Sulforaphane inhibits blue light-induced inflammation and apoptosis by upregulating the SIRT1/PGC-1α/Nrf2 pathway and autophagy in retinal pigment epithelial cells.

The present study elucidated mechanisms through which sulforaphane (SFN) protects retinal pigment epithelial (RPE) cells from blue light-induced impairment. SFN could activate the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and increase the expression of the heme oxygenease-1 (HO-1) gene and production of glutathione. SFN reduced blue light-induced oxidative stress, and effectively activated cytoprotective components including Nrf-2, HO-1, thioredoxin-1, and glutathione. The protective effect of SFN on blue light-induced injury was blocked by the Nrf2 inhibitor ML385, suggesting that the SFN-induced Nrf2 pathway is involved in the cytoprotective effect of SFN. SFN inhibited intercellular adhesion molecule-1 expression induced by TNF-α or blue light, suggesting the anti-inflammatory activity of SFN. The inhibitory effect of SFN was associated with the blocking of NF-κB p65 nuclear translocation in blue light-exposed RPE cells. SFN protected RPE cells from blue light-induced interruption of the mitochondrial membrane potential and reduction of the Bcl-2/Bax ratio and cleaved caspase-3 and PARP-1 expression, suggesting the antiapoptotic activity of SFN. SFN alone or together with blue light exposure increased the expression of the autophagy-related proteins LC3BII and p62. An autophagy inhibitor, 3-MA, inhibited the protective effect of SFN on blue light-induced cell damage. SFN increased sirtuin-1 (SIRT1) expression; however, treatment with blue light induced peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) expression. Our study results demonstrated that SFN exerts its protective effect under blue light exposure by maintaining the Nrf2-related redox state and upregulating SIRT1 and PGC-1α expression and autophagy.

Using Vibrating and Cold Device for Pain Relieves in Children: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

OBJECTIVE: Needle procedures are the most common source of pain, anxiety, and fear among children. A combination of a cooling ice-pack and/or a vibrating motor for pain management in children has been evaluated in trials, but their overall effects await a synthesis of the available evidence. METHOD: Comprehensive search was conducted using Cochrane, PubMed, EMBASE, PsycINFO, CINAHL and Airiti. We calculated pooled risk ratios (RR), mean difference (MD) and 95% CI using RevMan 5.3. A meta-regression was conducted to investigate the effects of mean age on MD of pain. RESULTS: A total of 1479 children from 16 publications were included. Compared with the control group, using cold-vibrating device significantly decreased pain level above the age of 2 (MD -3.03, 95% CI: -3.38, -2.68), as well as lower anxiety level among parents (MD -1.3, 95% CI: -1.9, -0.7). Meta-regression demonstrated a significant negative correlation of pain score with age. For children at 8.5 years, cold-vibration reduced the pain score by 0.13 averagely for every increment in year compared with controls (MD -0.13; 95% CI: -0.25, -0.01). No adverse events were reported in included studies. DISCUSSION: The cold-vibrating device reduced pain levels significantly among children without adverse effects. Variation of factors might contribute to the heterogeneity of our study, such as age, different needle procedures, psychological strategies…etc. CONCLUSIONS: Cool-vibration treatment reduced pain levels in children who underwent needle procedures and the treatment appears more effective in older children. The device is promising in clinical setting due to its non-invasiveness and ease of usage.

Exploring the efficacy of using hypertonic saline for nebulizing treatment in children with bronchiolitis: a meta-analysis of randomized controlled trials.

BACKGROUND: Inhaled hypertonic saline (HS) has shown benefit in decreasing airway edema in acute bronchiolitis which is the most common lower respiratory infection resulting in dyspnea among infants under 2 years old. The aim of this systematic review and meta-analysis was to evaluate the efficacy and safety of HS in the implementation of treatment with nebulized HS among children with bronchiolitis. METHODS: A systematic literature search was conducted using Cochrane Library, PubMed, EMBASE and Airiti Library (Chinese Database) for randomized controlled trials from inception to July 2019. We calculated pooled risk ratios (RR), mean difference (MD) and 95% CI using RevMan 5.3 for meta-analysis. RESULTS: There were 4186 children from 32 publications included. Compared to the control group, the HS group exhibited significant reduction of severity of respiratory distress, included studies used the Clinical Severity Score (n = 8; MD, - 0.71; 95% CI, - 1.15 to - 0.27; I2 = 73%) and full stop after Respiratory Distress Assessment Instrument (n = 5; MD, - 0.60; 95% CI, - 0.95 to - 0.26; I2 = 0%) for evaluation respectively. Further, the HS group decreased the length of hospital stay 0.54 days (n = 20; MD, - 0.54; 95% CI, - 0.86 to - 0.23; I2 = 81%). CONCLUSIONS: We conclude that nebulization with 3% saline solution is effective in decreasing the length of hospital stay and the severity of symptoms as compared with 0.9% saline solution among children with acute bronchiolitis. Further rigorous randomized controlled trials with large sample size are needed.

