Effect of changes in body mass index and waist-to-height ratio on blood pressure in 11- to 13-year-old children: a prospective population study.

BACKGROUND: Existing evidence about associations between change in body mass index (BMI) and waist-to-height ratio (WHtR) change and high blood pressure are relatively limited. AIMS: We aimed to investigate the associations of general overweight (based on BMI) and abdominal obesity (based on WHtR) change with high blood pressure in Chinese children. SUBJECTS AND METHODS: A school-based cohort study in Ningbo region (China) was conducted among children with baseline evaluations in October 2016 with follow-up two years later. A total of 1432 children aged 11-13 years participated in this study. RESULTS: Our results showed that a change from normal BMI or WHtR to overweight or abdominal obesity in children was associated with high blood pressure (adjusted odds ratio (AOR), 2.62; p<0.05 or AOR, 2.79; p<0.05, respectively). In addition, an increased risk of high blood pressure was observed in children who maintained overweight or abdominal obesity (AOR, 1.67; p<0.05 or AOR, 1.69; p<0.05, respectively), but not in children who experienced remission to non-excess weight. Interestingly, children who increased BMI or WHtR had greater impact on SBP than on DBP. CONCLUSION: The 2-year longitudinal study indicated that general overweight or abdominal obesity can predict the risk factor of high blood pressure in children. However, children who remitted to non-excess weight did not exhibit an increased risk of high blood pressure.

High Endogenously Synthesized N-3 Polyunsaturated Fatty Acids in Fat-1 Mice Attenuate High-Fat Diet-Induced Insulin Resistance by Inhibiting NLRP3 Inflammasome Activation via Akt/GSK-3ß/TXNIP Pathway.

High-fat (HF) diets and low-grade chronic inflammation contribute to the development of insulin resistance and type 2 diabetes (T2D), whereas n-3 polyunsaturated fatty acids (PUFAs), due to their anti-inflammatory effects, protect against insulin resistance. Interleukin (IL)-1ß is implicated in insulin resistance, yet how n-3 PUFAs modulate IL-1ß secretion and attenuate HF diet-induced insulin resistance remains elusive. In this study, a HF diet activated NLRP3 inflammasome via inducing reactive oxygen species (ROS) generation and promoted IL-1ß production primarily from adipose tissue preadipocytes, but not from adipocytes and induced insulin resistance in wild type (WT) mice. Interestingly, endogenous synthesized n-3 polyunsaturated fatty acids (PUFAs) reversed this process in HF diet-fed fat-1 transgenic mice although the HF diet induced higher weight gain in fat-1 mice, compared with the control diet. Mechanistically, palmitic acid (PA), the main saturated fatty acid in an HF diet inactivated AMPK and led to decreased GSK-3ß phosphorylation, at least partially through reducing Akt activity, which ultimately blocked the Nrf2/Trx1 antioxidant pathway and induced TXNIP cytoplasm translocation and NLRP3 inflammasome activation, whereas docosahexaenoic acid (DHA), the most abundant n-3 PUFA in fat-1 adipose tissue, reversed this process via inducing Akt activation. Our GSK-3ß shRNA knockdown study further revealed that GSK-3ß played a pivot role between the upstream AMPK/Akt pathway and downstream Nrf2/Trx1/TXNIP pathway. Given that NLRP3 inflammasome is implicated in the development of most inflammatory diseases, our results suggest the potential of n-3 PUFAs in the prevention or adjuvant treatment of NLRP3 inflammasome-driven diseases.

Docosahexaenoic acid monoglyceride induces apoptosis and autophagy in breast cancer cells via lipid peroxidation-mediated endoplasmic reticulum stress.

Epidemiologic and preclinical studieshave shown that marine n-3 polyunsaturated fatty acids (n-3 PUFAs) elicit promising chemoprevention against breast cancer. Docosahexaenoic acid monoglyceride (MAG-DHA), a docosahexaenoic acid sn-1-monoacylglycerol does not required pancreatic lipase to be absorbed, eliciting a better bioavailability when compared with other formulations such as DHA-free fatty acid, DHA-triglycerol, or DHA-ethyl ester. However, the anticancer actions and underlying mechanisms of MAG-DHA on breast cancer remain to be assessed. In this study, MAG-DHA induced significant growth inhibition in MCF-7 and MDA-MB-231 breast cancer cells in a dose-dependent manner. MAG-DHA treatment (80 µM) led to 83.8 and 94.3% growth inhibition between MCF-7 and MDA-MB-231 cells, respectively. MAG-DHA-induced growth inhibition was tightly associated with apoptosis, as evidenced by increased active forms of caspase-3, poly (ADP-ribose) polymerase (PARP) and caspase-12. In particular, MAG-DHA-induced apoptosis was triggered by oxidative stress-mediated endoplasmic reticulum (ER) stress, as evidenced by activation of the PERK-eIF2α pathway in ER. MAG-DHA treatment also strongly suppressed the growth of E0771 murine breast cancer xenografts, significant differences of tumor volume were found between MAG-DHA group (0.271 cm3 ) and control group (0.875 cm3 ) after 15 daily MAG-DHA treatments. The in vitro antibreast cancer mechanism of MAG-DHA was supported by the in vivo xenograft model. In addition, MAG-DHA-induced ER stress concomitantly triggered autophagy in these cancer cells, and the induction of autophagy suppressed its ability to induce apoptotic cell death. Our data suggested that MAG-DHA as dietary supplement, in combination with autophagy inhibitors may be a useful therapeutic strategy in treating breast cancer.

