Apple Polyphenol Extract Ameliorates Atherosclerosis and Associated Cognitive Impairment through Alleviating Neuroinflammation by Weakening TLR4 Signaling and NLRP3 Inflammasome in High-Fat/Cholesterol Diet-Fed LDLR-/- Male Mice.

Although studies have supported the beneficial effects of the ingredients of apple polyphenol extract (APE), a polyphenol mixture being extracted from whole fresh apples, on neurodegenerative diseases, the role of APE in atherosclerosis-related cognitive impairment remains unclear. To clarify the role of APE in regulating cognitive dysfunction in mice with atherosclerosis and the underlying mechanisms, high-fat/cholesterol diet-fed male LDLR-/- mice were gavaged with 125 or 500 mg/(kg·bw·d) APE solution or sterile double-distilled water for consecutive 8 weeks, and age-matched C57BL/6 male mice were employed as normal control. APE intervention increased the serum concentration of high-density apolipoprotein cholesterol, improved atherosclerosis, and ameliorated cognitive function of mice by inhibiting the phosphorylation of tau protein, supporting with significantly reduced platform latency and obviously increased swimming distance in the target quadrant according to the Morris water maze test. APE intervention alleviated neuroinflammation by attenuating the activation of microglia and astrocytes and inhibiting TLR4 signaling with reduced protein expression of NF-κB, MyD88, TRIF, and IKKß. Meanwhile, APE intervention inactivated NLRP3 inflammasome with downregulated protein expression of caspase-1, IL-18, and IL-1ß. Additionally, APE intervention improved the damaged brain barrier structure by upregulating the protein expression of ZO-1 and occludin. Therefore, our research supplemented new data, supporting the potential of APE as an effective dietary bioactive ingredient to improve atherosclerosis and associated cognitive impairment.

Effects of betaine supplementation on inflammatory markers: a systematic review and meta-analysis of randomised controlled trials.

Several studies have suggested that betaine is closely related to inflammatory biomarkers that contribute to the development of metabolic diseases, but the effect remains controversial. This meta-analysis aimed to assess the effects of betaine supplementation on inflammatory markers based on randomised controlled trials (RCTs). PubMed, Web of Science and ResearchGate databases were searched up to March 2023. A total of 6 RCTs with 7 intervention trials involving 277 participants were included. Betaine supplementation led to a slight reduction in levels of circulating IL-1ß of 0.65 pg/mL (95% CI, -1.23 to -0.06) with high heterogeneity (I2 = 95%). Betaine produced a small but nonsignificant reduction in levels of circulating CRP (0.33 mg/L; 95% CI, -1.79 to 1.14), IL-6 (0.47 pg/mL; 95% CI, -1.13 to 0.18) and TNF-α (0.25 pg/mL; 95% CI, -0.98 to 0.48). The present meta-analysis does not provide sufficient evidence to conclude that betaine supplementation improved the inflammation state.

Concentrations and homologue patterns of SCCPs and MCCPs in the serum of the general population of adults in Hangzhou, China.

Due to their ubiquitous presence in the environment and humans, chlorinated paraffins (CPs) are a major environmental and public health concern. CPs are known to persist, bioaccumulate and potentially threaten human health, but reports on their internal exposure in the adult general population are still scarce. In this study, serum samples collected from adults living in Hangzhou, China, were quantified for SCCPs and MCCPs using GC-NCI-MS methods. A total of 150 samples were collected and subjected to analysis. ∑SCCPs were detected in 98% of the samples with a median concentration of 721 ng/g lw. MCCPs were found in all serum samples with a median concentration of 2210 ng/g lw, indicating that MCCPs were the dominant homologous group. For SCCPs and MCCPs, ∑C10 and ∑C14 were found to be the dominant carbon chain length homologues. Our results showed that age, BMI and lifestyle were not found to be significantly associated with internal exposure to CPs for the samples in this study. Based on PCA analysis, an age-specific distribution of CP homologues was observed. This suggests that internal exposure to CPs in the general population is related to exposure scenarios and history. The results of this study may contribute to a better understanding of the internal exposure to CPs in the general population and may provide a direction for the investigation of the source of exposure to CPs in the environment and daily life.

Cereal fiber improves blood cholesterol profiles and modulates intestinal cholesterol metabolism in C57BL/6 mice fed a high-fat, high-cholesterol diet.