Effect of acetic acid on ethanol production by Zymomonas mobilis mutant strains through continuous adaptation.

BACKGROUND: Acetic acid is a predominant by-product of lignocellulosic biofuel process, which inhibits microbial biocatalysts. Development of bacterial strains that are tolerant to acetic acid is challenging due to poor understanding of the underlying molecular mechanisms. RESULTS: In this study, we generated and characterized two acetic acid-tolerant strains of Zymomonas mobilis using N-methyl-N'-nitro-N-nitrosoguanidine (NTG)-acetate adaptive breeding. Two mutants, ZMA-142 and ZMA-167, were obtained, showing a significant growth rate at a concentration of 244 mM sodium acetate, while the growth of Z. mobilis ATCC 31823 were completely inhibited in presence of 195 mM sodium acetate. Our data showed that acetate-tolerance of ZMA-167 was attributed to a co-transcription of nhaA from ZMO0117, whereas the co-transcription was absent in ATCC 31823 and ZMA-142. Moreover, ZMA-142 and ZMA-167 exhibited a converstion rate (practical ethanol yield to theorical ethanol yield) of 90.16% and 86% at 195 mM acetate-pH 5 stress condition, respectively. We showed that acid adaptation of ZMA-142 and ZMA-167 to 146 mM acetate increased ZMA-142 and ZMA-167 resulted in an increase in ethanol yield by 32.21% and 21.16% under 195 mM acetate-pH 5 stress condition, respectively. CONCLUSION: The results indicate the acetate-adaptive seed culture of acetate-tolerant strains, ZMA-142 and ZMA-167, could enhance the ethanol production during fermentation.

miR-122-mediated translational repression of PEG10 and its suppression in human hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC), a primary liver malignancy, is the most common cancer in males and fourth common cancer in females in Taiwan. HCC patients usually have a poor prognosis due to late diagnosis. It has been classified as a complex disease because of the heterogeneous phenotypic and genetic traits of the patients and a wide range of risk factors. Micro (mi)RNAs regulate oncogenes and tumor suppressor genes that are known to be dysregulated in HCC. Several studies have found an association between downregulation of miR-122, a liver-specific miRNA, and upregulation of paternally expressed gene 10 (PEG10) in HCC; however, the correlation between low miR-122 and high PEG10 levels still remains to be defined and require more investigations to evaluate their performance as an effective prognostic biomarker for HCC. METHODS: An in silico approach was used to isolate PEG10, a potential miR-122 target implicated in HCC development. miR-122S binding sites in the PEG10 promoter were evaluated with a reporter assay. The regulation of PEG10 by miR-122S overexpression was examined by quantitative RT-PCR, western blotting, and immunohistochemistry in miR-122 knockout mice and liver tissue from HCC patients. The relationship between PEG10 expression and clinicopathologic features of HCC patients was also evaluated. RESULTS: miR-122 downregulated the expression of PEG10 protein through binding to 3'-untranslated region (UTR) of the PEG10 transcript. In miR-122 knockout mice and HCC patients, the deficiency of miR-122 was associated with HCC progression. The expression of PEG10 was increased in 57.3 % of HCC as compared to paired non-cancerous tissue samples. However, significant upregulation was detected in 56.5 % of patients and was correlated with Okuda stage (P = 0.05) and histological grade (P = 0.001). CONCLUSIONS: miR-122 suppresses PEG10 expression via direct binding to the 3'-UTR of the PEG10 transcript. Therefore, while PEG10 could not be an ideal diagnostic biomarker for HCC but its upregulation in HCC tissue still has predictive value for HCC prognosis.

Effect of Metal Oxide Semiconductor Field-Effect Transistor Output Parasitic Capacitance on Efficiency in Full-Bridge LLC DC/DC Converters.