Algal oil rich in n-3 polyunsaturated fatty acids suppresses B16F10 melanoma lung metastasis by autophagy induction.

Melanoma is a malignant tumor that arises from epidermal melanocytes with high morbidity and mortality, and currently, there are no effective conventional genotoxic treatments or systematic treatment. Increasing evidence shows that n-3 polyunsaturated fatty acids (PUFAs) exhibit anti-melanoma activity, but their anti-melanoma mechanism remains elusive. Here, C57BL/6 mice were injected with B16F10 melanoma cells via a tail vein to establish a lung metastasis model. n-3 PUFAs were significantly increased in lung metastatic tissues from mice treated with algal oil, especially rich in docosahexaenoic acid (DHA). Algal oil treatment significantly suppressed pulmonary metastases and outgrowth of melanoma cells, which was associated with autophagy induction, as evidenced by an increase in LC3-II levels. In addition, algae oil-triggered autophagy was mediated by inactivation of the mammalian target of rapamycin (mTOR) and p38 mitogen-activated protein (MAP) kinase, and activation of c-Jun N-terminal kinases (JNKs), which led to a decrease in p62 accumulation and decreased secretion of proinflammatory cytokine interleukin-1ß (IL-1ß). These results suggest that algal oil exerts its antitumourigenic activities via autophagy-mediated p62 elimination and anti-inflammatory properties.

Sulforaphane ameliorates glucose intolerance in obese mice via the upregulation of the insulin signaling pathway.

Sulforaphane (SFN) is a dietary component with multiple bioactivities; however, its role in obesity-related metabolic derangement remains unclear. Here, the effect of SFN on the glucose intolerance of obese mice and the underlying mechanism were determined. C57B/6J male mice were randomly divided into two groups, having free access to water and a normal-fat diet (ND, n = 6) or a high-fat diet (HFD, n = 33) for 8 weeks; thereafter twelve mice having the greatest weight gain among the HFD-fed mice were considered as obese mice. These obese mice were randomly divided into two groups and treated orally for 6 weeks with or without SFN (100 µmol per kg bw, 3 times per week). During this period the animals were continuously maintained on a ND or a HFD. Blood glucose and serum insulin were examined; then glucose tolerance and insulin resistance were evaluated. In addition, the expression of insulin signaling pathway-related genes in the muscle was determined. Our data showed that the obese mice presented a marked insulin resistance and glucose intolerance as compared to the control group, while SFN treatment exerted a prominently protective effect. In addition, the SFN-treated obese mice had a significantly increased insulin receptor substrate 1 (IRS-1) protein level (P < 0.05), markedly elevated Akt activation, as well as dramatically enhanced phosphorylation of PDK-1 (P < 0.05) when compared with the SFN-untreated obese mice. Moreover, the SFN-treated obese mice exhibited a significantly enhanced translocation of GLUT4 (P < 0.05) to the plasma membrane in the muscle compared to the obese mice without SFN treatment. In conclusion, our results support the notion that SFN acts as a promising agent to improve glucose tolerance through the up-regulation of insulin signaling mainly involving the IRS-1/Akt/GLUT4 pathway in the muscle.

Sulforaphane protects MLE-12 lung epithelial cells against oxidative damage caused by ambient air particulate matter.

