Dietary Vitamin K Restriction and Effectiveness of Vitamin K Antagonists Prescribed at the CNHU-HKM University Cardiology Clinic/BENIN

Introduction: Their efficacy in preventing thrombotic and embolic events has been proven in numerous studies, but their narrow therapeutic index requires particular vigilance, especially in terms of biology. In addition, treatment-related hemorrhagic complications are not uncommon. This study explores the influence of dietary vitamin K restriction on the efficacy of antivitamin K treatment at the University Cardiology Clinic of CNHU-HKM. Methods: Cross-sectional and descriptive study that took place from 25 April to 29 August 2019. Patients’ dietary behaviors and successive INR values were collected. Information on dietary intake was obtained by 2 non-consecutive 24-hour recalls. The effectiveness of VKA treatment was assessed by the “Time in Therapeutic Range” (TTR) of the INR. VKA treatment was considered effective for a TTR greater than 65%. Results: At the end of this study, 40 patients were surveyed. The mean age of the participants was 58.05 years ± 13.32 years, with a sex ratio of 1.35. Complete arrhythmia due to atrial fibrillation was the main indication for VKA treatment (37.50%) and fluindione was the most commonly prescribed drug (77.50%). The duration of treatment was less than or equal to 2 years in 47.5% of the subjects surveyed. Before starting treatment, 85% of patients received advice on restricting vitamin K-rich foods, and 45% of patients reported “food burnout” after a period of compliance with the restriction. The majority of respondents (97.50%) complied with the restriction on vitamin K-rich foods. All respondents had high energy intakes and a poor distribution of macronutrients, with a predominance of carbohydrates and proteins. 2.5% of respondents were on effective anti-vitamin K therapy with a TTR of over 65%. Conclusion: Restriction of vitamin K-rich foods is not conducive to effective treatment with vitamin K antagonists.

Effects of dietary protein restriction on muscle fiber characteristics and m TORC1 pathway in the skeletal muscle of growing-finishing pigs

Background： To investigate the effects of dietary crude protein（CP） restriction on muscle fiber characteristics and key regulators related to protein deposition in skeletal muscle, a total of 18 growing-finishing pigs（62.30 ± 0.88 kg）were allotted to 3 groups and fed with the recommended adequate protein（AP, 16 % CP） diet, moderately restricted protein（MP, 13 % CP） diet and low protein（LP, 10 % CP） diet, respectively. The skeletal muscle of different locations in pigs, including longissimus dorsi muscle（LDM）, psoas major muscle（PMM） and biceps femoris muscle（BFM） were collected and analyzed.Results： Results showed that growing-finishing pigs fed the MP or AP diet improved（P 〈 0.01） the average daily gain and feed： gain ratio compared with those fed the LP diet, and the MP diet tended to increase（P = 0.09） the weight of LDM. Moreover, the ATP content and energy charge value were varied among muscle samples from different locations of pigs fed the reduced protein diets. We also observed that pigs fed the MP diet up-regulated（P 〈 0.05） muscular m RNA expression of all the selected key genes, except that myosin heavy chain（My HC） IIb,My HC IIx, while m RNA expression of ubiquitin ligases genes was not affected by dietary CP level. Additionally, the activation of mammalian target of rapamycin complex 1（m TORC1） pathway was stimulated（P 〈 0.05） in skeletal muscle of the pigs fed the MP or AP diet compared with those fed the LP diet.Conclusion： The results suggest that the pigs fed the MP diet could catch up to the growth performance and the LDM weight of the pigs fed the AP diet, and the underlying mechanism may be partly due to the alteration in energy status, modulation of muscle fiber characteristics and m TORC1 activation as well as its downstream effectors in skeletal muscle of different locations in growing-finishing pigs.

Dietary Restriction Reduces Blood Lipids and Ameliorates Liver Function of Mice with Hyperlipidemia

Dietary restriction（DR） can delay senescence, prolong lifespan of mammals and improve their learning-memory activity. The purpose of the study was to explore the effects of DR on hypolipidemic action and liver function of mice with hyperlipidemia. To investigate these effects, hyperlipidemia mouse models were established with high-fat diet（HFD）（34% of energy）, then randomly divided into HFD group, DR30% group and DR50% group. Mice in DR30% and DR50% group were respectively supplied with HFD as much as about 70% and 50% of the consumption of HFD in the mice of HFD group. Rats in control group were fed routinely. After DR for 5 weeks, the average body weight, liver weight, liver index, serum lipids and glucose levels in both DR groups decreased significantly as compared with the HFD group（P〈0.05 or P〈0.01）, so did alanine aminotransferase（ALT）, aspartate aminotransferase（AST）, lactate dehydrogenase（LDH） levels and the ratio of LDL-C/HDL-C in the DR50% group（P〈0.05 or P〈0.01）. Histopathology examination of liver tissues further proved ameliorative effect of DR on liver function. Western blotting showed that DR significantly increased the expression of silent mating type information regulation 2 homolog 1（SIRT1） in liver and adipose, while notably decreased the expression of peroxisome proliferators-activated receptors-gamma（PPARγ） in adipose（P〈0.05 or P〈0.01）. The increase of SIRT1 and decrease of PPARγ may be a mechanism by which DR reduces blood lipids and ameliorates liver function.