This study analyzed the efficiency impact of a MOSFET output parasitic capacitance (Coss) on a full-bridge LLC DC/DC converter. The core of the converter was the control chip for a half-bridge LLC DC/DC converter, and the output signal of the chip controlled the first-arm power transistors of the primary side of the converter. The coupling transformer reversed the output signal to control the primary side of the second arm of the power transistor. The full-bridge converter comprises a half-bridge control chip that converts the high-voltage DC power supply to a low-voltage DC power supply, which is then synchronously rectified and supplied to the load. The primary side of the power transistor achieves a zero-voltage switching (ZVS) state through the resonance of the LLC converter. This design gives the converter high power density and a simple structure. Furthermore, to determine the appropriate output parasitic capacitance for improving converter efficiency, this study analyzed the effect of the output parasitic capacitance on the switching loss and conduction loss of the power transistor on the basis of the output parasitic capacitance of the primary-side power transistor. A 1200 W converter prototype was fabricated in this study, and when the output was 300 W, efficiency increased from 92.603% to 93.462%, a 0.859% increase. The empirical results verified the feasibility of the proposed theory.

Soy yoghurts produced with efficient GABA (γ-aminobutyric acid)-producing Lactiplantibacillus plantarum ameliorate hyperglycaemia and re-establish gut microbiota in streptozotocin (STZ)-induced diabetic mice.

Soy yogurt has been gaining popularity as a vegan food produced simply by soymilk fermentation with proper microbial manipulation. It is well known that soy containing rich isoflavones is beneficial for ameliorating hyperglycaemic disorders. Soy fermentation can improve the bioavailability of these precious nutrients. Lactiplantibacillus plantarum is one of the most abundant and frequently isolated species in soymilk manufacturing. Soy yogurts produced with efficient GABA (γ-aminobutyric acid)-producing L. plantarum and the deglycosylating activity of L. plantarum were functionally assessed in a STZ-induced hyperglycaemic mouse model. Hyperglycaemic mice were assigned into groups and treated with daily gavage of either dH2O, soymilk, soy yoghurts produced with high GABA-producing L. plantarum GA30 (LPGA30), low GABA-producing L. plantarum PV30 (LPPV30) or the soy yoghurts fortified with additional 30 mg g-1 GABA counterparts (GA + GABA and PV + GABA groups). Except the dH2O group, all soy yoghurt groups retained body weight with improved glucose homeostasis, glucose tolerance test results and renal tissue integrity, while the soymilk group shows partial benefits. Plasma GABA concentrations in the daily soy yoghurt-supplemented groups (LPGA30 and LPPV30) plateaued at 5 times higher than the average 0.5 µM in dH2O and soymilk groups, and their GABA-fortified soy yoghurt counterparts (GA + GABA and PV + GABA) groups were accountable for the restored plasma insulin levels. Gut microbiome analysis revealed dysbiosis in STZ-induced hyperglycemic mice of the dH2O group with breached out facultative anaerobic Proteobacteria over the normal phyla Firmicutes and Bacteroidetes. Restored gut microbiota with transitionally populated Actinobacteria was demonstrated in the LPGA30 group but not in the LPPV30 group. Soy yoghurts produced with efficient GABA-producing L. plantarum GA30 showed exceptional benefits in modulating gut microbiota with dominant genera of Enterococcus, Lactobacillus and Bifidobacterium, and the presence of some minor beneficial microbial communities including Akkermansia muciniphila, Butyricicoccus pullicaecorum, Corynebacterium spp. and Adlercreutzia spp. Efficient GABA-producing L. plantarum GA30 fermented soymilk to produce soy yoghurts that exhibit profound synergistic protections over rich soy isoflavones to restore pancreatic ß-cell functions for insulin production in STZ-induced hyperglycaemic mice. Additionally, the probiotic role of GABA-producing L. plantarum in re-establishing healthy gut microbiota in hyperglycaemic mice implies a possible symbiotic relationship, awaiting further exploration.

In Vitro and In Vivo Assessments of Anti-Hyperglycemic Properties of Soybean Residue Fermented with Rhizopus oligosporus and Lactiplantibacillus plantarum.

