Protective Effects of Hydrolyzed Chicken Extract (Probeptigen®/Cmi-168) on Memory Retention and Brain Oxidative Stress in Senescence-Accelerated Mice.

The senescence-accelerated prone (SAMP8) mouse model shows age-dependent deterioration in learning and memory and increased oxidative stress in the brain. We previously showed that healthy subjects on a six-week supplementation of a chicken meat hydrolysate (ProBeptigen®/CMI-168) demonstrated enhanced and sustained cognitive performance up until two weeks after the termination of supplementation. In this study, we investigate the effect of ProBeptigen on the progression of age-related cognitive decline. Three-month old SAMP8 mice were orally administered different doses of ProBeptigen (150,300 or 600 mg/kg/day) or saline daily for 13 weeks. Following ProBeptigen supplementation, mice showed lower scores of senescence and improved learning and memory in avoidance tasks. ProBeptigen treatment also increased antioxidant enzyme activity and dopamine level while reducing protein and lipid peroxidation and mitochondrial DNA damage in the brain. Microarray analysis of hippocampus revealed several processes that may be involved in the improvement of cognitive ability by ProBeptigen, including heme binding, insulin growth factor (IGF) regulation, carboxylic metabolic process, oxidation-reduction process and endopeptidase inhibition. Genes found to be significantly altered in both ProBeptigen treated male and female mice include Mup1, Mup17, Mup21, Ahsg and Alb. Taken together, these results suggest a potential anti-aging effect of ProBeptigen in alleviating cognitive deficits and promoting the antioxidant defense system.

A Hydrolyzed Chicken Extract CMI-168 Enhances Learning and Memory in Middle-Aged Mice.

There has been increasing evidence that consumption of dietary supplements or specific nutrients can influence cognitive processes and emotions. A proprietary chicken meat extraction, Chicken Meat Ingredient-168 (CMI-168), has previously been shown to enhance cognitive function in humans. However, the mechanism underlying the CMI-168-induced benefits remains unclear. In this study, we investigated the effects of CMI-168 on hippocampal neuroplasticity and memory function in middle-aged (9⁻12 months old) mice. The mice in the test group (termed the "CMI-168 group") were fed dietary pellets produced by mixing CMI-168 and normal laboratory mouse chow to provide a daily CMI-168 dose of 150 mg/kg of body weight for 6 weeks. The control mice (termed the "Chow group") were fed normal laboratory mouse chow pellets. CMI-168 supplementation did not affect the body weight gain, food intake, or exploratory behavior of the mice. In the novel object recognition test, the CMI-168 group showed better hippocampus-related non-spatial memory compared to the control Chow group. However, spatial memory examined by the Morris Water Maze test was similar between the two groups. There was also no significant difference in the induction and maintenance of long-term potentiation and dendritic complexity of the hippocampal cornu ammonis region 1 (CA1) neurons, as well as the levels of neuroplasticity-related proteins in the hippocampi of the CMI-168 and Chow groups. Interestingly, we observed that CMI-168 appeared to protect the mice against stress-induced weight loss. In conclusion, dietary supplementation of CMI-168 was found to improve learning and memory in middle-aged mice, independent of structural or functional changes in the hippocampus. The resilience to stress afforded by CMI-168 warrants further investigation.

In Vitro and In Vivo Functional Characterization of Essence of Chicken as An Ergogenic Aid.