Dietary restriction to accompany the aging process in mice Can it be neuroprotective?

BACKGROUND： Prophylactic dietary restriction （DR）, whether lifelong or started in adulthood,retards the aging process and attenuates cognitive decline in rodents. However, whether the anti-aging and neuroprotective efficacy of DR initiate late in life or accompany the aging process remains unclear.OBJECTIVE： The present study sought to： （1） determine if DR could protect against behavioral decline in mice when implemented during the aging process induced by D-galactose and （2） examine neuronal apoptosis in these aged brains and whether DR could block apoptosis.DESIGN, TIME AND SETTING： The randomized controlled animal study. The experiment was performed at the Experimental Animal Center of Capital Medical University and the Laboratory Center of School of Public Health of Captial Medical University of China from April 2006 to October 2007.MATERIALS： D-galactose （D-gal） was purchased from Beijing Chemical-Regent Company （Beijing, China）. Terminal transferase dUTP nick end labeling （TUNEL） detection kit was obtained from Roche, Germany. Assay kits for antioxidant enzyme activities and malondialdehyde contents were purchased from Jiancheng Institute of Biotechnology （Nanjing, China）. Morris water maze （Friends Honesty Life Sciences Co. Ltd., Hong Kong, China） and Flow Cytometry （Coulter, USA） were used in this study.METHODS： A total of 40 male Institute of Cancer Research （lCR） mice, 3 months old, were equally and randomly divided into D-gal treatment, DR treatment, D-gal ＋ DR treatment and normal control groups, and were then randomly assigned to one of two feeding regimens： ad libitum access to food or DR which received a 70% amount of daily food intake as that by ad libitum fed mice. There were two replicates per feeding regimen and mice were fed for 10 weeks,with or without a daily subcutaneous injection of D-gal at 100 mg/kg.MAIN OUTCOME MEASURES： Animals＇ spatial learning and memory performance were tested in the Morris water maze. Neuronal apoptosis rates were evaluated by Annexin V/flow cytometry assay and TUNEL assay. Lipid peroxidation levels and antioxidant defense capacity of the brain were measured using testing kits.RESULTS： DR markedly reduced the prolonged escape latency of D-gal mice in the water maze test （P〈0.01）. Annexin V and TUNEL assays showed that the D-gal mice had a significant higher percentage of neuronal apoptosis compared with normal control mice （P〈0.05）, and that DR treatment markedly decreased this apoptotic cell death （P〈0.05）. DR also reversed the decline of total superoxide dismutase and glutathione peroxidase activities and the increase of malondialdehyde levels in the brain of D-gal mice （P〈0.05, respectively）.CONCLUSION： DR reduces the impact of D-gal-induced brain aging in mice and can reverse performance decline and neurobiochemical impairments. These results demonstrate that implementation of DR in conditions of chronic oxidative stress can be neuroprotective, and that senium DR can be beneficial for healthy aging.

The Effects of Dietary Restriction and Aging on in Vivo and in Vitro Binding of Aflatoxin B_1 to Cellular DNA

Laboratory animals maintained on a reduced calorie but nutritionally adequate diet have extended life spans and lowered incidences of spontaneous and chemically induced cancers compared to ad libitum- fed counterparts. Many of the effects of dietary restriction on laboratory animals have been suggested to be related to a deceleration of the aging process. The inhibition of age-related changes in xenobiotic metabolizing enzyme activities by dietary restriction has previously been reported. Alterations of these enzyme activities may cause changes in metabolic activation of carcinogens and, therefore, carcinogen-DNA binding. DNA-repair capability has also been reported to be enhanced in diet-restricted rats. Using AFB1 as a model carcinogen, we have studied in vivo and in vitro hepatic AFB1 -DNA binding, demonstrating that dietary restriction (60% of ad libitum consumption) may decrease the metabolic activation of AFB1, and subsequently reduce AFB 1-DNA binding. Our preliminary results obtained from the AFB 1-DNA binding experiments in isolated hepatocytes suggest that the observed age-dependent reduction in AFB 1-DNA binding which may be attributed to a loss of metabolic activating capability was delayed in the diet-restricted rats.