Soy isoflavones possess antioxidative, anti-inflammatory, anti-diabetic and phytoestrogenic properties. Soybean residue contains a fair amount of nutrients such as glycosylated isoflavones, minerals and dietary fibers, and is a substantial waste product produced from soymilk and tofu manufacturing. A solid-state fermentation of soybean residue by Rhizopus oligosporus or co-inoculated with Lactiplantibacillus plantarum improves the availability of isoflavones and GABA content which is attributed to ameliorated hyperglycemic symptoms in STZ-induced hyperglycemic mice. The effortless solid-state fermentation with present microbial manipulation supports an anti-hyperglycemia value-added application of soybean residue for functional food development. Background: Due to an awareness of the food crisis and with a rapidly rising prevalence of diabetes, recycling the substantial fibrous soybean residue disposed from soy industries has received consideration. Methods: Lactiplantibacillus plantarum was previously screened for active glutamate decarboxylase, and ß-glucosidase activities were adopted for the fermenting of soybean residue using a traditional tempeh solid-state fermenting process with fungal Rhizopus oligosporus. Fermented soybean residue was chemically analyzed and functionally assessed in in vitro and in vivo hyperglycemic conditions. Results: A 48 h longer solid-state fermentation of the soybean residue co-inoculated with R. oligosporus and L. plantarum showed improved contents of isoflavone aglycones and GABA which were attributed to augmented antioxidative capacity, lowered ROS level, improved blood biochemistry, and better blood glucose homeostasis in STZ-induced hyperglycemic mice. Conclusion: The advantages of a food industrial effortless fermentation process, and a health nutritional endorsing anti-hyperglycemic value-added property offer a practical alternative in recycled soybean residue.

Upregulation of NF-E2-related factor-2-dependent glutathione by carnosol provokes a cytoprotective response and enhances cell survival.

AIM: To explore whether glutathione (GSH) increased through Nrf-2 activation is involved in the cytoprotective effects of carnosol in HepG2 cells. METHODS: Human hepatoma cell line HepG2 were exposed to rosemarry essential oil or carnosol. Cell viability was measured using an Alamar blue assay. The production of intracellular GSH was determined using monochlorobimane. The level of protein or mRNA was examined by Western blotting or RT-PCR, respectively. RESULTS: Rosemarry essential oil (0.005%-0.02%) and carnosol (5 and 10 mol/L) increased the intracellular GSH levels and GSH synthesis enzyme subunit GCLC/GCLM expression. Rosemary essential oil and carnosol increased nuclear accumulation of Nrf2 and enhanced Nrf2-antioxidant responsive element (ARE)-reporter activity. Transfection of the treated cells with an Nrf2 siRNA construct blocks GCLC/GCLM induction. Furthermore, pretreatment of the HepG2 cells with essential oil and carnosol exerted significant cytoprotective effects against H(2)O(2) or alcohol. In TNFα-treated cells, the nuclear translocation and transcriptional activity of NF-κB was abolished for 12 h following carnosol pretreatment. Cotreatment with GSH also suppressed NF-κB nuclear translocation, whereas cotreatment with BSO, a GSH synthesis blocker, blocked the inhibitory effects of carnosol. CONCLUSION: This study demonstrated that Nrf2 is involved in the cytoprotective effects by carnasol, which were at least partially mediated through increased GSH biosynthesis.

Erythropoietin enhances endogenous haem oxygenase-1 and represses immune responses to ameliorate experimental autoimmune encephalomyelitis.

Both erythropoietin (EPO) and haem oxygenase-1 (HO-1), an anti-oxidative stress protein, have proven protective roles in experimental autoimmune encephalomyelitis (EAE), a reliable animal model of multiple sclerosis. In this study, EPO delivered intraperitoneally could reduce disease severity in myelin oligodendrocyte glycoprotein (MOG)­EAE mice. To assess the effect of EPO on endogenous HO-1 in EAE, we investigated expression of HO-1 mRNA by real-time polymerase chain reaction (RT­PCR), protein expression centrally and peripherally by Western blot and immunohistochemistry and mean fluorescence intensity of splenic HO-1 by flow cytometry. A significantly higher expression of HO-1 in both the central nervous system (CNS) and spleen was shown in EPO-treated MOG­EAE mice than in controls.We further examined the immunomodulatory effect of EPO in EAE, and via RT­PCR demonstrated significantly lower expression of interferon-γ, interleukin (IL)-23, IL-6 and IL-17 mRNA, and significantly higher expression of IL-4 and IL-10 mRNA in CNS of EPO-treated MOG­EAE mice than in controls. Using flow cytometry, we also observed a significantly decreased ratio of both T helper type 1 (Th1) and Th17 lymphocyte subsets isolated from CNS and a significantly increased ratio of splenic regulatory CD4 T cells in EPO-treated MOG­EAE mice. In addition, we demonstrated that MOG-specific T cell proliferation was lower in the EPO-treated group than in controls and showed amelioration of EAE by adoptive transfer of splenocytes from EPO-treated MOG­EAE mice. Together, our data show that in EAE, EPO induction of endogenous HO-1 and modulation of adaptive immunity both centrally and peripherally may involve the repression of inflammatory responses.

