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.

Assessment of causal factors for Parkinson's disease in European populations: A phenome-wide Mendelian randomisation analysis.

BACKGROUND AND OBJECTIVES: To assess the causality of potentially modifiable factors, including lifestyle, nutrients, lipids, anthropometric traits, and inflammatory factors of Parkinson's disease (PD), genetic instruments for modifiable factors were identified from genome-wide association studies (GWAS). METHODS AND STUDY DESIGN: Genetic associations for PD (1,239 cases and 451,025 matched controls) were extracted from the UK Biobank GWAS summary statistics. The causal effects of modifiable factors on the risk of PD were estimated using the multiplicative random-effects inverse variance weighted method (IVW). RESULTS: In the IVW analysis, a decreased risk for PD was causally associated with genetically predicted smoking cessation (odds ratio 0.41, [95% confidence interval] 0.32-0.78; p<0.001), and higher bone mineral density (0.43, 0.38 -0.71; p<0.001), higher concentrations of vitamin B-12 (0.56, 0.43-0.91; p<0.001), docosahexenoic acid (0.52, 0.37-0.71; p<0.001), and sIL-6R (0.69, 0.58-0.75; p<0.001). Instead, analysis further supported the role of apolipoprotein (a) isoform size(1.67, 1.36-1.71; p<0.001), being a genetically morning person (2.18, 1.12-4.72; p<0.001), and number of cigarette smoking (1.05, 1.01-1.08; p<0.001) in contributing to the risk of developing PD. CONCLUSIONS: Our findings provide new evidence for the potential positive causal association of cigarette smoking number and apolipoprotein (a) isoform size and the inverse causal association of vitamin B-12, docosahexaenoic acid, smoking cessation, and soluble interleukin-6 receptor with PD, which contributes to the development of new interventions for PD.

Differential effects of EPA and DHA on DSS-induced colitis in mice and possible mechanisms involved.

BACKGROUND: The anti-inflammatory effect of n-3 PUFAs has been widely documented. Emerging evidence suggests that the main component of n-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may have differential effects in ulcerative colitis (UC). It was aimed to clarify their differential effects in UC. METHODS: Eight-week-old male C57BL/6J mice were randomly divided into 7 groups, namely control, UC model, salicylazosulfapyridine (SASP), low-dose DHA, high-dose DHA, low-dose EPA, and high-dose EPA. DHA, EPA and SASP treatment groups were orally treated accordingly for 9 weeks. During the 5th to 9th week the control group was given distilled water, while other groups were given distilled water with 2% dextran sodium sulfate (DSS) to induce UC. Body weight loss, diarrhea, and stool bleeding were recorded to calculate the disease activity index (DAI). The level of tight junction proteins Claudin-1 and Occludin, and cytokines including TNF-α, IL-6, and IL-1ß as well as inflammatory cell markers such as MPO, F4/80, and MCP-1 in the intestinal epithelium were measured using western blotting. Activation of IL-6/STAT3 and NLRP3/IL-1ß inflammatory pathways was also assessed. Levels of proliferation-related proteins of the Wnt/ß-catenin pathway with c-myc, Cyclin-D1, and PCNA were detected. RESULTS: EPA, superior to DHA, significantly attenuated DSS-induced colitis evidenced by reduced DAI scores, cytokine production and inflammatory cell infiltration. Mechanically, EPA triggered a marked up-regulation of Claudin-1 and Occludin with down-regulation of their up-stream Akt and ERK. EPA also inhibited NLRP3/IL-1ß and IL-6/STAT3 inflammatory pathways and up-regulated the Wnt/ß-catenin pathway. CONCLUSIONS: EPA is more suitable to be used for the treatment of UC than DHA.

High n-3 fatty acids counteract hyperglycemia-induced insulin resistance in fat-1 mice via pre-adipocyte NLRP3 inflammasome inhibition.