Ambient air particulate matter with aerodynamic diameters ≤2.5 µm (PM2.5) can cause pulmonary injury. Oxidative stress is thought to be an important mechanism of PM2.5-mediated toxicity. Sulforaphane (SFN), a compound derived from cruciferous vegetables, is a well-known potent antioxidant; however, its protective effect on lung epithelial cells exposed to PM2.5 is unclear. The results showed that SFN pre-treatment markedly inhibited PM2.5-induced apoptosis of the type II alveolar epithelial cell line MLE-12 by elevating glutathione S-transferase levels and decreasing reactive oxygen species. SFN pre-treatment down-regulated the expression of the pro-apoptotic proteins Bax and Bad, and reduced the activity of caspase-3, while it up-regulated the expression of the anti-apoptotic protein Bcl-2. Moreover, SFN induced the activation of the Akt and ERK pathways, and up-regulated the expression of Nrf2 and its downstream antioxidant genes NQO-1 and HO-1. This is the first study to demonstrate that SFN could protect MLE-12 cells against PM2.5-induced oxidative damage via activation of the Nrf2 pathway and inhibition of the mitochondrial apoptotic pathway; therefore, SFN may be a promising compound for preventing PM2.5-triggered pulmonary cell damage.

Endogenously synthesized n-3 fatty acids in fat-1 transgenic mice prevent melanoma progression by increasing E-cadherin expression and inhibiting ß-catenin signaling.

Malignant melanoma is the most lethal form of skin cancer. Although preclinical studies have shown that n-3 polyunsaturated fatty acids (PUFAs) are beneficial for prevention of melanoma, the molecular mechanisms underlying the protective effects of n­3 PUFAs on melanoma remain largely unknown. In the present study, endogenously increased levels of n-3 PUFAs in the tumor tissues of omega­3 fatty acid desaturase (fat­1) transgenic mice was associated with a reduction in the growth rate of melanoma xenografts. This reduction in tumor growth in fat­1 mice compared with wild­type controls may have been associated, in part, to the: i) Increased expression of E­cadherin and the reduced expression of its transcriptional repressors, the zinc finger E­box binding homeobox 1 and snail family transcriptional repressor 1; ii) significant repression of the epidermal growth factor receptor/Akt/ß­catenin signaling pathway; and iii) formation of significant levels of n­3 PUFA­derived lipid mediators, particularly resolvin D2 and E1, maresin 1 and 15­hydroxyeicosapentaenoic acid. In addition, vitamin E administration counteracted n­3 PUFA­induced lipid peroxidation and enhanced the antitumor effect of n­3 PUFAs, which suggests that the protective role of n­3 PUFAs against melanoma is not mediated by n­3 PUFAs­induced lipid peroxidation. These results highlight a potential role of n­3 PUFAs supplementation for the chemoprevention of melanoma in high­risk individuals, and as a putative adjuvant agent in the treatment of malignant melanoma.

Α-eleostearic acid inhibits growth and induces apoptosis in breast cancer cells via HER2/HER3 signaling.

α-eleostearic acid (α-ESA) has been shown to possess antitumor activity in cancer cells. However, the underlying mechanism(s) remain largely unknown. The present study was designed to investigate the antitumor effect of α-ESA in breast cancer cells showing different expression levels of the human epidermal growth factor receptor 2 (HER2). α-ESA inhibited cell growth and induced apoptosis in the SKBR3 and T47D breast cancer cell lines. The mechanism by which cell growth was inhibited involved G0/G1 and G2/M cell cycle phase arrest. The MTT assay showed that SKBR3 cells are more sensitive to α-ESA compared to T47D cells. Western blot analysis revealed that α-ESA treatment not only reduced HER2/HER3 protein expression, but also increased the level of phosphorylated phosphatase and tensin homolog protein (PTEN), which led to decreased levels of phosphorylated Akt. Inactive Akt further reduced phosphorylation of glycogen synthase kinase-3ß (GSK-3ß) and B-cell lymphoma 2 (Bcl-2)­associated death promoter (BAD) proteins. Furthermore, the level of the anti-apoptotic protein Bcl-2 was found to be reduced following α-ESA treatment. Notably, nuclear factor κB (NF-κB) was activated by α-ESA treatment. Data of the present study showed that the antitumor activity of α-ESA is at least partly mediated by reduction of the HER2/HER3 heterodimer protein level, activation of the Akt/BAD/Bcl-2 apoptotic pathway and inhibition of the Akt/GSK-3ß survival pathway in the two breast cancer cell lines investigated in this study. Therefore, α-ESA may be considered a beneficial dietary factor for the prevention and treatment of invasive breast cancer in cells overexpressing HER2.

The novel dual PI3K/mTOR inhibitor GDC-0941 synergizes with the MEK inhibitor U0126 in non-small cell lung cancer cells.

