived neurotrophic factor (BDNF), which is a member of the neurotrophin family of growth factors. Oxidative stress can induce the dysregulated circadian rhythms. We also tested if CLOCK attenuates the damage of these core proteins expression in oxygen‐glucose deprivation (OGD) treated L6 muscle cells. OGD treatment significantly reduced 2‐NBDG uptake as measured by fluorescent microcopy and down‐regulated Clock, Bmal1 and Sirt1 protein levels in L6 muscle cells. CLOCK complex attenuated the damages‐induced by OGD on glucose uptake and the expression of these core proteins. These results indicate that the natural compound, CLOCK® may be beneficial on improving the dysfunction of circadian rhythms and likely circadian related diseases.Support or Funding InformationIn‐ingredients.com Funding

Background: We investigated the influence of a botanical agent to improve sleep quality and associated measures in men and women with self-reported difficulty sleeping. Methods: 32 individuals were randomly assigned in double blind manner to ingest a botanical agent (CLOCK?, containing Rosemary [Rosmarinus officinalis] and Daylily [Hemerocallis fulva]) or a placebo over a 6-week intervention. During weeks 1 and 2, subjects ingested one serving of the assigned condition, followed by a two-week washout. During weeks 5 and 6, subjects ingested two servings of the condition. The Leeds Sleep Evaluation Questionnaire was used as an outcome measure, as were subjective measures of sleep quality, energy level, and mood. Blood samples collected pre- and post-intervention were assayed for acetylcholine (ACH), brain-derived neurotrophic factor (BDNF), irisin, and melatonin. Results: No differences were noted between conditions in measures of sleep (p > 0.05). While no differences of statistical significance were noted in subjective feelings, during weeks 5 and 6 as compared to baseline, subjects assigned to the supplement noted an 8% increase in attentiveness, an 11% increase in alertness, a 12% increase in focus, a 14% increase in feeling energetic, a 12% increase in enthusiasm, a 23% increase in feeling well rested, an 11% decrease in feeling sluggish, and a 16% decrease in feeling depressed, without the same improvement observed for subjects in the placebo group. All biochemical measures were increased from pre- to post-treatment with two servings of the supplement; the largest percent increase noted for BDNF (27%) and the largest effect size noted for irisin (d = 1.36). Biochemical values for the placebo condition were unchanged. Conclusions: CLOCK? may have an impact on certain measurements of mood, with a significant impact on the biochemical marker, BDNF. Future studies using a larger sample size and perhaps a cross-over design may help to further clarify the impact of this dietary supplement on aspects of sleep quality, mood, and other related variables.

IL-25 or IL-17E is a member of IL-17 cytokine family and has immune-modulating activities. The role of IL-25 in maintaining lipid metabolic homeostasis remains unknown. We investigated the effects of exogenous IL-25 or deficiency of IL-25 on hepatic lipid accumulation. IL-25 expression was examined in paraffin-embedded tissue sections of liver from patients or in the livers from mice. Mouse model of steatosis was induced by feeding a high-fat diet (HFD). Extent of steatosis as well as expression of cytokines, key enzymes for lipid metabolic pathways, markers for Kupffer cells/macrophages, and lipid droplet (LD) proteins, were analyzed. Our results show that hepatic steatosis in mice was accompanied by increased LD proteins, but decreased IL-25 in the liver. Decreased hepatic IL-25 was also observed in patients with fatty liver. Administration of IL-25 to HFD-fed wild-type mice led to a significant improvement in hepatic steatosis. This effect was associated with increased expression of IL-13, development of alternatively activated Kupffer cells/macrophages, and decreased expression of LD proteins in the liver. In contrast, administration of IL-25 to HFD-fed mice deficient in STAT6 or IL-13 had no effects. In addition, stimulation of primary hepatocytes with IL-13, but not IL-25, resulted in downregulation of LD proteins. Finally, mice deficient in IL-25 had exacerbated hepatic lipid accumulation when fed the HFD. These data demonstrate that dysregulated IL-25 expression contributes to lipid accumulation, whereas exogenous IL-25 protects against hepatic steatosis through IL-13 activation of STAT6. IL-25 and IL-13 are potential therapeutic agents for hepatic steatosis and associated pathologies.