Essence of chicken is a popular Asian nutritional supplement that is often taken to improve metabolism and general health. Although used as a traditional remedy for combating fatigue and general health, there has been few studies investigating the ergogenic properties of chicken essence and its associated mechanism. We conducted a study to investigate the anti-fatigue and anti-oxidant properties of essence of chicken (EC) after exercise. Six weeks old male Institute of Cancer Research (ICR) mice were divided to four groups (10 mice/group) and were provided different doses of Essence of Chicken (EC): (1) Vehicle (water), (2) EC-0.5X (558 mg/kg), (3) EC-1X (1117 mg/kg), and (4) EC-2X (2234 mg/kg). EC supplementation could improve endurance and grip strength (p < 0.0001) and it had significant effects on the fatigue-related biochemical markers: ammonia, blood urea nitrogen (BUN), and creatine kinase (CK) levels were significantly lowered, while glucose blood levels and lactate clearance were improved after exercise challenge. Muscle and liver glycogen levels, muscle and liver superoxide dismutase (SOD), hepatic catalase (CAT), and glutathione (GSH) levels were observed to increase with EC supplementation. Preliminary in vitro data suggests that EC may have a beneficial effect in muscle mass and strength. No abnormalities were observed from pathohistological examination. Our study suggests that the EC could significantly improve exercise performance and endurance capacity and that the anti-oxidant properties of EC may be an important contributing factor to its anti-fatigue effects.

The involvement of sympathetic nervous system in essence of chicken-facilitated physiological adaption and circadian resetting.

AIM: The impact of the sympathetic nervous system (SNS) on the regulation of circadian rhythm and physiological functions is still not clear. Previous studies have found that essence of chicken (EC) supplementation facilitated the physiological adaption and circadian resetting in rats subjected to jet lag. Herein, the effects of SNS on the circadian clock and the hypothesis that EC-induced acceleration of circadian resetting is dependent on the SNS are investigated. MAIN METHODS: Male Wistar rats with superior cervical ganglionectomy (SCGx) were used to investigate the role of the SNS in circadian rhythm and physiological functions. SCGx rats were further fed with or without EC-containing diet for 2 weeks and subjected to artificial jet lag. KEY FINDINGS: Loss of SNS did not affect the circadian rhythm both in the hypothalamic suprachiasmatic nuclei (SCN) and peripheral clocks, including the liver and heart. The serum lipid levels were increased significantly in SCGx rats, together with the up-regulation of lipogenic gene expression in the liver and slight effect on serum hormones. The quicker resetting process of the clock genes in peripheral tissues of EC-fed rats was abolished after SCGx. In contrast, the phase shift of serum melatonin and corticosterone were faster in EC-fed rats, compared to that of control rats. SIGNIFICANCE: The SNS controls different aspects of physiological functions, and it has little effect on circadian system under normal light/dark condition. The effects EC on peripheral circadian synchrony and physiological functions were dependent on, at least partly, through the regulation of sympathetic nerve function.

Whole grain intake, determined by dietary records and plasma alkylresorcinol concentrations, is low among pregnant women in Singapore.

BACKGROUND AND OBJECTIVES: To quantify whole grain intake in pregnant women in Singapore in order to provide the first detailed analysis of whole grain intake in an Asian country and in pregnant women. METHODS AND STUDY DESIGN: Analysis of 24-h diet recalls in a cross-sectional cohort study and analysis of a biomarker of whole grain intake (plasma alkylresorcinols) in a subset of subjects. The Growing Up in Singapore Towards healthy Outcomes-mother offspring cohort study based in Singapore. 998 pregnant mothers with complete 24-h recalls taken during their 26-28th week of gestation. Plasma samples from a randomly select subset of 100 subjects were analysed for plasma alkylresorcinols. RESULTS: Median (IQR) whole grain intake for the cohort and the 30% who reported eating whole grains were 0 (IQR 0, 9) and 23.6 (IQR 14.6, 44.2) g/day respectively. Plasma alkylresorcinol concentrations were very low [median (IQR)=9 (3, 15) nmol/L], suggesting low intake of whole grain wheat in this population. Plasma alkylresorcinols were correlated with whole grain wheat intake (Spearman's r=0.35; p<0.01). CONCLUSIONS: Whole grain intake among pregnant mothers in Singapore was well below the 2-3 (60-95 g) servings of whole grains per day recommended by the Singapore Health Promotion Board. Efforts to increase whole grain intake should be supported to encourage people to choose whole grains over refined grains in their diet.