BACKGROUND: Dietary intake of cereal fiber has been reported to benefit lipid metabolism through multiple mechanisms. The present study aimed to discover the potential mechanisms by which cereal fiber could modify the intestinal cholesterol metabolism. DESIGN: Male C57BL/6 mice were fed a reference chow (RC) diet; high-fat, high-cholesterol (HFC) diet; HFC plus oat fiber diet; or HFC plus wheat bran fiber diet for 24 weeks. Serum lipids were measured by enzymatic methods. Western blot was used to determine the protein expressions involved in intestinal cholesterol metabolism. RESULTS: Our results showed that HFC-induced elevations of serum triglycerides, total cholesterol, and low-density lipoprotein cholesterol were normalized in both groups that received cereal fiber. At the protein level, compared with the HFC diet group, the two cereal fibers, especially the oat fiber, significantly increased the protein expression of peroxisome proliferator-activated receptor alpha, liver X receptor alpha, sterol regulatory element-binding protein (SREBP) 2, low-density lipoprotein receptor, adenosine triphosphate (ATP)-binding cassette A1, and ATP-binding cassette G1, while decreasing the protein expression of Niemann-Pick C1-like protein 1, SREBP-1, fatty acid synthase, and acetyl-coenzyme A carboxylase, which were involved in intestinal cholesterol metabolism. CONCLUSION: Taken together, increased intake of cereal fiber improved blood cholesterol profiles and increased the intestinal cholesterol efflux and cholesterol clearance in C57BL/6 mice fed a HFC diet. Oat fiber had a stronger effect than wheat bran fiber on cholesterol metabolism by modulating the PPARα, LXRα, and SREBP signaling pathways.

Lipolysis and thermogenesis in adipose tissues as new potential mechanisms for metabolic benefits of dietary fiber.

OBJECTIVE: Dietary fiber consumption is associated with reduced risk for the development of noncommunicable diseases. The aim of the present study was to evaluate the effects of cereal dietary fiber on the levels of proteins involved in lipolysis and thermogenesis in white adipose tissue (WAT) and brown adipose tissue (BAT) of C57 BL/6 J mice fed a high-fat diet (HFD). METHODS: Male C57BL/6 J mice were fed normal chow diet (Chow), HFD, HFD plus oat fiber (H-oat), or HFD plus wheat bran fiber (H-wheat) for 24 wk. Body weight and food intake were recorded weekly. Serum adiponectin was assayed by an enzyme-linked immunosorbent assay kit. Western blotting was used to assess the protein expressions of adipose triacylglycerol lipase (ATGL), cAMP protein kinase catalytic subunit (cAMP), protein kinase A (PKA), perilipin A, hormone-sensitive lipase (HSL), uncoupling protein 1 (UCP1), fibroblast growth factor 21 (FGF-21), ß3-adrenergic receptor (ß3AR), and proliferator-activated receptor gamma coactivator-1 α (PGC-1 α) in the WAT and BAT. RESULTS: At the end of the feeding period, body and adipose tissues weight in both H-oat and H-wheat groups were lower than in the HFD group. Mice in the H-oat and H-wheat groups showed an increasing trend in serum adiponectin level. Compared with the HFD group, cereal dietary fiber increased protein expressions involved in the lipolysis and browning process. Compared with the H-wheat group, H-oat was more effective in protein expressions of PKA, PGC-1 α, and UCP1 of the WAT samples. Compared with the H-oat group, H-wheat was more effective in protein expressions of PKA, ATGL, UCP1, ß3AR, and FGF-21 of the BAT samples. CONCLUSIONS: Taken together, our results suggested that cereal dietary fiber enhanced adipocyte lipolysis by the cAMP-PKA-HSL pathway and promoted WAT browning by activation of UCP1, and consequently reduced visceral fat mass in response to HFD feeding.

Chronic leucine supplementation improves lipid metabolism in C57BL/6J mice fed with a high-fat/cholesterol diet.

BACKGROUND: Leucine supplementation has been reported to improve lipid metabolism. However, lipid metabolism in adipose tissues and liver has not been extensively studied for leucine supplementation in mice fed with a high-fat/cholesterol diet (HFCD). DESIGN: C57BL/6J mice were fed a chow diet, HFCD, HFCD supplemented with 1.5% leucine (HFCD+1.5% Leu group) or 3% leucine (HFCD+3% Leu group) for 24 weeks. The body weight, peritoneal adipose weight, total cholesterol (TC), triglyceride in serum and liver, and serum adipokines were analyzed. In addition, expression levels of proteins associated with hepatic lipogenesis, adipocyte lipolysis, and white adipose tissue (WAT) browning were determined. RESULTS: Mice in the HFCD group developed obesity and deteriorated lipid metabolism. Compared with HFCD, leucine supplementation lowered weight gain and TC levels in circulation and the liver without changing energy intake. The decrease in body fat was supported by histological examination in the WAT and liver. Furthermore, serum levels of proinflammatory adipokines, such as leptin, IL-6, and tumor necrosis factor-alpha, were significantly decreased by supplemented leucine. At the protein level, leucine potently decreased the hepatic lipogenic enzymes (fatty acid synthase and acetyl-coenzyme A carboxylase) and corresponding upstream proteins. In epididymal WAT, the reduced expression levels of two major lipases by HFCD, namely phosphorylated hormone-sensitive lipase and adipose triglyceride lipase, were reversed when leucine was supplemented. Uncoupling protein 1, ß3 adrenergic receptors, peroxisome proliferator-activated receptor g coactivator-1α, and fibroblast growth factor 21 were involved in the thermogenic program and WAT browning. Leucine additionally upregulated their protein expression in both WAT and interscapular brown adipose tissue. CONCLUSION: This study demonstrated that chronic leucine supplementation reduced the body weight and improved the lipid profile of mice fed with a HFCD. This beneficial effect was ascribed to hepatic lipogenesis, adipocyte lipolysis, and WAT browning.