Dual mechanisms of NF-kappaB inhibition in carnosol-treated endothelial cells.

The increased adhesion of monocytes to injured endothelial layers is a critical early event in atherogenesis. Under inflammatory conditions, there is increased expression of specific cell adhesion molecules on activated vascular endothelial cells, which increases monocyte adhesion. In our current study, we demonstrate a putative mechanism for the anti-inflammatory effects of carnosol, a diterpene derived from the herb rosemary. Our results show that both carnosol and rosemary essential oils inhibit the adhesion of TNFalpha-induced monocytes to endothelial cells and suppress the expression of ICAM-1 at the transcriptional level. Moreover, carnosol was found to exert its inhibitory effects by blocking the degradation of the inhibitory protein IkappaBalpha in short term pretreatments but not in 12 h pretreatments. Our data show that carnosol reduces IKK-beta phosphorylation in pretreatments of less than 3 h. In TNFalpha-treated ECs, NF-kappaB nuclear translocation and transcriptional activity was abolished by up to 12 h of carnosol pretreatment and this was blocked by Nrf-2 siRNA. The long-term inhibitory effects of carnosol thus appear to be mediated through its induction of Nrf-2-related genes. The inhibition of ICAM-1 expression and p65 translocation is reversed by HO-1 siRNA. Carnosol also upregulates the Nrf-2-related glutathione synthase gene and thereby increases the GSH levels after 9 h of exposure. Treating ECs with a GSH synthesis inhibitor, BSO, blocks the inhibitory effects of carnosol. In addition, carnosol increases p65 glutathionylation. Hence, our present findings indicate that carnosol suppresses TNFalpha-induced singling pathways through the inhibition of IKK-beta activity or the upregulation of HO-1 expression. The resulting GSH levels are dependent, however, on the length of the carnosol pretreatment period.

Isolating a cytoprotective compound from Ganoderma tsugae: effects on induction of Nrf-2-related genes in endothelial cells.

Ganoderma tsugae is a medicinal fungus with several biological activities. It has long been used as a folk remedy for the promotion of health and longevity in China and other oriental countries. Here, a bioactive fraction of G. tsugae was progressively purified to be enriched in the activity of cytoprotective enzymes. The highest bioactivity was detected in the 20% EtOH-precipitated fraction, which was prepared from submerged fermentation filtrate of G. tsugae. Following further purification by gel filtration chromatography and acetone extraction, the most bioactive fraction, F5-2, was identified as a peptidoglycan-like compound. Extracts of G. tsugae (F5-2) induced heme oxygenase-1 (HO-1) and thioredoxin reductase-1 (TrxR1) expression in endothelial cells by increasing NF-E2-related factor-2 (Nrf2) nuclear translocation. Pretreatment with F5-2 increased intracellular glutathione (GSH) and protected against H(2)O(2), suggesting that induction of these antioxidant enzymes is important in protection against oxidative stress. Hence the bioactive peptidoglycan-like compound from G. tsugae might protect endothelial cells.

Sulforaphane inhibition of monocyte adhesion via the suppression of ICAM-1 and NF-kappaB is dependent upon glutathione depletion in endothelial cells.

Sulforaphane (SFN) is an isothiocyanate found in cruciferous vegetables. We here report that SFN is a potent inhibitor of LPS-induced monocyte adhesion, and also blocks the gene expression of the adhesion molecule, ICAM-1, at non-toxic concentrations. Downstream of ICAM-1, NF- kappaB activity was also found to be abolished in a dose-and time-dependent by SFN in LPS-treated endothelial cells (ECs). SFN exerts its suppressive effects on NF- kappaB activity in these cells by preventing the degradation of IkappaB-alpha. Interestingly, the inhibition of P65 translocation and IkappaB-alpha degradation was reversed slightly after 12 hours pretreatment. The intracellular GSH levels in SFN-treated ECs were observed to be reduced, the time course coincident with the suppression of P65 translocation and IkappaB-alpha degradation. NAC and GSH reverse the inhibitory effects of SFN upon p65 translocation and IkappaB-alpha degradation when preincubated with this agent. Furthermore, the use of BSO to decrease intracellular GSH levels further enhanced the effects of SFN. These data thus suggest that the anti-inflammatory mechanisms of SFN are dependent upon intracellular glutathione level.