Long-chain polyunsaturated fatty acid status during pregnancy and maternal mental health in pregnancy and the postpartum period: results from the GUSTO study.

OBJECTIVE: Studies have demonstrated a relationship between lower omega-3 long-chain polyunsaturated fatty acid (LC-PUFA) status and anxiety and depression. It is uncertain whether similar associations occur in pregnant women, when anxiety and depression could have long-term effects on the offspring. We examined the associations between plasma LC-PUFA status during pregnancy and perinatal mental health. METHOD: At 26-28 weeks' gestation, plasma LC-PUFAs were measured in mothers of the Growing Up in Singapore Toward healthy Outcomes (GUSTO) mother-offspring cohort study, who were recruited between June 2009 and September 2010. Maternal symptoms of anxiety and depression were assessed with the State-Trait Anxiety Inventory (STAI) and Edinburgh Postnatal Depression Scale (EPDS) during the same period and at 3 months' postpartum. The STAI-state subscale was used as a continuous measure of current anxiety, while EPDS scores ≥ 15 during pregnancy or ≥ 13 postpartum were indicative of symptoms of probable depression. RESULTS: In adjusted regression analyses (n = 698), lower plasma total omega-3 PUFA concentrations (ß = -6.49 STAI-state subscale scores/unit increase of omega-3 fatty acid; 95% CI, -11.90 to -1.08) and higher plasma omega-6:omega-3 PUFA ratios (ß = 6.58 scores/unit increase of fatty acid ratio; 95% CI, 1.19 to 12.66), specifically higher arachidonic acid (AA):docosahexaenoic acid, AA:eicosapentaenoic acid, and AA:docosapentaenoic acid ratios, were associated with increased antenatal anxiety (P < .05 for all), but not postpartum anxiety. There was no association between plasma PUFAs and perinatal probable depression. CONCLUSIONS: No association was found with probable depression in pregnancy or postpartum. Lower plasma omega-3 fatty acids and higher omega-6:omega-3 fatty acid ratios were associated with higher antenatal anxiety, but not postpartum anxiety. Replication in other studies is needed to confirm the findings and determine the direction of causality. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01174875.

Maternal PUFA status and offspring allergic diseases up to the age of 18 months.

Studies have suggested that maternal PUFA status during pregnancy may influence early childhood allergic diseases, although findings are inconsistent. We examined the relationship between maternal PUFA status and risk of allergic diseases in early childhood in an Asian cohort. Maternal plasma samples from the Growing Up in Singapore Towards Healthy Outcomes mother-offspring cohort were assayed at 26-28 weeks of gestation for relative abundance of PUFA. Offspring (n 960) were followed up from 3 weeks to 18 months of age, and clinical outcomes of potential allergic diseases (rhinitis, eczema and wheezing) were assessed by repeated questionnaires. Skin prick testing (SPT) was also performed at the age of 18 months. Any allergic disease with positive SPT was defined as having any one of the clinical outcomes plus a positive SPT. The prevalence of a positive SPT, rhinitis, eczema, wheezing and any allergic disease with positive SPT was 14·1 % (103/728), 26·5 % (214/808), 17·6 % (147/833), 10·9 % (94/859) and 9·4 % (62/657), respectively. After adjustment for confounders, maternal total n-3, n-6 PUFA status and the n-6:n-3 PUFA ratio were not significantly associated with offspring rhinitis, eczema, wheezing, a positive SPT and having any allergic disease with positive SPT in the offspring (P>0·01 for all). A weak trend of higher maternal n-3 PUFA being associated with higher risk of allergic diseases with positive SPT in offspring was observed. These findings do not support the hypothesis that the risk of early childhood allergic diseases is modified by variation in maternal n-3 and n-6 PUFA status during pregnancy in an Asian population.

Maternal folate status, but not that of vitamins B-12 or B-6, is associated with gestational age and preterm birth risk in a multiethnic Asian population.

