Emerging senolytic agents derived from natural products.

Cellular senescence is a hallmark of aging, it is a permanent state of cell cycle arrest induced by cellular stresses. During the aging process, senescent cells (SCs) increasingly accumulate in tissues, causing a loss of tissue-repair capacity because of cell cycle arrest in progenitor cells and produce proinflammatory and matrix-degrading molecules which are known as the senescence-associated secretory phenotype (SASP), and thereby contribute to the development of various age-related diseases. Genetic evidence has demonstrated that clearance of SCs can delay aging and extend healthspan. Senolytics, small molecules that can selectively kill SCs, have been developed to treat various age-related diseases. In recent years, emerging natural compounds have been discovered to be effective senolytic agents, such as quercetin, fisetin, piperlongumine and the curcumin analog. Some of the compounds have been validated in animal models and have great potential to be pushed to clinical applications. In this review, we will discuss cellular senescence and its potential as a target for treating age-related diseases, and summarize the known natural compounds as senolytic agents and their applications.

Dietary branched-chain amino acids intake exhibited a different relationship with type 2 diabetes and obesity risk: a meta-analysis.

AIM: To assess whether oral branched-chain amino acids (BCAA) supplementation exerts influence on circulating BCAA and the significance of dietary BCAA in type 2 diabetes and obesity risk. METHOD: We searched PUBMED, EMBASE and Cochrane library through June 2018 to retrieve and screen published reports for inclusion in the meta-analysis after methodological assessment. Heterogeneity of studies was evaluated using I2 statistics, while sensitivity analysis and funnel plot were used to evaluate the potential effect of individual studies on the overall estimates and publication bias, respectively, using RevMan 5.3. RESULT: Eight articles on randomized clinical trial of oral BCAA supplementation, and seven articles on dietary BCAA intake and type 2 diabetes/obesity risks were eligible for inclusion in our meta-analyses. Mean difference and 95% confidence interval (CI) of circulating leucine was 39.65 (3.54, 75.76) µmol/L, P = 0.03 post-BCAA supplementation. Also, OR and 95% CI for higher total BCAA intake and metabolic disorder risks were, 1.32 (1.14, 1.53), P = 0.0003-type 2 diabetes and 0.62 (0.47, 0.82), P = 0.0008-obesity. CONCLUSION: Oral BCAA supplementation exerts modest influence on circulating leucine profile and higher total BCAA intake is positively and contra-positively associated with type 2 diabetes and obesity risk, respectively.

Effects of Histidine Supplementation on Global Serum and Urine 1H NMR-based Metabolomics and Serum Amino Acid Profiles in Obese Women from a Randomized Controlled Study.

The aim of current study was to investigate the metabolic changes associated with histidine supplementation in serum and urine metabolic signatures and serum amino acid (AA) profiles. Serum and urine 1H NMR-based metabolomics and serum AA profiles were employed in 32 and 37 obese women with metabolic syndrome (MetS) intervened with placebo or histidine for 12 weeks. Multivariable statistical analysis were conducted to define characteristic metabolites. In serum 1H NMR metabolic profiles, increases in histidine, glutamine, aspartate, glycine, choline, and trimethylamine-N-oxide (TMAO) were observed; meanwhile, decreases in cholesterol, triglycerides, fatty acids and unsaturated lipids, acetone, and α/ß-glucose were exhibited after histidine supplement. In urine 1H NMR metabolic profiles, citrate, creatinine/creatine, methylguanidine, and betaine + TMAO were higher, while hippurate was lower in histidine supplement group. In serum AA profiles, 10 AAs changed after histidine supplementation, including increased histidine, glycine, alanine, lysine, asparagine, and tyrosine and decreased leucine, isoleucine, ornithine, and citrulline. The study showed a systemic metabolic response in serum and urine metabolomics and AA profiles to histidine supplementation, showing significantly changed metabolism in AAs, lipid, and glucose in obese women with MetS.

Effects of tea or tea extract on metabolic profiles in patients with type 2 diabetes mellitus: a meta-analysis of ten randomized controlled trials.

As consumption of tea has been confirmed as a protective factor for type 2 diabetes mellitus (T2DM), it would be interesting to know if T2DM patients could benefit from tea. Because of small sample sizes and inconsistent results of previous studies, we performed this meta-analysis to reevaluate the effects of tea or tea extract on all available outcomes in patients with T2DM. We systematically searched electronic databases of PubMed, Cochrane Library and EMBASE to identify randomized controlled trials of tea in T2DM patients up to January 2015. Weight mean differences for the changes in all outcomes were pooled by Review Manager 5.2 (Cochrane Collaboration, Oxford, England). A total of ten trials including 608 subjects were identified. The meta-analysis found that tea could alleviate the decrease of fasting blood insulin [1.30 U/L, 95% CI (0.36, 2.24)], and reduced waist circumference only in more than 8-week intervention [-2.70 cm, 95% CI (-4.72, -0.69)], whereas there were no statistically significant differences with regard to homeostasis model of insulin resistance 0.38 (-0.18, 0.95), fasting blood glucose -0.05 mmol/L (-0.51, 0.40), low density lipoprotein-cholesterol 0.07 mmol/L (-0.15, 0.29), high density lipoprotein-cholesterol 0.01 mmol/L (-0.08, 0.09), body mass index -0.15 kg/m(2) (-0.50, 0.21), SBP 0.35 mmHg (-3.54, 4.24), DBP -1.02 mmHg (-3.53, 1.48), triglycerides -0.11 mmol/L (-0.28, 0.05) and fasting cholesterol -0.05 mmol/L (-0.20, 0.11) in patients with T2DM, and leptin, ADPN, CRE and UA were also non-significant. The intervention of tea or tea extraction could maintain a stable fasting blood insulin and reduce waist circumference in the T2DM patients; however, the effects on other outcomes were not significant. Copyright © 2015 John Wiley & Sons, Ltd.