Lung cancer is a malignant disease with poor outcome, which has led to a search for new therapeutics. The PI3K/Akt/mTOR and Ras/raf/Erk pathways are key regulators of tumor growth and survival. In the present study, their roles were evaluated by MTT assay, flow cytometry and Western blotting in lung cancer cells. We found that a high efficacy of antitumor activity was shown with GDC-0941 treatment in two gefitinib-resistant non-small cell lung cancer (NSCLC) cell lines, A549 and H460. In addition, H460 cells with activating mutations of PIK3CA were relatively more sensitive to GDC-0941 than A549 cells with wild-type PIK3CA. Furthermore, GDC-0941 was highly efficacious in combination with U0126 in inducing cell growth inhibition, G0-G1 arrest and cell apoptosis. These antitumor activities of combined treatment may be attributed to the alterations of G0-G1 phase regulators, apoptosis-related proteins and eukaryotic translation initiation factor 4B (eIF4B), induced by concomitant blockade of the PI3K/Akt/mTOR and Ras/raf/Erk pathways. In conclusion, this study suggests that multi­targeted intervention is the most effective treatment for tumors. Additionally, the blockade of PI3K, mTOR and Erk with GDC-0941 and MEK inhibitors shows promise for treating gefitinib-resistant NSCLC.

Myricetin induces G2/M phase arrest in HepG2 cells by inhibiting the activity of the cyclin B/Cdc2 complex.

Myricetin, a naturally occurring flavonol, has been shown to inhibit the proliferation of human hepatoma HepG2 cells and to induce G2/M phase arrest. However, the underlying mechanisms of Myricetin activity have yet to be revealed. The aim of the present study was to clarify the molecular mechanisms of cell cycle arrest induced by myricetin in HepG2 cells. The MTT assay confirmed that exposure of HepG2 cells to myricetin triggered G2/M phase arrest. Western blot analysis showed that myricetin increased the protein levels of the p53/p21 cascade, and markedly decreased Cdc2 and cyclin B1 protein levels in HepG2 cells. Additionally, myricetin treatment resulted in the up-regulation of Thr14/Tyr15 phosphorylated (inactive) Cdc2 and p27, and the down-regulation of CDK7 kinase protein, as well as CDK7-mediated Thr161 phosphorylated (active) Cdc2. These data indicate that a decrease in cyclin B/Cdc2 complex activity mediated G2/M phase arrest induced by myricetin in HepG2 cells. This novel finding provides insight into the potential applications of myricetin in the treatment of hepatocellular carcinoma.

A novel dual PI3Kalpha/mTOR inhibitor PI-103 with high antitumor activity in non-small cell lung cancer cells.

PI-103, the first synthetic multitargeted compound which simultaneously inhibits PI3Kalpha and mammalian target of rapamycin (mTOR) shows high antitumor activity in glioma xenografts. In the present study, clear antitumor activity was observed with PI-103 treatment in two gefitinib-resistant non-small cell lung cancer (NSCLC) cell lines, A549 and H460, by simultaneously inhibiting p70s6k phosporylation and Akt phosphorylation in response to mTOR inhibition. In addition, H460 cells with activating mutations of PIK3CA were more sensitive to PI-103 than A549 cells with wild-type PIK3CA. PI-103 was found to inhibit growth by causing G0-G1 arrest in A549 and H460 cells. Western blotting showed that PI-103 induced down-regulation of cyclin D1 and E1 and simultaneously up-regulated p21 and p27, associated with arrest in the G0-G1 phase of the cell cycle. Furthermore, p53, the tumor suppressor which transcriptionally regulates p21, was also upregulated with PI-103 treatment. Collectively, our results suggest that multitargeted intervention is the most effective tumor therapy, and the cooperative blockade of PI3Kalpha and mTOR with PI-103 shows promise for treating gefitinib-resistant NSCLC.

[Surface-enhanced Raman spectra of oxidation damnification of fetal bovine serum by ozone].

Fetal bovine serum was treated by ozone for 1 hour and 3 hours before getting its surface-enhanced Raman spectra from 200 to 1 800 cm(-1). Treated with ozone for 1 hour, it shows a significant decrease in band intensity. Treated with ozone for 3 hours, the band intensity has a further decrease but not so obviously, which means that oxidation of ozone is short lived. Treated with ozone, the orderly conformations of main chains in protein such as alpha-helix, beta-sheet and beta-corner are damaged seriously. Aromatic side chains and C-S of Cys and Met also are damnified greatly. All this means that strong oxidation of ozone results in denaturation, conformational changes and even degradation in protein.

[Surface-enhanced Raman spectra of natural tissue and cancerous tissue of lung].

Surface-enhanced Raman spectra of natural tissue and cancerous tissue of lung from 300 to 1700 cm(-1) were measured. In the cancerous tissue of lung, the orderly conformations of amides III and amides I of the main chains in protein such as alpha-helix, beta-corner and no rules curly were damaged seriously; conversely, the extendable vibration of skeleton C-N and skeleton C-C increased. Side chains change became complicated. In general, the content of nucleic acids increases in the cancer tissue of lung. The lengthways conformations of lecithoid chains is out-of-order in the cancerous tissue of lung compared with the natural ones.