BACKGROUND: Maternal folate, vitamin B-12, and vitamin B-6 concentrations during pregnancy have been shown to influence birth outcomes, but the evidence is inconclusive. OBJECTIVE: We aimed to examine the associations of maternal B-vitamin status with gestational age, birth weight, and length in a birth cohort study in Singapore. METHODS: Maternal blood samples (n = 999) collected during weeks 26-28 of gestation were assayed for plasma folate, vitamin B-12, and vitamin B-6 concentrations. Birth weight and gestational age data were obtained from hospital records, and other anthropometric variables were measured within 72 h after birth. Relations between B-vitamin status and birth outcomes were assessed by linear or logistic regression with adjustment for potential confounders. RESULTS: Median (IQR) plasma concentrations were 34.4 (24.5-44.6) nmol/L for folate, 209 (167-258) pmol/L for vitamin B-12, and 61.8 (25.9-113) nmol/L for vitamin B-6. We found that higher plasma folate concentrations were associated with a longer gestational age (0.12 wk per SD increase in folate; 95% CI: 0.02, 0.21) and tended to be associated with lower risk of all preterm birth (delivery at <37 wk of gestation; OR: 0.79; 95% CI: 0.63, 1.00) and spontaneous preterm birth (OR: 0.76; 95% CI: 0.56, 1.04). Overall, concentrations of maternal folate, vitamin B-12, and vitamin B-6 were not independently associated with birth weight or being born small for gestational age (SGA; birth weight <10th percentile for gestational age). CONCLUSIONS: Higher maternal folate concentrations during late pregnancy were associated with longer gestational age and tended to be associated with a lower risk of preterm birth in this multiethnic Asian population. In contrast, the results of our study suggested little or no benefit of higher folate concentrations for reducing the risk of SGA or of higher vitamin B-6 and vitamin B-12 concentrations for reducing the risk of preterm birth or SGA.

Relationships of maternal folate and vitamin B12 status during pregnancy with perinatal depression: The GUSTO study.

UNLABELLED: Studies in the general population have proposed links between nutrition and depression, but less is known about the perinatal period. Depletion of nutrient reserves throughout pregnancy and delayed postpartum repletion could increase the risk of perinatal depression. We examined the relationships of plasma folate and vitamin B12 concentrations during pregnancy with perinatal depression. At 26th-28th weeks of gestation, plasma folate and vitamin B12 were measured in women from the GUSTO mother-offspring cohort study in Singapore. Depressive symptoms were measured with the Edinburgh Postnatal Depression Scale (EPDS) during the same period and at 3-month postpartum. EPDS scores of ≥15 during pregnancy or ≥13 at postpartum were indicative of probable depression. Of 709 women, 7.2% (n = 51) were identified with probable antenatal depression and 10.4% (n = 74) with probable postnatal depression. Plasma folate concentrations were significantly lower in those with probable antenatal depression than those without (mean ± SD; 27.3 ± 13.8 vs 40.4 ± 36.5 nmol/L; p = 0.011). No difference in folate concentrations was observed in those with and without probable postnatal depression. In adjusted regression models, the likelihood of probable antenatal depression decreases by 0.69 for every unit variation (increase) in folate (OR = 0.69 per SD increase in folate; 95% CI: 0.52, 0.94). Plasma vitamin B12 concentrations were not associated with perinatal depression. Lower plasma folate status during pregnancy was associated with antenatal depression, but not with postnatal depression. Replication in other studies is needed to determine the direction of causality between low folate and antenatal depression. CLINICAL TRIAL REGISTRY: NCT01174875.

Epigenetic state and expression of imprinted genes in umbilical cord correlates with growth parameters in human pregnancy.