System analysis of LWDH related genes based on text mining in biological networks.

Liuwei-dihuang (LWDH) is widely used in traditional Chinese medicine (TCM), but its molecular mechanism about gene interactions is unclear. LWDH genes were extracted from the existing literatures based on text mining technology. To simulate the complex molecular interactions that occur in the whole body, protein-protein interaction networks (PPINs) were constructed and the topological properties of LWDH genes were analyzed. LWDH genes have higher centrality properties and may play important roles in the complex biological network environment. It was also found that the distances within LWDH genes are smaller than expected, which means that the communication of LWDH genes during the biological process is rapid and effectual. At last, a comprehensive network of LWDH genes, including the related drugs and regulatory pathways at both the transcriptional and posttranscriptional levels, was constructed and analyzed. The biological network analysis strategy used in this study may be helpful for the understanding of molecular mechanism of TCM.

Histidine supplementation alleviates inflammation in the adipose tissue of high-fat diet-induced obese rats via the NF-κB- and PPARγ-involved pathways.

Obesity is considered to be accompanied by a chronic low-grade inflammatory state that contributes to the occurrence of many chronic diseases. Our previous study has demonstrated that histidine supplementation significantly ameliorates inflammation and oxidative stress in obese women. However, the in vivo potential mechanisms are not known. The present study was conducted to investigate the mechanisms underlying the effects of histidine on inflammation in a high-fat diet (HFD)-induced female obese rat model. An obese model was established in female Sprague-Dawley rats by HFD feeding for 8 weeks and followed by histidine supplementation for another 4 weeks. The results revealed that HFD-increased body weight and HFD-lowered serum histidine concentrations were significantly reversed by histidine supplementation (P< 0·05). In addition, the serum concentrations of TNF-α, IL-6, C-reactive protein (CRP) and malondialdehyde were significantly reduced and those of superoxide dismutase (SOD) were significantly increased by histidine supplementation when compared with those in obese rats (P< 0·05). Correspondingly, the mRNA expressions of TNF-α, IL-6 and CRP in the adipose tissue were significantly down-regulated and that of CuZnSOD was significantly up-regulated by histidine supplementation (P< 0·05). Histidine supplementation significantly reduced the HFD-induced translocation of NF-κB p65 into the nucleus (P= 0·032) by reducing the phosphorylation of the inhibitor of κBα in the adipose tissue. The results also revealed that the expression of adiponectin was markedly increased both in the serum and in the adipose tissue after histidine supplementation, accompanied by the activation of PPARγ (P= 0·021). These findings indicate that histidine is an effective candidate for ameliorating inflammation and oxidative stress in obese individuals via the NF-κB- and PPARγ-involved pathways.

[Comparison of the effects between maize germ oil and lard oil loading on blood lipids and fatty acid profile of mice].

OBJECTIVE: To investigate the changes in blood lipids and fatty acids profile of mice after different oil loading, and explore the effects of different dietary fatty acids on postprandial blood lipids and fatty acid profile. METHODS: Ninety-six C57BL/6 mice were randomly divided into 2 groups by weight ,maize germ oil group and lard oil group. The mice were given maize germ oil or lard oil by gavage at a dose of 1 ml/100 mg BW, respectively, after over-night fasting. At 0, 30, 60, 120, 180 and 240 min after oil loading, 8 mice were selected randomly from both groups, respectively, and blood was collected via orbital bleeding for postprandial blood lipids and fatty acid profile analysis. RESULTS: The serum triglycerides and total free fatty acids levels in mice loaded with lard oil were significantly higher than those in mice loaded with maize germ oil, respectively, at 120, 180, 240 min. The serum saturated fatty acids and monounsaturated fatty acids in mice loaded with lard oil were significantly higher, whereas serum polyunsaturated fatty acids were significantly lower than those in mice loaded with maize germ oil at 60, 120, 180 and 240 min (P < 0.05). Serum palmitic oil and oleic oil in mice loaded with lard oil were higher, whereas linoleic oil and arachidonic acid were lower than those in mice loaded with maize germ oil at 60, 120, 180 and 240 min (P < 0.05). CONCLUSION: Compared with maize germ oil, lard oil leads to higher postprandial serum triglycerides and saturated fatty acids levels, that may increase the risk of cardiovascular diseases.