Role of mitophagy in the hallmarks of aging

Aging, subjected to scientific scrutiny, is extensively defined as a time-dependent decline in functions that involves the majority of organisms. The time-dependent accretion of cellular lesions is generally a universal trigger of aging, while mitochondrial dysfunction is a sign of aging. Dysfunctional mitochondria are identified and removed by mitophagy, a selective form of macroautophagy. Increased mitochondrial damage resulting from reduced biogenesis and clearance may promote the aging process. The primary purpose of this paper is to illustrate in detail the effects of mitophagy on aging and emphasize the associations between mitophagy and other signs of aging, including dietary restriction, telomere shortening, epigenetic alterations, and protein imbalance.The evidence regarding the effects of these elements on aging is still limited. And although the understanding of relationship between mitophagy and aging has been long-awaited, to analyze details of such a relationship remains the main challenge in aging studies.

Telomerase and mTOR in the brain:the mitochondria connection

Telomerase is an enzyme that maintains telomeres in dividing cells using a template on its inherent RNA component.Additionally,the protein part TERT（Telomerase Reverse Transcriptase） has various non-canonical functions.For example,it can localize to mitochondria under increased stress and protect cells in vitro from oxidative stress,DNA damage and apoptosis.Recently it has been demonstrated that TERT protein persists in adult neurons in the brain and data emerge suggesting that it might have a protective function in these post-mitotic cells as well.We have recently published that TERT protein accumulated in mitochondria from brain tissue of mice that have undergone short-term dietary restriction（DR） and rapamycin treatment.This localization correlated to lower levels of oxidative stress in these brain mitochondria.Since rapamycin treatment decreases mTOR signaling which is also thought to play an important role for the beneficial effects of DR,we conclude that the mTOR pathway might be involved in the TERT localization and its effects in brain mitochondria in vivo.These data are in line with previous findings from our group about increased mitochondrial localization of TERT in Alzheimer＇s disease（AD） brains and a protective function of TERT protein in neurons in vitro against pathological tau.

Implications of oxidative damage to proteins and DNA in aging and its intervention by caloric restriction and exercise

In this short review we describe implications of age-related changes of protein and DNA oxidation as a public mechanism of biological aging. Oxidatively modified protein and DNA have been demonstrated to increase with advancing age in rodents. Half-life of proteins is extended and DNA repair activity declines in old animals. Dietary restriction initiated late in life can shorten the half-life of proteins to levels of young animals, thus contributing to reduce level of altered proteins in old animals by the regimen. Regular exercise reduced oxidatively modified proteins in the brain with improved cognitive functions. It attenuated oxidative stress in the liver, i.e., ameliorating activation of nuclear factor κB, increasing reduced glutathione, and decreasing oxidized guanine base in nuclear and mitochondrial DNA. These findings suggest that regular exercise has systemic effects in reducing oxidative stress. Thus, life-styles such as diet and exercise may extend health span, by up-regulating overall anti-oxidant capacities that include proteins involved in protein turnover and DNA repair, resulting in reduction of damaged proteins and DNA that potentially promote physiological and pathological aging.

Mechanisms of Steatosis-Derived Hepatocarcinogenesis:Lessons from HCV Core Gene Transgenic Mice

Hepatitis C virus(HCV)is a major cause of chronic hepatitis,liver cirrhosis,and hepatocellular carcinoma(HCC)worldwide.Among the structural proteins of HCV,the HCV core protein has the ability to regulate gene transcription,lipid metabolism,cell proliferation,apoptosis,and autophagy,all of which are closely related to the development of HCC.Transgenic mice carrying the HCV core gene exhibited age-dependent insulin resistance,hepatic steatosis,and HCC that resembled the clinical characteristics of chronic hepatitis C patients.Several dietary modifications,including calorie restriction and diets rich in saturated fatty acids,trans fatty acids,or cholesterol,were found to influence hepatic steatogenesis and tumorigenesis in HCV core gene transgenic mice.These strategies modulated hepatocellular stress and proliferation,in addition to hepatic fibrotic processes and the microenvironment,thereby corroborating a close interconnection between dietary habits and steatosis-related hepatocarcinogenesis.In this review,we summarize the findings obtained from mouse models transgenic for the HCV genome,with a special focus on HCV core gene transgenic mice,and discuss the mechanisms of steatogenesis and hepatocarcinogenesis induced by the HCV core protein and the impact of dietary habits on steatosis-derived HCC development.