Yellow and green pigments from Calophyllum inophyllum L. seed oil induce cell death in colon and lung cancer cells.

Natural compounds have been candidates for anticancer medicine over the last 20 years. During the process of isolating seed oil from Calophyllum inophyllum L., yellow and green pigments containing multiple compounds with an aromatic structure were identified. High-performance liquid chromatography and nuclear magnetic resonance analysis of these pigments revealed that the compounds present were identical, but the concentration of the compounds was different. Treatment with the pigments was able to induce the death of DLD-1 human colon cancer cells and increase the percentage of the cells in the sub-G1 and sub-G2/M phases in a dose-dependent manner. Additionally, the pigments were able to exhibit cytotoxic activity on A549 and H1975 human non-small cell lung cancer (NSCLC) cell lines at 24 h, with half-maximal inhibitory concentrations (IC50) values of 0.1206 and 0.0676%, respectively for green pigments, and 0.0434 and 0.0501%, respectively for yellow pigments. Furthermore, a decrease in IC50 value was associated with an increase in the duration of treatment. However, a sharp decrease in IC50 value of the yellow pigment was observed for H1975 cells at 48 h and for A549 cells at 72 h compared with no change in IC50 value for the green pigment with time, suggesting that the pigments function and induce cell death differently in the two cell lines. An investigation was performed into the synergistic effect of the green pigment and gefitinib (Iressa®, ZD1839), which is a selective epidermal growth factor receptor-tyrosine kinase inhibitor to block growth factor-mediated cell proliferation. The combination of the green pigment and gefitinib resulted in an enhancement of the decrease in viability of A549 and H1975 cells compared with treatment with gefitinib alone, which suggested that treatment with the green pigments was able to enhance the sensitivity of NSCLC cells to gefitinib. In conclusion, these pigments may be considered for development as anti-colon cancer agents.

Peanut arachidin-1 enhances Nrf2-mediated protective mechanisms against TNF-α-induced ICAM-1 expression and NF-κB activation in endothelial cells.

Arachidin-1 [trans-4-(3-methyl-1-butenyl)-3,5,3',4'-tetrahydroxystilbene] is a polyphenol produced by peanut kernels during germination. The aim of the present study was to investigate the mechanism underlying the anti-inflammatory effect of arachidin-1 in endothelial cells (ECs). The results of cell adhesion and western blotting assays demonstrated that arachidin-1 attenuated tumor necrosis factor (TNF)-α-induced monocyte/EC adhesion and intercellular adhesion molecule-1 (ICAM-1) expression. Arachidin-1 was demonstrated to exert its inhibitory effects by the attenuation of TNF-α-induced nuclear factor-κB (NF-κB) nuclear translocation and inhibitor of κB-α (IκBα) degradation. Furthermore, arachidin-1 upregulated nuclear factor-E2-related factor-2 (Nrf-2), a known mediator of phase II enzyme expression, and increased the transcriptional activity of antioxidant response element. Transfection of ECs with Nrf-2 siRNA blocked the inhibitory effect of arachidin-1 on ICAM-1 expression, NF-κB nuclear translocation and IκBα degradation. In addition, arachidin-1 induced the expression of the phase II enzymes thioredoxin-1, thioredoxin reductase-1, heme oxygenase-1, glutamyl-cysteine synthetase and glutathione S-transferase. Following arachidin-1 pretreatment, the H2O2-induced generation of reactive oxygen species was reduced. Therefore, the present results indicate that arachidin-1 suppresses TNF-α-induced inflammation in ECs through the upregulation of Nrf-2-related phase II enzyme expression.

Chalcone inhibits the activation of NF-kappaB and STAT3 in endothelial cells via endogenous electrophile.

