Bigu-Style Fasting Affects Metabolic Health by Modulating Taurine, Glucose, and Cholesterol Homeostasis in Healthy Young Adults.

BACKGROUND: Dynamic orchestration of metabolic pathways during continuous fasting remains unclear. OBJECTIVE: We investigated the physiological effects of Bigu-style fasting and underlying metabolic reprogramming in healthy adults. METHODS: We conducted a 5-d Bigu trial in 43 healthy subjects [age 23.2 ± 2.4 y; BMI (in kg/m2) 22.52 ± 1.79]. Physiological indicators and body composition were monitored daily during fasting day 1 (F1D) to F5D and after 10-d refeeding postfasting (R10D) and R30D. Blood samples were collected in the morning. Risk factors associated with inflammation, aging, cardiovascular diseases, malnutrition, and organ dysfunction were evaluated by biochemical measurements. Untargeted plasma metabolomics and gut microbial profiling were performed using plasma and fecal samples. Data were analyzed by repeated measures ANOVA with Greenhouse-Geisser correction. Correlation analyses for metabolite modules and taurine were analyzed by Spearman's rank and Pearson tests, respectively. RESULTS: Heart rate was accelerated throughout the fasting period. Risk factors associated with inflammation and cardiovascular diseases were significantly lowered during or after Bigu (P < 0.05). Body composition measurement detected an overconsumption of fat starting from F3D till 1 mo after refeeding. Metabolomics unveiled a coupling between gluconeogenesis and cholesterol biosynthesis beyond F3D. Plasma taurine significantly increased at F3D by 31%-46% followed by a reduction to basal level at F5D (P < 0.001), a pattern inversely correlated with changes in glucose and de novo synthesized cholesterol (r = -0.407 and -0.296, respectively; P < 0.001). Gut microbial profiling showed an enrichment of taurine-utilizing bacteria at F5D, which was completely recovered at R10D. CONCLUSIONS: Our data demonstrate that 5-d Bigu is potentially beneficial to health in young adults. A starvation threshold of 3-d fasting is necessary for maintaining glucose and cholesterol homeostasis via a taurine-microbiota regulatory loop. Our findings provide novel insights into the physiological and metabolic responses of the human body to continuous Bigu-style fasting. This trial was registered at http://www.chictr.org.cn as ChiCTR1900022917.

Tai Chi exercise improves age-associated decline in cerebrovascular function: a cross-sectional study.

BACKGROUND: Tai Chi exercise has been reported to enhance physical and mental health in the older adults; however, the mechanism remains elusive. TRIAL DESIGN: We recruited 289 older adults practicing Tai Chi for over 3 years, together with 277 age-matched older and 102 young adults as controls. 168 Tai Chi practitioners were successfully matched to 168 older controls aged 60-69 based on a propensity score for statistics. METHODS: Cerebrovascular function was evaluated by measuring the hemodynamics of the carotid artery. Spearman correlation was performed to validate the age-associated physiological parameters. RESULTS: Cerebrovascular function in older adults significantly degenerated compared with the young, and was substantially correlated with age. Compared with the older control group, Tai Chi practitioners showed significant improvements in CVHI (cerebral vascular hemodynamics indices) Score (P = 0.002), mean blood flow velocity (P = 0.014), maximal blood flow velocity (P = 0.04) and minimum blood flow velocity (P < 0.001), whereas the age-related increases in pulse wave velocity (P = 0.022), characteristic impedance (P = 0.021) and peripheral resistance (P = 0.044) were lowered. CONCLUSIONS: These data demonstrate a rejuvenation role of Tai Chi in improving the age-related decline of the cerebrovascular function. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR1900025187).

Exercise interventions for the effect of endothelial function in hypertensive patients: A systematic review and meta-analysis.