Although n-3 polyunsaturated fatty acids (n-3 PUFAs) have potential anti-insulin resistance activity, the mechanism remains largely unknown. In this study, increased glucose resistance, insulin sensitivity, and lower glycemia were observed upon streptozotocin (STZ) treatment in n-3 PUFA-enriched fat-1 mice compared to wild type (WT) mice. Endogenous n-3 PUFAs in fat-1 mice were found to impair hyperglycemia or high glucose level-induced nucleotide-binding domain and leucine-rich repeat pyrin 3 domain (NLRP3) inflammasome activation and inhibit IL-1ß secretion in adipose tissues. In addition, endogenous n-3 PUFAs also inhibited high glucose-induced caspase-1 activity and IL-1ß secretion in pre-adipocyte-enriched stromal vascular fractions (SVF) isolated from adipose tissues. Furthermore, in 3T3-L1 pre-adipocytes, high levels of glucose induced thioredoxin interacting protein (TXNIP) expression and activated the NLRP3 inflammasome, which was counteracted by docosahexaenoic acid (DHA), the major n-3 PUFA in fat-1 mice, by downregulating TXNIP via the phosphatidylinositol-3-kinase (PI3K)/Akt pathway. Our results suggest that n-3 PUFA-mediated insulin sensitivity is at least partly associated with inflammasome inhibition in pre-adipocytes. Our findings highlight the potential clinical use of dietary n-3 PUFAs in the prevention or intervention of T2D and other NLRP3 inflammasome-driven inflammatory diseases.

Circulating vitamin E and cardiometabolic measures: a Mendelian randomization analysis.

Although a large body of literature reported that high intake of vitamin E played a possible role in reducing risk of cardiometabolic diseases, conflicting results were also found in some observational studies due to confounding factors. Hence, we used a Mendelian randomization study as an alternative way to examine the causality between circulating vitamin E and cardiometabolic diseases. Summary-level data were extracted from consortia and three single nucleotide polymorphisms were used as instrumental variables. Our study showed that a one-SD increase in circulating vitamin E levels was causally associated with an increased risk of coronary artery disease [odds ratio (OR) 3.16 (95%CI 1.74, 5.73); p = 1.91 × 10-3] at the Bonferroni-adjusted level of significance (p<0.005). Moreover, a one-SD increase in circulating vitamin E levels was associated with a 0.572-SD increase in low density lipoprotein cholesterol (mg/dl), a 0.693-SD increase in total cholesterol (mg/dl), and a 1.45-SD increase in triglyceride (mg/dl), but a 0.502-SD decrease in high density lipoprotein cholesterol (mg/dl) at the Bonferroni-adjusted level of significance (p<0.0028). Our findings indicated that genetically elevated vitamin E was associated with increased risk of coronary artery disease, suggesting an adverse causality between circulating vitamin E and coronary artery disease.

Potatoes Consumption and Risk of Type 2 Diabetes: A Meta-analysis.

BACKGROUND: Evidence of increased type 2 diabetes (T2D) risk associated with potatoes consumption is equivocal. We aimed to perform a meta-analyses on the association between potatoes consumption and T2D risk in prospective cohort studies. METHODS: Studies published prior to 31 Aug 2016 were identified in PubMed, EMBASE, and Web of Science. Pooled relative risks (RR) and 95% confidence intervals (95%CI) based upon the highest vs. lowest category of potatoes consumption in each study were calculated in meta-analysis using random-effects models. Dose-response meta-analysis was fitted using generalized least squares regression in order to quantify the association between potatoes consumption and T2D risk. RESULTS: The pooled RR comparing the highest vs. lowest category of potato consumption was 1.077 (95%CI: 1.005, 1.155). Dose-response meta-analysis revealed T2D risk increased 3.5% (RR=1.035, 95% CI: 1.004-1.067) for additional three serving per week serving of potato. The pooled RR comparing the highest vs. lowest category of French fries consumption was 1.362 (95%CI: 1.004, 1.850). Dose-response meta-analysis indicated T2D risk increased 18.7% (RR = 1.187, 95% CI: 1.067-1.321) for additional three serving per week of French fries. CONCLUSION: This meta-analysis support a significant positive association between high potatoes consumption and risk of T2D, especially the consumption of French fries.

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 and myricetin act synergistically to induce apoptosis in 3T3­L1 adipocytes.