Chalcone, an alpha,beta-unsaturated flavonoid, possesses anti-inflammatory properties. In our present study, we have demonstrated chalcone inhibited IL-6- and LPS-induced ICAM-1 gene expression. In adhesion assay, chalcone reduced the LPS-induced adhesion of THP-1 cells to endothelial cells (ECs). Chalcone was found to abrogate the activation of STAT3 and NF-kappaB in a dose- and time-dependent manner, in IL-6- and LPS-treated ECs. Other flavonoids, quercetin and cyanidin, which lack alpha,beta-unsaturated carbonyl group, showed weaker or no inhibitory effect on both IL-6-induced STAT3 phosphorylation and LPS-induced p65 translocation. However, the electrophilic compounds curcumin and crotonaldehyde, which also contain an alpha,beta-unsaturated carbonyl moiety, mimic the inhibitory effects of chalcone with different efficiencies. In addition, N-acetyl-L-cysteine (NAC) could reverse the inhibition of STAT3 phosphorylation when preincubated with chalcone. The use of buthionine sulfoximine (BSO) to decrease intracellular GSH levels further enhanced the effects of chalcone. On the other hand, in ECs treated with BSO only no abrogation of IL-6-induced STAT3 phosphorylation was observed. We also found that chalcone could reduce the GSH level in vitro. Furthermore, the cellular GSH levels were rapidly reduced after 25 microM chalcone treatment. Following 6 h exposure, however, chalcone treatment rescued the GSH levels in ECs, coincident with the inhibition of STAT3 and NF-kappaB activation. In contrast, chalcone induced expression of thioredoxin reductase and heme-oxygenase genes after prolonged treatment. Furthermore, chalcone upregulated the levels of the transcription factor Nrf2 in nuclear extracts and increased antioxidant response element (ARE)-luciferase activity and thioredoxin reductase promoter activity. Hence, our present findings indicate that chalcone suppresses both IL-6- and LPS-induced signaling pathways through the thiol-dependent intracellular redox state. In addition, chalcone may provide distinct cytoprotective effects at different durations of pretreatment.

Lycopene inhibits NF-κB activation and adhesion molecule expression through Nrf2-mediated heme oxygenase-1 in endothelial cells.

The endothelial expression of cell adhesion molecules plays a leading role in atherosclerosis. Lycopene, a carotenoid with 11 conjugated double bonds, has been shown to have anti-inflammatory properties. In the present study, we demonstrate a putative mechanism for the anti-inflammatory effects of lycopene. We demonstrate that lycopene inhibits the adhesion of tumor necrosis factor α (TNFα)-stimulated monocytes to endothelial cells and suppresses the expression of intercellular cell adhesion molecule-1 (ICAM-1) at the transcriptional level. Moreover, lycopene was found to exert its inhibitory effects by blocking the degradation of the inhibitory protein, IκBα, following 6 h of pre-treatment. In TNFα-stimulated endothelial cells, nuclear factor-κB (NF-κB) nuclear translocation and transcriptional activity were abolished by up to 12 h of lycopene pre-treatment. We also found that lycopene increased the intracellular glutathione (GSH) level and glutamate-cysteine ligase expression. Subsequently, lycopene induced nuclear factor-erythroid 2 related factor 2 (Nrf2) activation, leading to the increased expression of downstream of heme oxygenase-1 (HO-1). The use of siRNA targeting HO-1 blocked the inhibitory effects of lycopene on IκB degradation and ICAM-1 expression. The inhibitory effects of lycopene thus appear to be mediated through its induction of Nrf2-mediated HO-1 expression. Therefore, the findings of the present study indicate that lycopene suppresses the activation of TNFα-induced signaling pathways through the upregulation of Nrf2-mediated HO-1 expression.

Analysis of the associations among Helicobacter pylori infection, adiponectin, leptin, and 10-year fracture risk using the fracture risk assessment tool: A cross-sectional community-based study.