Oxidative stress may contribute to vascular endothelial injury leading to impaired cerebral vascular function following stroke related to diabetes. A cinnamon extract (Cinnulin PF) has been shown to reverse the negative effects of oxidative stress. The aim of this study was to investigate the effects of Cinnulin in an oxygen glucose deprivation (OGD)‐induced injury model, of mouse brain microvascular endothelial (bEnd.3) cells. Cell viability and the expression of the Bcl‐xl; a structural integrity protein, HSP90; and TNFα and phospho‐Nf‐kB p65 were evaluated. A 3h OGD/24h reperfusion insult decreased cell viability and induced Bcl‐xl, HSP90, TNFα, and phospho‐p65 proteins, while the addition of Cinnulin significantly attenuated these effects. A 3h OGD treatment decreased glucose uptake measured by fluorescence microscopy which was also reversed by Cinnulin. PGE2 is an important mediator of many biological functions, including vasodilation, antiinflammatory actions. OGD/24h reperfusion down regulated PGE2 secretion into the media and cellular PGE2 expression. Cinnulin attenuated these effects and also induced SIRT1 protein expression, which is required for the inhibition of apoptosis and inflammatory effects. These effects were inhibited by SIRT1 inhibitor IV. In summary, Cinnulin protects against ischemic injury in bEnd.3 cells and thus cinnamon extract may be beneficial in oxidative stress related chronic diseases.

Prostaglandin E2 (PGE2) is an important mediator of many biological functions, including vasodilation, both anti‐ and proinflammatory actions, and modulation of sleep/wake cycles. It is well known that cinnamon polyphenols have anti‐oxidant properties and that oxidative stress damages endothelial cells. We investigated the mechanisms underlying protective effects of an aqueous extract of cinnamon, high in polyphenols, in 3 hr oxygen‐glucose deprivation (OGD) treated mouse brain microvascular endothelial (bEnd.3) cells. Immunoprecipitation/Western blotting and immunofluorescent analyses showed that OGD/reperfusion down regulated PGE2 secretion into the media and cellular PGE2 expression. Cinnamon polyphenols reversed these damages and also induced sirtuin (SIRT)1 expression. Further studies showed that the effects were reversed by a SIRT1 inhibitor IV. Cinnamon polyphenols also inhibited the expression of the anti‐apoptotic protein, Bcl‐xl, and induced the expression of the pro‐apoptotic protein, Bax, in OGD treated cells. The OGD‐induced inflammatory factors, TNF‐α and phospho‐Nf‐kB p65, were suppressed by cinnamon polyphenols. Taken together, these results suggest protective roles of cinnamon on PGE2 production and that cinnamon polyphenols may be neuroprotectants for ischemia‐related injury.Grant Funding Source: This work was supported in part by a USDA Cooperative Research and Development Agreement (CRADA No.5

the influence of DPP-4 inhibitors on colorectal neoplasia in patients with type-2 diabetes is unknown.This study therefore evaluated the effect of the DPP-4 inhibitor, sitagliptin (STG), on diabetes-related colon carcinogenesis in mice.Materials and Methods: Six-week-old male wild-type (WT) and leptin-deficient (ob/ob) C57BL/6J mice were used in this study.The mice received 1,2-dimethlhydrazine (DMH) subcutaneously at a dose of 20 mg/kg body weight three times within a week, and chronic colitis was then induced by administration of two cycles of DSS (each cycle: 3% DSS for 7 days followed by distilled water for 14 days).Sitagliptin (3 mg/kg) was administered to the mice by oral gavage every day during the entire experimental period.The mice were divided into the following three groups: WT group; obob group; and obob+STG group.The mice were sacrificed 28 days after the completion of both cycles of DSS.Results: During the DSS administration cycle, mean body weight decreased significantly in the WT group compared with the obob and obob+STG groups.The disease activity index (DAI) was also increased significantly in the WT group.However, administration of STG did not affect the DAI or body weight.The mean number of tumors was 7.8±4.5,10.6±3.3, and 6.7±2.4 in the WT, obob, and obob+STG groups, respectively.STG significantly suppressed the occurrence of neoplasia in the obob mice.Mucosal DPP-4 activity and the mucosal concentration of GLP-2 were not significantly different in the three groups.Conclusion: Administration of STG exerts a suppressive effect on the development of colon neoplasia in a murine model of type 2 diabetes.However, STG does not affect the mucosal DPP-4 activity.Because DPP-4 mRNA/DPP-4 activity are highly expressed/detected in the small intestine and DPP-8 and 9 are expressed predominantly in the colon, DPP-4 inhibitors may suppress colon carcinogenesis independent of the GLP pathway.