Endothelial dysfunction is crucial factor to the hypertension occurrence, and controversy remains regarding the effect of exercise on improving endothelial function in hypertensive patients. The authors used meta-analysis to evaluate the intervention effect of exercise on endothelial function in hypertensive patients and to investigate exercise protocols that may have a greater intervention effect. A total of 37 studies and a total of 2801 participants were included. The results were as follows: endogenous nitric oxide (NO)[SMD = .89, 95% CI (.48, 1.30), p < .0001], endothelin-1 (ET-1): [SMD = -.94, 95% CI (-1.15, -.73), p <. 0001], flow-mediated dilation (FMD) [SMD = -.57, 95% CI (.36, .79), p < .000001]. In subgroup analysis, high-intensity aerobic exercise, with a single exercise duration of 35-50 min, 3-4 times/week for a total of 10-12 weeks, had the largest amount of intervention effect on NO, and moderate-intensity resistance exercise, with a single exercise duration of ≥60 min, 6 times/week for a total of 15-18 weeks, had the largest amount of intervention effect on ET-1. In conclusion, exercise can improve NO levels, FDM levels, and reduce ET-1 secretion of hypertension patients, thereby improve their endothelial function. The ideal intervention effect of improving NO level was more likely to be obtained by taking the exercise prescription of high-intensity aerobic exercise with a single exercise duration of 35-50 min, 3-4 times/week for 10-12 weeks; the ideal intervention effect of improving ET-1 was more likely to be obtained by taking the exercise prescription of oderate -intensity resistance exercise with a single exercise duration of ≥60 min, 6 times/week for 15-18 weeks.

Shifting as an executive function separate from updating and inhibition in old age: Behavioral and genetic evidence.

This study aimed to examine the organization of executive functions (EFs), specifically working memory updating, prepotent response inhibition, and mental-set shifting in old age, with a particular focus on determining whether the shifting function was behaviorally and genetically separated from the other functions. A total of 248 healthy older Chinese individuals participated, and multiple measures of executive functions were collected. Additionally, measures of fluid intelligence were included to explore the varying relationships between the three executive functions and this higher-order cognitive ability. Furthermore, genetic data were gathered and analyzed to investigate the associations between EFs and six candidate single-nucleotide polymorphisms (SNPs) mapped to dopaminergic, serotonergic, or glutamatergic genes. The results indicated that both the three-factor model and the two-factor model, which combined updating and inhibition, demonstrated a good fit. Furthermore, shifting was found to be behaviorally separated from the other two functions, and the correlation between shifting and fluid intelligence was smaller compared to the correlations between updating and inhibition with fluid intelligence. Moreover, the DRD2 SNPs showed significant associations with shifting, rather than with updating and inhibition. These findings provide evidence that shifting is distinct and separate from updating and inhibition, highlighting the diversity of EFs among older adults.

Targeting FABP4 in elderly mice rejuvenates liver metabolism and ameliorates aging-associated metabolic disorders.

INTRODUCTION: Aging is characterized by progressive metabolic dyshomeostasis that increases morbidity and mortality. Solutions for optimizing healthy aging are challenged by lacking appropriate biomarkers. Moreover, druggable targets to rejuvenate the aging-associated metabolic phenotypes remain unavailable. METHODS: Proteomics analysis was performed in a cohort of young and elderly adults. Circulating levels of insulin-like growth factor 1 (IGF-1) and fatty acid binding protein 4 (FABP4) were evaluated by ELISA. FABP4 was silenced in elderly mice by adeno-associated virus. Metabolic activities were measured by metabolic cages. Cognitive function was evaluated by Morris water maze. Glucose and lipid metabolism were evaluated by biochemistry assays with blood samples. RNA-seq in mouse liver was performed for transcriptome analysis. RESULTS: Among 9 aging-sensitive proteins shared by both male and female, FABP4 was identified as a reliable aging biomarker in both human and mouse. Silencing FABP4 in elderly mice significantly rejuvenated the aging-associated decline in metabolic activities. FABP4 knockdown reversed the aging-associated metabolic disorders by promoting degradation of cholesterol and fatty acids, while suppressing gluconeogenesis. Transcriptome analysis revealed a restoration of the pro-aging gene reprogramming towards inflammation and metabolic disorders in the liver after FABP4 knockdown. FABP4 overexpression promoted human LO2 cell senescence. Moreover, administration of an FABP4 inhibitor BMS309403 delivered metabolic benefits in elderly mice. CONCLUSION: Our findings demonstrate FABP4 as a reliable aging biomarker as well as a practicable target to improve healthy aging in the elderly.