The combination of 1α,25dihydroxyvitaminD3 with resveratrol improves neuronal degeneration by regulating endoplasmic reticulum stress, insulin signaling and inhibiting tau hyperphosphorylation in SH-SY5Y cells.

Endoplasmic reticulum (ER) stress is a critical factor involved in the pathogenesis of Alzheimer's disease (AD). Vitamin D and resveratrol are two nutritional factors that have reported neuroprotective effects, and findings from cellular models suggest that resveratrol could potentiate vitamin D's effects. We aimed to determine the effects of vitamin D & resveratrol on ER stress mediated neurodegeneration and whether synergistic effects existed. Tunicamycin and Aß25-35 was utilized to induce ER stress in SH-SY5Y cells, cells were then incubated with vitamin D and resveratrol. The combination of vitamin D & resveratrol completely reversed tunicamycin and Aß25-35 induced cytotoxicity in SH-SY5Y cells, as well as elevation in ER stress markers (i.e.GRP78, p-eIF2α and CHOP), insulin signaling disruption (i.e. elevation in p-IRS-1serine307 and reduction in p-Akt serine473) and tau phosphorylation (i.e. reduction in p-GSK3ß serine9, and elevation in p-Tau serine396 &404). Further studies are required to clarify whether the observed synergistic effects in the present study would also existed in vivo, this will lay scientific foundation whether the combination of vitamin D with resveratrol might be an effective maneuver in the treatment of AD in human subjects.

Depot-specific effects of treadmill running and rutin on white adipose tissue function in diet-induced obese mice.

White adipose tissue (WAT) is a critical organ involved in regulating metabolic homeostasis under obese condition. Strategies that could positively affect WAT function would hold promise for fighting against obesity and its complications. The aim of the present study is to explore the effects of treadmill exercise training and rutin intervention on adipose tissue function from diet-induced obese (DIO) mice and whether fat depot-specific effects existed. In epididymal adipose tissue, high-fat diet (HFD) resulted in reduction in adiponectin mRNA expression, peroxisome proliferator-activated receptors (PPAR)-γ and DsbA-L protein expression, elevation in endoplasmic reticulum (ER) stress markers including 78 kDa glucose-regulated protein (GRP-78), C/EBP homologous protein (CHOP) and p-c-Jun N-terminal kinase (JNK). Isoproterenol-stimulated lipolysis and insulin stimulated Akt phosphorylation ex vivo were blunted from HFD group. The combination of rutin with exercise (HRE) completely restored GRP78 and p-JNK protein expression to normal levels, as well as blunted signaling ex vivo. In inguinal adipose tissue, HFD led to increased adiponectin mRNA expression, PPAR-γ, GRP78, and p-JNK protein expression, and reduction in DsbA-L. HRE is effective for restoring p-JNK, PPAR-γ, and DsbA-L. In conclusion, depot-specific effects may exist in regard to the effects of rutin and exercise on key molecules involved in regulating adipose tissue function (i.e., ER stress markers, PPAR-γ and DsbA-L, adiponectin expression, and secretion, ex vivo catecholamine stimulated lipolysis and insulin stimulated Akt phosphorylation) from DIO mice.

Whole-grain intake and total, cardiovascular, and cancer mortality: a systematic review and meta-analysis of prospective studies.