BACKGROUND: Genomic imprinting is a process causing genes to be expressed according to parental origin. Imprinting acts to coordinate fetal and prenatal growth, as well as control postnatal adaptations. Studies on human imprinting are confounded by tissue availability, sampling variability and limitations posed by tissue-specific expression and cellular heterogeneity within tissues. The human umbilical cord is an easily available, embryonic-derived fetal tissue with the potential to overcome many of these limitations. METHODS: In a sensitive, gene-specific quantitative expression analysis, we show for the first time robust imprinted gene expression combined with methylation analysis in cords isolated from Asian Chinese full-term births. RESULTS: Linear regression analyses revealed an inverse correlation between expression of pleckstrin homology-like domain, family A, member 2 (PHLDA2) with birth weight (BW). Furthermore, we observed significant down-regulation of the paternally expressed gene 10 (PEG10) in low BW babies compared to optimum BW babies. This change in PEG10 gene expression was accompanied by concomitant methylation alterations at the PEG10 promoter. CONCLUSIONS: These data are the first to demonstrate relative expression of an imprinted gene associated with epigenetic changes in non-syndromic fetal growth restriction in babies. They show that perturbed expression in compromised fetal growth may be associated with in utero modulation of the epigenetic state at the imprinting control regions and implicate specific imprinted genes as new biomarkers of fetal growth.

Tumor hypoxia blocks Wnt processing and secretion through the induction of endoplasmic reticulum stress.

Poorly formed tumor blood vessels lead to regions of microenvironmental stress due to depletion of oxygen and glucose and accumulation of waste products (acidosis). These conditions contribute to tumor progression and correlate with poor patient prognosis. Here we show that the microenvironmental stresses found in the solid tumor are able to inhibit the canonical Wnt/beta-catenin signaling pathway. However, tumor cells harboring common beta-catenin pathway mutations, such as loss of adenomatous polyposis coli, are insensitive to this novel hypoxic effect. The underlying mechanism responsible is hypoxia-induced endoplasmic reticulum (ER) stress that inhibits normal Wnt protein processing and secretion. ER stress causes dissociation between GRP78/BiP and Wnt, an interaction essential for its correct posttranslational processing. Microenvironmental stress can therefore block autocrine and paracrine signaling of the Wnt/beta-catenin pathway and negatively affect tumor growth. This study provides a general paradigm relating oxygen status to ER function and growth factor signaling.

HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption.

The HIF-1 transcription factor drives hypoxic gene expression changes that are thought to be adaptive for cells exposed to a reduced-oxygen environment. For example, HIF-1 induces the expression of glycolytic genes. It is presumed that increased glycolysis is necessary to produce energy when low oxygen will not support oxidative phosphorylation at the mitochondria. However, we find that while HIF-1 stimulates glycolysis, it also actively represses mitochondrial function and oxygen consumption by inducing pyruvate dehydrogenase kinase 1 (PDK1). PDK1 phosphorylates and inhibits pyruvate dehydrogenase from using pyruvate to fuel the mitochondrial TCA cycle. This causes a drop in mitochondrial oxygen consumption and results in a relative increase in intracellular oxygen tension. We show by genetic means that HIF-1-dependent block to oxygen utilization results in increased oxygen availability, decreased cell death when total oxygen is limiting, and reduced cell death in response to the hypoxic cytotoxin tirapazamine.

Cellular reaction to hypoxia: sensing and responding to an adverse environment.

Multicellular organisms have developed sophisticated physiologic mechanisms by which they maintain their tissues at the optimal oxygen concentration. This level is important so that the benefits of free oxygen can be realized, while limiting the potential harms. Despite these efforts, there exist physiologic and pathophysiologic conditions where oxygen delivery drops below what is necessary for the tissue. Under these circumstances, the cell then goes through a series of coordinated responses in a time and oxygen concentration-dependent manner. The gene expression changes are designed to maintain cellular and tissue viability, and are comprised of transcriptional as well as post-transcriptional events. As we understand more about the hypoxic response, we realize how it can impact normal development, wound healing, and the malignant progression of a solid tumor.