Abstract Polyphenols possess antioxidant and anti-inflammatory properties. Oxidative stress (OS) and inflammation have been implicated in the pathogenesis of cytotoxic brain edema in cerebral ischemia. In addition, OS and pro-inflammatory cytokines also damage the endothelial cells and the neurovascular unit. Endothelial cell swelling may contribute to a leaky blood–brain barrier which may result in vasogenic edema in the continued presence of the existing cytotoxic edema. We investigated the protective effects of polyphenols on cytotoxic cell swelling in bEND3 endothelial cultures subjected to 5 hours oxygen-glucose deprivation (OGD). A polyphenol trimer from cinnamon (cinnamtannin D1), a polyphenol-rich extract from green tea, and resveratrol prevented the OGD-induced rise in mitochondrial free radicals, cell swelling, and the dissipation of the inner mitochondrial membrane potential. Monocyte chemoattractant protein (also called CCL2), a chemokine, but not tumor necrosis factor-α or interleukin-6, augmented the cell swelling. This effect of monochemoattractant protein 1-1 was attenuated by the polyphenols. Cyclosporin A, a blocker of the mitochondrial permeability transition pore, did not attenuate cell swelling but BAPTA-AM, an intracellular calcium chelator did, indicating a role of [Ca2+]i but not the mPT in cell swelling. These results indicate that the polyphenols reduce mitochondrial reactive oxygen species and subsequent cell swelling in endothelial cells following ischemic injury and thus may reduce brain edema and associated neural damage in ischemia. One possible mechanism by which the polyphenols may attenuate endothelial cell swelling is through the reduction in [Ca2+]i.

AIMS:It is well established that the brain is particularly susceptible to oxidative damage due to its high consumption of oxygen. The objective of this study was to investigate the protective effects of a water soluble polyphenol-rich extract of cinnamon and the possible mechanisms, under conditions of oxidative stress-induced by hydrogen peroxide, in rat C6 glioma cells.MAIN METHODS:After 24h of H2O2 incubation, the secretion and intracellular expression of S100β were determined by immunoprecitation/immunoblotting and immunofluorescence imaging.KEY FINDINGS:Cinnamon polyphenols (CP) counteracted the oxidative effects of H2O2 on S100β secretion and expression. CP also enhanced the impaired protein levels of sirtuins 1, 2, and 3, which are deacetylases important in cell survival. H2O2 also induced the overexpression of the proinflammatory factors, TNF-α, phospho-NF-κB p65, as well as of Bcl-xl, Bax and Caspase-3, which are all the members of the Bcl-2 family. CP not only suppressed the expression of these proteins but also attenuated the phosphorylation induced by H2O2. CP also upregulated the decreased Bcl-2 protein levels in H2O2 treated C6 cells. The effects of CP on H2O2-induced downregulation of S100β secretion were blocked by SIRT1 siRNA demonstrating that SIRT1 plays a regulatory role in CP-mediated prevention by H2O2.SIGNIFICANCE:These data demonstrate that Cinnamon polyphenols may exert neuroprotective effects in glial cells by the regulation of Bcl-2 family members and enhancing SIRT1 expression during oxidative stress.

Polyphenols possess anti‐oxidant and anti‐inflammatory properties. Oxidative stress (OS)and inflammation have been implicated in the pathogenesis of brain edema in cerebral ischemia. OS and pro‐inflammatory cytokines damage endothelial cells/neurovascular unit. The resultant breakdown of the blood‐brain barrier contributes to vasogenic edema and may also contribute to endothelial cell swelling, a component of cytotoxic edema. We investigated the protective effects of polyphenols in bEND3 endothelial cultures subjected to 5 hr oxygen‐glucose deprivation (OGD). A polyphenol‐rich extract from green tea (GT), a polyphenol trimer from cinnamon, and resveratrol prevented the OGD‐induced rise in mitochondrial free radicals, cell swelling, and the dissipation of the inner mitochondrial membrane potential. Monocyte chemoattractant protein (MCP‐1), a chemokine, but not TNF‐α or IL‐6, augmented the cell swelling. The effect of MCP‐1 was attenuated by the polyphenols. Cyclosporin A, a blocker of the mitochondrial permeability transition pore, did not attenuate cell swelling but BAPTA‐AM, an intracellular calcium chelator did, indicating a role of [Ca2+] but not the mPT in cell swelling. These results indicate that the polyphenols reduce mitochondrial ROS and subsequent cell swelling in endothelial cells following ischemic injury and thus may reduce brain edema and associated neural damage in ischemia.