Helicobacter pylori (H. pylori) infection may induce inflammatory cytokines or adipokines that influence bone turnover and bone fracture risk. This study aimed to evaluate the association among H. pylori infection, adipokines, and 10-year fracture risk using the Fracture Risk Assessment Tool scale. From August 2013 to February 2016, a community-based cohort was surveyed by Keelung Chang-Gung Memorial Hospital. Subjects were included if they were older than 40 years and not pregnant. All participants underwent a standardized questionnaire survey, physical examination, urea breath test, and blood tests. A total of 2,689 participants (1,792 women) were included in this cross-sectional study. In both sexes, participants with a high fracture risk were older and had higher adiponectin values than participants without a high fracture risk (mean age, female: 72.9 ± 5.6 vs. 55.8 ± 7.3 years, P < 0.0001; male: 78.9 ± 4.7 vs. 58.1 ± 8.9 years, P < 0.001) (adiponectin, female: 10.8 ± 6.3 vs. 8.7 ± 5.2 ng/ml, P < 0.001; male: 9.7 ± 6.1 vs. 5.5 ± 3.8 ng/ml, P < 0.001). Adiponectin was correlated with high fracture risk in both sexes, but H. pylori infection and leptin was not. In logistic regression analysis, adiponectin could not predict high fracture risk when adjusting the factor of body mass index (BMI) in men group. In conclusion, H. pylori infection and leptin could not predict 10-year fracture risk in either sex. Adiponectin was correlated with bone fracture risk in both sexes and the correlation might be from the influence of BMI.

Carbon monoxide releasing molecule induces endothelial nitric oxide synthase activation through a calcium and phosphatidylinositol 3-kinase/Akt mechanism.

The production of nitric oxide (NO) by endothelial NO synthase (eNOS) plays a major role in maintaining vascular homeostasis. This study elucidated the potential role of carbon monoxide (CO)-releasing molecules (CORMs) in NO production and explored the underlying mechanisms in endothelial cells. We observed that 25µM CORM-2 could increase NO production and stimulate an increase in the intracellular Ca2+ level. Furthermore, ethylene glycol-bis(ß-aminoethyl ether)-N,N,N',N'-tetra acetic acid caused CORM-2-induced NO production, which was abolished by 1,2-bis(2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid tetraacetoxy-methyl ester (BAPTA-AM), indicating that intracellular Ca2+ release plays a major role in eNOS activation. The inhibition of the IP3 receptor diminished the CORM-2-induced intracellular Ca2+ increase and NO production. Furthermore, CORM-2 induced eNOS Ser1179 phosphorylation and eNOS dimerization, but it did not alter eNOS expression. CORM-2 (25µM) also prolonged Akt phosphorylation, lasting for at least 12h. Pretreatment with phosphatidylinositol 3-kinase inhibitors (wortmannin or LY294002) inhibited the increases in NO production and phosphorylation but did not affect eNOS dimerization. CORM-2-induced eNOS Ser1179 phosphorylation was intracellularly calcium-dependent, because pretreatment with an intracellular Ca2+ chelator (BAPTA-AM) inhibited this process. Although CORM-2 increases intracellular reactive oxygen species (ROS), pretreatment with antioxidant enzyme catalase and N-acetyl-cysteine did not abolish the CORM-2-induced eNOS activity or phosphorylation, signifying that ROS is not involved in this activity. Hence, CORM-2 enhances eNOS activation through intracellular calcium release, Akt phosphorylation, and eNOS dimerization.

The Associations Between Helicobacter pylori Infection, Serum Vitamin D, and Metabolic Syndrome: A Community-Based Study.

The associations between Helicobacter pylori infection, serum vitamin D level, and metabolic syndrome (MS) are controversial. The present community-based study aimed to investigate the effect of H pylori infection and serum vitamin D deficiency on MS development.Individuals from the northeastern region of Taiwan were enrolled in a community-based study from March, 2014 to August, 2015. All participants completed a demographic survey and underwent the urea breath test (UBT) to detect H pylori infection as well as blood tests to determine levels of vitamin D, adiponectin, leptin, and high-sensitivity C-reactive protein. The ATP III criteria for MS were used in this study.A total of 792 men and 1321 women were enrolled. The mean age was 56.4 ±â€Š13.0 years. After adjusting for age and sex, the estimated odds of MS development for a UBT-positive subject were 1.503 (95% confidence interval [CI]: 1.206-1.872, P < 0.001) when compared to a UBT-negative subject. For participants with vitamin D deficiency (<20 ng/mL), the odds of MS development were 1.423 (95% CI: 1.029-1.967, P = 0.033) when compared to those with sufficient vitamin D level (>30 ng/mL). For participants with both H pylori infection and vitamin D deficiency, the odds of MS development were 2.140 (95% CI: 1.348-3.398, P = 0.001) when compared to subjects without H pylori infection and with sufficient vitamin D levels.H pylori infection and vitamin D deficiency could be predictors of MS. For individuals with both H pylori infection and vitamin D deficiency, the odds of MS development were 2.140 when compared to individuals without H pylori infection and with sufficient vitamin D levels.