Development and validation of a simple-to-use nomogram for self-screening the risk of dyslipidemia.

This study aimed to help healthy adults achieve self-screening by analyzing the quantitative relationship between body composition index measurements (BMI, waist-to-hip ratio, etc.) and dyslipidemia and establishing a logical risk prediction model for dyslipidemia. We performed a cross-sectional study and collected relevant data from 1115 adults between November 2019 and August 2020. The least absolute shrinkage selection operator (LASSO) regression analysis was performed to select the best predictor variables, and multivariate logistic regression analysis was used to construct the prediction model. In this study, a graphic tool including 10 predictor variables (a "nomogram," see the precise definition in the text) was constructed to predict the risk of dyslipidemia in healthy adults. A calibration diagram, receiver operating characteristic (ROC) curve, and decision curve analysis (DCA) were used to verify the model's utility. Our proposed dyslipidemia nomogram showed good discriminative ability with a C-index of 0.737 (95% confidence interval, 0.70-0.773). In the internal validation, a high C-index value of 0.718 was achieved. DCA showed a dyslipidemia threshold probability of 2-45%, proving the value of the nomogram for clinical application for dyslipidemia. This nomogram may be useful for self-screening the risk of dyslipidemia in healthy adults.

Phosphoglycerate dehydrogenase activates PKM2 to phosphorylate histone H3T11 and attenuate cellular senescence.

Vascular endothelial cells (ECs) senescence correlates with the increase of cardiovascular diseases in ageing population. Although ECs rely on glycolysis for energy production, little is known about the role of glycolysis in ECs senescence. Here, we report a critical role for glycolysis-derived serine biosynthesis in preventing ECs senescence. During senescence, the expression of serine biosynthetic enzyme PHGDH is significantly reduced due to decreased transcription of the activating transcription factor ATF4, which leads to reduction of intracellular serine. PHGDH prevents premature senescence primarily by enhancing the stability and activity of pyruvate kinase M2 (PKM2). Mechanistically, PHGDH interacts with PKM2, which prevents PCAF-catalyzed PKM2 K305 acetylation and subsequent degradation by autophagy. In addition, PHGDH facilitates p300-catalyzed PKM2 K433 acetylation, which promotes PKM2 nuclear translocation and stimulates its activity to phosphorylate H3T11 and regulate the transcription of senescence-associated genes. Vascular endothelium-targeted expression of PHGDH and PKM2 ameliorates ageing in mice. Our findings reveal that enhancing serine biosynthesis could become a therapy to promote healthy ageing.

Family sports interventions for the treatment of obesity in childhood: a meta-analysis.

BACKGROUND: Obesity in children has become one of the key concerns of the World Health Organization, and the incidence of related non-communicable diseases is also rising. This study evaluates the effect of family sports participation on the treatment and prevention of obesity in children aged 0-14 years by systematic analysis. METHOD: A literature review from 2000 to 2020 was conducted. According to PRISMA-IPD (Preferred Reporting Items for MetaAnalyses of individual participant data) guidelines. The two researchers independently assessed the risk and bias of the articles, obtained a comprehensive, high-quality result, and extracted the data based on the Cochrane intervention system review manual. Randomized controlled trials (RCTs) were selected from the searches that used family sports interventions or family sports combined with dietary adjustments and behavioral habits change. Only studies targeting overweight or obese children aged 0-14 years were included. RESULTS: The search resulted in a total of 16 studies. Across all 16 studies, there were a total of 1680 participants in the experimental groups and 1701 participants in the control groups. The results are as follows: body mass index (BMI) (SMD-RE = - 4.10, 95% CI (- 0.84 to 0.02), Z = 1.88, p = 0.06); Body weight (SMD-RE = - 0.77, 95% CI (- 1.53 to - 0.01), Z = 2.00, p = 0.05); Waist circumference (SMD-RE = - 0.45, 95% CI (- 1.36 to 0.47), Z = 0.96, p = 0.34); and Body fat rate (SMD-FE = - 0.06, 95% CI (- 0.22 to 0.11), Z = 0.69, p = 0.49). Hence, through family sports intervention among obese children, juvenile and obese body composition-BMI, body weight, waist circumference, and body fat rate-are all reduced. But only body weight was statistically significant. CONCLUSIONS: Compared with the samples without family sports, the weight of obese children participating in family sports decreased, but there were no significant differences in other relevant physical indicators. Follow-up research should examine large-scale clinical trials with family sports as a single factor intervention, which are needed to provide stronger evidence of the intervention effect. However, family activities can help obese children grow and develop by improving their exercise capacity, enhancing their lifestyles, and facilitating communication and relationships with their parents. In the future, long-term sports training plans for children with obesity should be implemented.