Future foods,dietary factors and healthspan

Ageing is a universal decline of physiological functions accompanied by an increase in risks of developing morbidity,diseases,and death.Calorie restriction(CR)without malnutrition has been shown to improve lifespan from simple model organisms to mammals,and extensive research over the past decades have identified several universally conserved signalling pathways by which CR regulates lifespan.More recently,emerging evidence has suggested that modulation of intake levels of macronutrients and micronutrients can also impact healthspan and lifespan in model organisms.These findings propose potentially promising and cost-effective approaches to promote healthy ageing and longevity in humans through personalised nutrition.In this review,we summarise the mechanisms by which CR promotes healthspan and longevity,focusing on the mitochondrial reactive oxygen species(ROS)and several universally conserved geroprotective nutrient-sensing pathways(insulin/insulin-like growth factor(IGF-1),AMP-activated protein kinase(AMPK),mTOR).We further discuss the accumulating data supporting that changes in dietary pattern,levels of nutrient intake(both macronutrient and micronutrient)and functional foods can impact healthspan through acting on the key components of nutrient-sensing and immunoprotective pathways,providing fundamental support for future research and development of anti-ageing diets and dietary regimes.

Dietary restriction and brain health

The benefits of dietary restriction （DR） on health and aging prevention have been well recognized. Recent studies suggest that DR may enhance brain functions including learning and memory, synaptic plasticity, and neurogenesis, all of which are associated with brain health. Under the stress stimulated by DR, a favorable environment is established for facilitating neuronal plasticity, enhancing cognitive function, stimulating neurogenesis and regulating inflammatory response. DR-induced expressions of factors such as heat shock proteins （HSPs）, neurotrophic factors, and Sirtuin1 （SIRT1） are responsible for the effect of DR on the brain. Due to the difficulty in practising long-term DR in human, the potential mimics of DR are also discussed.

Molecular mechanisms of dietary restriction in aging—insights from Caenorhabditis elegans research

Dietary restriction(DR) is one of the most robust environmental manipulations that not only extend life span but also delay the onset of age-related diseases in almost every species examined. Caenorhabditis elegans plays an important role in aging studies due to its simple life cycle, easy genetic manipulations and highly conserved genome. Recent studies have demonstrated that the beneficial effects of DR are mediated by the highly conserved transcription factors and signaling pathways in C. elegans. Here we review recent progress in the methodology and molecular mechanisms of DR using C. elegans as a model, as well as prospects for future research.

Regulation of the urea cycle by CPS1 O-GlcNAcylation in response to dietary restriction and aging

O-linked N-acetyl-glucosamine glycosylation(O-GlcNAcylation)of intracellular proteins is a dynamic process broadly implicated in age-related disease,yet it remains uncharacterized whether and how O-GlcNAcylation contributes to the natural aging process.O-GlcNAc transferase(OGT)and the opposing enzyme O-GlcNAcase(OGA)control this nutrient-sensing protein modification in cells.Here,we show that global O-GlcNAc levels are increased in multiple tissues of aged mice.In aged liver,carbamoyl phosphate synthetase 1(CPS1)is among the most heavilyO-GlcNAcylated proteins.CPS1O-GlcNAcylation is reversed by calorie restriction and is sensitive to genetic and pharmacological manipulations of theO-GlcNAc pathway.High glucose stimulates CPS1O-GlcNAcylation and inhibits CPS1 activity.Liver-specific deletion of OGT potentiates CPS1 activity and renders CPS1 irresponsive to further stimulation by a prolonged fasting.Our results identify CPS1 O-GlcNAcylation as a key nutrient-sensing regulatory step in the urea cycle during aging and dietary restriction,implying a role for mitochondrial O-GlcNAcylation in nutritional regulation of longevity.

Lifespan Modulation in Mice and the Confounding Effects of Genetic Background

We are currently in the midst of a revolution in ageing research, with several dietary, genetic and pharmacological interventions now known to modulate ageing in model organisms. Excitingly, these interventions also appear to have beneficial effects on late-life health. For example, dietary restriction （DR） has been shown to slow the incidence of age-associated cardiovascular disease, metabolic disease, cancer and brain ageing in non-human primates and has been shown to improve a range of health indices in humans. While the idea thai DR＇s ability to extend lifespan is often thought of as being universal, studies in a range of organisms, including yeast, mice and monkeys, suggest that this may not actually be the case. The precise reasons underlying these differential effects of DR on lifespan are currently unclear, but genetic background may be an important factor in how an individual responds to DR. Similarly, recent findings also suggest that the responsiveness of mice to specific genetic or pharmacological interventions that modulate ageing may again be influenced by genetic background. Consequently, while there is a clear driver to develop interventions to improve late-life health and vitality, under- standing precisely how these act in response to particular genotypes is critical if we are to translate these findings to humans. We will consider of the role of genetic background in the efficacy of various lifespan interventions and discuss potential routes of utilising genetic heterogeneity to further understand how particular interventions modulate lifespan and healthspan.