BACKGROUND: The potential role of whole grain in preventing various mortality outcomes has been inconsistently reported in a wealth of prospective observational studies. OBJECTIVE: We evaluated the relations between whole-grain intake and risks of dying from any cause, cardiovascular disease (CVD), and cancer through a meta-analytic approach. DESIGN: Relevant studies were identified by searching PubMed and EMBASE databases and bibliographies of retrieved full publications. Summary RRs with 95% CIs were calculated with a random-effects model. RESULTS: Thirteen studies on total mortality (104,061 deaths), 12 on CVD mortality (26,352 deaths), and 8 on cancer mortality (34,797 deaths) were included. Three studies reported whole-grain intake, and the remaining studies reported whole-grain product intake. In the dose-response analysis in which the intake of whole-grain products was converted to the amount of whole grain, the summary RRs for an increment in whole-grain intake of 50 g/d were 0.78 (95% CI: 0.67, 0.91) for total mortality, 0.70 (95% CI: 0.61, 0.79) for CVD mortality, and 0.82 (95% CI: 0.69, 0.96) for cancer mortality. A similar reduction was observed for the mortality from ischemic heart disease (RR: 0.68; 95% CI: 0.55, 0.84) but not from stroke (RR: 0.93; 95% CI: 0.54, 1.62). There was evidence of nonlinear associations of whole-grain intake with total (P-nonlinearity < 0.001) and CVD mortality (P-nonlinearity <0.001), but not with cancer mortality (P-nonlinearity = 0.12), with the curves for the associations appearing slightly steeper at lower ranges (<35 g/d) of the intake than at higher ranges. CONCLUSIONS: Our findings suggest significant inverse relations between whole-grain intake and mortality due to any cause, CVD, or cancer. The findings support the recommendation of increasing whole-grain intake to improve public health.

Effects of whey protein and leucine supplementation on insulin resistance in non-obese insulin-resistant model rats.

OBJECTIVE: Whey protein (WP) has been reported to reduce body weight gain and improve glucose metabolism in obese individuals. This study aims to assess and compare the effects of WP and its hydrolysate-leucine (Leu) supplementation in non-obese, insulin-resistant (IR) rat models, particularly the effects on insulin sensitivity, lipid profile, and antioxidant activity. METHODS: Wistar rats were fed a diet consisting of 38.5% fat for 12 wk and 51.3% fat for an additional 4 wk to establish non-obese IR rats. The IR rats were then switched to regular AIN-93 diet containing 0% WP, 5% WP, 15% WP or 1.6% Leu for 8 wk. The Leu content was the same in the 15% WP and 1.6% Leu groups based on high-performance liquid chromatography. The IR rats' body weight, fasting blood glucose, fasting insulin, and homeostasis model assessment-insulin resistance were measured before and after supplementation. An oral glucose tolerance test was performed after supplementation. Body composition, plasma concentrations of the lipids profile, and antioxidant index also were analyzed. RESULTS: No significant difference was observed in body weight, energy intake, and fasting blood glucose in the non-obese IR rats at the end of the experiment. Compared with the 0% WP group, the fasting insulin and homeostasis model assessment-insulin resistance significantly decreased in the 15% WP and 1.6% Leu groups. Furthermore, the blood glucose area under the curve of the oral glucose tolerance test was significantly less in the 15% WP and 1.6% Leu groups. There were no differences in the lipids profile, except for the increase in the high-density lipoprotein cholesterol in the 15% WP and 1.6% Leu groups. For the antioxidant index, the 15% WP group had significantly increased plasma levels for total antioxidation capacity, superoxide dismutase, and glutathione, and a decreased malondialdehyde concentration. The 1.6% Leu group was shown to have the same effect as the 15% WP group, except for the glutathione. CONCLUSION: Our findings demonstrate that the supplementation of WP and Leu may improve IR and antioxidant stress without resulting in changes in body weight and energy intake in non-obese IR rats.

[Effects of genistein on apoptosis in HCT-116 human colon cancer cells and its mechanism].

OBJECTIVE: To investigate the effects of genistein on cell proliferation and apoptosis in HCT-116 human colon cancer cells and its possible mechanism. METHODS: After treatment with genistein, cell proliferation was determined by MTT assay. Cell cycle, cell apoptosis, intracellular reactive oxygen species ( ROS) and mitochondrial membrane potential were determined by flow cytometry. Furthermore, ultrastructural change was observed using transmission electron microscopy (TEM). RESULTS: Genistein inhibited cell proliferation in a dose- and time-dependent manner. Genistein treatment in 0 - 100 micromol/L resulted in G2/M cell cycle arrest. The ratio of Sub-G1 increased from (1.63 +/- 0.44)% to (8.33 -1.51)% (P < 0.01). The ratio of early apoptosis increased from (1.93 +/- 0.32)% to (7.25 +/- 0.86)% (P < 0.01). Genistein caused characteristic apoptotic changes in TEM observation. Genistein treatment in 100 micromol/L increased intracellular ROS level to a peak at 2 h [2 h, (15.53 +/- 1.55)% vs. 0 h, (8.57 +/- 0.35)%, P < 0.01] and decreased mitochondrial membrane potential to a bottom at 1 h [1 h, (0.82 +/- 0.02)% vs. 0 h, (6.70 +/- 0.21)%, P < 0.01). CONCLUSION: Our findings indicated that genistein inhibits cell proliferation, induces G2/M cell cycle arrest and apoptosis in colon cancer cell line HCT-116, with the increase of intracellular ROS level and decrease of mitochondrial membrane potential.