The aim of the present study was to investigate whether sulforaphane (SFN) and myricetin (Myr) synergistically induce apoptosis in adipocytes. The viability of mature 3T3­L1 adipocytes treated with 40 µM SFN and/or 100 µM Myr was assessed using an MTT assay. Apoptosis was assessed by Hoechst 33258 nuclear staining, and by detection of single­stranded DNA using an enzyme­linked immunosorbent assay. Compared with the effects of each compound alone, the combination of SFN and Myr synergistically reduced cell viability, induced apoptosis, increased pro­apoptotic Bcl­2 associated X protein expression, decreased anti­apoptotic B­cell lymphoma­2 expression, enhanced Bcl­2­associated death promoter (Bad) translocation from the cytoplasm to the mitochondria, and reduced Bad phosphorylation at Ser112. These effects were accompanied by increased cleavage of caspase 3 and poly­ADP­ribose­polymerase. In addition, combined SFN and Myr treatment significantly decreased the protein expression levels of phosphorylated AKT serine/threonine kinase 1 (Akt) at Ser473, as well as the phosphorylation of the downstream protein ribosomal protein, S6 kinase ß­1. Therefore, SFN plus Myr was a more potent inducer of apoptosis in 3T3­L1 adipocytes than either compound alone. The results of the present study suggest that the mechanism of SNF/Myr­induced apoptosis involved activation of the Akt­mediated mitochondrial apoptotic pathway. This may aid treatment of animal models of obesity and preclinical testing.

Author Correction: Dipeptidyl peptidase-4 inhibitors and cancer risk in patients with type 2 diabetes: a meta-analysis of randomized clinical trials.

A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.

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.

Dipeptidyl peptidase-4 inhibitors and cancer risk in patients with type 2 diabetes: a meta-analysis of randomized clinical trials.

Some recent studies have suggested that the use of dipeptidyl peptidase-4 inhibitors (DPP4i) is associated with cancer development. However, some other studies suggest no such association. The aim of the present study was to evaluate the effect of DPP4i on the risk of developing cancers. The electronic databases PubMed, Medline, EMBASE, Web of Science and Cochrane Library and the clinical trial registry were searched for published and unpublished randomized clinical trials on humans. Eligible studies were RCTs conducted in patients with type 2 diabetes mellitus, comparing DPP4i with a placebo or other active drugs. A total of 72 trials with 35,768 and 33,319 patients enrolled for DPP4i and the comparison drugs, respectively. Overall, no significant associations were detected between the use of DPP4i and cancer development, in comparison with the use of other active drugs or placebo. The results were consistent across pre-defined subgroups stratified by type of DPP4i, type of cancer, drug for comparison, trial duration, or baseline characteristics. The results of this meta-analysis suggest that patients with type 2 diabetes treated with DPP4i do not have a higher risk of developing cancers than patients treated with a placebo or other drugs.

Elevated SLC26A4 gene promoter methylation is associated with the risk of presbycusis in men.

Presbycusis affects approximately one-third of people over the age of 65 and is a worldwide health problem. In the current study, whether the methylation level of solute carrier family 26 member 4 (SLC26A4) predicted an increased risk of presbycusis was investigated. Peripheral blood samples from 102 patients with presbycusis and 104 controls were collected, and the methylation of the CpG sites of SLC26A4 was measured by applying pyrosequencing technology combined with sodium bisulfate DNA conversion chemistry. Within the SLC26A4 promoter region, one CpG site (CpG3) exhibited a significantly (P<0.0001) greater methylation level in the patients with presbycusis (26.5±5.56%) compared with the controls (23.8±3.85%). Significantly different CpG3 methylation levels were observed between the patients with presbycusis and the controls among the male participants (P=0.0004). In addition, a significant decrease in the transcriptional level of SLC26A4 in peripheral blood was observed in the patients with presbycusis compared with the controls. Furthermore, analyses of the receiver operating characteristic (ROC) curves indicated that CpG3 methylation at the SLC26A4 promoter predicted the risk of presbycusis in the male participants (AUC=0.684, 95% CI=0.584­0.784, P=0.001). The results demonstrated the significance of the CpG site methylation level of SLC26A4, and thus provides a potential marker for the diagnosis of presbycusis.

Dihydromyricetin induces mitochondria-mediated apoptosis in HepG2 cells through down-regulation of the Akt/Bad pathway.