CHFR regulates chemoresistance in triple-negative breast cancer through destabilizing ZEB1.

Failures to treat triple-negative breast cancer (TNBC) are mainly due to chemoresistance or radioresistance. We and others previously discovered that zinc finger E-box-binding homeobox 1 (ZEB1) is a massive driver causing these resistance. However, how to dynamically modulate the intrinsic expression of ZEB1 during cell cycle progression is elusive. Here integrated affinity purification combined with mass spectrometry and TCGA analysis identify a cell cycle-related E3 ubiquitin ligase, checkpoint with forkhead and ring finger domains (CHFR), as a key negative regulator of ZEB1 in TNBC. Functional studies reveal that CHFR associates with and decreases ZEB1 expression in a ubiquitinating-dependent manner and that CHFR represses fatty acid synthase (FASN) expression through ZEB1, leading to significant cell death of TNBC under chemotherapy. Intriguingly, a small-molecule inhibitor of HDAC under clinical trial, Trichostatin A (TSA), increases the expression of CHFR independent of histone acetylation, thereby destabilizes ZEB1 and sensitizes the resistant TNBC cells to conventional chemotherapy. In patients with basal-like breast cancers, CHFR levels significantly correlates with survival. These findings suggest the therapeutic potential for targeting CHFR-ZEB1 signaling in resistant malignant breast cancers.

EZH2 RIP-seq Identifies Tissue-specific Long Non-coding RNAs.

BACKGROUND: Polycomb Repressive Complex 2 (PRC2) catalyzes histone methylation at H3 Lys27, and plays crucial roles during development and diseases in numerous systems. Its catalytic subunit EZH2 represents a key nuclear target for long non-coding RNAs (lncRNAs) that emerging to be a novel class of epigenetic regulator and participate in diverse cellular processes. LncRNAs are characterized by high tissue-specificity; however, little is known about the tissue profile of the EZH2- interacting lncRNAs. OBJECTIVE: Here we performed a global screening for EZH2-binding lncRNAs in tissues including brain, lung, heart, liver, kidney, intestine, spleen, testis, muscle and blood by combining RNA immuno- precipitation and RNA sequencing. We identified 1328 EZH2-binding lncRNAs, among which 470 were shared in at least two tissues while 858 were only detected in single tissue. An RNA motif with specific secondary structure was identified in a number of lncRNAs, albeit not in all EZH2-binding lncRNAs. The EZH2-binding lncRNAs fell into four categories including intergenic lncRNA, antisense lncRNA, intron-related lncRNA and promoter-related lncRNA, suggesting diverse regulations of both cis and trans-mechanisms. A promoter-related lncRNA Hnf1aos1 bound to EZH2 specifically in the liver, a feature same as its paired coding gene Hnf1a, further confirming the validity of our study. In addition to the well known EZH2-binding lncRNAs like Kcnq1ot1, Gas5, Meg3, Hotair and Malat1, majority of the lncRNAs were firstly reported to be associated with EZH2. CONCLUSION: Our findings provide a profiling view of the EZH2-interacting lncRNAs across different tissues, and suggest critical roles of lncRNAs during cell differentiation and maturation.

[Miniature quadrupole mass spectrometer array and its applications in manned spaceflight].

This paper explained the working method of the quadrupole mass spectrometer array and its features of volume, weight, power, sensitivity to many kinds of gases as well as flexibility when used together with a miniature gas chromatograph (GC) and a thermal-conductivity detector (TCD). Three types of structure formed in its development are also described. Finally, the applications of the quadrupole mass spectrometer array in the field of manned spaceflight were summarized.