Calcium supplementation increases circulating cholesterol by reducing its catabolism via GPER and TRPC1-dependent pathway in estrogen deficient women.

BACKGROUND: Limited studies have addressed the effects of calcium supplementation (CaS) on serum total cholesterol (TC) in postmenopausal women and the results are inconclusive. Moreover, the potential mechanisms through which CaS regulates cholesterol metabolism in the absence of estrogen are still sealed for the limitation of human being study. METHODS: Cross-sectional survey, animal and in vitro experiments were conducted to investigate the effect of CaS on endogenous cholesterol metabolism in estrogen deficiency and identify its potential mechanisms. Ovariectomized rats were used to mimic estrogen deficiency. In vitro, HepG2 cell line was exposed to estradiol and/or calcium treatment. RESULTS: We demonstrated that CaS significantly increased serum TC and the risk of hypercholesterolemia and myocardial infarction in postmenopausal women. Increased serum TC in estrogen deficiency was caused mainly by decreased cholesterol catabolism rather than increased synthesis. This was mediated by reduced 7α-hydroxylase resulting from increased liver intracellular Ca(2+) concentrations, reduced intracellular basal cAMP and subsequent up-regulation of SREBP-1c and SHP expression. Estrogen had a protective role in preventing CaS-induced TC increase by activating the G-protein coupled estrogen receptor, which mediated the estrogen effect through the transient receptor potential canonical 1 cation channel. CONCLUSIONS: CaS increases endogenous serum TC via decreasing hepatic cholesterol catabolism in estrogen deficiency. G-protein coupled estrogen receptor is shown to be a key target in mediating CaS-induced TC increase. CaS should be monitored for the prevention of serum TC increase during menopause.

[Effects of curcumin intake on kidney and liver pathological changes in T2DM rats].

OBJECTIVE: To investigate whether curcumin intake could improve kidney, liver pathological changes in type 2 diabetes (T2DM) rats. METHODS: 100 male Wistar rats were randomly divided into two groups: 10 rats in the control group; 90 in the T2DM model rats, the using low-dose treptozotocin (30 mg/kg BW) combined high sugar and high fat diet to induce T2DM model. After the success of the model induction, 39 T2DM rats met the selection criteria, which were randomly divided into 4 groups: T2DM model control group, low-dose curcumin group (50 mg/kg BW), curcumin dose group (150 mg/kg BW) and curcumin high-dose group (250 mg/kg BW), given intervention. After 45 days treatment, rats from each group were randomly selected four for pathological testing and observation of kidney and liver changes. RESULTS: Compared with the control group, the results showed that blood glucose and lipids in T2DM model group were significantly increased (P < 0.05). Compared to the T2DM control group, curcumin treatment significant improved kidney and liver pathological changes. CONCLUSION: Curcumin can improve liver and kidney pathological changes in T2DM rats.

Dietary calcium but not elemental calcium from supplements is associated with body composition and obesity in Chinese women.

OBJECTIVE: We assessed whether dietary calcium intake or calcium supplements associated with body composition and obesity in a Chinese population. METHODS: A cross-sectional survey was performed in a population of 8940, aged 20 to 74 y. 8127 participants responded (90.9%). Height, weight, fat mass (FM), waist circumference (WC) and hip circumference were measured. Obesity definition: body mass index (BMI) ≥28 kg/m(2) (overall obesity); WC ≥85 cm for men or ≥80 cm for women (abdominal obesity І) and waist hip ratio (WHR) ≥0.90 for men or ≥0.85 for women (abdominal obesity П). The data on dietary calcium and calcium supplements were collected using food-frequency questionnaire and self-report questionnaire. Multivariate linear and multivariable logistic regressions were used to examine the associations between dietary calcium intake or calcium supplements and body composition and obesity. PRINCIPAL FINDINGS: The average dietary calcium intake of all subjects was 430 mg/d. After adjusting for potential confounding factors, among women only, negative associations were observed between habitual dietary calcium intake and four measures of body composition (ß, -0.086, P<0.001 for BMI; ß, -0.072, P<0.001 for WC; ß, -0.044, P<0.05 for WHR; and ß, -0.058, P<0.01 for FM, respectively) and both measures of abdominal obesity (Odds Ratio [OR] = 0.86, 95% Confidence Interval [CI], 0.80-0.93; P<0.001, for abdominal obesity I; OR = 0.92, 95% CI, 0.86-0.99; P = 0.026, for abdominal obesity II). These associations were not observed among men (P>0.05). Similarly, among both men and women, we did not observe significant associations between calcium supplements and any measures of body composition or abdominal obesity (P>0.05). CONCLUSIONS: Dietary calcium from food rather than elemental calcium from calcium supplements has beneficial effects on the maintenance of body composition and preventing abdominal obesity in Chinese women.