The plant flavonol dihydromyricetin (DHM) was reported to induce apoptosis in human hepatocarcinoma HepG2 cells. This study was undertaken to elucidate the underlying molecular mechanism of action of DHM. In the study, DHM down-regulated Akt expression and its phosphorylation at Ser473, up-regulated the levels of mitochondrial proapoptotic proteins Bax and Bad, and inhibited the phosphorylation of Bad at Ser136 and Ser112. It also inhibited the expression of the antiapoptotic protein Bcl-2 and enhanced the cleavage and activation of caspase-3 as well as the degradation of its downstream target poly(ADP-ribose) polymerase. Our results for the first time suggest that DHM-induced apoptosis in HepG2 cells may come about by the inhibition of the Akt/Bad signaling pathway and stimulation of the mitochondrial apoptotic pathway. Dihydromyricetin may be a promising therapeutic medication for hepatocellular carcinoma.

STAT3 stimulates adipogenic stem cell proliferation and cooperates with HMGA2 during the early stage of differentiation to promote adipogenesis.

Signal transducer and activator of transcription 3 (STAT3) is abundantly expressed in the adipose tissue of obese mice and humans, but the role of STAT3 in adipogenesis is still not fully understood. In the present study, we discovered an activation of STAT3 during the early differentiation stage of mouse 3T3-L1 preadipocytes. Stat3 knockdown using siRNA blocked cell cycle progression of both preadipoctes and early differentiating cells. Moreover, accumulation of lipid droplets was inhibited by Stat3 knockdown. Importantly, in the nucleus of early differentiating cells, we demonstrated that STAT3 protein co-localized with high-mobility-group protein AT-hook 2 (HMGA2), which was reported to promote adipogenesis in a previous study. Taken together, our data indicate that STAT3 and HMGA2 cooperatively promote adipogenesis which highlight a more detail understanding of STAT3 related transcription factor network during adipogenesis.

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.

Geniposide Inhibits Alpha-Naphthylisothiocyanate-Induced Intrahepatic Cholestasis: The Downregulation of STAT3 and NF[Formula: see text]B Signaling Plays an Important Role.

Traditional medicinal formulation of Yin-zhi-huang (YZH) is widely used in the clinic for the treatment of jaundice and chronic liver diseases in East Asian countries. However, the pharmacologically active components of YZH and the underlying mechanism are still unknown. Geniposide (GEN) was recently identified as one of the most abundant circulating components in YZH. In this study, we investigated the protective effect of GEN against liver injuries induced by alpha-naphthylisothiocyanate (ANIT). 50[Formula: see text]mg/kg of GEN was administered to ICR mice once daily for 5 days, and challenge of ANIT 75[Formula: see text]mg/kg was performed on the 4th day. Blood and liver tissues were collected on day 6 and subjected to biochemical, histopathological and pathway analyses. The biochemical and pathological findings showed that GEN almost totally attenuated ANIT-induced cholestasis and liver injury compared with the vehicle/ANIT group. The altered gene transcription related to bile acid metabolism and transport was normalized by co-treatment with GEN. The expressions of tumor necrosis factor-[Formula: see text] and the suppressor of cytokine signaling 3 were significantly decreased in the GEN/ANIT group. Western blot revealed that GEN inhibited the activation and expression of STAT3 and NF[Formula: see text]B. These data suggest GEN inhibits ANIT-induced hepatotoxicity. The protective effect is associated with the downregulation of STAT3 and NF[Formula: see text]B signaling.

Sulforaphane induces apoptosis in adipocytes via Akt/p70s6k1/Bad inhibition and ERK activation.

Sulforaphane (SFN), an isothiocyanate isolated from cruciferous vegetables, possesses anti-oxidant and anti-cancer bioactivities. Moreover, SFN exerts its pro-apoptotic effects in some cancer lines. However, the effects and mechanisms of SFN on the regulation of apoptosis of adipocytes are still unknown. In this study, we found that SFN induced significant apoptosis in 3T3-L1 adipocytes and markedly decreased the cellular lipid content. Western blot demonstrated that SFN-induced apoptosis was mediated via the mitochondrial apoptosis pathway based on increased cleavage of poly-ADP-ribose-polymerase (PARP), release of cytochrome c into the cytoplasm, and activation of caspase-3, as well as decreased Bcl-2/Bax ratio. In addition, SFN markedly decreased phosphorylation of Akt and downstream proteins, p70s6k1 and Bad, and increased phosphorylation of ERK. Therefore, our findings clarified that SFN could induce 3T3-L1 adipocyte apoptosis via down-regulation of the Akt/p70s6k1/Bad pathway and up-regulation of the ERK pathway, suggesting SFN may be a promising agent for the treatment or prevention of obesity.